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1
Emanuel, Robyn M., Zhenya Senyak, Archie McCallister, Mary Cotter, Barbara VanHusen, Claire N. Harrison i Ruben A. Mesa. "The MPN Fatigue Project: Stage 1 Results Of The MPN Forum Internet-Based Survey Among 879 MPN Patients". Blood 122, nr 21 (15.11.2013): 1595. http://dx.doi.org/10.1182/blood.v122.21.1595.1595.
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Abstract Background Symptom burden among MPN patients is severe compared to age-matched controlled and other individuals with cancer. MPN-Related Fatigue (MRF) is among one of the most frequent and debilitating of symptoms among MPN patients and contributes greatly to the loss of quality of life. To date, little is known regarding the breadth and efficacy of strategies to reduce or palliate MRF. Methods A 17-item internet-based survey was hosted on the MPN Forum website during February of 2013. The survey included data on demographics, type of fatigue (chronic, sporadic, or both), strategies to reduce fatigue, and symptom burden using the MPN-SAF TSS. The MPN-SAF TSS also included a validated 1-item measure to assess worst fatigue in the last 24 hours (scored on a 0 (absent/as good as it can be) to 10 (worst-imaginable/as bad as it can be) scale). Results 879 MPN patients responded to the online survey. The majority of patients had been diagnosed with their MPN for more than one year (5.8% less than one year, 34.4% one to five years, 30.3% five to ten years, and 27.6% more than 10 years). Mean age of MPN diagnosis was 49.3 (range 12-84). A near equal mix was seen of chronic (35.3%), sporadic (29.9%) and both chronic and sporadic fatigue (28.8%). Average symptom burden was very severe (mean MPN-SAF TSS =31.9), with an average worst 24-hr fatigue rated as 5.9/10. Many strategies to reduce MPN-related fatigue were mentioned via open and categorical responses (Table 1). Exercise was the most commonly mentioned fatigue reduction strategy, followed by diet and social interaction. Diet strategies included the consumption of fruits and vegetables and using foods to combat specific nutrient deficiencies (e.g., iron). Interventions to increase rest included obtaining >8 hours of sleep at night, taking frequent naps if needed, and strategically timing naps (e.g., sleeping prior to activity). Timing strategies were implemented to maximize energy levels, including scheduling activities at time periods during the day when patients felt most awake. Stress-reduction strategies included massages, meditation and yoga. Some respondents felt work was both source of energy and motivation, although others mentioned cutting back work hours or obligations in order to reduce fatigue. New activities such as gardening and enjoying the outdoors were also mentioned. Use of non-prescription supplementation, including caffeine and over-the counter energy supplementation, was common. Prescription energy stimulants included MPN-specific treatments (e.g., ruxolitinib, hydroxurea, ASA, interferon), steroids, noradrenergic stimulants (e.g., methyphenidate, modafinil), prescription vitamin supplements (e.g., vitamin B12 injections), erythropoietin analogues, and blood thinners. Conclusions Overall patients were very symptomatic of disease (previously reported MPN-SAF TSS scores 18.7 ET, 21.8 PV, and 25.3 MF) and worst 24-hr fatigue (previously reported as 4.0 ET, 4.4 PV, and 5.0 MF) than previously published MPN cohorts (JCO 2012 20;30(36):4590). Many intervention strategies are utilized to reduce MRF. Future trials investigating pharmacologic, psychosocial, and activity-related interventions to reduce MRF are needed. Disclosures: Harrison: NOVARTIS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; Sbio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
2
Baljevic, Muhamed, Cristina Gasparetto, Gary J. Schiller, Sascha A. Tuchman, Natalie S. Callander, Suzanne Lentzsch, Jorge Monge i in. "Selinexor-Based Regimens in Patients with Multiple Myeloma after Prior Anti-B-Cell Maturation Antigen Treatment". Blood 138, Supplement 1 (5.11.2021): 2751. http://dx.doi.org/10.1182/blood-2021-150998.
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Abstract Background Multiple myeloma (MM) is considered an incurable hematologic malignancy despite a plethora of standard and novel agents. There is no consensus on the optimal sequencing of available therapies in relapsed/refractory MM (RRMM), even in the second line setting. Novel agents such as selinexor (XPOVIO [X]), an oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, or those that target B-cell maturation antigen (BCMA), have shown significant activity in RRMM. X is approved with bortezomib (V) and dexamethasone (XVd) in patients (pts) with at least 1 prior therapy and is not associated with known long-term clinically significant toxicities such as visual loss, cardiac dysfunction, renal failure, neuropathy, irreversible bone marrow suppression, second malignancies, venous thromboembolism, or rash. Currently, BCMA-targeting agents include 1 form each of chimeric antigen receptor T cell (CAR-T cell) and antibody drug conjugate (ADC) therapy approved in RRMM: idecabtagene vicleucel and belantamab mafodotin, respectively. BCMA-refractory MM represents an area of unmet need in MM without known standards for best treatment. Various novel combinations with X have demonstrated strong benefit in RRMM after 1 or more lines of therapy and activity even in CAR-T cell BCMA-refractory MM (N=7): 1 pt stringent complete (sCR), 3 very good partial (VGPR), 2 partial (PR), and 1 minimal (MR) response (Chari BJH 2020). Here we report on the outcomes of heavily pretreated RRMM pts, a majority of whom had received ADC-BCMA, and who were treated with X-containing regimens on the STOMP trial. Methods STOMP (NCT02343042) is a phase 1b/2, multi-arm, open-label trial of various combinations of X with backbone agents for pts with RRMM or newly diagnosed MM. Here we report on all pts in STOMP with prior anti-BCMA treatment who were treated on STOMP with X+pomalidomide +dexamethasone (XPd); XVd; X+carfilzomib+d (XKd); XPVd; and XPd+elotuzumab (E) (XPEd). Results In total, 11 pts with prior anti-BCMA therapy (6 pts with belantamab mafodotin; 1 each with MEDI2228, SEA-BCMA, BCMA BITE; 2 with idecabtagene vicleucel) were treated with 5 X-containing regimens (Table 1): 9 pts were treated with triplets XPd (4), XVd (3), or XKd (2) and 2 pts with quadruplets XPVd (1) or XPEd (1). Median age was 71 years (range 46-85), 7 pts (63.6%) were women, 11 pts were white. Median duration from MM diagnosis to treatment with a STOMP regimen was 6.9 years (range 2.3-12.8). Five pts (45.5%) had high-risk cytogenetics; pts received median of 6 prior therapies (range 4-10). Eight pts (72.7%) received anti-BCMA in their immediate prior line of therapy. Ten pts (90.9%) were previously treated with all backbone drugs of the STOMP treatments (i.e., X was the only new drug). The overall response rate (ORR) and clinical benefit rate (CBR) for the prior anti-BCMA-containing regimens were 40.0% (2 pts VGPR, 2 PR, 5 stable disease [SD], 1 progressive disease, 1 unknown). Median progression free survival (PFS) was 1.8 months (95% CI: 1.5, NE), and the 6-month PFS probability was 12.5% (95% CI: 2.1, 76.2). ORR for the X-based treatments was 54.5% and CBR was 81.8%: 1 pt VGPR, 5 PR, 3 MR, 2 SD. Median PFS was not reached (95% CI: 5.9, NE) and the 6-month PFS probability was 68.6% (95% CI: 40.3, 100.0). Median overall survival was 10.5 months (95% CI: 9.6, NE) and median time to discontinuation was 8.1 months (95% CI: 6.1, NE). The most common treatment-emergent adverse events were nausea and thrombocytopenia. Nausea was Grade (G) 1/2 (n=8, 72.7%); thrombocytopenia G1-4 in 8 pts (72.7%), 4 with ≥G3; there were no concurrent bleeding events. One pt on XPEd died of pulmonary nocardiosis considered to be associated with the 4-drug regimen. No new safety signals or long-term toxicities due to X were reported. Conclusions In this follow-up cohort of heavily pretreated pts, a majority of whom with MM refractory to ADC-BCMA, we demonstrate impressive potency and durability of the X-based treatments, particularly as compared to that of their prior anti-BCMA therapies. These data support the rationale for the development of novel regimens containing X plus immunomodulatory drugs or proteasome inhibitors in earlier lines of therapy, including first relapse, and further suggest their strong value in the emerging BCMA RRMM space. Figure 1 Figure 1. Disclosures Baljevic: Exelixis: Research Funding; Amgen: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen Research: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto: Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau. Schiller: Sangamo: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Geron: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PrECOG: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; FujiFilm: Research Funding; Gamida Cell Ltd.: Research Funding; Constellation Pharmaceuticals: Research Funding; Mateon: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Tolero: Research Funding; Samus: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Lentzsch: Sanofi: Consultancy, Research Funding; Celularity: Consultancy; AbbVie: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Monge: Karyopharm: Research Funding; BMS: Consultancy. Kotb: Celgene: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BMS: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy. White: Forus: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sutherland: GSK: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Amgen: Consultancy. Madan: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Celgene/BMS: Research Funding; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag: Janssen: Research Funding; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding.
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Lentzsch, Suzanne, Brea Lipe, Sascha A. Tuchman, Nizar J. Bahlis, William I. Bensinger, Michael Sebag, Heather J. Sutherland i in. "Efficacy and Safety of Selinexor-Containing Regimens in Patients with Multiple Myeloma Previously Treated with Anti-CD38 Monoclonal Antibodies (αCD38 mAb)". Blood 138, Supplement 1 (5.11.2021): 1651. http://dx.doi.org/10.1182/blood-2021-150232.
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Abstract Background: Once multiple myeloma (MM) becomes refractory to αCD38 mAb, pts have limited effective treatment options and poor prognoses. With standard therapies, overall response rate (ORR) to the first regimen after refractoriness to an αCD38 mAb is 31%, median progression-free survival (PFS) - 3.4 months and median overall survival (OS) - 9.3 months (Gandhi et al, Leukemia, 2019). Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins. XPO1 is required for MM cell growth, is associated with poor prognosis and mediates resistance to standard MM and other anticancer therapies. Selinexor (SEL) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound approved for patients (pts) with previously treated MM as well as DLBCL. The doublet SEL-dexamethasone (Xd) achieved ORR ~26% in triple-class (Immunomodulatory drug [IMiD], proteosome inhibitor [PI], αCD38 mAb) refractory MM and improved OS over matched cohorts in community (Richardson et al, eJHaem, 2021) and academic (Cornell et al, AJH, 2020) settings. Hence, SEL-based triplets could be more effective in this triple class-treated population. We analyzed the efficacy and safety of SEL-containing triplets in pts in the STOMP study who were previously treated with regimens containing αCD38 mAb. Methods: STOMP is a multi-arm, open-label, Phase 1b/2 study evaluating SEL in various combinations (NCT02343042). Here, we analyzed ORR, clinical benefit rate (CBR), duration of response (DOR), PFS, OS, and treatment-emergent adverse events (TEAEs) of pts who received Xd plus pomalidomide (XPd, n=23) or carfilzomib (XKd, n=23) after prior therapy with αCD38 mAb. Results: Among 46 pts treated, median age was 64 yrs (XPd), 70 yrs (XKd), females 57% (XPd) and 39% (XKd), median time from diagnosis was 5 yrs, and median number of prior regimens 4 (range, 2-10). All pts were previously treated with a PI and IMiD and αCD38 mAb; 78% (XPd) and 52% (XKd) had triple refractory MM. Prior treatment with αCD38 mAb included daratumumab (XPd: 91%, XKd: 100%) and isatuximab (XPd: 9%); 52% (XPd) and 74% (XKd) had αCD38 mAb in their most recent prior regimen. Refractoriness to daratumumab was documented in 87% (XPd) and 96% (XKd); isatuximab in 9% (XPd). Median durations from end of most recent αCD38 mAb therapy to first dose of study treatment were 8 weeks (XPd), 4 weeks (XKd). Among evaluable pts, ORR and CBR were 52% and 76%, respectively in the XPd arm (n=21; 2 pts were not efficacy evaluable) and 65% and 74%, respectively in the XKd arm. In the XPd arm median PFS was 8.7 months (95% CI: 7.6, NE), median DOR was 7.9 months (95% CI: 3.9, NE), and median OS was 21.8 months (95% CI: 8, NE). In the XKd arm median PFS was 15 months (95% CI: 12.0, NE), median DOR was 13.1 months (95% CI: 10.2, NE), and median OS was 33.0 months (95% CI: 20.4, NE). Among the evaluable pts, response to SEL-containing triplets compared favorably to the prior αCD38 mAb-containing regimen used at least 1 line earlier: XPd arm (n=21), ORR 52% vs 58% for prior regimen, CBR 76% vs 58%, median PFS 8.7 months (95% CI: 7.6, NE) vs 10.2 months (95% CI: 5.2, 20.5); XKd arm (n=23), ORR 65% vs 52%, CBR 74% vs 57%, median PFS 15.0 months (95% CI: 12.0, NE) vs 8.5 months (95% CI: 5.9, 17.3). The most common hematological TEAEs (total; grade≥3) were thrombocytopenia (XPd: 35%; 30%; XKd: 78%; 39%), anemia (XPd: 57%; 39%; XKd: 57%; 22%), and neutropenia (XPd: 57%; 48%; XKd: 35%; 4%). Other common TEAEs (total; grade≥3) were nausea (XPd: 74%; 0; XKd: 74%; 4%), fatigue (XPd: 61%; 4%; XKd: 52%; 4%) and decreased appetite (XPd: 48%; 4%; XKd: 48%; 4%). No cases of severe bleeding with thrombocytopenia occurred. Three pts (13%, all XPd) had febrile neutropenia (the outcome of which was fatal in 1 pt, deemed related to SEL and pomalidomide). TEAEs were managed with standard supportive care and dose modifications. Summary/Conclusion: XPd and XKd administered to pts with heavily pretreated MM, including prior αCD38 mAb therapy, exhibit tolerability and comparable effectiveness to that of the prior αCD38 mAb-containing regimen. These results suggest that the use of SEL-containing triplets, implementing the novel XPO1 inhibition mechanism, can provide prolonged disease control with good tolerability rather than recycling previously utilized drugs/mechanisms. The all oral XPd regimen will be evaluated in Study EMN29 against elotuzumab-Pd in patients who have received lenalidomide, a PI and an αCD38 mAb. Disclosures Lentzsch: Janssen: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Bahlis: Takeda: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Sebag: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Janssen: Research Funding. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Monge: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Research Funding. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Connect Registry: Membership on an entity's Board of Directors or advisory committees. Baljevic: Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board; BMS/Celgene: Consultancy; Amgen: Research Funding. Venner: Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; BMS: Honoraria; GSK: Honoraria; Takeda: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Kotb: Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Schiller: Celator: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Tolero: Research Funding; Constellation Pharmaceuticals: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Sangamo: Research Funding; Trovagene: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Cyclacel: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Forma: Research Funding; Daiichi-Sankyo: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Delta-Fly: Research Funding; FujiFilm: Research Funding; Deciphera: Research Funding; Arog: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Regimmune: Research Funding; Ono: Consultancy; Samus: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Madan: Karyopharm: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) .
4
Roose, Elien, An-Sofie Schelpe, Edwige Tellier, György Sinkovits, Gilles Kaplanski, Maelle Le Besnerais, Ilaria Mancini i in. "Open ADAMTS13 Conformation in Immune-Mediated Thrombotic Thrombocytopenic Purpura Is Induced By Anti-ADAMTS13 Autoantibodies and Corresponds with an Ongoing ADAMTS13 Pathology". Blood 132, Supplement 1 (29.11.2018): 222. http://dx.doi.org/10.1182/blood-2018-99-113762.
Pełny tekst źródłaStreszczenie:
Abstract Background. Deficient ADAMTS13 activity (TS13:act <10%) induced by anti-ADAMTS13 autoantibodies (autoAbs) causes immune-mediated thrombotic thrombocytopenic purpura (iTTP). Recently we showed that an open ADAMTS13 conformation is characteristic for acute iTTP patients, while folded ADAMTS13 was found in 78% of iTTP patients in remission with an TS13:act >50%. However, also iTTP patients in remission with a persistent (<10%) or moderately restored (10-50%) TS13:act have been described, but their ADAMTS13 conformation is unknown. Intriguingly, the factor responsible for inducing open ADAMTS13 in iTTP patients remains elusive. Identifying the cause of open ADAMTS13 in iTTP will help better understand the pathophysiology of iTTP and could help appreciate the prognosis and better manage the prevention of subsequent relapses. Aim. Determine ADAMTS13 conformation in plasma of iTTP patients during acute TTP and remission when TS13:act is <10%, moderately restored (10-50%) or >50% and investigate if anti-ADAMTS13 autoAbs induce conformational changes in ADAMTS13. Methods. TS13:act was determined in 120 iTTP plasma samples from 4 different centers (Marseille, Milan, Budapest, Utrecht). Samples were categorized according to the presence of clinical symptoms (acute versusremission) and their TS13:act in remission (>50%, 10-50%,<10%). Next, ADAMTS13 conformation was determined in all samples using our ADAMTS13 conformation ELISA. Additionally, presence of anti-ADAMTS13 autoAbs was also determined via ELISA. Finally, IgG's from 18 acute iTTP plasma samples were purified and added to folded ADAMTS13 from healthy donor (HD) plasma to test whether iTTP IgG's are able to induce the open HD ADAMTS13 conformation. Results. Of the 120 iTTP plasma samples, 46 were obtained during the acute (clinical signs present) and 74 during the remission phase (clinical signs absent). Further subdividing remission samples showed that TS13:act was >50% in 41, 10-50% in 14 and <10% in 19 samples. ADAMTS13 was open in 98% (45/46) of the acute samples and folded in 71% (29/41) of the remission samples with TS13:act >50%, confirming our previous results. Interestingly, ADAMTS13 was open in 93% and 89% of remission samples with TS13:act 10-50% and <10%, respectively (chi square, P<0.0001). Since anti-ADAMTS13 autoAbs influence TS13:act in iTTP patients, we next could demonstrate that open ADAMTS13 conformation was linked with presence of anti-ADAMTS13 autoAbs (chi square, P<0.0001) suggesting that anti-ADAMTS13 autoAbs could be a factor able to induce an open ADAMTS13 conformation in iTTP patients. To further test this hypothesis, we purified IgG's from 18 acute iTTP plasma's with open ADAMTS13 and added them to HD plasma containing closed ADAMTS13, where 14 of the 18 patient IgG pools (78%) did induce the open conformation in HD ADAMTS13, indicating that patient anti-ADAMTS13 autoAbs indeed can induce conformational changes in ADAMTS13. Conclusion. We show that ADAMTS13 is not only in the open conformation in iTTP patient plasma during the acute phase but also in remission when TS13:act is <10% or 10-50%. Hence, the presence of open ADAMTS13 in those remission patients indicates that the underlying pathophysiology is still ongoing, emphasizing the need for a close monitoring of those patients. In addition, anti-ADAMTS13 autoAbs were identified as a factor responsible for the change in conformation in ADAMTS13 in iTTP. Disclosures Peyvandi: Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria. Coppo:Ablynx: Consultancy. Veyradier:LFB: Other: Investigator. Vanhoorelbeke:Shire: Consultancy; Ablynx: Consultancy.
5
Stein, Eytan M., Courtney D. DiNardo, Amir T. Fathi, Alice S. Mims, Michael R. Savona, Anthony S. Stein, Richard M. Stone i in. "Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation". Blood 138, Supplement 1 (5.11.2021): 1276. http://dx.doi.org/10.1182/blood-2021-146507.
Pełny tekst źródłaStreszczenie:
Abstract Background: Ivosidenib (IVO) and enasidenib (ENA) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, FDA-approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated response and survival results from a phase 1 study of these agents when combined with intensive chemotherapy in patients with newly diagnosed m IDH1/2 AML. Methods: The design of this open-label, multicenter, phase 1 study (NCT02632708) has been previously described. Briefly, eligible patients with newly diagnosed m IDH1 or m IDH2 AML were treated with induction therapy (daunorubicin 60 mg/m 2/day or idarubicin 12 mg/m 2/day × 3 days with cytarabine 200 mg/m 2/day × 7 days) in combination with either IVO 500 mg once daily (for m IDH1) or ENA 100 mg once daily (for m IDH2). After induction, patients received up to 4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who completed or were ineligible for consolidation continued on maintenance IVO or ENA until the end of the study. IDH mutation clearance and measurable residual disease (MRD) negativity were assessed using BEAMing digital PCR and multiparameter flow cytometry (Stein et al. Blood 2021). Results: As of 16-Jan-2020, 153 patients had been treated: 60 in the IVO cohort (median age 62.5 years, range 24-76) and 93 in the ENA cohort (median age 63.0 years, range 27-77); 2 patients assigned to start ENA on Day 8 had an ongoing adverse event or died on Day 8, and therefore never received ENA and were not included in the efficacy analysis. Secondary AML (sAML; arising after an antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 18/60 (30.0%) IVO-treated patients and in 35/93 (37.6%) ENA-treated patients. In patients with sAML, 4 (22.2%) and 17 (48.6%) IVO-treated and ENA-treated patients, respectively, had previously received a hypomethylating agent. IVO or ENA combined with induction and consolidation were well tolerated (Stein et al . Blood 2021). Among the 60 IVO-treated patients, a response of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with incomplete platelet recovery (CRp) was achieved in 37/42 (88.1%) patients with de novo AML and in 10/18 (55.6%) patients with sAML. Among the 91 ENA-treated patients, a response of CR, CRi, or CRp was achieved in 45/56 (80.4%) patients with de novo AML and in 22/35 (62.9%) patients with sAML. Best overall response is reported in Table 1. Patients achieving CR, CRi, or CRp who had available samples were analyzed for IDH mutation clearance and MRD negativity. In those treated with IVO, the IDH1 mutation was cleared in 16/41 (39.0%) patients, and 16/20 (80.0%) were considered MRD negative. In those treated with ENA, the IDH2 mutation was cleared in 15/64 (23.4%) patients, and 10/16 (62.5%) were MRD negative (Stein et al . Blood 2021). Thirty-five (58.3%) IVO-treated patients received ≥1 cycle of consolidation therapy, 18 (30.0%) patients received maintenance after consolidation, 1 (1.7%) patient received maintenance after induction, and 29 (48.3%) patients proceeded to hematopoietic stem cell transplantation (HSCT). Forty-six (49.5%) ENA-treated patients received ≥1 cycle of consolidation therapy, 17 (18.3%) patients received maintenance after consolidation, 7 (7.5%) patients entered maintenance without consolidation, and 43 (46.2%) patients proceeded to HSCT. Median durations of follow-up were 21.2 and 23.7 months for IVO and ENA, respectively. For patients who entered maintenance, median duration of active maintenance was 13.8 and 11.0 months for IVO and ENA, respectively. Of patients who achieved CR, 7/42 (16.7%) of those treated with IVO and 7/51 (13.7%) of those treated with ENA experienced relapse or death. Overall survival is reported in Figure 1. Updated data from July 2021 will be presented. Conclusion: IVO or ENA in combination with induction and consolidation therapy have shown acceptable safety profiles, with ≥80% CR+CRi/CRp remission rates in patients with m IDH de novo AML. With over 21 months of follow-up, overall survival rates were high, with 12-month survival probabilities of >75% for both the IVO- and ENA-treated patients. The clinical benefit of adding IVO or ENA to induction, consolidation, and maintenance therapy for patients with newly diagnosed m IDH AML is being further evaluated in the ongoing HOVON150AML randomized phase 3 trial (NCT03839771). Figure 1 Figure 1. Disclosures Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding. Fathi: Kite: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Mims: Syndax Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding; Glycomemetics: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Stone: Boston Pharmaceuticals: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Winer: Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Döhner: AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Ulm University Hospital: Current Employment; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria. Pollyea: Syndax: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Karyopharm: Consultancy, Honoraria; Foghorn: Honoraria; Kiadis: Honoraria; Syros: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Teva: Research Funding; Amgen: Honoraria; Aprea: Honoraria; Jazz: Honoraria; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. McCloskey: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Amgen: Speakers Bureau; Incyte: Speakers Bureau; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Ossenkoppele: Agios: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Patel: Aptevo Therapeutics: Research Funding; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Frattini: Celgene/BMS: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Lersch: Celgene, a Bristol-Myers Squibb Company: Current Employment. Nabhan: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Almon: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Saatcioglu: Servier Pharmaceuticals: Current Employment. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Cooper: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Servier: Current Employment. Kantarjian: Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Tallman: Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. OffLabel Disclosure: Ivosidenib and enasidenib are indicated for the treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation (ivosidenib) or an IDH2 mutation (enasidenib) as detected by an FDA-approved test. Enasidenib and ivosidenib are investigational products in tumors other than relapsed/refractory AML.
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Peyvandi, Flora, Bruce A. Schwartz i Sigurd Knaub. "Efficacy and Pharmacokinetics of a New Fibrinogen Concentrate in Treating Acute Bleeding in Adolescent Patients with Congenital Fibrinogen Deficiency". Blood 132, Supplement 1 (29.11.2018): 2501. http://dx.doi.org/10.1182/blood-2018-99-116572.
Pełny tekst źródłaStreszczenie:
Abstract Introduction: Individuals with congenital afibrinogenemia can experience frequent and/or severe bleeding episodes (BE). Human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. We investigated the efficacy, safety and pharmacokinetics (PK) of a new highly purified, double virus-inactivated HFC (Fibryga, Octapharma) in adolescent patients. Methods: Data were analyzed from two multinational, prospective, open-label studies. FORMA-01 studied the PK of the new HFC vs. comparator (Haemocomplettan P), as well as surrogate efficacy and safety, after single infusion of 70 mg/kg. Surrogate efficacy was defined as thromboelastometric maximum clot firmness (MCF). FORMA-02 was a Phase 3 study in which the primary endpoint was the hemostatic efficacy of the new HFC for on-demand treatment of the first bleeding event. A 4-point objective scale, which was adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC), was used for evaluation of efficacy. In addition, MCF and safety were evaluated for all BEs that occurred during the study period. Results: Data were available for 12 patients aged 12-17 years with afibrinogenemia. FORMA-01 included 5 patients aged 12-17 years (1 was excluded due to a protocol deviation); PK data for new HFC vs. comparator are shown in Table 1. For comparison, in adults from the same study AUCnorm was also larger and clearance slower for new HFC vs. comparator (both p=0.0027). At 1 h following infusion of new HFC or comparator, mean±SD MCF (n=6) increased from 0 mm to 9.0±2.0 and 8.8±2.6 mm, respectively (9.9±3.3 and 10.4±4.9 mm in adults). In FORMA-02, 6 adolescent patients received new HFC individually dosed for treatment of a BE. Hemostatic efficacy for treatment of the first BE was rated as excellent for all patients (success: 100%; 90% CI: 0.655-1.000). When taking all BEs into account (n=23), efficacy was again classed as excellent for all patients. Mean MCF increased by 4.83±0.98 mm from baseline to 1 h after first infusion (7.06±3.36 mm in adults). There were no related serious adverse events, severe allergic, hypersensitivity reactions, or thromboembolic events, and no inhibitory anti-fibrinogen antibodies were detected. Conclusions: This analysis of data from two prospective studies demonstrated favorable efficacy, safety, and PK parameters of the new HFC in adolescents with afibrinogenemia. PK parameters were broadly comparable with those of the comparator HFC. After infusion of the new HFC, MCF increased statistically significantly and hemostatic efficacy was rated excellent in all patients. No safety concerns relating to the new HFC were identified in these study patients. Disclosures Peyvandi: Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria. Schwartz:Octapharma US: Employment. Knaub:Octapharma AG: Employment.
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Jurczak, Wojciech, Caroline Dartigeas, Marta Coscia, Peter S. Ganly, Ghassan Al-Jazayrly, Chunxiao Wang, Katherine Bao, Ching Ching Leow, Safi Shahda i Pier Luigi Zinzani. "BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)". Blood 138, Supplement 1 (5.11.2021): 3732. http://dx.doi.org/10.1182/blood-2021-145938.
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Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In a phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397, 10277:892-901). Study Design and Methods: BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC). Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients. Disclosures Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Coscia: Gilead: Honoraria; AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Bao: Loxo Oncology at Lilly: Current Employment; Genentech: Ended employment in the past 24 months. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zinzani: Eusapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Celtrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.
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Carlo-Stella, Carmelo, Pier Luigi Luigi Zinzani, Anna Sureda, Luís Francisco Araújo, Olivier Casasnovas, Cecilia Carpio, Su-Peng Yeh i in. "A Phase 1/2, Open-Label, Multicenter Study of Isatuximab in Combination with Cemiplimab in Patients with Lymphoma". Blood 138, Supplement 1 (5.11.2021): 4362. http://dx.doi.org/10.1182/blood-2021-148431.
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Abstract Introduction: Immune checkpoint blockade of programmed death-1 (PD-1) receptor and its ligand (PD-L1) has contributed to efficacy in many tumor types, with clinical responses observed in a proportion of patients (pts) with Hodgkin lymphoma and rare non-Hodgkin lymphoma subtypes. A recent study demonstrated that combination treatment with anti-PD-L1 and anti-CD38 agents contributed to a stronger anti-tumor immune response compared with anti-PD-L1 monotherapy. Isatuximab, an anti-CD38 monoclonal antibody, is approved for use in multiple myeloma. Cemiplimab, an anti-PD-1 monoclonal antibody, is approved for use in cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Methods: This Phase 1/2 open-label study (NCT03769181) was designed to assess the safety, tolerability, and efficacy of isatuximab in combination with cemiplimab (Isa+Cemi) in pts with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). The primary objectives of Phase 1 were to characterize the safety and tolerability of Isa+Cemi and to confirm the recommended Phase 2 dose. Phase 2 used a Simon's 2-stage design to assess the complete response rate in Cohort A1 (anti-PD-1/PD-L1 naïve cHL; n=18; median age, 36 years; 55.6% male; ≥2 prior regimens, 100%) and to assess the objective response rate in Cohorts A2 (cHL progressing after PD-1/PD-L1 therapy; n=12; median age, 33 years; 58.3% male; ≥2 prior regimens, 100%), B (DLBCL; n=17; median age, 64 years; 70.6% male; ≥2 prior regimens, 100%), and C (PTCL; n=11; median age, 69 years; 63.6% male; ≥2 prior regimens, 9.1%). Pts received Isa+Cemi for up to 96 weeks. In Phase 1, the isatuximab dose was 10 mg/kg every week (Cycle 1), every 2 weeks (Cycle 2-6), or every 3 weeks (Cycle 7+). The cemiplimab dose was 250 mg every 2 weeks (Cycle 1-6) or 350 mg every 3 weeks (Cycle 7+). An interim analysis was performed when the last pt in Phase 2 was followed up for 24 weeks. The efficacy evaluation was based on Simon's 2-stage design with 85% power at a 5% 1-sided alpha level for each cohort. At least 8 (44.4%) and 3 (30.0%) responses were required in Cohorts B and C, respectively, in Phase 2 Stage 1 to advance to Phase 2 Stage 2. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed, confirming the recommended Phase 2 dose. Treatment-emergent adverse events (TEAEs) were reported in 83.3% (Cohort A1) and 100% (Cohorts A2, B, C) of pts. Grade ≥3 TEAEs occurred in 5.6%, 8.3%, 70.6%, and 81.8% of pts in Cohorts A1, A2, B, and C, respectively. There were no pts in Cohorts A1 or A2 who reported TEAEs leading to definitive discontinuation; 5.9% and 27.3% of pts in Cohorts B and C experienced TEAEs leading to definitive discontinuation. No Grade 5 TEAEs with fatal outcome were reported in Cohorts A1 or A2. There were 4 deaths reported during the on-treatment period in Cohort B (progressive disease, n=2; intestinal perforation, n=1; urinary tract infection, n=1) and 2 in Cohort C (unknown, n=1; progressive disease, n=1). Infusion reactions were reported in 38.9%, 75.0%, 52.9%, and 72.7% of pts in Cohorts A1, A2, B, and C, respectively; there was 1 (9.1%) Grade ≥3 infusion reaction reported in Cohort C. Pharmacokinetics (PK) analyses suggested no effect of cemiplimab on isatuximab PK, and vice versa. Based on Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of pts in the all-treated population achieved a complete or partial response. Median progression-free survival was 8.38 months (95% CI: 2.72-not calculable [NC]), 8.28 months (95% CI: 2.6-NC), 2.37 months (95% CI: 0.46-2.69), and 2.66 months (95% CI: 0.43-2.99) in Cohorts A1, A2, B, and C, respectively. Conclusion: In this study, Isa+Cemi had a manageable safety profile. Clinical efficacy was observed in pts with cHL, with increased responses observed in pts who had not previously received anti-PD-1/PD-L1 therapy compared with those who progressed on anti-PD-1/PD-L1 therapy. For Cohorts B (DLBCL) and C (PTCL), results of the interim efficacy analysis did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Most pts with DLBCL were primary refractory/bulky and discontinued rapidly, which may have contributed to the lack of activity with this combination. Disclosures Carlo-Stella: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Casasnovas: TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy; ROCHE: Consultancy, Research Funding. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Bouabdallah: Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Kim: Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Sanofi: Research Funding; IGM Biosciences: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Roche: Research Funding. Cordoba: Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Alves: Janssen, Cilag, Gilead, Takeda, Astrazeneca, Roche, Abbvie: Consultancy, Honoraria. Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Abbadessa: Sanofi: Current Employment. Meng: Sanofi: Current Employment. Ji: Sanofi: Current Employment. Lepine: Sanofi: Other: Contractual relationship. Saleem: Sanofi: Current Employment. Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Based on the Phase III ICARIA-MM study, isatuximab (Sarclisa) is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase III IKEMA study, isatuximab in combination with carfilzomib and dexamethasone is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy, and in the European Union for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Cemiplimab (Libtayo) is an anti-PD-1 antibody approved for the treatment of the following: 1) patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation; 2) patients with locally advanced or metastatic basal cell carcinoma previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate; and 3) patients with NSCLC and high tumor PD-L1 expression as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations, and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic.
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Jurczak, Wojciech, Pier Luigi Zinzani, Georg Hess, Gianluca Gaidano, Mariano Provencio, Zsolt Nagy, Tadeusz Robak i in. "A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma: Long-Term Follow-up, Final Analysis". Blood 134, Supplement_1 (13.11.2019): 4078. http://dx.doi.org/10.1182/blood-2019-124297.
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Background: CD19 is broadly and homogeneously expressed across different B-cell malignancies and represents an attractive target antigen in patients with B-cell non-Hodgkin's lymphoma (NHL). Tafasitamab (MOR208) is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody. This ongoing study is investigating the single agent antitumor activity in adult patients with relapsed or refractory (r/r) NHL who had received at least one prior rituximab-containing therapy. Patients and Methods: The study enrolled 92 r/r NHL patients: diffuse large B-cell lymphoma (DLBCL; n=35), mantle cell lymphoma (MCL; n=12), follicular lymphoma (FL; n=34), or other indolent NHL (iNHL; n=11). The median number of prior systemic therapies was three (range 1-15) for the entire patient population. The primary efficacy endpoint was investigator-assessed overall response rate (ORR) based on the revised International Working Group Response Criteria (Cheson et al., et al. J Clin Oncol 2007). Secondary objectives were to evaluate the time-to-response, duration of response (DoR), time to progression and progression-free survival (PFS), and to establish the safety and tolerability of tafasitamab. Patients received up to three 28-day cycles with weekly infusions of 12 mg/kg body weight of tafasitamab. Premedication, including antipyretics, histamine H1 receptor blockers and glucocorticosteroids, was administered for the first three infusions. Patients with ongoing at least partial remission (PR) at the end of Cycle 3 received further tafasitamab treatment until disease progression, either monthly or every second week. Results: The investigator-assessed best response (intent-to-treat analysis) in the different subgroups at cut-off date (28 Sep 2018) is shown in Table 1. Five patients in complete remission (CR) (one DLBCL, two FL, two other iNHL) were ongoing and still on tafasitamab treatment at the cut-off date. These patients were on treatment for more than 4 years. The median DoR was 20.1 months in DLBCL and 24 months in FL (Table 2). The median PFS was 2.7 (95% confidence interval [CI] 2.1-13.2 months) and 6.6 months (95% CI 5.3-20.5 months) in DLBCL and FL, respectively. The PFS rate at 12 months was 34.3% and 39.2% for DLBCL and FL, respectively (Table 2). Similar PFS was observed in rituximab-refractory as well as non-refractory patients. Patients with a peripheral blood natural killer (NK) cell count >100 cells/µL at baseline had a median PFS of 4.2 months (DLBCL) or 8.8 months (FL/iNHL), as compared with patients who had <100 NK cells/µL at baseline showing a median PFS of 2.1 months (DLBCL) or 3.2 months (FL/iNHL), respectively. Tafasitamab was well tolerated in patients with r/r NHL. Most treatment-emergent adverse events (TEAEs) were mild in nature. The most common grade ≥3 TEAEs were neutropenia (9.8%), thrombocytopenia (4.3%), anemia (3.3%) and pneumonia (3.3%). Four patients (4.3%) experienced serious adverse reactions (febrile neutropenia, genital herpes zoster, infusion-related reaction and myelodysplastic syndrome). There was no evidence of grade ≥3 late toxicity during the long-term follow-up period; no treatment-related deaths occurred. Conclusion: Tafasitamab monotherapy until progression resulted in durable responses and was well tolerated in patients with both aggressive and indolent NHL subtypes. Disclosures Jurczak: Celgene: Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Servier: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Gilead: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Incyte: Research Funding. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hess:Janssen: Consultancy, Honoraria, Other: personal fees; Celgene: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Pfizer: Other: personal fees, Research Funding; CTI: Consultancy, Employment, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Provencio:Takeda: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Novartis: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; AstraZeneca: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Pierre Fabre: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Boehringer Ingelheim: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; MSD: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau. Nagy:Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Robak:Morphosys AG: Research Funding; BeiGene: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding. Maddocks:Teva: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buske:Amgen: Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Hexal: Honoraria, Speakers Bureau. Ambarkhane:MorphoSys: Employment. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Dirnberger-Hertweck:MorphoSys: Employment. Tillmanns:MorphoSys AG: Employment. Weirather:MorphoSys: Employment.
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Peyvandi, Flora, Bruce A. Schwartz i Sigurd Knaub. "Efficacy and Safety of Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and for Surgical Prophylaxis in Subjects with Congenital Fibrinogen Deficiency — a Phase 3 Study". Blood 132, Supplement 1 (29.11.2018): 2502. http://dx.doi.org/10.1182/blood-2018-99-116440.
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Abstract Introduction: Congenital afibrinogenemia is a rare inherited disorder characterized by an absence of plasma fibrinogen. Affected individuals have a highly variable bleeding tendency, which can be severe and include life-threatening bleeding and spontaneous/trauma-related bleeds. Therapeutic substitution with human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. The FORMA-02 study investigated the hemostatic efficacy of a new plasma-derived, double virus-inactivated HFC (Fibryga, Octapharma) for on-demand treatment of bleeding episodes (BEs) and for surgical prophylaxis in patients with afibrinogenemia. Methods: FORMA-02 was a prospective, open-label, uncontrolled, multicenter Phase 3 study. A total of 25 patients with congenital afibrinogenemia (≥12 years) received the new HFC for treatment of a BE and/or for surgical prophylaxis. HFC was individually dosed to achieve a recommended target fibrinogen plasma level dependent on the bleeding type or surgery type (minor or major). The primary endpoint was the efficacy of the new HFC for on-demand treatment of the first BE after signed consent was obtained. Secondary endpoints included hemostatic efficacy of the HFC for the treatment of all BEs during the study period and its efficacy in preventing bleeding during and after surgery. Hemostatic efficacy was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) using objective four-point scales, with treatment success defined as a rating of excellent or good. Thromboelastometry maximum clot firmness (MCF) was also investigated as a surrogate marker of efficacy. Results: A total of 25 patients received the new HFC for treatment of a BE (N=24) and/or surgical prophylaxis (N=9). The mean±SD dose of HFC was 65.51±26.47 mg/kg per BE (89 events) and 40.45±30.78 mg/kg per surgery for surgical prophylaxis (12 events). Hemostatic efficacy for treatment of the first BE (primary endpoint) was rated as excellent or good for all patients by both the investigator and the IDMEAC (Success: 100%; 90% CI 0.89-1.00). When all BEs were evaluated (N=89 BEs in 24 patients), hemostatic efficacy was rated as excellent or good for 96.6% of events by the investigator and 98.9% by the IDMEAC. The first HFC infusion for treatment of the first BE for each patient led to a mean increase in blood fibrinogen concentration of 114.74±25.28 mg/dL 1 hour after administration, while the MCF increased by a mean of 6.48±3.07 mm. Intraoperative hemostatic efficacy for surgical prophylaxis was rated by the surgeon and the IDMEAC as excellent or good for 100% of the 12 surgeries that were performed (success: 100%; 90%CI 0.82-1.00). Postoperative efficacy was also rated as excellent or good in all cases. The first HFC infusion for each surgery led to a mean increase in blood fibrinogen concentration of 104.55±43.64 mg/dL at 1 hour after administration. A total of 15 serious adverse events (SAEs) occurred in 5 patients; only one was deemed to be related to the HFC by the investigator. This was a digital ischemia that resolved without sequelae. No inhibitory anti-fibrinogen antibodies were detected and there were no severe allergic or hypersensitivity reactions related to the HFC. Conclusions: These data indicate that the new HFC was efficacious for on-demand treatment of acute bleeding and for surgical prophylaxis in patients with congenital afibrinogenemia, with hemostatic efficacy rated as 100% in both settings. The HFC showed an acceptable safety profile in this study population. Disclosures Peyvandi: Grifols: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau. Schwartz:Octapharma US: Employment. Knaub:Octapharma AG: Employment.
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Kornauth, Christoph, Tea Pemovska, Gregory Ian Vladimer, Günther Bayer, Michael Bergmann, Sandra Eder, Ruth Eichner i in. "Treatment Guided By Next Generation Functional Drug Screening Provides Clinical Benefit in Advanced Aggressive Hematological Malignancies: Final Evaluation of the Open Label, Single Arm Exalt Trial". Blood 136, Supplement 1 (5.11.2020): 2–4. http://dx.doi.org/10.1182/blood-2020-140831.
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Background: Aggressive hematological malignancies in relapsed/refractory setting bear a dire prognosis with low cure rates and short survival. Matching these patients to therapies is challenged by complexity due to spatial and temporal tumor evolution and incomplete understanding of genotype to phenotype correlations. Direct functional testing could address these impediments. The EXALT trial is an interventional, one-arm study designed to assess the clinical value of next generation functional drug screening (ngFDS). An interim analysis on 17 patients suggested a clinical benefit (Snijder et al., Lancet Hematol. 2017). Methods: We applied image-based ngFDS to quantify differential ex-vivo sensitivity of primary patient tumor cells to respective non-tumor cells towards 136 small molecule drugs, including EMA approved for any indication or experimental. We screened bone marrow, peripheral blood or lymph node material from 143 patients who suffered from late stage aggressive hematological malignancies (acute leukemias, aggressive B- and T-cell lymphomas) , discussed the results in a multidisciplinary tumor board and recommended treatments to physicians (A). The primary endpoint of this study was the percentage of patients reaching a PFS-ratio (PFS(ngFDS treatment)/PFS(previous treatment)) of ≥1.3 with an H0 hypothesis < 15% patients. The secondary endpoint was overall response rate (ORR) defined as proportion of patients reaching complete remission (CR) or partial remission (PR). Additionally, we performed a post hoc analysis to evaluate the matching of ngFDS to drugs used in actual treatment (matching score of received treatment). Results: 56 (39%) patients were evaluable and treated according to ngFDS based recommendations. With 30 of 56 (54%) ngFDS guided patients experiencing a PFS ratio of ≥1.3, the primary study endpoint was reached. 11 patients (37%) had ongoing response at censoring date (B). The median follow-up was 718 days. The median number of days from sampling to treatment was 21 (range 4-77). The ngFDS treatment regimens consisted of a median of 2 drugs (range: 1-6). ORR was 55% for all evaluable ngFDS treated patients, 60% for the lymphoid subgroup and 41% for the myeloid subgroup. Patients on ngFDS guided treatment with performance status ECOG ≤ 1 had a median PFS of 207 days compared to a median PFS of 29 days for patients with higher ECOG (p < 0.001, C). 24 of 39 (62%) patients with ECOG ≤ 1 had a PFS ratio of ≥1.3 (D). In disease specific subgroup analysis median PFS of T-cell lymphoma patients was 235 days versus 60 days for B-cell lymphoma patients (p = 0.018, E). Age (≤60 vs. >60), sex, lineage (myeloid vs. lymphoid), number of previous treatment lines (≤2 vs. >2), and clinical presentation (leukemia vs. lymphoma) did not have an impact on PFS of ngFDS guided treatment. Post hoc analysis including additional 17 non-ngFDS treated patients demonstrated that only patients receiving treatment with a positive ngFDS matching score demonstrated clinical benefit (HR: 0.53, p=0.005; vs. HR: 1.4, p=0.4). ngFDS matched treatments resulted in higher PFS for patients with tumor samples that had a cancer cell fraction of 10-50% in comparison to patients with samples of lower or higher cancer cell percentage (HR:0.35, p=0.01). Conclusion: ngFDS could be integrated in the routine clinical work flow. ngFDS guided treatments led to high rates of PFS prolongation compared to previous treatments of individual patients. ngFDS guided treatment is feasible and effective in patients with late stage aggressive hematological malignancies. These results prompted a prospective randomized trial comparing treatment guidance based on ngFDS or comprehensive genomic profiling or physician's choice (EXALT-2 trial, NCT04470947). Figure Disclosures Vladimer: Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Jaeger:Karyopharm: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Krall:Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Valent:Allcyte GmbH: Research Funding; Cellgene: Honoraria, Research Funding; Pfizer: Honoraria. Wolf:Celgene: Honoraria, Research Funding. Zielinski:MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Imugene: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Merrimack: Consultancy, Honoraria, Speakers Bureau; Merck KGaA: Consultancy, Honoraria, Speakers Bureau; Fibrogen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Tesaro: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Speakers Bureau; Athenex: Consultancy, Honoraria, Speakers Bureau. Superti-Furga:Allcyte GmbH: Current equity holder in private company, Other: Founder. Snijder:Allcyte GmbH: Current equity holder in private company, Other: Founder. Staber:Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Celgene/ BMS: Consultancy, Honoraria; msd: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.
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Young, Guy, Robert F. Sidonio, Ri Liesner, Johannes Oldenburg, Tiffany Chang, Marianne Uguen, Christophe Dhalluin i in. "HAVEN 2 Updated Analysis: Multicenter, Open-Label, Phase 3 Study to Evaluate Efficacy, Safety and Pharmacokinetics of Subcutaneous Administration of Emicizumab Prophylaxis in Pediatric Patients with Hemophilia A with Inhibitors". Blood 130, Suppl_1 (7.12.2017): 85. http://dx.doi.org/10.1182/blood.v130.suppl_1.85.85.
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Abstract Introduction Emicizumab, a bispecific humanized monoclonal antibody administered subcutaneously, bridges FIXa and FX to restore the function of missing FVIIIa, and is being developed to prevent bleeds in patients with hemophilia A (PwHA) with and without inhibitors. An interim analysis of the HAVEN 2 study (n=20) in patients aged 2-12 years (data cutoff 28 Oct, 2016) showed that subcutaneous, once-weekly emicizumab prophylaxis successfully prevented or reduced bleeds, provided clinically meaningful reductions in annualized bleed rate (ABR) versus prior bypassing agent (BPA) treatment, and was well tolerated (Young et al. RPTH 2017;1 (S2):Abstract OC 24.1). Here we present an updated, much larger (40 additional patients, 60 total) analysis of efficacy, safety and pharmacokinetics (PK) of once-weekly subcutaneous (SC) emicizumab prophylaxis in pediatric PwHA with inhibitors. Methods The study (NCT02795767) enrolled PwHA with inhibitors aged 2-12 years (or 12-17 years if <40 kg), and currently enrolling those <2 years of age, previously treated with BPAs to receive emicizumab prophylaxis for ≥52 weeks. Efficacy analyses included ABR and bleed reduction vs ABR on prior BPA treatment from prospective non-interventional study (NIS; NCT02476942). Health-related quality of life (HRQoL), aspects of caregiver burden and safety parameters were also assessed. Results The updated analysis (8 May, 2017 cutoff) included approximately 6 additional months of data vs the first interim analysis; 60 PwHA with inhibitors aged 1-15 (median 7) years; 57 aged <12 years including 2 aged <2 years were included in the efficacy analyses. Three patients aged ≥12 years and <40kg were enrolled. The median observation time was 9 (range 1.6-41.6) weeks; 20 patients had been observed ≥24 weeks, and 2 patients aged <2 years for approximately 5 and 2 weeks. Efficacy data for patients aged <12 years are shown in the Table. Overall, 54/57 (94.7%) patients had zero treated bleeds. Only 3 treated bleeds were reported, with 1 occurring in a joint, 1 occurring in a muscle, and 1 hip bleed that was classified as "other"; all were safely treated with rFVIIa. Only 1 of these 3 treated bleeds was a spontaneous bleed. In total, 37/57 patients (64.9%) reported no bleeds. A total of 65 bleeds were reported in 20 patients, with 8 occurring in a joint, 2 occurring in a muscle, and 55 being classified as "other"; of the 55 "other'' bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) traumatic and 3 (4.6%) due to procedure/surgery. Twenty-three patients <12 years of age were followed for ≥12 weeks and therefore included in the ABR population calculation. The ABR was 0.2 (95% CI 0.06; 0.62) for treated bleeds (Table). Eighteen patients <12 years old had previously participated in the NIS. Of these, 13 patients had been on HAVEN 2 for ≥12 weeks and were therefore included in the intra-individual comparison; a substantial reduction in ABR of 99% with emicizumab prophylaxis vs prior BPA treatment was observed in these patients. Individual patient data are shown in Fig 1. Considerable improvements in HRQoL, and aspects of caregiver burden were observed. Emicizumab was well tolerated; the most common AEs were viral upper respiratory tract infection and injection site reactions (16.7% of patients each). Six patients experienced 7 serious AEs (2 muscle hemorrhage, 1 eye pain, 1 catheter site infection, 1 device-related infection, 1 mouth hemorrhage, 1 appendicitis), with none deemed related to emicizumab; no thromboembolic or thrombotic microangiopathy events were reported. No patients tested positive for anti-drug antibodies. Mean steady state trough emicizumab concentrations of approximately 50 µg/mL were maintained with longer follow-up (Fig 2). PK profiles were consistent across age groups and body weight. Conclusion HAVEN 2 is the largest study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis prevented or substantially reduced bleeds and was well tolerated in this patient population. PK remained consistent with that seen in adolescent/adult PwHA. Weekly subcutaneous emicizumab has the potential to reduce overall treatment and disease burden and may provide a new standard of care for hemophilia management by providing an effective, safe and convenient option for pediatric PwHA with inhibitors. Disclosures Young: CSL Behring: Honoraria; Novo Nordisk: Consultancy. Sidonio: Bioverativ: Research Funding; Novo Nordisk: Consultancy; Shire: Consultancy, Research Funding; Grifols: Research Funding; CSL Behring: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy. Liesner: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bio Products Laboratory: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI/Bioverativ: Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Investigator Clinical Studies and Research Funding, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies and Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Chang: Genentech: Employment, Equity Ownership. Uguen: F. Hoffmann-La Roche Ltd: Employment. Dhalluin: F. Hoffmann-La Roche Ltd: Employment. Schmitt: F. Hoffmann-La Roche Ltd: Employment. Levy: Genentech, Inc.: Employment. Shima: Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Mahlangu: Catalyst Biosciences: Consultancy, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biotest: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau.
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Oldenburg, Johannes, María Teresa Alvarez Román, Giancarlo Castaman, Maissaa Janbain, Tadashi Matsushita, Karina Meijer, Sabine Friedl, Martin Sanabria i Mark Reding. "Real-World Effectiveness and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) in Previously Treated Patients with Hemophilia A (HEM-POWR): Online Patient Portal and LIFE-ACTIVE Sub-Study". Blood 134, Supplement_1 (13.11.2019): 4943. http://dx.doi.org/10.1182/blood-2019-128140.
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Background and Rationale: BAY 94-9027 (damoctocog alfa pegol) is a site-specifically PEGylated B-domain deleted recombinant factor VIII (FVIII) with an extended half-life, approved for prophylaxis or treatment of bleeds in previously treated patients (PTPs) aged ≥12 with hemophilia A. The efficacy and safety of BAY 94-9027 was demonstrated in two phase II/III clinical studies in PTPs with severe hemophilia A, however, real-world data are still being gathered. The aim of the HEM-POWR study is to assess the effectiveness and long-term safety of BAY 94-9027 in the real-world clinical setting. Patients will be introduced to an online patient portal that provides study information as well as access to eDiaries and electronic patient-reported outcomes (ePROs) to patients to facilitate retention over the duration of the study. Patients will also be given the opportunity to participate in LIFE-ACTIVE, a sub-study analyzing the relationship between the patients' regular daily activity and the efficacy parameters collected during HEM-POWR. Here we present the features of the patient portal and describe the LIFE-ACTIVE sub-study design. Study Design and Methods: HEM-POWR (NCT03932201) is a multinational, multicenter, non-interventional, open-label, prospective, phase IV, cohort study. It aims to enroll ≥200 PTPs with hemophilia A receiving BAY 94-9027 (on-demand, prophylaxis, or intermittent prophylaxis [as per local label]). Key exclusion criteria are presence or history of FVIII inhibitor (≥0.6 Bethesda units), diagnosis of any bleeding or coagulation disorder other than hemophilia A, or treatment with immune tolerance induction at enrollment. The primary objective of HEM-POWR is to assess the effectiveness of prophylaxis with BAY 94-9027 in the real-world setting through the collection of total bleeding events and analysis of annualized bleeding rate. Secondary objectives include long-term safety, joint health, location and number of target joints, hemostasis during surgery and PROs. Patient enrollment, adherence and retention can be difficult in observational hemophilia studies. The patient portal for this study aims to overcome these challenges by providing study- and product-related information. It also aims to lessen the burden for patients in the study by providing e-solutions to collect their study data, including the ability to complete the study diary, and PRO measures online. The portal also includes videos explaining the study and study procedures, and is country-customized with links to relevant websites. Patients participating in LIFE-ACTIVE will be asked to wear an ActiGraph CP Insight activity-tracking smart watch continually for four 30-day periods, at their initial visit and then at months 12, 24 and 36. Measurements recorded will include physical activity intensity and duration, general mobility, and sleep quality and duration. All data will be transferred to a secure, cloud-based system and patients will not be aware of the values measured by the device. Participating countries include, but may not be limited to Austria, Belgium/Luxemburg, Canada, Colombia, Finland, Germany, Greece, Italy, Japan, Netherlands, Portugal, Saudi Arabia, Denmark, Norway, Sweden, Slovenia, Spain, Switzerland, Taiwan, and USA. The study will run from 2019 until 2025, with an observation period of ≥60 months. Disclosures Oldenburg: Octapharma: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Takeda (Shire): Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Swedish Orphan Biovitrum: Consultancy, Speakers Bureau. Alvarez Román:CSL Behring: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Sobi: Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire (Takeda): Research Funding, Speakers Bureau. Castaman:Shire: Speakers Bureau; Uniqure Kedrion: Speakers Bureau; Pfizer: Research Funding; CSL Behring: Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Janbain:Shire (Vonvendi): Speakers Bureau; Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; HTRS-MRA (Bioverativ Sanofi): Research Funding. Matsushita:uniQure: Consultancy, Honoraria; CSL: Consultancy, Honoraria; Bioverative: Research Funding; Pfizer: Consultancy, Honoraria; KM biologists: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria. Meijer:Sanquin: Research Funding; Pfizer, Sanquin, Uniqure: Research Funding; Uniqure, BMS, Aspen, Boehringer Ingelheim, Sanquin, Bayer: Consultancy, Honoraria; Bayer: Research Funding. Sanabria:Bayer: Employment. Reding:Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Biomarin: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.
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Miesbach, Wolfgang A., Giovanni Di Minno, Elena Santagostino, Dr Klamroth, Inga Bayh, Amaryllis Soto i Cedric Hermans. "Efficacy and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) Prophylaxis in Patients with Severe Hemophilia a and Comorbidities: A Post Hoc Analysis of PROTECT VIII Data". Blood 134, Supplement_1 (13.11.2019): 1117. http://dx.doi.org/10.1182/blood-2019-128486.
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Background: The availability of factor (F)VIII replacement products has dramatically improved life expectancy for patients with hemophilia A (HA). However, older patients face distinct challenges. Age-related comorbidities such as cardiovascular disease (CVD), often involving treatments that can increase the risk of bleeding, and patients who received treatment before the advent of recombinant products, are more likely to have been exposed to blood-borne viruses carrying chronic infections. It is important to understand clinical outcomes with FVIII products in patients with HA and these comorbidities. BAY 94-9027 (damoctocog alfa pegol; Jivi) is a B-domain deleted recombinant FVIII, site-specifically PEGylated with a 60 kDa (2×30 kDa) polyethylene glycol to extend its half-life. Efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe HA were demonstrated in the phase II/III PROTECT VIII trial and its Extension. This post hoc analysis assessed bleeding rates and safety outcomes for prophylaxis patients in PROTECT VIII and its Extension, based on the presence or absence of comorbidities of interest. Patients/Methods: PROTECT VIII (NCT01580293) was a partially randomized, open-label trial of 134 males aged 12-65 years with severe HA (FVIII <1%) and ≥150 FVIII exposure days. Prophylaxis patients (n=114) received BAY 94-9027 25 IU/kg twice weekly (2×W) for a 10-week run-in period. Patients with ≤1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days or 60 IU/kg every 7 days for the main 26-week study; patients enrolling after the randomization arms were full, or with ≥2 bleeds in the run-in period, received 30-40 IU/kg 2×W. Patients completing the main study could enter an extension, continuing BAY 94-9027 on any regimen used in the main study. Baseline characteristics, annualized bleeding rates (ABR) and safety were examined for patients on prophylaxis treatment during main study and its Extension with and without comorbidities of interest. Comorbidities included human immunodeficiency virus (HIV) infection, hepatitis B or C infection (HBV or HCV), and risk factors for CVD (hypertension, hypercholesterolemia, hypertriglyceridemia and hyperlipidemia). Results: A total of 104 patients who received BAY 94-9027 prophylaxis during the main study and the Extension (data cut-off: Jan 2018) were included in this analysis. Mean (SD) age of patients was 34.3 (13.0) years with a median (Q1;Q3) of 7 (2;15) bleeds in the 12 months before enrolment. Most patients (72.1%) had target joint(s) at baseline. Before study, 22 (21.2%) patients were receiving on-demand treatment; the remaining 82 were on regular prophylaxis. Most patients (n=66, 63.5%) had ≥1 comorbidity of interest. Of those, chronic HCV infection (HCV detection, asymptomatic) was most common (40/66, 60.6%), followed by acute HCV infection (HCV detection, symptomatic, 26/66, 39.4%), HBV infection (20/66, 30.3%), hypertension (17/66, 25.8%), hyperlipidemia (7/66, 10.6%), HIV infection (5/66, 7.6%), and hypertriglyceridemia (2/66, 3.0%). Patients with comorbidities of interest were older (mean age: 41.5 vs 21.9 years, respectively) and had a higher median (Q1;Q3) number of joint bleeds in the previous 12 months (5 [1;12] vs 3 [0;10], respectively) than patients without comorbidities (n=38). Pre-study, median ABR was 6.0 and 7.0 in patients with and without comorbidities of interest respectively, which decreased to 2.9 and 1.5 respectively during the main study, and further to 1.8 and 1.2 respectively during the Extension (Figure). In all patients with comorbidities of interest, robust improvements in median ABR were observed between the 12-month pre-study period and the main study period, and were maintained or improved in the Extension. Patients with comorbidities of interest had similar numbers of drug-related adverse events (AEs; 10.6% vs 23.7%), serious AEs (39.4% vs 28.9%) and discontinuations due to AEs (1.5% vs 2.6%) than those without comorbidities of interest during main study and Extension. Conclusions: The majority of patients (63.5%) in PROTECT VIII had ≥1 comorbidity of interest. The results from this post hoc analysis indicate that long-term BAY 94-9027 prophylaxis provided excellent control of bleed rates and was well tolerated in patients with severe HA and comorbidities of interest: HIV, HBV or HCV infection or risk factors for CVD. Figure Disclosures Miesbach: Biotest: Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Freeline: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Biomarin: Consultancy, Honoraria; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; UniQure: Consultancy, Honoraria, Research Funding; CSL: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bayer: Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Di Minno:Sanofi: Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Kedrion: Speakers Bureau; CSL: Speakers Bureau; Pfizer: Speakers Bureau; Novo Nordisk: Speakers Bureau. Santagostino:Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Spark: Speakers Bureau; Kedrion: Consultancy, Speakers Bureau; Bioverativ: Consultancy, Speakers Bureau; UniQure: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; CSL: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Bayh:Bayer: Employment. Soto:Bayer: Employment. Hermans:LFB: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; CAF-DCF: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; CSL: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Kedrion: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau.
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Kojima, S., T. Iwamoto, Y. Kobayashi, M. Kato, F. Takizawa, T. Ida, Y. Toda i in. "POS0572 IMMUNOGENICITY AND SAFETY OF ADJUVANTED RECOMBINANT ZOSTER VACCINE IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS". Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 554.2–555. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1608.
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BackgroundHerpes zoster (HZ) is caused by the reactivation of latent varicella-zoster virus (VZV) due to a decline in VZV-specific cell-mediated immunity (CMI) with increasing age and immunocompromised conditions [1]. Patients with rheumatoid arthritis (RA) treated with disease-modifying anti-rheumatic drugs (DMARDs) are at a high risk of developing HZ [2, 3]. An adjuvanted recombinant VZV glycoprotein E (gE) subunit vaccine (RZV) has been shown to be effective in preventing HZ in immunocompetent elderly populations. However, its efficacy and safety profile remain largely unknown in RA patients.ObjectivesThis study aimed to determine the immunogenicity and safety of RZV in patients with RA treated with DMARDs.MethodsThis longitudinal prospective study enrolled 53 RA patients treated with DMARDs (csDMARDs, n=20; bDMARDs, n=23; and tsDMARDs, n=10) and 10 individuals with no history of immunosuppressive treatment as controls. All the participants were aged ≥50 years. The participants received two intramuscular RZV injections 2 months apart. VZV-specific CMI and humoral immunity (HI) were assessed at 0 and 3 months after the first vaccination using flow cytometry and enzyme immunoassay. To assess CMI, the frequencies of VZV gE-specific CD4+CD40L+T cells expressing at least one activation cytokine (CD4[2+] T cells): IFN-γ, IL-2, and TNF-α were examined by flow cytometry. CMI responders were defined as a CD4[2+] T cell frequency ≥320 per 106CD4+T cells counted (for participants with pre-vaccination frequencies below 320 per 106CD4+T cells counted) or a ≥2-fold increase in CD4[2+] T cells (for those CD4[2+] T cells were already ≥320 per 106CD4+T cells counted at the time of pre-vaccination). CMI and HI response rates were compared between all patients with RA (n=53) and controls (n=10). The participants were followed up for 6 months after the first RZV administration for HZ onset. Baseline characteristics and information regarding adverse events were collected.ResultsPatients’ age and disease duration were 70 years old and 11 years, respectively. DAS28-CRP and CDAI scores at enrollment were 1.4 and 2.1, respectively. Thirty-six percent of RA patients had a history of HZ before the administration of RZV. VZV-specific CMI (controls: p=0.002, csDMARDs: p=0.012, bDMARDs: p=0.001, and tsDMARDs: p=0.002) (Figure 1A) and HI (controls: p=0.002, csDMARDs: p<0.001, bDMARDs: p<0.001, tsDMARDs: p=0.002) were significantly increased in DMARDs-treated RA patients after RZV administration, and the magnitudes of those responses were not significantly different between DMARDs-treated RA patients and controls. However, the vaccine response rate of CMI of DMARDs-treated RA patients was significantly lower than that of the controls (51% vs. 90%, p=0.034) (Figure 1B), whereas the response rate of HI was not (66% vs. 70%, p>0.999). In addition, no significant baseline factors affecting CMI responses, including DMARDs use, were identified between RA patients with and without CMI responses. RZV-related adverse events were generally mild, and all participants received two doses of RZV. RZV-induced RA flares occurred in two patients (3.8%) but were also mild and controllable.Figure 1.CMI responses to VZV in patients with RA and controls before and after RZV administration.(A) The frequencies of VZV gE-specific CD4[2+] T cells were examined by flow cytometry.(B) Vaccine response rate of CMI in all participants.ConclusionRZV is robustly immunogenic and has a clinically acceptable safety profile in elderly RA patients receiving DMARDs.References[1]Cohen JI. N Engl J Med. 369, 255-263 (2013)[2]Veetil BM, et al. Arthritis Care Res (Hoboken). 65, 854-861 (2013)[3]Redeker I, et al. Ann Rheum Dis. 81, 41-47 (2022)[4]Strezova A, et al. Open Forum Infect Dis. 23, ofac485 (2022)AcknowledgementsThis work was supported in part by grants from Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA), Japan Agency for Medical Research and Development.Disclosure of InterestsShotaro Kojima: None declared, Taro Iwamoto: None declared, Yoshihisa Kobayashi: None declared, Manami Kato: None declared, Fumiyoshi Takizawa: None declared, Tomoaki Ida: None declared, Yosuke Toda: None declared, Kazusa Miyachi: None declared, Junya Suzuki: None declared, Arifumi Iwata: None declared, Shunsuke Furuta: None declared, Kei Ikeda Speakers bureau: KI has received research grants from Mitsubishi-Tanabe Pharma, all unrelated to the current manuscript., Grant/research support from: KI has received honoraria for lectures from Abbvie, Mitsubishi-Tanabe Pharma, Eli Lilly Japan, Novartis, Pfizer Japan, Janssen Pharmaceutical, Eisai, Gilead Sciences and Bristol Myers Squibb, all unrelated to the current manuscript., Kotaro Suzuki: None declared, Hiroshi Nakajima Speakers bureau: HN has received honoraria for lectures from Chugai Pharmaceutical, Abbvie, Takeda Pharmaceutical, Astellas Pharma, Eli Lilly Japan, Asahikasei Pharma, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Eisai, Bristol Myers Squibb and Nippon Kayaku, all unrelated to the current manuscript., Grant/research support from: HN has received research grants from Chugai Pharmaceutical, Abbvie, Takeda Pharmaceutical, Astellas Pharma, Eli Lilly Japan, Asahikasei Pharma, Pfizer Japan, UCB Japan, Eizai, Mitsubishi Tanabe Pharma and Bristol Myers Squibb, all unrelated to the current manuscript.
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Peyvandi, Flora, Spero R. Cataland, Marie Scully, Paul Coppo, Paul Knöbl, Johanna A. Kremer Hovinga, Ara Metjian i in. "Integrated Efficacy Results from the Phase II and Phase III Studies with Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura". Blood 132, Supplement 1 (29.11.2018): 373. http://dx.doi.org/10.1182/blood-2018-99-112125.
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Abstract Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy, in which accumulation of ultra large von Willebrand factor (ULvWF) multimers leads to an increased risk of thrombus formation in small blood vessels due to platelet adhesion. A combination of plasma exchange (PE) and immunosuppression is the current mainstay of treatment for aTTP. The efficacy of caplacizumab in aTTP patients, in conjunction with PE and immunosuppression, was demonstrated in both placebo-controlled Phase II TITAN study and Phase III HERCULES study. Herein, we present the results of the integrated efficacy analyses of both studies. Methods : All randomized patients in the TITAN and HERCULES studies were integrated and included in the analysis population. Patients had a single-blind (SB, TITAN) or a double-blind (DB, HERCULES) treatment period followed by a follow-up period of 30 days. Patients in the HERCULES study could enter an open-label treatment period (i.e., in case of exacerbation during the DB treatment period). The primary endpoint was time to platelet count response, analyzed according to the corresponding platelet count response definition for each individual study (Figure 1). Secondary endpoints included: (i) the proportion of patients with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event; (ii) the proportion of patients with a recurrence of TTP during the DB/SB treatment period and the overall study period; (iii) the proportion of patients with refractory TTP (defined as the absence of platelet count doubling after 4 days of standard treatment, and LDH above normal); (iv) mortality rate during the DB/SB treatment period and the overall study period; (v) the number of PE days during the DB/SB treatment period. Results : 220 patients were randomized in both studies, 108 to the caplacizumab group and 112 to the placebo group. The groups were balanced with respect to demographics and baseline disease characteristics except for an imbalance relating to a history of previous TTP episode (Table 1). There was a statistically significant difference in favor of caplacizumab in time to platelet count response (p <0.001; platelet count normalization rate ratio [95% CI] of 1.65 [1.24, 2.20]) (Figure 1, Table 2). Treatment with caplacizumab resulted in a 72.6% reduction in the percentage of patients with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event during the DB/SB treatment period compared to placebo (p <0.0001) (Table 2). Treatment with caplacizumab resulted in an 84.0% reduction in the percentage of patients who had a recurrence of TTP during the DB/SB treatment period (p <0.0001), and a 49.4% reduction in recurrences during the overall study period (p <0.005), compared to placebo (Table2). No patients in the caplacizumab group had refractory TTP during the DB/SB treatment period compared to 7 patients (6.3%) in the placebo group (p <0.01) (Table 2). There was a statistically significant lower rate of death in the caplacizumab group (no deaths) compared to the placebo group (4 deaths) during the DB/SB treatment period (p <0.05) (Table 2). During the overall study period, one patient randomized to caplacizumab died (during the treatment-free follow-up period, judged unrelated to caplacizumab by the Investigator), compared to 5 patients randomized to placebo (Table 2). During the overall treatment period, there was a reduction in the mean number of PE days of 3.9 days in the caplacizumab group compared to the placebo group (Table 2). Conclusions : This integrated efficacy analyses confirmed results from the individual Phase II and III studies showing that treatment with caplacizumab significantly reduces the time to platelet count response compared to treatment with placebo. In addition, treatment with caplacizumab was associated with clinically meaningful and statistically significant reductions in: (i) the proportion of patients with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event; (ii) the proportion of patients who died from TTP during the study drug treatment period; (iii) the proportion of patients with a recurrence of TTP during treatment and overall; (iv) the number of patients refractory to therapy; (v) the mean number of days of plasma exchange. Disclosures Peyvandi: Kedrion: Consultancy; Roche: Speakers Bureau; Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Kedrion: Consultancy. Cataland:Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. Kremer Hovinga:Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Metjian:Ablynx: Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment.
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Raje, Noopur, Paul Richardson, Parameswaran N. Hari, Anuj Mahindra, Sarah Kaster, Christine Connolly, Linda Rivera i in. "An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma." Blood 114, nr 22 (20.11.2009): 3856. http://dx.doi.org/10.1182/blood.v114.22.3856.3856.
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Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.
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Chavez, Julio C., Neta Goldschmidt, Felipe Samaniego, Tomasz Wrobel, Federica Cavallo, Gustavo Fonseca, Sung-Soo Yoon i in. "The Combination of Umbralisib Plus Ublituximab Is Active in Patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL): Results from the Phase 2 Global Unity-NHL Trial". Blood 138, Supplement 1 (5.11.2021): 45. http://dx.doi.org/10.1182/blood-2021-147425.
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Abstract Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody dependent cellular cytotoxicity (ADCC) that targets a unique epitope on CD20. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration-directed Phase 2 study designed to evaluate the safety and efficacy of the umbralisib + ublituximab (umbra+ubli, U2) combination in patients with previously treated NHL . Umbra has been recently approved for the treatment (tx) of previously treated marginal zone lymphoma (MZL) based on reported data (Fowler JCO 2021), and the U2 combination has been shown to be active with a manageable safety profile in patients with relapsed/refractory (R/R) NHL (Lunning Blood 2019). In contrast with other PI3Kis, there has been a low incidence of immune-mediated toxicities with umbra, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the MZL cohort treated with U2. Methods: Eligible patients had histologically confirmed MZL (splenic, nodal, extranodal) and were R/R to ≥1 prior lines of tx which must have included an anti-CD20. Patients were treated with U2: umbra was given orally at 800 mg once daily until progression or unacceptable tolerability and ubli was administered intravenously on Days 1, 8, and 15 of Cycle 1, on Day 1 of Cycles 2-6, and on Day 1 every 3 cycles until Cycle 24 in 28-day tx cycles. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Results: 72 MZL patients were enrolled and received U2. The median age was 70 years (range 40-89), 53% were female, 74% had stage III or IV disease, and 25% were refractory to their immediate prior therapy. Patients had received a median of 2 prior regimens (range 1-9). As of the cutoff date, 41 patients remain on tx. The ORR was 68%, with 19% achieving complete response (CR). At a median follow-up of 16 months, median DoR was not reached (12 - not estimable). 90% of patients had a reduction in disease burden from baseline while on U2. Figure 1a depicts efficacy data for U2, and Figure 1b shows the best % change in target lesions from baseline for MZL patients treated with at least 1 dose of U2. The most common adverse events (AEs) were diarrhea (all grades: 49%, grade ≥3: 13%), nausea (all grades: 30%, grade ≥3: 0%), and fatigue (all grades: 36%, grade ≥3: 6%). Other AEs of interest included non-infectious colitis (all grades: 2.8 %, grade ≥3: 2.8%) and rash (all grades: 11%, grade ≥3: 0%). Four patients (5.6%) discontinued due to an AE. Conclusions: U2 was highly active in patients with R/R MZL, with improved efficacy when compared to a prior cohort of MZL patients treated in this study with umbra mono (Fowler JCO 2021). The safety profile of the U2 combination was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. Figure 1 Figure 1. Disclosures Chavez: Bristol Myers Squibb: Speakers Bureau; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Epizyme: Speakers Bureau; MorphoSys: Speakers Bureau; Karyopharm Therapeutics: Consultancy; Merck: Research Funding; Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Kite/Gilead: Consultancy. Goldschmidt: AbbVie: Consultancy, Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Servier: Speakers Bureau. Fonseca: Sanofi: Honoraria; Karyopharm: Honoraria; Epizyme: Honoraria; Dava Oncology: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Honoraria. Drgona: Abbvie: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sandoz: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Teva: Honoraria; Viatris: Honoraria. Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Specialised Therapeutics: Consultancy; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Regeneron: Speakers Bureau; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Levi: AbbVie: Consultancy, Research Funding. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Zinzani: ROCHE: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; SANDOZ: Other: Advisory board; BMS: Other: Advisory board, Speakers Bureau; Incyte: Other, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; ADC Therap.: Other.
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Noy, Ariela, Sven de Vos, Catherine Thieblemont, Peter Martin, Christopher Flowers, Franck Morschhauser, Graham P. Collins i in. "Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study". Blood 128, nr 22 (2.12.2016): 1213. http://dx.doi.org/10.1182/blood.v128.22.1213.1213.
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Abstract Background: Marginal zone lymphoma (MZL) accounts for approximately 10% of cases of non-Hodgkin's lymphoma (NHL). Rituximab in combination with chemotherapy has substantially improved treatment outcomes, but relapse is common. Although therapies for indolent NHL are FDA approved, no agents are specifically approved for the treatment of MZL. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is indicated by the US FDA for the treatment of patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with del17p, mantle cell lymphoma with at least one prior therapy, and Waldenstrom's macroglobulinemia, and allows for treatment without chemotherapy. MZL is often linked to chronic infection, which can induce B-cell receptor signaling, resulting in aberrant B-cell growth and survival. By blocking BTK, a critical component of B-cell receptor signaling, ibrutinib may be an ideal therapy for the treatment of MZL. This study evaluated the efficacy and safety of single-agent ibrutinib in pts with relapsed/refractory (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS of ≤2, life expectancy >3 months (mo) and had previously received ≥1 prior therapy including at least one CD20 monoclonal antibody (mAb)-containing regimen or monotherapy rituximab (RTX). All pts received ibrutinib 560 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) according to 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Sixty-three pts (extranodal [n=32], nodal [n=17], and splenic [n=14]) were enrolled. Median age was 66 years (range, 30-92); 92% had ECOG PS of 0-1. Median number of prior systemic therapies was 2 (range, 1-9) with 35% receiving ≥3 prior therapies. Four (6%) pts had a prior splenectomy, and 9 (14%) pts received prior radiotherapy. Seventeen pts (27%) had received only monotherapy RTX, and 40 (64%) had received at least one CD20 mAb-containing chemoimmunotherapy regimen; 33% of the pts had bone marrow involvement. The median time on study was 16.6 mo, and the median duration of therapy 11.7 mo. Per investigator assessment, ORR was 51% (6 CRs and 26 PRs). Thirty-eight percent of total pts had stable disease (SD), and the clinical benefit rate (CR+PR+SD) was 89%, with 87% having some tumor reduction (Figure). The overall median DOR was 19 mo (95% CI: 8.0-not reached [NR]). The median time to initial response was 4.2 mo, and the median PFS was 18 mo (95% CI: 12.2-NR). The most common adverse events (AEs ≥20%) of any grade included: fatigue (44%), diarrhea (43%), anemia (35%), nausea and thrombocytopenia (25% each), peripheral edema (24%), cough and arthralgia (22% each), dyspnea and URTI (21% each). Grade ≥3 AEs occurred in 40 pts (63%). The most common events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious AEs of any grade occurred in 28 pts (44%), with grade 3/4 pneumonia being the most common AE (5 pts [8%]). Atrial fibrillation occurred in 4 pts (6%; all grade 1/2). Any-grade bleeding events occurred in 57% of pts, with 1 grade 3 event of hematemesis and 1 grade 5 cerebral hemorrhage. Three treatment-emergent AEs resulted in death due to disease progression, cerebral hemorrhage, and parainfluenza virus infection leading to multiple organ failure. Overall, 38 pts (60%) discontinued treatment (PD: 30%; AEs: 19%, pt decision: 5%; physician decision: 6%) and 40% continue treatment. The most common AE leading to treatment discontinuation was diarrhea in 2 pts (3%). At least 2 pts appeared to have experienced pseudoprogression at weeks 9 and 13, respectively, confirmed by further follow up. Conclusions: Single-agent ibrutinib achieved a high ORR and durable responses, and produced clinically meaningful tumor shrinkage yielding a high clinical benefit rate. Overall, the treatment was well tolerated. These results support BTK signaling blockade via single-agent ibrutinib as an effective, chemotherapy-free targeted strategy for R/R MZL. Disclosures Noy: Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Martin:Novartis: Consultancy; Celgene: Consultancy, Honoraria; Teva: Research Funding; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Gilead: Consultancy, Other: travel, accommodations, expenses; Acerta: Consultancy. Flowers:Infinity: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; NIH: Research Funding; Millenium/Takeda: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Mayo Clinic: Research Funding; ECOG: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Coleman:Celgene: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Pfizer: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Immunomedies: Equity Ownership, Other: Leadership; AbbVie: Equity Ownership; Karyoharm: Research Funding. Peles:Takeda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Celgene: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Onyx: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; SGN: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Florida Cancer Specialists: Employment, Equity Ownership. Smith:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Munneke:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Dimery:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Beaupre:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses, Leadership, Patents & Royalties, Research Funding. Chen:Merck: Consultancy, Research Funding; Genentech: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.
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Kremer Hovinga, Johanna A., Marie Scully, Spero R. Cataland, Flora Peyvandi, Paul Coppo, Paul Knöbl, Javier De La Rubia i in. "Safety of Caplacizumab for the Treatment of Patients with Acquired Thrombotic Thrombocytopenic Purpura - Results Normalized to Time of Exposure in a Double-Blind, Placebo-Controlled, Phase 3 Hercules Study". Blood 132, Supplement 1 (29.11.2018): 3744. http://dx.doi.org/10.1182/blood-2018-99-112177.
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Abstract Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy. A severe deficiency in ADAMTS13 activity caused by inhibitory autoantibodies leads to accumulation of ultra large von Willebrand factor (ULvWF) multimers and formation of microthrombi in small blood vessels with associated thrombocytopenia, hemolytic anemia, tissue ischemia and organ dysfunction (e.g., brain, heart, and kidneys). Caplacizumab directly blocks the interaction of the vWF A1 domain with the GPIb platelet receptor and prevents formation of microthrombi. The key efficacy and safety results of the double-blind (DB), placebo-controlled, phase 3 HERCULES study of caplacizumab for the treatment of aTTP were reported previously (Scully et al., Blood 2017 130:LBA-1). Herein, we present the results of a post-hoc analysis of the safety results normalized to time of exposure during the DB treatment period. Methods : Patients with an acute episode of aTTP who had received one plasma exchange (PE) treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug. In case of a recurrence during the DB treatment period, patients were switched to open-label (OL) caplacizumab, together with re-initiation of daily PE and immunosuppression, while maintaining the blind for the initial treatment allocation. Analysis of treatment-emergent adverse events (TEAEs) was performed on the study's safety population (i.e., all patients who received at least 1 administration of study drug). To control for differences in time of exposure, incidence rates (IR) per 100 patients months were calculated as 100 x number of events / (total number of months observed within analysis period, summed for all patients in the treatment group). Results : The safety population consisted of 71 caplacizumab-treated and 73 placebo-treated patients. 31 patients experienced an exacerbation during the DB period, 28 in the placebo group and 3 in the caplacizumab group; 28 of them were switched to OL treatment with caplacizumab (26 of the 28 placebo-treated patients and 2 of the 3 caplacizumab-treated patients). As a consequence, the median (min; max) duration of study drug treatment during the DB treatment period, was 35 (1; 65) days for the DB caplacizumab group and 23 (2; 66) days for the DB placebo group. During the overall study period, at least one TEAE was reported in 69 patients (97.2%) in the caplacizumab group and 71 patients (97.3%) in the placebo group; the most frequent (occurring in >10% of patients in at least one of the treatment groups) TEAEs are presented in Table 1. After normalization for the time of exposure, the IR of any TEAE was lower in the caplacizumab group (535.6) vs. placebo group (821.7). TEAEs with a higher IR (≥5/100 patients months difference) in the caplacizumab group vs. placebo were epistaxis (39.1 vs. 3.3) and gingival bleeding (14.9 vs 1.7); TEAEs with a higher IR in the placebo group vs. caplacizumab were TTP (48.3 vs. 3.4), hypokalemia (25.0 vs 5.7), contusion (40.0 vs 8.0), rash (16.7 vs 5.7), insomnia (13.3 vs 8.0) and hypertension (13.4 vs 4.6). The IR of any SAE was 26.4 in the caplacizumab group and 83.3 in the placebo group. There were no SAEs with a higher IR (≥5/100 patients months difference) in the caplacizumab group compared to placebo. SAEs with an IR higher in the placebo group vs. caplacizumab were TTP (48.3 vs. 3.4) and anaphylactic transfusion reaction (5.0 vs. 0). Conclusions : After normalization to time of exposure, TEAEs occuring more frequently in the caplacizumab group were epistaxis and gingival bleeding, while TTP, hypokalemia, contusion, rash, imsomnia and hypertension occurred more frequently in the placebo group. This post-hoc analysis confirms the overall good tolerability of caplacizumab for the treatment of aTTP with mucocutaneous bleeding being the most relevant risk, consistent with the mechanism of action of this drug. Disclosures Kremer Hovinga: Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Cataland:Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Peyvandi:Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Shire: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Sousa:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment. Metjian:Ablynx: Other: Member of Advisory Board.
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Siegel, David S., Gary J. Schiller, Christy J. Samaras, Michael Sebag, Jesus G. Berdeja, Siddhartha Ganguly, Jeffrey V. Matous i in. "Pomalidomide, Dexamethasone, and Daratumumab after Lenalidomide Treatment in Relapsed Refractory Multiple Myeloma: Updated Results from an Open-Label, Multicenter, Phase 2 Trial". Blood 136, Supplement 1 (5.11.2020): 16–17. http://dx.doi.org/10.1182/blood-2020-134189.
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Introduction: Lenalidomide (LEN), a standard of care for newly diagnosed multiple myeloma, is routinely administered until disease progression. However, patients with disease that has relapsed after or become refractory to LEN have been poorly represented in recent trials investigating triplet regimens after ≤ 3 prior treatment (Tx) lines. Consequently, patients who have exhausted the benefits of LEN in early relapse are a clinically relevant population in need of proven Tx options. The trial that led to approval of pomalidomide (POM) + dexamethasone (DEX) + daratumumab (DARA) evaluated patients with heavily pretreated (median of 4 prior lines of therapy) relapsed refractory multiple myeloma (RRMM; Chari et al. Blood 2017). The phase 2 MM-014 trial (NCT01946477), which is composed of 3 cohorts, was specifically designed to investigate the outcomes of sequencing POM-based therapy immediately after first- or second-line LEN-based Tx failure in patients with RRMM. In an earlier report from cohort B of MM-014, POM + DEX + DARA demonstrated promising efficacy and safety results: the overall response rate (ORR) was 77.7%, and the 1-year progression-free survival (PFS) rate was 75.1% at a median follow-up of 17.2 months (Siegel et al. Leukemia 2020). Updated efficacy and safety results from cohort B are reported here. Methods: Patients with RRMM treated with 1-2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during/after their last line of Tx received POM + DEX + DARA. POM 4 mg/day was given orally on days 1-21; DEX 40 mg/day (20 mg/day in patients aged > 75 years) was given orally on days 1, 8, 15, and 22; and DARA 16 mg/kg was given intravenously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 for cycles 3-6, and day 1 for cycles 7+. ORR was the primary endpoint; secondary endpoints included PFS and safety. Results: In the intention-to-treat (ITT) population of 112 patients, the median age was 66.5 years, all patients had prior LEN, and 77.7% had prior bortezomib. Overall, 84 patients (75%) had LEN-refractory MM and 28 (25%) had MM that relapsed after prior LEN Tx; most patients (70 [62.5%]) received 1 vs 2 (42 [37.5%]) prior Tx lines. As of March 24, 2020, 31 patients (27.7%) were still on treatment; median follow-up was 28.4 months. The most common reasons for discontinuation in 81 patients (72.3%) were progressive disease (46 patients [56.8%]), withdrawal by patient (19 patients [23.5%]), and adverse events (AEs; 7 patients [8.6%]). The efficacy-evaluable (EE) population comprised 109 patients who received ≥ 1 dose of study Tx and had ≥ 1 post-baseline assessment and was used for supportive efficacy analyses. ORR was 77.7% (≥ very good partial response [VGPR], 52.7%) and 79.8% (≥ VGPR, 54.1%) in the ITT and EE populations, respectively. ORR was similar in patients with LEN-relapsed and LEN-refractory disease (82.1% and 76.2%, respectively). The median PFS was reached: 30.8 months in both the ITT and EE populations (Figure). Overall, 97.3% of patients had ≥ 1 grade 3/4 AE, with neutropenia (64.3%; febrile 9.8%) being the most common grade 3/4 hematologic Tx-emergent AE, followed by anemia (17.9%) and thrombocytopenia (14.3%). Grade 3/4 infections were noted in 36.6% of patients, including 16.1% with grade 3/4 pneumonia. Conclusions: POM + DEX + DARA administered in early-line Tx immediately after LEN failure continues to show a high response rate and a consistent safety profile, demonstrating the benefit of maintaining continuous immunomodulation with POM following LEN. These updated results continue to demonstrate the efficacy and safety of POM-based therapy as early as second line in patients with RRMM, even immediately after LEN failure, indicating that switching from the immunomodulatory agent class is not necessary. Furthermore, these findings support the use of POM + DEX as the foundation of novel combinations in MM. Figure 1 Disclosures Siegel: Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Schiller:Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; FujiFilm: Research Funding; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Celator: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Pfizer: Current equity holder in publicly-traded company, Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Poseida: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Constellation: Research Funding. Ganguly:KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau; Kadmon: Other: Ad Board. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Bar:Bristol-Myers Squibb Company: Consultancy. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Fonseca:Bristol-Myers Squibb Company: Speakers Bureau. Reece:Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding; Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria. Lee:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Agarwal:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.
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Dreyling, Martin, Panayiotis Panayiotidis, George A. Follows, Luigina Mollica, Arnon Nagler, Muhit Özcan, Armando Santoro i in. "Long-Term Efficacy and Safety of Copanlisib in Multiply Relapsed or Refractory Patients with Marginal Zone Lymphoma". Blood 134, Supplement_1 (13.11.2019): 1531. http://dx.doi.org/10.1182/blood-2019-121932.
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Introduction: Marginal zone lymphoma (MZL) is an indolent B-cell malignancy comprising >10% of non-Hodgkin lymphomas. The Bruton's tyrosine kinase inhibitor ibrutinib was the first systemic therapy approved by the US Food and Drug Administration (FDA) for the treatment of patients (pts) with relapsed or refractory MZL, based on a Phase II study reporting an objective response rate (ORR) of 48% (3% complete responses [CR]) and a median progression-free survival (PFS) of 14.2 months (mo) in 60 pts (Noy A et al. Blood 2017). Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with potent activity against the α and δ isoforms, approved for the treatment of relapsed follicular lymphoma in pts who have received ≥2 prior systemic therapies. In May 2019, the FDA granted Breakthrough Therapy designation for copanlisib for adults with MZL who have received ≥2 prior systemic therapies. We report results from 23 heavily pretreated pts with relapsed or refractory MZL treated with copanlisib from the Phase II CHRONOS-1 study (NCT01660451; Part B). Methods: Pts enrolled in the open-label, single-arm CHRONOS-1 trial with histologically confirmed MZL who had relapsed after or were refractory to ≥2 prior systemic therapies, including rituximab and an alkylating agent, were included in the analysis. Copanlisib 60 mg was administered via a 1-hour i.v. infusion on an intermittent schedule of days 1, 8, and 15 of a 28-day cycle and continued until progression or unacceptable toxicity. The primary efficacy endpoint was ORR, defined as the proportion of pts who had CR or partial response as best response after ≥4 cycles, per independent assessment (Cheson BD et al. J Clin Oncol 2007). Secondary efficacy endpoints included duration of response (DoR), PFS, and overall survival (OS). Adverse events (AEs) were reported using MedDRA (v.20.1). The last pt was enrolled in Feb 2016, with an initial data cut-off of June 2016. The long-term follow-up reported here is based on a data cut-off of Feb 2018. Results: Of the 23 MZL pts enrolled, 15 (65%) had nodal MZL, 4 (17%) had mucosa-associated lymphoid tissue (MALT) lymphoma, and 4 (17%) had splenic MZL. Pts had a median age of 69 years (range 39-81) and a median of 3 (range 2-9) prior systemic therapies; 48% were refractory to the last regimen and 44% were refractory to rituximab. As of Feb 2018, the median duration of copanlisib treatment was 23 weeks (range 1-191), and pts received a median of 5.8 cycles of treatment. Overall, 18 pts achieved an objective response (ORR 78%); CRs were observed in 3 (13%) pts, all with splenic MZL (3/4 pts). ORRs were 87% (13/15 pts) in nodal MZL, 75% (3/4 pts) in splenic MZL, and 50% (2/4 pts) in MALT MZL. Overall median DoR was 17.4 mo (range 0-37.6), with an estimated 45% in response after 2 years (Figure A) and a median DoR of 16.1 mo (range 0-37.6) in nodal MZL. Median PFS was 24.1 mo (range 0-41.1) (Figure B). Median OS was not reached (range 0.2-44.1) and estimated survival rate at 720 days was 83%. Of the 18 responding pts, median PFS was 24.2 mo (range 2.3-41.1); once remission was achieved, median DoR was 17.4 mo (range 0-37.6), with ~45% in remission beyond 2 years. The most common treatment-emergent AEs (TEAEs; all grade/grade 3+) were fatigue (52.2%/13.0%), hyperglycemia (47.8%/39.1%), and diarrhea (47.8%/13.0% all grade 3). Five pts had AEs leading to a dose reduction. The most common drug-related TEAEs were hyperglycemia (47.8%/39.1%), hypertension (43.5%/39.1% all grade 3), diarrhea (26.1%/13.0% all grade 3), and neutropenia (26.1%/8.7%). Hyperglycemia and hypertension were infusion related and were transient and manageable. Laboratory toxicities of interest were principally grade 1, including increased aspartate transaminase (31.8% all grade/22.7% grade 1) and increased alanine transaminase (27.3%/13.6%). No grade 5 TEAEs were reported. Tumor gene expression analysis from a subset of MZL pts demonstrated anti-tumor activity of copanlisib in MZL tumors characterized by PI3K pathway activation and/or B-cell receptor signaling. Conclusions: Copanlisib demonstrated a promising ORR of 78% (CR 13%) and a manageable safety profile in pts with MZL who had received ≥2 prior systemic therapies. Responses were durable, with a median DoR of 17.4 mo and PFS of 24.1 mo, exceeding previous benchmarks. Phase III studies are underway to confirm the efficacy and safety of copanlisib in combination with other therapies in pts with indolent lymphoma, including MZL. Disclosures Dreyling: Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board. Panayiotidis:Bayer: Other: Support of clinical trial. Follows:Abbvie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau. Özcan:Novartis: Research Funding; BMS: Other: Travel; Janssen: Research Funding, Travel; AbbVie: Research Funding; MSD: Research Funding; Celgene: Research Funding; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Other: Travel, Research Funding; Archigen: Research Funding; Takeda: Honoraria, Research Funding; Bayer: Research Funding; Jazz: Other: Travel; Sanofi: Other: Travel; Abdi Ibrahim: Other: Travel. Santoro:Arqule: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Stevens:Astellas: Consultancy. Hiemeyer:Bayer AG: Employment. Liu:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Garcia-Vargas:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Childs:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Copanlisib received U.S. FDA Breakthrough Designation in May 2019 for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least 2 prior therapies, though copanlisib is not currently approved for this indication.
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Perkins, Andrew Charles, Kate Burbury, Thomas Lehmann, David M. Ross, Andreas Reiter, Vikas Gupta, Claire Harrison i in. "Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis". Blood 136, Supplement 1 (5.11.2020): 52–53. http://dx.doi.org/10.1182/blood-2020-140408.
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INTRODUCTION Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by megakaryocyte proliferation and progressive bone marrow fibrosis. Additional clinical features include splenomegaly due to extramedullary hematopoiesis, cytopenias resulting from bone marrow failure, and constitutional symptoms. MF can develop de novo (primary MF) or from the progression of antecedent MPNs, in particular polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). At diagnosis, nearly one-quarter of patients (pts) are red blood cell transfusion dependent, and nearly 40% exhibit hemoglobin levels < 10 g/dL. Additionally, pts with MF have a shortened survival and reduced quality of life (QOL). Ruxolitinib (RUX), a first-in-class JAK1/JAK2 inhibitor, is the standard of care for MF and was approved on the basis of the COMFORT studies. In these studies, RUX demonstrated superiority over placebo (COMFORT-I) and best available therapy (COMFORT-II) in improving splenomegaly, MF-related symptoms, and QOL. An overall survival benefit was also observed with RUX (Harrison CN, et al. Leukemia. 2016). However, RUX is not a curative therapy and cytopenias remain a challenge in the management of MF. Additionally, not all pts respond to RUX, with some losing response while on treatment and some discontinuing treatment due to adverse events. RUX in combination with novel agents may offer superior disease control and transformative clinical benefits, including prolonged progression-free survival and improved cytopenias and QOL, and may reduce the malignant clone and bone marrow fibrosis. METHODS ADORE (NCT04097821) is a 3-part, open-label, multicenter, Phase 1/2 open-platform study that will assess the safety and efficacy of RUX in combination with ≥ 3 novel compounds (siremadlin [HDM2 inhibitor], crizanlizumab [P-selectin inhibitor], or sabatolimab [TIM-3 inhibitor]) for the treatment of MF (Figure). The study will include pts ≥ 18 years old who have primary MF, PPV-MF, or PET-MF, splenomegaly (a palpable spleen ≥ 5 cm from the left costal margin or spleen volume ≥ 450 cm3 by MRI or CT scan), hemoglobin level < 10 g/dL, and platelet count ≥ 75 × 109/L (≥ 50 × 109/L in Parts 2 and 3). Pts must have been treated with RUX for ≥ 24 weeks and have received a stable dose for ≥ 8 weeks prior to study entry. Key exclusion criteria include splenic irradiation within 6 months or blood platelet transfusion within 28 days of study start. Part 1 (Phase 1b) includes a Dose-escalation arm to determine the recommended Phase 2 dose (RP2D) for the combination of siremadlin and RUX, and 2 safety run-in arms to confirm the doses of crizanlizumab plus RUX and sabatolimab plus RUX combinations. RUX will be administered at the same stable dose used prior to study entry. A Bayesian logistic regression model will be used to identify the maximum tolerated dose and/or RP2D for the siremadlin and RUX combination. Pts will be treated for a planned duration of ≥ 6 cycles (24 weeks). The primary endpoint for Part 1 is the incidence of dose-limiting toxicities within the first 2 cycles. The combination treatments evaluated as safe and tolerable in Part 1 will proceed to Part 2. In Part 2 (Phase 2; early efficacy assessment, Selection), pts will be randomized with equal probability to 1 of the selected combination treatments or RUX monotherapy and treated for ≥ 12 cycles (48 weeks). After all Part 2 pts have completed 24 weeks of treatment, an interim analysis will be conducted to determine which treatment should be dropped for futility or considered in Part 3 (Phase 2; efficacy, Expansion). In Part 3, pts will be randomized 2:1:1 to the combination treatment arm, RUX cessation arm (novel agent monotherapy), or RUX monotherapy arm and treated for ≥ 12 cycles. Pts in the RUX cessation arm will be treated with RUX combination therapy for 12 weeks, followed by tapering of RUX. The primary endpoint for Parts 2 and 3 is the response rate for the composite endpoint of anemia improvement (increase in hemoglobin of ≥ 1.5 g/dL), no spleen volume progression, and no symptom worsening at the end of 6 treatment cycles (24 weeks). Secondary efficacy endpoints include hemoglobin improvement, change in spleen size, progression-free survival, change in symptoms, and bone marrow fibrosis improvement. The study will end 24 months after the last pt has initiated Part 3. Planned enrollment for the study with the current 3 combinations is 130 pts. Enrollment is currently ongoing. Disclosures Perkins: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lehmann:Novartis: Consultancy, Research Funding. Reiter:Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding; Gilead: Other: travel support . Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Roche: Honoraria; Sierra Oncology: Honoraria; Promedior: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wondergem:Celgene: Other: Educational talks; Novartis: Other: Educational talks. Pack:Novartis Pharma AG: Current Employment. Wroclawska:Novartis Pharma AG: Current Employment. Wilke:Novartis Pharma AG: Current Employment, Other: Stock owner. Zhang:Novartis Pharma AG: Current Employment. Heidel:Novartis: Consultancy, Honoraria, Research Funding.
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Zinzani, Pier Luigi, Armando Santoro, Luigina Mollica, Sirpa Leppä, George A. Follows, Georg Lenz, Won Seog Kim i in. "Copanlisib, a PI3K Inhibitor, Demonstrates a Favorable Long-Term Safety Profile in a Pooled Analysis of Patients with Hematologic Malignancies". Blood 134, Supplement_1 (13.11.2019): 4009. http://dx.doi.org/10.1182/blood-2019-131779.
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Introduction: Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor, is approved in the US for the treatment of patients (pts) with relapsed follicular lymphoma (FL) who have received ≥2 prior systemic therapies; it also has Breakthrough Therapy designation for pts with relapsed marginal zone lymphoma who have received ≥2 prior therapies. The Phase II CHRONOS-1 study in pts with indolent lymphoma treated with copanlisib (NCT01660451; Part B) demonstrated an objective response rate of 59.2% with manageable safety and low rates of severe adverse events (AEs) (Dreyling M et al. J Clin Oncol 2017). We report pooled safety data from 8 Phase I and II studies of pts with hematologic malignancies following long-term treatment with copanlisib. Methods: Pts with hematologic malignancies treated with copanlisib monotherapy in completed open-label Phase I or II studies were included. Copanlisib 60 mg (i.v.) was administered intermittently on days (d) 1, 8, and 15 of a 28-d cycle until disease progression (PD) or unacceptable toxicity. AEs were reported using MedDRA (v.21.1) and assessed by time of onset (worst grade or new AEs occurring ≤180 d, 181-360 d, or ≥361 d) and treatment duration. Results: A total of 364 pts received copanlisib (data cut-off Feb 2019). Median age was 65 years (range 22-93); the predominant histology was FL (42.0%). At data cut-off, 34 pts (9.3%) remained on treatment. Duration of treatment ranged from 0.2 to 62.1 months, with 56 pts (15.4%) treated for >1 year. All-grade treatment-emergent AEs (TEAEs) were reported in 97.8% of pts; 51.4% had TEAEs of worst grade [g] 3, and 24.7% had TEAEs of worst g4. The most common (≥20%) TEAEs (all grade / g3 / g4) were hyperglycemia (50.5% / 28.3% / 4.4%), hypertension (38.7% / 29.1% / 0%), diarrhea (37.1% / 4.9% / 0%), nausea (28.3% / 1.4% / 0%), fatigue (27.2% / 2.7% / 0%), pyrexia (23.1% / 3.0% / 0%), and neutropenia (23.1% / 9.3% / 9.6%). Hyperglycemia and hypertension were infusion related, transient, and manageable. Events generally were reported early, with higher incidence at ≤180 d (n=364) vs 181-360 d (n=118) or ≥361 d (n=56), and no increased incidence of g≥3 events with prolonged exposure, with the exception of diarrhea (all grade [g≥3]): hyperglycemia (49.2% [31.6%] / 21.2% [11.0%] / 19.6% [10.7%]), hypertension (37.4% [27.2%] / 21.2% [15.3%] / 21.4% [17.9%]), diarrhea (32.7% [3.0%] / 20.3% [4.2%] / 30.4% [12.5%]), nausea (27.5% [1.4%] / 0.8% [0%] / 3.6% [0%]), fatigue (24.2% [2.5%] / 5.9% [0.8%] / 10.7% [1.8%]), pyrexia (19.2% [2.7%] / 16.1% [0.8%] / 10.7% [0%]), and neutropenia (19.5% [16.2%] / 13.6% [8.5%] / 21.4% [16.1%]). A similar trend was observed in pts treated for >1 year (Table), though these pts had a broad range of exposures, with 22 pts treated for ≥2 years. Incidences of g≥3 diarrhea in pts treated for >1 year remained stable and were comparable with prolonged exposure (≤180 d 8.9%; 181-360 d 7.1%; ≥361 d 12.5%). Pneumonitis was infrequent overall (all grade / g≥3: 5.2% / 2.7%) and in pts treated for >1 year (10.7% / 3.6%). Copanlisib-related TEAEs of all grades / g3 / g4 were reported for 88.7% / 54.1% / 18.4% of pts; most events were reported early (≤180 d) with generally no increase in incidence or severity observed in pts treated for >1 year. Serious AEs (SAEs) occurred in 57.1% of pts, most commonly (≥2%; all grade / g≥3) pneumonia (6.0% / 5.5%), general physical health deterioration (5.2% / 4.9%), pyrexia (4.1% / 1.4%), hyperglycemia (4.1% / 4.1%), pneumonitis (4.1% / 2.7%), lung infection (3.0% / 2.2%), and febrile neutropenia (2.2% / 2.2%). All-grade / g3 / g4 copanlisib-related SAEs were reported for 30.2% / 18.7% / 5.8% of pts. As with TEAEs, SAEs mostly occurred early with no general increase in incidence or severity with treatment >1 year. Thirty-nine pts died either during copanlisib treatment or within 35 d post discontinuation of treatment (10.7%), most commonly due to PD (4.7%). No g4 late-onset colitis, hepatotoxicity, or other intestinal toxicity occurred after 6 months of treatment. Conclusions: These data provide evidence for the manageable safety profile of long-term copanlisib treatment, with no late-onset toxicities or worsening of severity of TEAEs, and few severe gastrointestinal TEAEs. Transient, manageable hyperglycemia and hypertension were among the most common TEAEs; no new unexpected safety issues were identified. These results support the known safety profile and approved indication of copanlisib. Disclosures Zinzani: IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Santoro:Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Takeda: Speakers Bureau; Abb-Vie: Speakers Bureau; Sandoz: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; MSD: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Roche: Speakers Bureau. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Follows:AZ: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Lenz:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Kim:Celltrion: Research Funding; Mundipharma: Research Funding; J&J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Donga: Research Funding. Panayiotidis:Bayer: Other: Support of clinical trial. Demeter:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol- Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Angelini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Miriyala:Bayer HealthCare Pharmaceuticals, Inc.: Employment. Benson:Bayer HealthCare Pharmaceuticals, Inc.: Employment. Garcia-Vargas:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Childs:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Dreyling:Novartis: Other: Scientific advisory board; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. OffLabel Disclosure: Copanlisib is approved in the U.S. for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies and received U.S. FDA Breakthrough Designation in May 2019 for the treatment of adult patients with relapsed marginal zone lymphoma (MZL) who have received at least 2 prior therapies. We present here Phase I and II clinical trial data of patients with a range of hematological malignancies, including FL and MZL, treated with copanlisib.
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Dadwal, Sanjeet S., Michael Shuster, Gary Douglas Myers, Keith Boundy, Marshelle Warren, Elizabeth Stoner, Thuy Truong i Joshua A. Hill. "Posoleucel (ALVR105), an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Viral Infections Post-HCT: Results from an Open-Label Cohort of a Phase 2 Trial". Blood 138, Supplement 1 (5.11.2021): 1760. http://dx.doi.org/10.1182/blood-2021-152553.
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Abstract Background: Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are at high risk of reactivation or de novo infection with double-stranded (ds) DNA viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), adenovirus (AdV), BK virus (BKV), and JC virus (JCV). After allo-HCT, up to 90% patients develop detectable viremia by PCR. EMR data collected between 2018 and April 1, 2021, from over 1400 high-risk allo-HCT patients at 21 US centers suggest that 40-50% develop clinically significant viral infection or disease associated with ≥1 of these dsDNA viruses within 200 days of transplant. Multiple studies demonstrate increased morbidity and mortality associated with viremia, with or without end-organ disease. Prophylactic and preemptive therapies have substantial side effects and can lead to the development of resistance, especially in CMV. HCT donor-derived virus-specific T-cells have shown promise in preventing single virus infections in prior clinical trials but were infeasible for wide-scale use. There is an urgent unmet medical need for preventive strategies targeting multiple viruses in patients undergoing high-risk allo-HCT. Methods: We are conducting a clinical trial (NCT04693637) to evaluate the safety and efficacy of posoleucel (ALVR105, Viralym-M) for preventing clinically significant viral infections due to CMV, EBV, HHV-6, AdV, BKV, and JCV in high-risk allo-HCT recipients. Posoleucel is an ex-vivo expanded, partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product generated from healthy, third-party donors targeting CMV, EBV, HHV-6, AdV, BKV, and JCV. In the open-label portion of the study, patients receive up to seven infusions of 4×10 7 cells of posoleucel administered once every 14 days. High-risk patients are those who received a graft from a sibling or unrelated donor with ≥1 HLA mismatch; from a haploidentical donor; from umbilical cord blood or with T-cell-depletion; as well as patients with lymphocytes <180/mm 3 or CD4 T cells <50/mm 3 at enrollment. Patients must be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD as well as those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment are ineligible. Patients are tested weekly for viremia using quantitative PCR assays and are monitored every other week for adverse events. The primary endpoint is the number of clinically significant viral infections or episodes of end-organ disease due to CMV, EBV, HHV6, AdV, BKV, or JCV by week 14. Results: Data are available for 12 of 25 planned participants thus far (Table 1). No patient developed a clinically significant infection within 14 weeks, the primary study endpoint. Over the entire study duration, defined as the primary 14-week treatment period plus the additional 12-week follow-up, 11 (92%) patients have remained free of any clinically significant viral infections, the key secondary endpoint. One patient, a 49-year-old female haploidentical transplant recipient, developed clinically significant AdV viremia after receiving over a month of high-dose methylprednisolone exceeding 0.5 mg/kg/day for recurrent aGVHD. This patient was administered IV cidofovir in week 15 of the study. During the primary study efficacy period one participant received 2 doses of valganciclovir following transient CMV viremia deemed not to be clinically significant by the principal investigator. Posoleucel has been well tolerated to date, with no drug-related serious adverse events, new-onset acute GVHD, or cytokine release syndrome. Safety and efficacy data from the entire open-label cohort will be presented. Conclusions: Preliminary results in this open-label cohort show that in high-risk allo-HCT patients receiving off-the-shelf posoleucel, clinically significant viral infections or disease from the 6 targeted dsDNA viruses were uncommon. No clinically significant infections were observed among participants treated in accordance with the protocol. These results, combined with the favorable safety and tolerability profile of posoleucel, support its continued evaluation in high-risk allo-HCT recipients for the prevention of CMV, EBV, HHV6, AdV, BK virus, or JC virus infection and disease. Figure 1 Figure 1. Disclosures Dadwal: Shire/Takeda: Research Funding; Astellas: Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AlloVir: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Shuster: Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company; Rafael: Research Funding; Celgene: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; Beigene: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Actinium: Research Funding; GSK: Research Funding; Pharmcyclics: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AlloVir: Research Funding; Janssen: Consultancy, Speakers Bureau; Astellas: Consultancy, Research Funding, Speakers Bureau; MorphSys: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau. Myers: Novartis: Consultancy, Speakers Bureau; AlloVir: Research Funding; Eliana: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boundy: AlloVir: Current Employment, Current equity holder in publicly-traded company. Warren: AlloVir: Consultancy. Stoner: AlloVir: Current Employment, Current equity holder in publicly-traded company. Hill: Octapharma: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; Allogene therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Karius: Research Funding.
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Paschka, Peter, Hervé Dombret, Xavier Thomas, Christian Recher, Sylvain Chantepie, Pau Montesinos Fernandez, Evelyn Acuña-Cruz i in. "Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls". Blood 136, Supplement 1 (5.11.2020): 18–19. http://dx.doi.org/10.1182/blood-2020-136957.
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Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs < 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p < 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.
27
Kumagai, Takashi, Kazunori Murai, Hiroshi Ureshino, Hideo Tanaka, Kaichi Nishiwaki, Satoshi Wakita, Koiti Inokuchi i in. "Very Low-Dose Dasatinib Is a Safe and Effective Therapy for Elderly Patients with Newly-Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results from the Davlec Study, a Single-Arm, Multicenter, Phase 2 Trial". Blood 138, Supplement 1 (5.11.2021): 3601. http://dx.doi.org/10.1182/blood-2021-149483.
Pełny tekst źródłaStreszczenie:
Abstract Introduction: Tyrosine kinase inhibitors (TKIs) dramatically improved the prognosis of chronic myelogenous leukemia (CML), as nearly half of CML patients presenting with a deep molecular response (DMR) over several years could achieve treatment-free remission. DASISION study reported dasatinib (DAS), a second-generation TKI was superior to imatinib to achieve faster and deeper response in treating newly-diagnosed chronic CML. However, standard initial dosage of 100 mg DAS/day might be too potent for patients aged >70 years with CML, possibly owing to the presence of other health conditions that threaten the life spans (e.g., lung and cardiovascular disease), thereby preventing TKI continuation. In this open-label, multicenter, single-arm, phase 2 study (DAVLEC), we evaluated the efficacy and safety of a reduced initial dose of DAS (20 mg/day) in the elderly with chronic CML. Patients and Methods: We included CML patients aged >70 years with an ECOG performance status of 0-2 and adequate organ function. After diagnosis, they began orally taking 20 mg of DAS per day. BCR-ABL mRNA values were measured and aligned to an international scale at a central laboratory to evaluate the drug's efficacy at 3, 6, 9, and 12 mo of therapy, per recommendations by European LeukemiaNet. The dosage was maintained in case of the optimal, increased by 20 mg/day when the warning appeared and could be decreased when an adverse event (AE) > grade 3 appeared. Patients were excluded if the respond was the failure or disease progression was detected. Primary endpoint was the cumulative major molecular response (MMR) rate at 12 mo. Secondary endpoints included the rates of the cumulative DMR, treatment discontinuation due to AEs, and failure to DAS treatment or disease progression. The non-inferiority of primary endpoint MMR (non-inferiority limit of 38%) was evaluated by binomial test with normal approximation. Other differences were investigated by Mann-Whitney tests, with p < 0.05 indicating significance. Results: Among the 56 patients enrolled from 25 centers, 4 declined participation, and so 52 (median age, 77.5 years) began taking 20 mg/day of DAS. In total, 73.1% of the patients had comorbidities. Median BCR-ABL values at 3, 6, and 12 mo were 1.47%, 0.23%, and 0.03%, respectively; cumulative MMR rate at 3, 6, 9, and 12 mo were 11.5%, 36.5%, 40.4%, and 59.6%, respectively. Calculated MMR at 12 mo was higher than 38%, a value selected based upon findings from the DASISION trial, accounting for a non-inferiority margin of 10% (p=0.047). At 12 mo, among the 31 patients achieving MMR, 23 were only given 20 mg DAS/day, and 14 and 7 respectively achieved MR4.0 and 4.5. Patients discontinued the study due to treatment failure (n=3), content withdrawal (n=2), drug-related AEs (Long QT Syndrome; n=1), or others (n=2). No patient discontinued it due to disease progression. Treatment-related AEs of all grades were noted in 96.2%and that of grade 3 or 4 events in 23.1% of the patients. Median dose interruptions for a median of 7 days (range: 5-36) were respectively noted in 3 and 2 patients due to hematological and non-hematological AEs. Furthermore, 4 patients experienced pleural effusion < grade 2, and 1 had lymphocytosis. Patients who achieved MMR at 12 mo (n=31) had a significantly lower BCR-ABL value at 3 mo (0.41% vs. 4.26%, p=0.0020) and a lower halving time from diagnosis to 3 mo (11.35 vs. 18.34 days, p=0.0050) than those who did not (n=21). Patients who achieved MMR by 12 mo with only 20 mg/day of DAS (n=23) had lower BCR-ABL values at 1 and 3 mo (25.51 vs. 63.63 %, p=0.00028; 0.33 vs. 5.89%, p<0.0001) and a lower halving time from diagnosis to 3 mo (10.45 vs. 19.44 days, p<0.0001) than others (n=29). Patients who achieved MMR at 12 mo (n=31) had higher plasma DAS concentration (23.5 vs. 8.0 ng/mL, p<0.0001) 2 h post-intake of DAS at 12 mo than those who failed to achieve it (n=13). Conclusion: This study discovered that prescribing a starting very-low dose DAS (20 mg/day) while monitoring IS and AEs was a successful initial therapeutic strategy for the elderly with chronic CML comparable to previous studies using standard-dose. Notably, rapid BCR-ABL downregulation, early molecular responses at 1 and 3 mo, a shortened halving time from diagnosis to 3 mo, and sufficient increase in plasma DAS concentrations 2 h post-intake after 12 mo of treatment were key indicators for successful low-dose therapy. Disclosures Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Murai: Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria. Tanaka: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria. Nishiwaki: Kyowa-Kirin: Research Funding; Alexion: Honoraria. Inokuchi: Bristol-Myers Squibb: Research Funding. Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis KK,: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Uoshima: Janssen: Honoraria; Eisai: Honoraria. Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Mundipharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Shibayama: Chugai: Research Funding; Eizai: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Kyowa Kirin: Speakers Bureau; AbbVie: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Mundi Pharma: Speakers Bureau; Otsuka: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Kondo: Abbvie: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding. Kimura: Eisai: Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; PharmaEssentia: Speakers Bureau; Astellas: Speakers Bureau; Sanifi: Speakers Bureau; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding; Chugai: Research Funding, Speakers Bureau; Mundi: Research Funding; Yakult: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; SymBio: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding.
28
Stilgenbauer, Stephan, Francesc Bosch, Véronique Leblond, Osman Ilhan, Jens Kisro, Béatrice Mahé, Eva Mikuskova i in. "Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Final Results from the Phase IIIb GREEN Safety Study with a Focus on Efficacy". Blood 134, Supplement_1 (13.11.2019): 3035. http://dx.doi.org/10.1182/blood-2019-123419.
Pełny tekst źródłaStreszczenie:
Introduction: Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 antibody that has demonstrated substantial activity in chronic lymphocytic leukemia (CLL). Results from the primary analysis of the phase IIIb, non-randomized, open-label, single-arm GREEN safety study (NCT01905943), have previously shown that G alone or in combination with chemotherapy has a manageable toxicity profile in first-line (1L; fit and unfit) and relapsed/refractory (R/R) patients (pts) with CLL (Stilgenbauer et al. Blood 2017; Leblond et al. Haematologica 2018). Here, we report the final analysis of the GREEN study. Methods: Enrolled pts were aged ≥18 years with documented CLL and Eastern Cooperative Oncology Group performance status 0-2. Pts received intravenous (IV) G 1000mg alone (fit or unfit pts, G-mono) on Day (D) 1, 8 and 15 of Cycle (C)1, and D1 of C2-6 (6 x 28-day cycles), with the C1D1 dose administered over 2 days, or with chemotherapy: investigator's choice of fludarabine and cyclophosphamide (G-FC) for fit pts (Cumulative Illness Rating Scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min) only; chlorambucil (G-Clb) for unfit pts (CIRS >6 and/or CrCl <70mL/min) only; or bendamustine (G-Benda) for any pt. All pts received IV corticosteroids 1h pre-dose on C1D1 and C1D2 to reduce the risk of infusion-related reactions. The primary endpoint was safety. Secondary efficacy measures included best overall response rate (BOR), complete response rate (CR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), time-to-next-treatment (TTNT) and minimal residual disease (MRD). Subgroup analyses were performed on suspected prognostic biomarkers in 1L CLL. No formal statistical hypothesis tests were performed. The database lock was January 31, 2019. Results: Of 972 enrolled pts, 630 received 1L CLL treatment (340 fit, 290 unfit; 1 unfit pt was enrolled but was never treated), and 341 had R/R CLL. In total, 63.5% were male. The mean (range) age was 65.4 (33-90) years. Median (range) observation time was 43.7 (0.3-59.2) months. Of the 630 pts receiving 1L treatment and 341 pts who were treated for R/R disease, 488 (77.5%) and 170 (49.9%), respectively, completed the study. At final analysis, no new safety signals were observed compared with the primary safety analysis. In total, 82.7% of pts receiving 1L treatment and 84.5% of pts who were treated for R/R disease experienced grade (Gr) ≥3 adverse events (AEs), and 58.1% and 62.5% experienced serious AEs. As expected, the most common Gr 3-5 events were neutropenia (50.5% 1L, 53.4% R/R) and thrombocytopenia (14.6% 1L, 19.1% R/R). The most common non-hematological AEs were infection (any Gr: 57.6% 1L, 61.3% R/R; Gr 3-5: 21.7% 1L, 30.8% R/R) and nausea (any Gr: 27.9% 1L, 27.6% R/R; Gr 3-5: 0.8% 1L, 1.2% R/R). BOR and CR were generally higher, and DoR, PFS and TTNT were longer for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms (Table 1). Median OS was not reached at the time of analysis in any arm. The median duration of MRD-negativity was longer for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms except for pts receiving G-mono (Table 1). In addition, the MRD negative status at final response assessment in blood and bone marrow was higher for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms with the exception of pts receiving G-Clb (Table 1). Table 2 shows the PFS event-free rate by genetic marker for 1L G-Benda and G-FC over 4 years, indicating that pts with mutated immunoglobulin heavy chain variable (IGHV), del(13q) and trisomy 12 derived the most benefit. Conclusions: In this final analysis of GREEN, no new safety signals were identified. Efficacy outcomes suggest a favorable benefit/risk profile in both 1L and R/R CLL, irrespective of chemotherapy regimen. PFS outcome for pts with 12q trisomy, del(13q) and IGHV mutated were favorable across treatment arms, while del(11q), del(17q), and unmutated IGHV showed a worse outcome. Multivariate analyses including treatment, clinical and laboratory parameters are currently being performed to identify pts who derive the most benefit. Disclosures Stilgenbauer: Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bosch:AstraZeneca: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Leblond:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mikuskova:Novartis: Honoraria; Roche: Honoraria; Johnson & Johnson: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; National Oncology Institute: Employment. Tausch:Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau. Wójtowicz:Roche: Honoraria, Other: Sponsorship of 2019 EHA participation; Acerta Pharma/AstraZeneca: Honoraria; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Honoraria; Takeda: Honoraria; Amgen: Consultancy. Perretti:F. Hoffmann-La Roche Ltd: Employment. Van Hoef:F. Hoffman-La Roche: Employment. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia, and in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.
29
Shapiro, Amy, Giancarlo Castaman, Katarina Cepo, Lone Hvitfeldt Poulsen, Christian Hollensen, Tadashi Matsushita, Guy Young, Silva Zupancic-Salek i Victor Jimenez-Yuste. "Efficacy and Safety of Subcutaneous Prophylaxis with Concizumab in Patients with Hemophilia a or B with Inhibitors: Results from explorer4, a Phase 2, Randomized, Open-Label, Controlled Trial". Blood 134, Supplement_1 (13.11.2019): 1139. http://dx.doi.org/10.1182/blood-2019-122809.
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Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present results from the main part (at least 24 weeks) of the concizumab explorer4 phase 2 trial (NCT03196284) in hemophilia A/B with inhibitor (HAwI/HBwI) patients. Methods The primary objective was to assess the efficacy of once-daily subcutaneous concizumab in preventing bleeds in HAwI/HBwI patients. Secondary objectives were the assessment of safety, including concomitant use of recombinant activated factor VII (rFVIIa), and immunogenicity. Patients were randomized 2:1 to concizumab prophylaxis or rFVIIa on-demand treatment via an interactive web-response system. A concizumab loading dose (0.5 mg/kg) was administered, followed by 0.15 mg/kg daily with potential dose escalation to 0.20 and 0.25 mg/kg. Efficacy was evaluated as the number of bleeding episodes (annualized bleeding rate [ABR]) at last dose level. The number of adverse events (AEs) and the occurrence of anti-drug antibodies (ADAs), as well as coagulation-related parameters were evaluated. Concizumab and free TFPI plasma levels were measured by ELISA, and peak thrombin generation (TG) potential using a standardized assay. Results 26 patients were randomized; 9 HAwI and 8 HBwI patients were exposed to concizumab, and 9 patients to rFVIIa (7 with HAwI and 2 with HBwI). All 25 patients who completed the main 24-week part of the trial chose to continue to the extension part. The estimated ABR at the last dose level for concizumab prophylaxis was 4.5 (95% CI: 3.2−6.4) and for rFVIIa on demand, 20.4 [95% CI: 14.4−29.1] (Figure 1). There was a 78, 88 and 79% reduction in all treated bleeds and in spontaneous and joint bleeds, respectively, with concizumab prophylaxis compared with on-demand treatment (Figure 1). Concizumab concentration varied considerably between patients on the same dose level. Increasing concizumab dose was associated with lower free TFPI and normalized TG potential (Figure 2). No deaths, thromboembolic events or AE-related withdrawals occurred. No safety concerns with concomitant use of concizumab and rFVIIa were identified. Three patients had positive (very-low to medium-titer) ADA tests (titer range: 1 to 128), but with no apparent clinical effect. As expected, elevated prothrombin fragment 1+2 and D-dimers were observed across all concizumab dose levels, reflecting the hemostatic effect of concizumab. Conclusions In the phase 2 explorer4 trial, concizumab was efficacious and safe as a subcutaneous prophylactic treatment in HAwI patients, as well as in HBwI patients for whom there is currently no prophylactic regimen available. There was no difference in safety and efficacy across hemophilia subtypes, including with the concomitant use of concizumab and the bypassing agent rFVIIa. The phase 2 trial results, which include the explorer5 trial in HA without inhibitors, support further development of concizumab as a prophylactic treatment for all hemophilia patients and have guided selection of the phase 3 dosing regimen. Disclosures Shapiro: Sangamo Biosciences Inc: Consultancy, Other: Clinical Research Protocol with the company; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Novo Nordisk Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; OPKO: Other: Clinical Research Protocol with the company; Octapharma: Other: Clinical Research Protocol with the company; Prometic Life Sciences: Consultancy; Shire/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company, Research Funding; Bayer: Other: Clinical Research Protocol with the company; Kedrion Biopharma: Other: Clinical Research Protocol with the company; Agios: Other: Clinical Research Protocol with the company; Prometic Bio Therapeutics: Other: Clinical Research Protocol with the company; BioMarin: Other: Clinical Research Protocol with the company; Daiichi Sankyo: Other: Clinical Research Protocol with the company; Glover Blood Therapeutics: Other: Clinical Research Protocol with the company; Novartis: Other: Clinical Research Protocol with the company; Pfizer: Other: Clinical Research Protocol with the company; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cepo:Novo Nordisk A/S: Employment. Hvitfeldt Poulsen:Novo Nordisk: Other: Clinical trials - investigator, Funding meetings and congresses; Bayer Health Care: Other: Clinical trials - investigator, Funding meetings and congresses; Pfizer: Other: Funding meetings and congresses; Sobi: Other: Funding meetings and congresses. Hollensen:Novo Nordisk: Employment. Matsushita:Bioverative: Research Funding; Pfizer: Consultancy, Honoraria; KM biologists: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; CSL: Consultancy, Honoraria; uniQure: Consultancy, Honoraria. Young:Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria. Zupancic-Salek:Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.
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Jurczak, Wojciech, Pier Luigi Luigi Zinzani, David Cunningham, Michel Azoulay, Wenying Huang, Weiming Xu i Vincent Ribrag. "Coastal: A Phase 3 Study of the PI3Kδ Inhibitor Zandelisib with Rituximab (R) Versus Immunochemotherapy in Patients with Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)". Blood 138, Supplement 1 (5.11.2021): 2430. http://dx.doi.org/10.1182/blood-2021-148015.
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Abstract Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor is administered using a unique schedule consisting of 60 mg given daily over the first two 28-day cycles for response induction followed by Days 1-7 only of each subsequent cycle as maintenance therapy, with the treatment-free intervals intended for regulatory T-cells repopulation and mitigation of delayed immune-related toxicities. In a phase 1 study, zandelisib achieved an 87% response rate, with median duration of response not reached in patient with relapsed iNHL when given as a monotherapy or in combination with R. A low rate (< 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors was also observed in patients administered zandelisib (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy. Eligible pts must have received an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria include: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects are randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial is open and will enroll approximately 534 pts in ~200 sites globally. Clinical trial information: NCT04745832 Disclosures Jurczak: AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding. Zinzani: Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cunningham: Clovis Oncology: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Research Funding; 4SC: Research Funding; MedImmune: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding. Azoulay: Kyowa Kirin Co.: Current Employment. Huang: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Xu: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Astex Pharmaceuticals: Research Funding; Epizyme: Honoraria, Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Zandelisib is an investigational PI3Kdelta inhibitor being evaluated in patients with B cell malignancies. The trials-in-progress abstract describes a clinical trail evaluating zandelisib plus rituximab vs. immunochemotherapy in patients with relapsed iNHL.
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Mato, Anthony R., William G. Wierda, John M. Pagel, Matthew S. Davids, Pier Luigi Zinzani, Yi Lu, Hui Liu i in. "BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)". Blood 138, Supplement 1 (5.11.2021): 3742. http://dx.doi.org/10.1182/blood-2021-145936.
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Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today's standard of care. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population. Study Design and Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure). Eligible patients are adults with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Disclosures Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Genmab: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding. Wierda: GSK/Novartis: Research Funding; Xencor: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Gilead Sciences: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy. Davids: Astra-Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding. Zinzani: ROCHE: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; MSD: Consultancy, Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau. Lu: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Liu: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tam: Beigene: Honoraria; Loxo: Honoraria; Abbvie: Research Funding; Janssen: Research Funding; Beigene: Research Funding; Janssen: Honoraria; Abbvie: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Eyre: Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding.
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Usmani, Saad Z., Maria-Victoria Mateos, Hareth Nahi, Sebastian Grosicki, Vladimir I. Vorobyev, Ivan Spicka, Vania T. M. Hungria i in. "Randomized, Open-Label, Non-Inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous (IV) Daratumumab (DARA) Administration in Patients with Relapsed or Refractory Multiple Myeloma: Columba Update". Blood 134, Supplement_1 (13.11.2019): 1865. http://dx.doi.org/10.1182/blood-2019-122765.
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INTRODUCTION: Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38, is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma (MM).To improve safety and reduce patient and healthcare provider burden, a subcutaneous (SC) formulation of DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label, non-inferiority COLUMBA study (NCT03277105) evaluated the efficacy, PK, and safety of DARA SC vs DARA IV in patients (pts) with RRMM. The results, showing the study met both co-primary endpoints (overall response rate [ORR] and Ctrough) at a median follow-up of 7.5 months, were previously presented. Here, we present updated data with longer follow-up. METHODS: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV infusion) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR; analyzed by Farrington-Manning test, with non-inferiority defined as 60% retention of ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1; non-inferiority defined as the lower bound of 90% confidence interval [CI] for the ratio of the geometric means [GM] ≥80%). Secondary endpoints included rates of infusion-related reactions (IRRs), progression-free survival (PFS), very good partial response or better (≥VGPR), and complete response or better (≥CR). RESULTS: A total of 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median age was 67 yrs (20% ≥75 yrs). Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% of pts were previously treated with both PI(s) and IMiD(s). 82.2% of pts were refractory to the last line of prior therapy, and 49.4% were refractory to both PI and IMiDs. 26.3% and 17.3% of pts had a high-risk cytogenetic abnormality at baseline in the DARA SC and DARA IV groups, respectively. After a median follow-up of 13.8 months, ORR was improved from 41.1% to 43.7% for DARA SC and 37.1% to 39.4% for DARA IV (Figure). ORR were comparable across all subgroups, including body weight. Rates of deep responses (≥VGPR, ≥CR) were similar between DARA SC and DARA IV, and deeper with longer follow-up (Figure). Median duration of treatment (~5.5 months) was similar for DARA SC and DARA IV. A significantly lower rate of IRRs was observed with DARA SC vs DARA IV. At the time of data cutoff, 118 pts (evenly distributed across both arms) continued treatment on study. CONCLUSIONS: With longer follow-up, safety and efficacy data continue to support that DARA SC and DARA IV have similar safety profiles with a statistically significant reduction in IRR rates. DARA SC has a reduced treatment burden due to a considerably shorter administration duration, and DARA SC pts reported higher treatment satisfaction. Collectively, the data demonstrate a favorable benefit/risk profile for the use of an 1800 mg flat dose of DARA SC. Disclosures Usmani: Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Mateos:Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hungria:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Teijin Pharma: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Astellas: Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Bahlis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.
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Matsumura, Itaru, Shigeki Ohtake, Yoshiko Atsuta, Mio Kurata, Yosuke Minami, Naoto Takahashi, Chiaki Nakaseko i in. "Nilotinib Vs. Dasatinib in Achieving MR4.5 for Newly Diagnosed Chronic Myeloid Leukemia: Results of the Prospective Randomized Phase 3 Study, JALSG CML212". Blood 136, Supplement 1 (5.11.2020): 40–41. http://dx.doi.org/10.1182/blood-2020-134168.
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Background: Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequisite condition to discontinue a tyrosine kinase inhbitor (TKI). In ENESTnd and DASISION trials, both nilotinib and dasatinib achieved DMR more effectively than imatinib. However, there is no direct comparative study to determine which TKI is better to achieve DMR for de novo CML-CP. So, we conducted a randomized phase 3 JALSG CML212 study to compare the achievement of MR4.5 (BCR-ABL IS≤0.0032%) between nilotinib and dasatinib. Methods: The JALSG CML212 study is a multicentral open-labeled prospective randomized controlled phase 3 study for de novo CML-CP. This study was reviewed and approved by the institutional review board of each institute and registered in the UMIN Clinical Trials Registry (#UMIN000007909). All patients provided written informed consent before enrollment. Diagnosis of CML was done by a cytogenetic study (G-banding or FISH) and/or detection of BCR-ABL by RT-PCR. The primary endpoint is a rate of cumulative achievement of MR4.5 by 18 mon. Major secondary endpoints were safety, continuity, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and cytogenetic and molecular responses. A total of 461 patients were registered from 82 institutes and 454 patients were randomly assigned to the nilotinib arm or dasatinib arm (both, n=227) with Sokal risk scores as a stratification factor. Treatment doses were 300 mg, bid for nilotinib and 100 mg, qd for dasatinib. Treatment responses were evaluated by ELN2009. Patients were allowed to stop study treatment if judged as failure by ELN2009 or showed intolerance (repetitive ≥Grade 3 or continuous Grade 2 side effects) to the allocated TKI. BCR-ABL mRNA levels were monitored every three months with international scales using a MolecularMD, ODK-1201, or M135R kit with ≥MR4.5 sensitivities. Adverse events were evaluated by the CTCAE ver 4.0. Results: The median age of the patients was 53 years old in both arms. The proportions of Sokal low, intermediate, and high risk groups were 44.1%, 37.0%, and 18.9% in the nilotinib arm and 44.5%, 37.0%, and 18.5% in the dasatinib arm, respectively, without a significant difference. Also, there was no significant difference in ECOG PS, EUTOS risk groups, complications, or frequencies of additional chromosomal abnormalities in both arms. In the ITT population, the cumulative achievement rates of MR4.5 by 18 mon were 33.0% (75/227) (95% CI:27.0-39.6%) in the nilotinib arm and 30.8% (70/227) (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference with a CMH test (p=0.62). This finding was also confirmed in the per-protocol (PP) population (33.5% in the nilotinib arm and 31.8% in the dasatinib arm, p=0.72). At 18 mon, 75.9% and 79.6% of the patients continued the allocated TKI in the nilotinib and dasatinib arms, respectively (p=0.36) (in the PP population).There was no significant difference in PFS, EFS, or OS between two arms by log-rank tests (the estimated rates at 36 mon: 98.8%, 67.2%, and 98.8% in the nilotinib arm; 99.0%, 65.4%, and 99.0% in the dasatinib arm). In addition, PFS, EFS and OS didn't differ between both arms regardless of Sokal and EUTOS risk groups. The cumulative CCyR rates by 12, 18, 24, and 36 mon were 77.1%, 78.0%, 78.4%, and 78.4% in the nilotinib arm and 78.4%, 78.9%, 78.9%, and 78.9% in the dasatinib arm, respectively without no significant difference. The MMR rates by 12, 18, 24, and 36 mon were 62.6%, 67.0%, 72.3%, and 73.1% in the nilotinib arm and 68.7%, 73.1%, 75.3%, and 77.1% in the dasatinib arm, respectively, without no significant difference. The MR4.5 rates by 12, 24, and 36 mon were 25.6%, 37.4%, and 40.5% in the nilotinib arm and 23.4%, 36.6%, and 44.5% in the dasatinib arm, respectively, with no significant difference. In the safety population, Grade 3/4 adverse events observed with ≥10% frequencies were lipase elevation (11.5%) in the nilotinib arm and neutropenia (12.8%) and thrombocytopenia (16.8%) in the dasatinib arm. Any new safety issue was observed in neither of the arms. Conclusions: Based on these results, we consider that nilotinib and dasatinib are equally effective for de novo CML-CP patients in achieving MR4.5 as well as in achieving CCyR and MMR in terms of both frequencies and times to achievement with similar continuity. Figure Disclosures Matsumura: Kyowa Kirin Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau. Minami:Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria. Takahashi:Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Iriyama:Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau. ONO:Mundipharma K.K.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria. Fujisawa:Janssen Pharmaceutical K.K: Speakers Bureau; Celgene: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Kobayashi:Pfizer Japan Inc.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; SymBio Pharmaceuticals Limited.: Consultancy. Asou:Fuji Pharma Co.,Ltd.: Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria, Speakers Bureau; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Honoraria; Asahi Kasei Pharma.: Speakers Bureau. Kiyoi:Celgene Corporation: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Astellas Pharma Inc.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Research Funding; Amgen Astellas BioPharma K.K.: Consultancy; Kyowa Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Perseus Proteomics Inc.: Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Naoe:Sysmex co.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau.
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Hampton, Kingsley, Pratima Chowdary, Scott Dunkley, Silke Ehrenforth, Lotte Jacobsen, Anne T. Neff, Elena Santagostino i in. "First Report on the Safety and Efficacy of a Long-Acting Recombinant FVIII (turoctocog alfa pegol, N8-GP) during Major Surgery in Patients with Severe Hemophilia a". Blood 126, nr 23 (3.12.2015): 2283. http://dx.doi.org/10.1182/blood.v126.23.2283.2283.
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Abstract Introduction N8-GP (turoctocog alfa pegol) is an extended half-life, recombinant factor VIII (FVIII) that has a site-specific glycoPEGylation in the truncated B-domain. Upon activation, the glycopegylated domain is cleaved from N8-GP yielding FVIIIa, which is identical to endogenous FVIIIa. PathfinderTM 2 and pathfinder™3 (www.ClinicalTrials.gov identifiers: NCT01480180 and NCT01489111, respectively) are ongoing international, open-label, non-randomized, phase 3 clinical trials of N8-GP in patients aged ≥12 years with severe hemophilia A and with a documented history of at least 150 exposure days to other FVIII products, in line with regulatory guidelines. All patients in the pivotal pathfinderTM 2 trial are offered entry into pathfinderTM 3 if major surgery is required, thus enabling patients to undergo surgery without having to switch to another FVIII product. After completion of pathfinderTM 3, patients returned to the prophylactic or on-demand treatment arm in pathfinderTM 2 as per their prior participation in the trial. We report a planned main phase interim analysis of the single-arm pathfinderTM 3 trial evaluating the efficacy and safety of N8-GP during surgical procedures in patients with severe hemophilia A. Methods Patients recruited into the pathfinderTM 3 trial were males aged ≥12 years (aged ≥18 years in France and the Netherlands) with severe hemophilia A (FVIII activity level <1 IU/dl). Eligible patients undergoing major surgery received N8-GP before, during, and after surgery. At screening (0-3 weeks prior to surgery), all eligible patients received a single dose of N8-GP 50 U/kg at the clinic to evaluate FVIII activity recovery and required dose level for surgery. On the day of surgery, all patients received a fixed pre-operative loading dose of N8-GP (50 U/kg), up to 2 hours prior to the start of surgery. During and after surgery, N8-GP dosing was at the investigators' discretion. The dose level of N8-GP during this trial was chosen so that FVIII activity levels recommended by World Federation of Hemophilia (WFH) guidelines were targeted; higher levels could be necessary depending on type of surgery and standard practice at the site. Postoperative assessments, including monitoring for FVIII activity, were conducted daily for Days 1-6, and once between Days 7-14. Efficacy of N8-GP during surgical procedures was assessed using a 4-point scale of "excellent, good, moderate, or poor". In addition, transfusion requirements, consumption and estimated blood loss were recorded as part of the efficacy assessment. Blood sampling for FVIII activity and laboratory safety parameters was done at all trial visits. Results The main phase interim analysis includes results from 16 patients (median age of 36.5 years; range: 15−66 years) who underwent 18 major surgical procedures (including synovectomy, joint replacement, ankle arthrodesis, and psoas pseudo tumor excision). All surgeries were effectively performed with N8-GP. Hemostasis was successful (i.e., rated as 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures, and no change of treatment regimen was needed in any patient. For one procedure (complicated total hip replacement) the hemostatic response was rated 'moderate' (5.6%) in a patient with multiple comorbidities and low platelet count at day of surgery. The postsurgical hemostatic effect success rate with N8-GP was 100%. N8-GP was well tolerated and no safety issues were identified during this trial; no FVIII inhibitors were detected, and no thromboembolic events occurred. Conclusions As the first report for a longer-acting glycoPEGylated FVIII product, the results from pathfinder™ 3 indicate that N8-GP is effective and well tolerated with a favorable safety profile for perioperative management of major surgical procedures in patients with severe hemophilia A. Disclosures Hampton: Novo Nordisk: Honoraria. Chowdary:CSL Behring: Consultancy, Research Funding; Bayer: Consultancy; SOBI: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Dunkley:Baxter: Consultancy; Novo Nordisk: Honoraria; Bayer: Honoraria; Pfizer: Honoraria. Ehrenforth:Novo Nordisk: Employment. Jacobsen:Novo Nordisk: Employment. Neff:Alexion: Speakers Bureau; Baxter: Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau. Santagostino:Bayer: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau; Biogen/Sobi: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; CSL Behring: Speakers Bureau; Kedrion: Speakers Bureau. Takedani:Novo Nordisk: Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau; Kaketsuken: Speakers Bureau; Pfizer: Speakers Bureau. Takemoto:Novo Nordisk: Research Funding; Mast Therapeutics: Speakers Bureau. Négrier:Biogen/Sobi: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; LFB: Consultancy; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding.
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Neelapu, Sattva S., Mohamed A. Kharfan-Dabaja, Olalekan O. Oluwole, Patel Krish, Ran Reshef, Peter A. Riedell, Parveen Shiraz i in. "A Phase 2, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination with Either Rituximab or Lenalidomide in Patients with Refractory Large B-Cell Lymphoma (ZUMA-14)". Blood 134, Supplement_1 (13.11.2019): 4093. http://dx.doi.org/10.1182/blood-2019-126369.
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Background: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adult patients who have relapsed/refractory large B cell lymphoma (LBCL) and have had ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 83% (complete response rate, 58%), with ongoing responses in 39% after a median follow-up of 27.1 months (Locke FL, et al. Lancet Oncol. 2019). Despite the success of axi-cel, approximately 60% of patients have no response or relapse after treatment, indicating that additional strategies are needed for patients with relapsed/refractory LBCL. Preclinical murine studies have shown that rituximab augmented the tumor-suppressing effects of anti-CD19 CAR T cells, and the combination led to higher rates of tumor reduction (Mihara K, et al. Br J Haematol. 2010; Rufener GA, et al. Cancer Immunol Res. 2016). The IMiD® immunomodulatory agent lenalidomide has shown activity in patients with relapsed/refractory diffuse large B cell lymphoma and has also been shown to enhance the antitumor functions of anti-CD19 and anti-CD20 CAR T cells in mice (Otahal P, et al. Oncoimmunology. 2016). In ZUMA-14, the aim is to investigate the efficacy and safety of axi-cel in combination with rituximab or lenalidomide in adult patients with refractory LBCL. Methods: This Phase 2 study (NCT04002401) has a planned enrollment of approximately 60 patients aged ≥ 18 years with refractory LBCL, defined as a response of either progressive disease or stable disease to previous chemotherapy or progressive disease or relapse ≤ 12 months after an autologous stem cell transplant. Patients with prior IMiD® treatment, including lenalidomide, prior CAR T cell therapy, and/or prior CD19-targeted therapy are excluded. After leukapheresis, patients will be assigned 1:1 to receive axi-cel with either rituximab (Cohort 1) or lenalidomide (Cohort 2). Patients will receive lymphodepleting chemotherapy of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) on days -5 to -3 before axi-cel infusion (2 × 106 cells/kg) on Day 0. Cohort 1 will receive rituximab (375 mg/m2) every 28 days starting on Day -5 for a total of 6 doses. Cohort 2 will receive lenalidomide (10 mg) daily starting 7 days after leukapheresis through Day 3 and for 5 additional cycles (20 mg, first 21 days of each 28-day cycle) beginning after axi-cel infusion starting on Day 21. Patients may not receive any therapy other than conditioning therapy and rituximab or lenalidomide, as specified by cohort, between leukapheresis and axi-cel infusion. The primary endpoint is investigator-assessed complete response rate per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints include safety, objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (levels of blood CAR T cells over time). Exploratory endpoints for both cohorts include pharmacodynamic assessment of cytokine profiles and the rate of CD19-negative relapses. An additional exploratory endpoint for Cohort 2 is to investigate immunomodulation of the tumor microenvironment, including the number and activation of T cells and natural killer cells. Enrollment is expected to start in September 2019. Disclosures Neelapu: Cell Medica: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Acerta: Research Funding; Karus: Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Allogene: Consultancy; Poseida: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Krish:Celgene: Consultancy, Research Funding, Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Curis: Research Funding; MEI Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Xencor: Research Funding; Roche: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis: Consultancy, Research Funding. Reshef:BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Goyal:Kite, a Gilead Company: Employment. Kawashima:Kite, a Gilead Company: Employment, Equity Ownership. Milletti:Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Oliva:Kite, a Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding. OffLabel Disclosure: ZUMA-14 is a clinical trial evaluating the investigational combination of axicabtagene ciloleucel with either rituximab or lenalidomide in refractory large B cell lymphoma
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Bailey, Neil, Tenzin Tsomo, Jennie Szeto, William I. Bensinger, Daniel Egan, Livia Hegerova, Raya Mawad i in. "Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma". Blood 136, Supplement 1 (5.11.2020): 34. http://dx.doi.org/10.1182/blood-2020-141074.
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Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy. Achievement of CR with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve complete response (CR) with RICE chemotherapy alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. The goal of this study is to examine the feasibility and efficacy of adding the BTKi, acalabrutinib, to standard second-line therapy as a means to improve disease response. Establishing the feasibility of combining acalabrutinib with RICE chemotherapy in autologous hematopoietic cell transplantation (HCT) eligible and HCT ineligible patients with R/R DLBCL may provide the foundation for a larger study of efficacy and long-term outcomes of the combination therapy for patients with R/R DLBCL. Study Design and Methods: The primary objective of this phase 2 trial is to evaluate the tolerability, feasibility, and efficacy of combining acalabrutinib with RICE as second line therapy in R/R DLBCL patients. There are two study cohorts. Cohort A is open to R/R DLBCL patients who are eligible for autologous HCT. Cohort B is open to R/R DLBCL patients who are considered medically ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to HCT in patients undergoing second-line therapy. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Secondary endpoints include assessment of the proportion of patients completing 3 cycles of acalabrutinib with RICE and proceeding with HCT or 2 additional cycles of maintenance acalabrutinib for HCT ineligible patients, overall response rate, incidence of Grade 3/4 adverse events, and incidence of SAEs. Patients in cohort A receive 2 cycles of standard RICE salvage chemoimmunotherapy in combination with acalabrutinib, 100mg BID day 1-21 of a 21 day cycle. After 2 cycles of therapy, patients in cohort A undergo autologous stem cell mobilization and collection. Patients then receive a 3rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is performed 14-21 days after day 1 of cycle 3 to assess response. Those patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. After adequate hematopoietic recovery, patients restart acalabrutinib 100mg BID as maintenance therapy for a period of 12 additional months. Patients in cohort B receive 3 cycles of RICE salvage chemoimmunotherapy in combination with acalabrutinib 100mg BID day 1-21 of a 21-day cycle followed by PET-CT (PET3) 14-21 days after start of Cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but their outcomes continue to be recorded and will be included in the final data analysis. Historical outcomes from completed, published prospective clinical trials using RICE chemoimmunotherapy serve as a reference for statistical calculations. This trial is currently ongoing and additional information can be found on clinicaltrials.gov NCT listing NCT03736616 Disclosures Bensinger: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mawad:Abbvie: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau. Glennie:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau. Patel:Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Kite: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy. OffLabel Disclosure: Acalabrutinib is used an investigational agent for DLBCL in this study.
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Elsawy, Mahmoud, Julio C. Chavez, Irit Avivi, Jean-François Larouche, Luciano Wannesson, Kate Cwynarski, Keren Osman i in. "Patient-Reported Outcomes in a Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard of Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma (ZUMA-7)". Blood 138, Supplement 1 (5.11.2021): 430. http://dx.doi.org/10.1182/blood-2021-147598.
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Abstract Background: Outcomes are poor for patients with large B-cell lymphoma (LBCL) who relapse early or are refractory to first-line therapy. Furthermore, patients receiving second-line standard-of-care (SOC) therapy often report poor health-related quality of life (QoL; Lin V, et al. J Clin Oncol. 2020;38:e20070). In the ZUMA-7 (NCT03391466) pivotal Phase 3, randomized, open-label, multicenter study of axi-cel (an autologous anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) versus SOC, we conducted the first comparative analysis of patient-reported outcomes (PROs) with CAR T-cell therapy versus SOC as second-line treatment in relapsed/refractory (R/R) LBCL. Methods: PRO instruments, including the EORTC QLQ-C30 (cancer-specific 30-item questionnaire including global health status, functional, and symptom scales) and the EQ-5D-5L (a general questionnaire with 5 QoL domains plus a global assessment), were administered at baseline (prior to treatment), Day 50, Day 100, Day 150, Month 9, and every 3 months from randomization up to 24 months or time of event-free survival event (disease progression, death from any cause, or new lymphoma therapy), whichever occurred first. The QoL analysis set was defined as all patients who had a baseline PRO and ≥1 measure completed at Day 50, Day 100, or Day 150. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QoL, and EQ-5D-5L visual analog scale [VAS]) were tested using a mixed-effect model with repeated measures at Day 100 and subsequent time points if previous time points were statistically significant. False Discovery Rate was used to adjust P values across key endpoints; sensitivity analyses were conducted to control for covariates and patterns of missingness. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score and 7 points for EQ-5D-5L VAS score. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed. Results: Of 359 patients enrolled in the ZUMA-7 study, 296 patients (165 axi-cel, 131 SOC) had baseline PROs and ≥1 follow-up measure and were included for analysis. Overall, 70% of patients had primary refractory disease, 42% had high second-line age-adjusted International Prognostic Index (2-3), and 30% were ≥65 years old. For patients in the QoL analysis set treated with axi-cel versus SOC, there was a statistically significant (P<.0001) and clinically meaningful difference in mean change of scores from baseline at Day 100 in favor of axi-cel on all prespecified PRO domains (Figure). Sensitivity analyses showed similar results with retained significance at Day 100. Furthermore, scores also significantly favored axi-cel over SOC for EORTC QLQ-C30 Global Health Status/QoL (P=.0124) and EQ-5D-5L VAS (P=.0004) at Day 150. For the prespecified endpoints, the mean estimated scores for the axi-cel arm had numerically returned to or exceeded scores at baseline by Day 150 versus on or after Month 9 for the SOC arm. After Month 9, attrition (eg, due to disease progression, new lymphoma therapy, or death) in the QoL analysis set was substantial, particularly in the SOC arm. Additional exploratory analyses of PRO endpoints (eg, EORTC QLQ-C30 role functioning, social functioning, fatigue, nausea/vomiting, dyspnea, insomnia, appetite loss, diarrhea, and EQ-5D-5L index [US value set]) also showed improvements with axi-cel over SOC. Conclusion: ZUMA-7, the first randomized, global, multicenter Phase 3 study of axi-cel versus SOC in second-line R/R LBCL, showed that treatment with axi-cel results in clinically meaningful improvement in QoL over SOC at Day 100 as measured by multiple validated PRO instruments. Score comparisons at later timepoints warrant cautious interpretation, particularly in the SOC arm, as attrition due to disease progression, new lymphoma therapy, or death may select patients with the best outcomes. The data also suggest faster recovery to pretreatment QoL with axi-cel compared with SOC. The superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line R/R LBCL. These data are reported on behalf of all ZUMA-7 investigators and contributing Kite members. Figure 1 Figure 1. Disclosures Elsawy: Kite, a Gilead Company: Consultancy, Honoraria; Celgene/BMS: Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy. Chavez: MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; AstraZeneca: Research Funding; BMS: Speakers Bureau; Merk: Research Funding. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Larouche: Gilead: Consultancy. Wannesson: Novartis: Consultancy, Research Funding; MSD: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; Roche: Consultancy, Research Funding. Cwynarski: Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau. Osman: Kite, a Gilead Company: Consultancy. Davison: Merck: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Celegene: Consultancy. Rudzki: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; MSD: Consultancy; Roche: Consultancy, Speakers Bureau; BMS-Celgene: Consultancy. Dahiya: Jazz Pharmaceuticals: Research Funding; Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; BMS: Consultancy. Dorritie: OncLive/Institutional Perspectives on Cancer presentation: Honoraria; Janssen: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Juno/BMS: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Kite, a Gilead Company: Research Funding; Genmab: Research Funding; SITC presentation: Honoraria. Jaglowski: CRISPR Therapeutics: Consultancy; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Radford: AstraZeneca: Current holder of individual stocks in a privately-held company; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Morschhauser: Servier: Consultancy; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees. Cunningham: AstraZeneca: Research Funding; Clovis Oncology: Research Funding; MedImmune: Research Funding; Roche: Research Funding; Celgene: Research Funding; Bayer: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy; Takeda: Honoraria; Novartis: Consultancy; Eusa Pharma: Consultancy; Clinigen: Consultancy; Kyowa Kirin: Consultancy; Morphosys: Consultancy; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Tzachanis: Partner: Consultancy; Takeda: Consultancy, Speakers Bureau; EUSA: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Kyowa Kirin: Consultancy; Magenta: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding. Karmali: Roche: Consultancy; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Genentech: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy, Speakers Bureau; Takeda: Research Funding. Kekre: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Enblad: Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Malladi: Gilead: Honoraria, Other: Travel support; Gilead Science: Consultancy. Joshi: Open Health: Current Employment; Kite, a Gilead Company: Consultancy, Research Funding; various clients via employment: Consultancy, Research Funding. Wang: Kite, a Gilead Company: Consultancy, Research Funding; additional companies through employment with Open Health: Consultancy, Current Employment, Research Funding. Solem: OPEN Health: Current Employment; Kite, a Gilead Company: Consultancy; multiple clients through employment at OPEN Health: Research Funding. Thornton Snider: Kite, a Gilead Company: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Gilead: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. To: Kite, a Gilead Company: Current Employment, Other: stock or other ownership ; NantWorks: Ended employment in the past 24 months. Kersten: BMS/Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Celgene: Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding.
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Stewart, A. Keith, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek i in. "Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients (Pts) with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study". Blood 124, nr 21 (6.12.2014): 79. http://dx.doi.org/10.1182/blood.v124.21.79.79.
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Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care used for pts with relapsed multiple myeloma (RMM). The randomized, open-label, multicenter, phase 3 study ASPIRE (NCT01080391) is comparing carfilzomib, lenalidomide, and dexamethasone (KRd) to Rd in pts with RMM. The primary end point is progression-free survival (PFS; assessed by an independent review committee). Secondary end points include overall survival (OS), overall response rate (ORR), duration of response (DOR), health-related quality of life (EORTC QLQ-C30 Global Health Status/QoL), and safety. Methods: Adults with RMM who received 1–3 prior regimens were eligible. Pts were randomized (1:1) to receive KRd or Rd and were stratified by β2-microglobulin levels (<2.5 vs ≥2.5 mg/L), prior bortezomib (no vs yes), and prior R (no vs yes). All pts received lenalidomide (25 mg) on days 1–21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 of a 28-day cycle. In addition, KRd pts received K as a 10-min infusion on days 1, 2, 8, 9, 15, and 16 during cycles 1–12 (20 mg/m2 [days 1 and 2 of cycle 1]; 27 mg/m2 thereafter); K was omitted on days 8 and 9 during cycles 13–18 and was not administered beyond 18 cycles. Cycles were repeated until disease progression, unacceptable toxicity, or withdrawal of consent. The study had 90% power to detect a 25% reduction in risk for PFS events for KRd vs Rd (hazard ratio [HR]=0.75) at a 1-sided significance level of 0.025. A stratified log-rank test was used for the PFS comparison. Results: Data are presented for KRd followed by Rd throughout the abstract. Between July 2010 and March 2012, 792 pts from 20 countries were randomized. Baseline characteristics were balanced between the 2 groups. Median age was 64.0 years (range: 31.0‒91.0). Pts received a median of 2 prior regimens in each group. In both the KRd and Rd groups, 66% of pts received prior bortezomib; 20% of pts in each arm received prior R. Median treatment exposure was 22 cycles (KRd) and 14 cycles (Rd). At the time of the prespecified interim analysis, the study met the primary end point for PFS (HR=0.69; 95% confidence interval [CI]: 0.57–0.83; P<.0001), with a longer duration of median PFS in the KRd group (26.3 months [mo]; 95% CI: 23.3–30.5) compared with the Rd group (17.6 mo; 95% CI: 15.0–20.6). Median OS was not reached in either group; however, there was a trend toward longer OS with KRd compared with Rd (HR=0.79; 95% CI: 0.63–0.99; P=.018), which did not meet the prespecified statistical boundary at the interim analysis of survival (P=.005). The Kaplan-Meier OS event-free rates at 24 mo were 73.3% (95% CI: 68.6‒77.5) and 65.0% (95% CI: 59.9‒69.5). The ORR was 87.4% (95% CI: 83.7–90.5) with KRd and 66.9% (95% CI: 62.0–71.5) with Rd. Median DOR was 28.6 mo (95% CI: 24.9–31.3) and 21.2 mo (95% CI: 16.7–25.8). In the KRd and Rd groups, 31.8% vs 9.4% achieved a stringent complete response (sCR) or complete response (CR) (sCR: 14.1% vs 4.3%; CR: 17.7% vs 5.1%), and 70.4% and 40.7% achieved ≥very good partial response. KRd consistently improved Global Health Status/QoL compared with Rd over 18 cycles of treatment (P=.0001). Treatment discontinuation due to an adverse event (AE) occurred in 15.2% (KRd) and 17.4% (Rd) of pts. In each group, 7.7% and 8.5% of pts died while still on study treatment or within 30 days of receiving the last dose of study treatment. The most common hematologic treatment-emergent AEs (TEAEs) (≥grade 3) included neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%). The most common nonhematologic TEAEs (all grade) included diarrhea (42.3% vs 33.7%), fatigue (32.9% vs 30.6%), and cough (28.8% vs 17.2%). The most common nonhematologic TEAEs (≥grade 3) included pneumonia (12.5% vs 10.5%), hypokalemia (9.4% vs 4.9%), and hypophosphatemia (8.4% vs 4.6%). Other TEAEs of interest (grouped terms; all grade) included dyspnea (22.4% vs 18.0%), hypertension (preferred term; all grade: 14.3% vs 6.9%; grade 3: 4.3% vs 1.8%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), and ischemic heart disease (5.9% vs 4.6%). Rates of peripheral neuropathy (PN) (grouped terms; all grade) were 17.1% and 17.0%; ≥grade 3 PN was infrequent (2.6% and 3.1%). Conclusion: The addition of carfilzomib to lenalidomide and dexamethasone in pts with RMM resulted in a statistically significant and clinically meaningful improvement in PFS. KRd had an acceptable safety and tolerability profile and represents a potential new standard of care. Disclosures Stewart: Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding; Celgene: Consultancy. Off Label Use: Carfilzomib is approved in the United States for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. ASPIRE is a randomized, multi-center, phase 3 study investigating the use of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1–3 prior regimens.. Dimopoulos:Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spicka:Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Hájek:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Siegel:Onyx: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Niesvizky:Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Jakubowiak:Onyx Pharmaceticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Millinnium: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Research Funding, Speakers Bureau; Takeda Celgene: Research Funding, Speakers Bureau; Bristol-Myers: Research Funding, Speakers Bureau. Zojwalla:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Tonda:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Xing:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria; Janseen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Inc,: Consultancy, Honoraria; Array BioPharma: Honoraria.
39
Bussel, James B., Francesco Rodeghiero, Roger M. Lyons, Barry Firstenberg, Joanne Joseph, Craig M. Kessler, Louis Terriou, Roberto Stasi, Paul Chang i Susie Jun. "Sustained Hemostatic Platelet Counts in Adults with Immune Thrombocytopenia (ITP) Following Cessation of Treatment with the TPO Receptor Agonist Romiplostim: Report of 9 Cases",. Blood 118, nr 21 (18.11.2011): 3281. http://dx.doi.org/10.1182/blood.v118.21.3281.3281.
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Abstract Abstract 3281 Background: While romiplostim is often perceived as a long-term treatment for adults with chronic ITP, previous data suggest that some patients can maintain hemostatic platelet counts when romiplostim is permanently discontinued, as occurred in 7 of 83 romiplostim-treated patients in the pivotal trials (Kuter et al, Lancet 2008) and as presented at the 2011 EHA meeting (Newland et al, 2011). Methods: We describe 9 patients from an open-label extension study (N = 291, Bussel et al, Blood 2009) who had ITP of various durations unresponsive to treatments such as splenectomy, corticosteroids, IVIg, anti-D, danazol, azathioprine, and rituximab. Romiplostim was administered at the same dose as in the previous study or at 1 μg/kg (if patients had previously received placebo) and adjusted by no more than 1 μg/kg weekly to maintain platelet counts at 50–200×109/L. These patients were selected for this report because romiplostim was discontinued and hemostatic platelet counts maintained for at least 6 months. Results: In these cases, patients had ITP ranging in duration from 0.1 to 5.5 years and between 2 and 5 prior ITP therapies before entering romiplostim clinical trials (Table). The duration over which romiplostim was received in these cases (previous study and extension study combined) ranged from 37 to 139 weeks. No clinically significant bleeding (grade ≥3) was observed with romiplostim in these patients during the initial studies; during the open-label extension, epistaxis in Week 10 and gastrointestinal hemorrhage in Week 18 were reported for Case 6. Examination of these 9 cases indicates that there are no factors that appear to predict which patients, after discontinuing romiplostim, will achieve hemostatic platelet counts off treatment. Of note, as this was a post hoc analysis and not a prespecified endpoint, there may be other cases in which hemostatic platelet counts were maintained without romiplostim treatment. Summary/conclusions: Dose adjustment rules allow romiplostim to be discontinued when appropriate. These case reports indicate that some patients may not require romiplostim indefinitely. In the absence of other ITP treatments (e.g., immunosuppressive therapies), hemostatic platelet counts can be maintained in certain cases after cessation of romiplostim. We believe that more such cases will become known, allowing us to gain greater insights into which ITP patients are able to discontinue romiplostim and to the relationship to the natural history of ITP and possible remission. Potential mechanisms for this phenomenon should be explored, including what role is played by the improvement of T-regulatory cell function in the presence of hemostatic platelet counts (Bao et al, Blood 2010). Table Patient data Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Rodeghiero:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Suppremol: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kessler:Amgen: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Griffols: Consultancy, Research Funding. Terriou:Amgen: Honoraria; GSK: Honoraria. Stasi:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Suppremol: Consultancy, Honoraria; Nycomed: Honoraria; Bayer: Honoraria; Baxter: Honoraria. Chang:Amgen: Employment, Equity Ownership. Jun:Amgen: Employment, Equity Ownership.
40
Zinzani, Pier Luigi, Felipe Samaniego, Wojciech Jurczak, Nilanjan Ghosh, Enrico Derenzini, James A. Reeves, Wanda Knopinska-Posluszny i in. "Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global Unity-NHL Trial". Blood 136, Supplement 1 (5.11.2020): 34–35. http://dx.doi.org/10.1182/blood-2020-134851.
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Background: Umbralisib is an oral, once-daily, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration directed Phase 2 study designed to evaluate the safety and efficacy of umbralisib in previously treated NHL patients (pts). Previously reported results in pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) demonstrated that umbralisib was active with a manageable safety profile. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with umbralisib, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the final analysis of the iNHL population treated with single agent umbralisib. Methods: Eligible pts had histologically confirmed iNHL: MZL (splenic, nodal, extranodal), follicular lymphoma (FL; Gr 1, 2, 3a), or small lymphocytic lymphoma (SLL). MZL pts were R/R to ≥1 prior lines of treatment, which must have included an anti-CD20, while FL and SLL pts were R/R to ≥2 prior lines, which had to include an anti-CD20 and an alkylating agent. Umbralisib was administered orally at 800 mg once-daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee (IRC), according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Pneumocystis jiroveci pneumonia (PCP) and anti-viral prophylaxis were mandated for all pts. Results: 208 iNHL pts received at least 1 dose of umbralisib, including 69 MZL, 117 FL, and 22 SLL pts. The median duration of exposure was 8.4 mos (range 0.2 - 27.0), median age was 66, and 56.7% were male. Pts had received a median of 2 prior regimens (range 1 - 10) with 46.1% having received ≥ 3 regimens. FL patients had a median of 3 prior regimens. With a median follow up of 27.8 mos, MZL pts had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. ORR was consistent amongst MZL subtypes. The median TTR was 2.8 months (95% CI 2.7 - 2.9). The median profession-free survival (PFS) was not reached (95% CI 12.1 mos - not evaluable [NE]) with an estimated 12-month PFS rate of 64.2%. The median DoR was not reached (95% CI 10.3 mos - NE), and no pts who achieved CR have experienced disease progression to date. With a median follow up of 27.5 mos, FL pts had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 mos (95% CI 3.0 - 5.6). The median PFS was 10.6 mos (95% CI 7.2 - 13.7) with an estimated 12-month PFS rate of 45.9%. The median DoR was 11.1 mos (95% CI 8.3 - 15.6). With a median follow up of 29.3 mos, SLL pts had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 mos (95% CI 2.4 - 2.8). The median PFS was 20.9 mos (95% CI 7.4 - 24.1) with an estimated 12-month PFS rate of 62.6%. The median DoR was 18.3 mos (95% CI 2.4 - NE). Best % change in target lesions form baseline for pts with at least one post-baseline assessment is shown in the figure. At the data cut-off, 60 pts (26 MZL, 27 FL, 7 SLL) remained on treatment. The most common ≥G3 AEs were neutropenia (11.5%), diarrhea (10.1%) and increased ALT/AST (7.2%). Other AEs of interest included pneumonitis (All G 1.4%; ≥G3 1.0%), and colitis (All G 1.4%; ≥G3 0.5%). Serious AEs were reported in 28.1% of pts, with 24.6% ≥G3. One patient with SLL had a fatal myocardial infarction (unrelated to umbralisib); there were no other G5 AEs. A total of 31 pts (14.9%) discontinued due a treatment-related adverse event (AE). Treatment-related AEs leading to dose reductions occurred in 20 (9.6%) pts. Conclusions: In the Phase 2 UNITY-NHL study, umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Figure Disclosures Zinzani: Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Sandoz-Novartis: Consultancy; Afimed: Research Funding; Acerta: Consultancy, Research Funding; Pharmacyclics: Research Funding; Bayer: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics, Inc.: Research Funding; Celgene: Research Funding; Servier: Research Funding; Takeda: Research Funding; Roche: Research Funding; Merck: Research Funding; MEI Pharma: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency,: Consultancy; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Epizyme: Consultancy; Gilead Sciences: Research Funding; MorphoSys: Research Funding; Nordic Nanovector: Research Funding. Ghosh:Kite/Gilead: Consultancy, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding; Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol-Myers Squibb: Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau. Derenzini:TG Therapeutics, Inc.: Research Funding. Cheah:Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria; Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding. Phillips:Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: travel expenses; Cardinal Health: Consultancy; Bayer: Consultancy, Research Funding; Pharmacyclics: Consultancy. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Cheson:Abbvie: Consultancy, Research Funding; Kite: Consultancy; TG Therapeutics: Speakers Bureau; Morphosys: Consultancy; Symbio: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Research Funding; Jannsen: Consultancy; Parexel: Consultancy; Trillium: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Caimi:Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding. Leslie:BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chavez:Karyopharm: Consultancy; BeiGene: Speakers Bureau; Bayer: Consultancy; Merck: Research Funding; AbbVie: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Celgene: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Consultancy; Pfizer: Consultancy. Fonseca:Bristol-Myers Squibb Company: Speakers Bureau. Babu:Merck: Research Funding; Syndax: Research Funding; AbbVie: Research Funding; Janssen Oncology: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Lutheran Hospital: Other; Argenx: Consultancy, Research Funding; Nektar: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; AstraZeneca/MedImmune: Research Funding; AstraZeneca: Consultancy, Honoraria; Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Boehringer Ingelheim: Consultancy. Hodson:Gilead Sciences: Research Funding. Burke:Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Morphosys: Consultancy; Adaptive: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Roche: Consultancy. Sharman:TG Therapeutics: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. O'Connor:Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Servier: Consultancy; Mundipharma: Other: Consulting; Nomocan: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding. Miskin:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Weiss:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Vannucchi, Alessandro M., Heinz Gisslinger, Claire N. Harrison, Haifa Kathrin Al-Ali, Ester Pungolino, Jean-Jacques Kiladjian, Francoise Boyer-Perrard i in. "EXPAND: A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis (MF) and Low Platelet Counts (50 × 109/L to 99 × 109/L) at Baseline". Blood 126, nr 23 (3.12.2015): 2817. http://dx.doi.org/10.1182/blood.v126.23.2817.2817.
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Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated superiority over standard therapies in the treatment of MF. In the phase 3 COMFORT studies, patients (pts) receiving RUX had improvements in splenomegaly and symptoms as well as longer survival compared with pts in the control arms. Study 258 extended these findings to pts with a platelet (PLT) count of 50 to ˂ 100 × 109/L (pts excluded from the COMFORT studies) and showed that starting at 5 mg bid with dose escalation to ≥ 10 mg bid offered similar benefits (Talpaz 2013). EXPAND aims to evaluate the safety of RUX and establish a maximum safe starting dose (MSSD) in pts with low PLTs. METHODS: EXPAND is a phase 1b, dose-finding study (NCT01317875) in pts with MF and baseline PLTs 50 to 99 × 109/L. The study has 2 phases: dose escalation and safety expansion. In the dose-escalation phase, RUX doses were 5 mg bid, 5 mg AM/10 mg PM, 10 mg bid, 10 mg AM/15 mg PM, and 15 mg bid. A Bayesian logistic regression model with overdose control was used to guide dose escalation; intra-pt dose modification was allowed up to the MSSD in each stratum. Pts were assigned to 2 strata based on their baseline PLTs: S1, 75 to 99 × 109/L; S2, 50 to 74 × 109/L; doses in S2 were open if that dose and the next were deemed safe in S1. At data cutoff (20 Jan 2015), enrollment was ongoing in the safety expansion phase at the MSSDs; this interim analysis was preplanned for when the last patient enrolled in the dose escalation phase completed the core study (day 168). RESULTS: 46 pts (S1, n = 27; S2, n = 19) received RUX; 12 pts were treated at each of the MSSDs for S1 (15 mg bid) and S2 (10 mg bid). Baseline pt characteristics were generally balanced across strata in all pts: 65% were aged ≥ 65 y, 48% were male, 74% had PMF (20% PPV-MF, 7% PET-MF), and 54% had high-risk MF. Median (range) baseline spleen length was 16 (5-30) and 12 (4-33) cm in S1 and S2, and median (range) hemoglobin was 104.7 (83-138) g/L in S1 and 100.0 (58-133) g/L in S2. Overall, 10 (37%) and 11 (58%) pts were still receiving treatment in S1 and S2. The primary reason for discontinuation was AEs (S1, 22%; S2, 21%). At the MSSDs, 1 pt (8.3%) in each group ended treatment due to AEs; 67% and 75% of pts at MSSDs in S1 and S2 were still on treatment at data cutoff. There were no DLTs in S1 and 1 DLT in S2 at 10 mg bid (grade 4 thrombocytopenia). AEs were consistent with the known safety profile of RUX. At the MSSDs, thrombocytopenia was the most common reason for dose modifications (S1, n = 8; S2, n = 8) but led to discontinuation for only 1 pt (S2). Deaths during the study included 1 cardiac arrest (S1), 1 sudden death (S1), 1 multi-organ failure (S2), and 1 transformation to AML (S2; ˃ 30 days after discontinuation), none of which were assessed as related to study drug. The most common AEs overall (S1, S2) were thrombocytopenia (all grade: 82%, 79%; grade 3/4: 63%, 79%) and anemia (all grade: 56%, 37%; grade 3/4: 33%, 26%). Other common AEs (> 30% in either stratum) included diarrhea (33%) in S1, and cough (42%), nasopharyngitis (32%), and diarrhea (32%) in S2. At the MSSDs, the most frequent AE was also thrombocytopenia (Table). A ≥ 50% reduction in spleen length (spleen response) was achieved at week 24 in 41% of pts (7/17) in S1 and 30% of pts (3/10) in S2; 50% (13/26) in S1 and 68% (13/19) in S2 achieved a response at any time (Figure). At the MSSDs, 37.5% (3/8) and 40% (2/5) of pts in S1 and S2 achieved a spleen response at week 24; 50% (6/12) and 67% (8/12) of pts achieved a response at any time. CONCLUSIONS: RUX was tolerated at starting doses of up to 10 or 15 mg bid in pts with MF and low PLTs (PLTs 50 to 74 × 109/L and 75 to 99 × 109/L). AEs were consistent with the known safety profile of RUX with no new or unexpected adverse findings. Spleen length reductions were observed across all dose levels, including the MSSDs, and are similar to those observed in pts without low PLTs. The study is currently open for enrollment and aims to evaluate the benefit vs risk of RUX further in this subgroup of pts, with emphasis on optimal dosing and long-term safety. Disclosures Vannucchi: Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy. Harrison:Sanofi: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Shire: Speakers Bureau. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy; Incyte Corporation: Consultancy. Nicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mo:Novartis Pharmaceuticals Corporation: Employment. Atienza:Novartis Pharmaceuticals Corporation: Employment. Gopalakrishna:Novartis Pharma AG: Employment. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy.
42
Santagostino, Elena, Kathelijn Fischer, Christoph Koenigs, Claudia Djambas Khayat, Samantha Lucas, Blanca Salazar, Andres Brainsky, Thomas Chung, Brahm Goldstein i Johnny Mahlangu. "Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)". Blood 134, Supplement_1 (13.11.2019): 162. http://dx.doi.org/10.1182/blood-2019-123981.
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Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII <1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of <0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer <5 BU/mL). Seven of 11 inhibitor negative subjects achieved >50 EDs, 1 achieved 47 EDs, and 3 achieved <20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.
43
Lonial, Sagar, Stefano R. Tarantolo, Ralph V. Boccia, Habte Yimer, Moshe Y. Levy, Rafat Abonour, Meera Mohan i in. "Phase 1b/2 Study of the First-in-Class SUMO-Activating Enzyme Inhibitor TAK-981 in Combination with Monoclonal Antibodies in Patients with Triple-Class Refractory Multiple Myeloma". Blood 138, Supplement 1 (5.11.2021): 2742. http://dx.doi.org/10.1182/blood-2021-148385.
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Abstract Background: SUMOylation, a post-translational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in the immune system by regulating type I interferon (IFN-I) expression, thereby functioning to constrain the innate immune response (Decque Nat Immunol 2016), and limit tumor immune surveillance. The SUMOylation pathway is often overexpressed in multiple myeloma (MM) and is associated with poor outcomes (Driscoll Blood 2010). TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme, which blocks the SUMOylation cascade (Langston J Med Chem 2021) and increases IFN-I production and signaling in innate immune cells (Nakamura AACR 2019). In ex vivo assays, TAK-981 activated the IFN-I pathway, increased phagocytic activity of monocyte-derived macrophages, and increased natural killer (NK) cell cytotoxicity via IFN-I signaling (Nakamura AACR 2019). The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1). Patients with MM who have disease refractory to the three most effective classes of anti-myeloma therapies (proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], and anti-CD38 mAbs) have a poor prognosis, with median survival 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complex mechanisms of resistance, continued efforts to better understand MM biology at the time of relapse and to translate this into effective treatment combinations are needed. Combination therapies that engage the immune system to treat MM may offer substantial clinical benefit. Methods: To be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018), patients must have failed at least 3 prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to ≥1 PI and ≥1 IMiD, and refractory to ≥1 anti-CD38 mAb), and have demonstrated disease progression on their last therapy. Prior CAR-T therapy is allowed. Patients will be assigned to TAK-981 plus subcutaneous (SC) meza (Phase 1 Part 1) or SC dara (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary objectives of Phase 1b are to determine safety and tolerability, and to select the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary objectives are to evaluate preliminary antitumor activity, to characterize TAK-981 pharmacokinetics (PK), and to explore pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. Approximately 30 patients will participate in the Phase 1b Part 1 dose escalation of TAK-981 plus meza (~15 patients per dosing schedule), and ~15 patients will participate in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The primary objective of Phase 2 is to evaluate the efficacy of TAK-981 at the RP2D in combination with an anti-CD38 mAb; ~36 patients will be enrolled. In Phase 1b, patients will receive TAK-981 via a 1-hour intravenous infusion either on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or on days, 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. Meza 600 mg SC or dara 1800 mg SC will be given 8x weekly, 8x every other week, then monthly, in a 28-day cycle (Figure 2). Treatment will continue until disease progression or unacceptable toxicity (max. 24 cycles). TAK-981 dose escalation will proceed from 60 mg BIW, a dose shown to be pharmacologically active in a first-in-human, single-agent TAK-981 study (TAK-981-1002; data on file). Dose escalation will be guided by Bayesian Optimal Internal Design with Informative Prior (iBOIN) plus consideration of other safety, clinical, PK, and PD data. The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021. Figure 1 Figure 1. Disclosures Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria. Boccia: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Morphosis: Honoraria, Speakers Bureau. Yimer: Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Levy: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau. Abonour: Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding. Mohan: Medical College of Wisconsin: Current Employment. Girnius: BMS: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Genentech: Honoraria; GSK: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Speakers Bureau. Rosenbaum: Takeda: Honoraria; Akcea: Honoraria; Janssen: Honoraria. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Zhang: Takeda: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Novartis: Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. OffLabel Disclosure: Study of the investigational agent TAK-981 in combination with daratumumab and hyaluronidase-fihj or the investigational agent mezagitamab (TAK-079).
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Chiaretti, Sabina, Renato Bassan, Antonella Vitale, Loredana Elia, Alfonso Piciocchi, Cristina Puzzolo, Martina Canichella i in. "Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial". Blood 134, Supplement_1 (13.11.2019): 740. http://dx.doi.org/10.1182/blood-2019-128759.
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Background. The management of adult patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL), including the elderly, has changed since the introduction of tyrosine kinase inhibitors (TKI). A significantly better survival is observed in patients who become minimal residual disease (MRD)-negative. Aims. To increase the rate of MRD-negative patients, we designed a front-line chemo-free induction-consolidation trial (D-ALBA, GIMEMA LAL2116) based on the combination of the second-generation TKI dasatinib with the bispecific monoclonal antibody blinatumomab. The primary endpoint of the study was the rate of patients who achieved a complete molecular remission (CMR) or a positive non-quantifiable (PNQ) disease after at least two cycles of blinatumomab. Secondary endpoints included disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR) and safety. We also sought to evaluate the prognostic impact of additional genomic lesions - performed on diagnostic samples - and the potential changes in the immunologic compartment, in terms of T cells and T-regulatory cells (Tregs), evaluated by flow cytometry (CD3+/CD4+, CD3+/CD8+ and CD3+/CD4+/CD25+/FOXp3+, respectively). Methods. This multicenter phase II study enrolled Ph+ ALL patients aged 18 years or older, with no upper age limit. Prior to dasatinib, patients received a 7-day steroids pre-phase: steroids were continued for further 24 days and stopped at day 31. Dasatinib (140 mg/day) was administered as induction for 85 days. Thereafter, patients who obtained a complete hematologic response (CHR) received a post-induction consolidation treatment with blinatumomab at a flat dose of 28 μg/day. A minimum of 2 cycles was mandatory, while the administration of up to 3 additional cycles was allowed based on the response to blinatumomab and medical decision. Dasatinib was continued during treatment with blinatumomab. CNS prophylaxis was carried out during the whole treatment. Post-consolidation treatment was open. Results. Between May 2017 and January 2019, 63 patients have been enrolled. Median age was 54.5 years (range: 24.1-81.7), 54% were female, the median white blood cell count (WBC) was 42 x109/l (range: 0.63-63.5) and 65.1% carried the p190 fusion. Copy number aberration analysis showed that the most frequent lesion was, as expected, IKZF1 deletion (54%): 23.9% of patients were thus classified as IKZF1plus (i.e. IKZF1 and/or PAX5 and/or CDKN2A/B deletions). The median follow-up is 10 months (range: 0.9-21.5). So far, 61 patients have completed induction, 55 the 1st cycle of blinatumomab, 47 the 2nd cycle, 33 the 3rd, 26 the 4th and 17 the 5th. Two patients have gone off protocol for medical decision and toxicity, and 1 died during induction. At the end of the induction with dasatonib, 17/58 pts (29.3%) had a molecular response (6 CMR and 11 PNQ). At the primary endpoint (end of the 2nd cycle of blinatumomab), 27/47 (56.3%) had a molecular response (17 CMR and 10 PNQ). The rates of molecular responses further increased after subsequent cycles of blinatumomab: 65.7% after the 3rd cycle and 80% after the 4th cycle. ABL1 mutational analysis was carried out in 15 patients with evidence of a MRD increase: 8 cases were WT, while mutations were detected in 7 (6 T315I, and 1 E255K). All mutations but 1 occurred prior to the start of blinatumomab and all were "cleared" by blinatumomab. The analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (19.8% before the start of blinatumomab and 29% after the 5th cycle, p=0.04) and a significant reduction in the rate of Tregs (11% before blinatumomab and 3.7% after the 5th cycle, p=0.02). Overall, 5 relapses have been recorded (2 hematologic, 2 isolated CNS and 1 nodal). The 12-month OS and DFS are 94.2% and 87.8%. A significantly inferior DFS (61.4%, p=0.01) was observed in IKZF1plus cases: these patients were prone to develop deleterious mutations. So far, 12 patients have been allografted and no transplant-related mortality has been recorded. Conclusions. In the first chemo-free induction-consolidation protocol for adult Ph+ ALL patients of all ages based on a combination of a targeted and immunotherapeutic strategy, the rates of molecular responses and survival are highly promising; patients harboring IKZF1 plus represent, also in this setting, a clinical challenge. Disclosures Chiaretti: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Bassan:Amgen Inc.: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Bonifacio:BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Vignetti:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training. Rambaldi:Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.
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Ducore, Jonathan M., Shadan Lalezari, Elena Santagostino, Sanjay P. Ahuja, Monika Maas Enriquez, Claudia Tueckmantel i Mark Reding. "Improvement in Quality of Life Outcomes and Bleeding Rates among Patients Switching from On-demand FVIII to Prophylactic BAY 94-9027 in the PROTECT VIII Study". Blood 134, Supplement_1 (13.11.2019): 1129. http://dx.doi.org/10.1182/blood-2019-123947.
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Background: BAY 94‐9027 is a B-domain deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60 kDa (2×30 kDa) polyethylene glycol to extend its half-life. Efficacy and safety of BAY 94-9027 as prophylactic (PPX) and on-demand (OD) therapy for patients with severe hemophilia A (HemA) were demonstrated in the phase II/III PROTECT VIII trial (NCT01580293) and its Extension. BAY 94-9027 has been approved in the US, EU, Japan and Canada for previously treated patients ≥12 years old. Extended dosing (e.g. once-weekly PPX) is an attractive therapeutic approach for patients previously treated OD. This post hoc analysis was conducted to confirm the anticipated bleeding and quality of life (QoL) outcomes among patients who were previously treated with OD FVIII and switched to BAY 94-9027 PPX in PROTECT VIII. Patients/Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with HemA (FVIII <1%) and ≥150 FVIII exposure days. At enrolment, prior OD patients could select PPX or continue OD therapy. PPX patients received BAY 94-9027 25 IU/kg twice weekly (2×W) for a 10-week run-in period. Patients with ≤1 spontaneous joint or muscle bleeds during this period were randomized to 45‒60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period. Patients enrolling after the randomization arms were full, or with ≥2 bleeds in the run-in period, received 30-40 IU/kg 2×W. Patients completing the main study could enter an extension and continue, or switch regimens. Patients switching after Extension start were evaluated as a 'variable' group (VAR). The primary efficacy outcome was annualized bleeding rate (ABR). QoL was assessed using the hemophilia-specific health-related quality of life questionnaire for adults (Hemo-QoL-A) and the Work Productivity and Activity Impairment (WPAI) questionnaire. All analyses were descriptive and reported outcomes by pre-study treatment regimen. Results: Of 43 patients on prior OD therapy, 20 selected OD BAY 94-9027 [OD→OD] and 23 selected PPX BAY 94-9027 [OD→PPX] in the main PROTECT study. Of 39 patients on prior OD therapy who continued into the Extension, 14 continued OD, and 25 switched to PPX [OD→PPX], including 3 patients who switched from OD at the Extension start. A total of 89 patients on prior PPX therapy received PPX during the main study [PPX→PPX] and 82 continued to receive PPX during the Extension. At data cut-off (Feb 2017), median time in the study was 3.9 years (3.2 years in the Extension). See Table for baseline characteristics. At the end of the main study, median ABR was 23.4, 2.1, and 2.1 in the OD→OD, OD→PPX and PPX→PPX groups, respectively. During the Extension, median ABR was 33.5, 1.3 and 1.6 in the OD→OD, OD→PPX and PPX→PPX groups, respectively. Robust improvements in median ABR were observed for patients previously on OD treatment in both the main study and Extension, irrespective of which PPX regimen they received (Figure). Hemo-QoL-A total score was maintained or improved from baseline during the main study all PPX regimens with greater benefit among OD→PPX (median change from baseline: 2.5 for all PPX and 4.3 for OD→PPX), and greatest improvement in OD→E7D PPX (median change from baseline: 13.8; almost twice the minimal clinically important difference [7-8]). OD patients prior to study entry also saw higher benefit in WPAI activity and work impairment sub-scores compared with prior PPX patients (mean changes from baseline: -15.9 vs -4.9 and -16.4 vs -1.7, respectively). As of August 2018, E7D PPX had a similar number of infusions per year to OD treatment (52 vs 47) and double median consumption (3048 vs 1394 IU/kg/year for E7D and OD, respectively). Conclusions: Despite entering PROTECT VIII with higher ABR than PPX→PPX patients, OD→PPX patients experienced a major decrease in ABR with BAY 94-9027 treatment during the first 6 months, achieving a similar rate to that observed in patients who received PPX before the trial. OD→PPX patients experienced larger improvements in QoL and WPAI sub-scores from baseline compared with PPX→PPX patients. Prior OD patients who switched to BAY 94‐9027 E7D had the greatest improvement in QoL. Further, the number of infusions/year was only slightly higher with E7D dosing than with OD treatment, and the difference in median consumption between PPX and OD was smaller than seen in previous studies. Disclosures Ducore: BioMarin: Research Funding; HEMA Biologics: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Research Funding; Spark Therapeutics: Research Funding; Bayer: Consultancy, Honoraria, Other: speaker (not bureau). Lalezari:Bayer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Teva: Consultancy, Honoraria; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Santagostino:CSL Behring: Speakers Bureau; Bayer: Speakers Bureau; Grifols: Speakers Bureau; Bioverativ Sanofi: Speakers Bureau; Kedrion: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma: Speakers Bureau; Pfizer: Speakers Bureau; Shire/Takeda: Speakers Bureau; Sobi: Speakers Bureau; UniQure: Speakers Bureau; Roche: Speakers Bureau; Spark: Speakers Bureau. Ahuja:XaTexk Inc.: Consultancy, Patents & Royalties, Research Funding; Rainbow Children's Foundation: Research Funding; Genentech: Consultancy; Biovertiv Sanofi: Consultancy; Bayer: Consultancy. Maas Enriquez:Bayer AG: Employment. Tueckmantel:Bayer: Employment. Reding:Takeda: Consultancy, Honoraria, Speakers Bureau; Biomarin: Research Funding; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau.
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Jimenez-Yuste, Victor, Midori Shima, Katsuyuki Fukutake, Michaela Lehle, Sammy Chebon, Sylvie Retout, Agnès Portron i Gallia G. Levy. "Emicizumab Subcutaneous Dosing Every 4 Weeks for the Management of Hemophilia A: Preliminary Data from the Pharmacokinetic Run-in Cohort of a Multicenter, Open-Label, Phase 3 Study (HAVEN 4)". Blood 130, Suppl_1 (7.12.2017): 86. http://dx.doi.org/10.1182/blood.v130.suppl_1.86.86.
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Abstract Introduction Emicizumab is a novel, subcutaneously (SC) administered, recombinant, humanized, bispecific monoclonal antibody that is under investigation for the prevention of bleeds in persons with hemophilia A (PwHA). Emicizumab restores the function of activated coagulation FVIII, which is deficient in PwHA, by bridging activated FIX and FX to enable effective hemostasis. Due to its mechanism of action, emicizumab is not expected to induce or be affected by anti-FVIII antibodies (inhibitors) and is thus being assessed in PwHA both with and without inhibitors. Once-weekly emicizumab prophylaxis was shown to substantially reduce bleed rates by 87% in PwHA with inhibitors compared with no prophylaxis in the Phase 3 HAVEN 1 study (Oldenburg et al. NEJM 2017; July 10: epub). An interim analysis of the HAVEN 2 study showed that once-weekly emicizumab also prevented or reduced bleeds in pediatric PwHA with inhibitors (<12 years of age) (Young et al. RPTH 2017;1 (S2): Abstract OC 24.1). The ongoing HAVEN 3 study (NCT02847637) will assess emicizumab prophylaxis in PwHA without inhibitors. The ongoing multicenter, open-label, Phase 3 HAVEN 4 study (NCT03020160) is assessing emicizumab administered every 4 weeks (Q4W) to PwHA with and without inhibitors; the study consists of a pharmacokinetic (PK) run-in phase followed by an expansion phase. The objective of the PK run-in phase of HAVEN 4 reported here was to investigate the PK and preliminary efficacy and safety outcomes of an emicizumab dose that was previously not assessed in a phase 1 study. Methods Eligible patients in the HAVEN 4 study were aged ≥12 years with congenital hemophilia A with or without inhibitors. In the PK run-in phase, patients must have been receiving episodic (on-demand) treatment with FVIII replacement therapy or bypassing agents with documentation of treatment for ≥24 weeks prior to study entry; the on-study regimen is 6 mg/kg Q4W. The regimen being investigated in the subsequent expansion cohort includes a loading dose of 3 mg/kg SC QW for 4 weeks followed by emicizumab 6 mg/kg Q4W for ≥24 weeks. Results At the data cutoff of April 10, 2017, 7 patients with severe hemophilia A had enrolled into the PK run-in cohort - 4 patients without inhibitors and 3 patients with inhibitors, of which 6 patients were aged ≥18 years of age and followed for a minimum of 6 weeks. Individual observed PK profiles were within the 95% prediction interval computed from a population PK model based on clinical data from a 1.5 mg/kg QW regimen (Figure). Emicizumab PK parameters derived after single SC administration of 6 mg/kg emicizumab (Table) were consistent with values observed in previous studies with emicizumab (Uchida et al. Blood 2016; 127 (13):1633-1641). During the observation period (median, 8 weeks), 14 adverse events (AEs) were reported in 5 patients at the time of data cut-off, including 1 Grade 3 serious AE (worsening of hypertension); no AEs were considered related to study drug. No anti-drug antibodies were detected. Also, 6 of 7 patients had no bleeds while receiving Q4W emicizumab; 1 patient experienced 3 spontaneous nose bleeds on Study Days 12, 14 and 21, which did not require treatment. Conclusions Preliminary data from the HAVEN 4 study showed that Q4W dosing of emicizumab at 6 mg/kg exhibited a PK behavior that was consistent with prior predictions, leading to an expected steady-state concentration average similar to the clinically confirmed dosing regimen (i.e., 1.5 mg/kg/QW). The safety and efficacy results from this PK run-in cohort enabled the opening of the HAVEN 4 expansion cohort, and provided promising support for a Q4W emicizumab prophylaxis regimen for the management of hemophilia A. The HAVEN 4 study is fully enrolled (N=48, including the PK run-in cohort patients). Disclosures Jimenez-Yuste: Roche: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding. Shima: Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Fukutake: EPS: Research Funding; Cimic: Research Funding; Sekisui Medical: Consultancy, Honoraria, Speakers Bureau; Roche Diagnostics: Honoraria, Speakers Bureau; Bioverative: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbott: Honoraria, Speakers Bureau; Kaketsuken: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Pharmaceutical Co., Ltd: Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LSI Medience: Consultancy; SRL Inc: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding; Chuugai: Consultancy, Honoraria, Speakers Bureau; Octapharma AG: Honoraria; Torii Pharmaceutical Co., Ltd: Speakers Bureau. Lehle: F. Hoffmann La Roche: Employment. Chebon: F. Hoffmann-La Roche Ltd: Employment. Retout: F. Hoffmann La Roche: Employment. Portron: F. Hoffmann La Roche: Employment. Levy: Genentech, Inc.: Employment.
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Mackensen, Andreas, Linda Hanssens, Matthias Stelljes, Wolfgang A. Bethge, Tobias Feuchtinger, Annette Künkele, Michael Aigner i in. "A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts". Blood 138, Supplement 1 (5.11.2021): 3836. http://dx.doi.org/10.1182/blood-2021-152452.
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Abstract Introduction This phase I first-in-human clinical study assesses the safety and preliminary efficacy of a CD19-directed, CAR (4-1BBz) gene-modified, autologous T-cell immunotherapy (MB-CART19.1) intended for use in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL). The study also evaluates the feasibility of a hybrid manufacturing model, combining central and academic manufacturing capabilities with central QP oversight. Methods MB-CART19.1 is evaluated in a Phase I (EudraCT 2017-002848-32) multi-center, open label, dose escalation trial enrolling 33 to 48 patients in three disease cohorts, defined by disease biology and age. Pediatric (1-17 years) and adult patients are eligible if diagnosed with relapsed/refractory (r/r) CD19-expressing B-cell ALL or B-cell high-grade and low-grade (adults) NHL, including chronic lymphocytic leukemia (CLL). Enrollment is still ongoing. The starting material, a fresh patient leukapheresis product, is enriched for CD4/CD8 T-cells, transduced with a lentiviral vector (LV) and expanded using the CliniMACS Prodigy System allowing a high degree of control and consistency of the manufacturing process in both a central and decentralized facilities. MB-CART19.1 is presented as fresh cellular dispersion for single infusion and undergoes central release. Subjects undergo lymphodepletion with fludarabine (25 mg/m 2 daily for 3 days) and cyclophosphamide (1000 mg/m 2 on day -3). Dose escalation includes 3 dose levels (DL) 5x10 5 (DL I), 1x10 6 (DL II), 3x10 6 (DL III) CAR T cells/kg BW, respectively, and a safety dose level 0. The primary objective is to determine the recommended dose of MB-CART19.1. Secondary objectives are preliminary efficacy parameters evaluation of as well as CART persistence. Results Disease cohort I: pediatric ALL and aggressive NHL, 1-17 years. Up to the data lock point for interim analysis (DLP, 02 June 2021), 9 pediatric ALL patients were treated, 6 at DL I and 3 at DL II. All 9 patients completed the 28 days safety follow-up. At DL I, 5 of 6 patients experienced CRS (4 grade I-II, 1 grade III,) starting 5 to 7 days after IMP infusion. Two CRS cases were managed with tocilizumab and resolved within 1-2 weeks. 1 patient developed signs of neurotoxicity (grade IV seizure) concurrently with grade II CRS, which was effectively managed and fully resolved within 48 hours. The event was evaluated as DLT and led to the extension of the dose group from 3 to 6 patients. No further neurotoxicities occurred. Four of 6 patients treated at DL I finished the active part of the trial (12 months after administration of IMP) in CR-MRD and entered the long term follow-up. Two patients had CD19-negative relapses 4 and 10 months post MB-CART19.1 infusion. At DL II, 1 patient completed the 6 months follow up in ongoing CR, and 2 patients relapsed. Disease cohort II adult ALL: Up to the DLP, 4 adult ALL patients were treated at DL I. 1 patient died due to progression of disease on day 20 after the IMP infusion. All 4 adult patients experienced a grade I or II CRS all cases were reversible within 1-2 weeks , 1 patient received tocilizumab One patient developed neurologic symptoms (grade III visual impairment and grade III muscle weakness right-sided) with onset 41 and 72 days after administration of MB-CART19.1, respectively. 2 of the 3 patients who completed the safety follow-up finished the active part of the trial and entered the long-term follow-up, both in molecular CR up to Month 6. Disease cohort III adult NHL/CLL: 4 patients were enrolled with the starting dose of 1x10 6 CAR+ cells/kg (DL II). 1 patient experienced grade III CRS and was treated with tocilizumab. 3 patients completed the 28 days safety follow up. One patient with CLL achieved a CR, which is maintained at 6 months. Another CLL patient was in PR at the assessment visit Day 28. Data from the 2 other patients, 1 with MCL and 1 with DLBCL were in PR at month 3. Later data is not yet available. Conclusions 18 of 19 patients completed the follow-up safety period of 28 days defined as observation period for dose limiting toxicity (DLT). One DLT was observed as well as 3 grade III CRS events and 1 grade III neurological event. Early efficacy results are very encouraging. Longer follow-up will establish whether treatment results in durable responses. The hybrid manufacturing model provides flexibility and a timely delivery of the fresh drug product to the patients Disclosures Hanssens: Miltenyi Biomedicine GmbH: Current Employment. Stelljes: MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Yakushina: Miltenyi Biomedicine GmbH: Current Employment. Holtkamp: Miltenyi Biomedicine GmbH: Current Employment. Assenmacher: Miltenyi Biotec: Current Employment. Jurk: Miltenyi Biotec: Current Employment. Rauser: Miltenyi Biomedicine GmbH: Current Employment. Schneider: Employee of Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Rossig: AdBoards by Amgen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS and Celgene: Honoraria.
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Zinzani, Pier Luigi, Vincent Delwail, Shankara Paneesha, Simon Rule, Alejandro Martin Garcia-Sancho, Ana Marin-Niebla, Gilles Salles i in. "Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)". Blood 136, Supplement 1 (5.11.2020): 43–44. http://dx.doi.org/10.1182/blood-2020-134609.
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Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). Bruton's tyrosine kinase (BTK) inhibitors, eg ibrutinib, are indicated for treatment of adults with MCL who have received ≥1 prior therapy. Primary and acquired resistance to ibrutinib is common and linked with poor outcomes, and remains an unmet medical need. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for parsaclisib monotherapy in a cohort of pts with R/R MCL who were previously treated with ibrutinib in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R disease to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments (including ibrutinib). Prior treatment with PI3Ki was prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 47 pts were treated (WG, n = 12; DG, n = 35). Enrollment is ongoing. At cut-off, 70% of pts had discontinued treatment, most commonly due to progressive disease (62%). Median exposure (range) was 2.2 (0.1-18.0) months. Median age was 70 years and 79% of pts were men. Median time since initial diagnosis was 4.7 years. Most pts (85%) had ECOG PS ≤1 and 51% had high-risk MCL International Prognostic Index. The median number of prior systemic therapies was 3; 38% of pts had prior hematopoietic stem cell transplant, and 38% were refractory to most recent systemic therapy. At data cut-off, 46 pts were evaluable for efficacy, including 12 in WG and 34 in DG (Table). Median follow-up (range) for this population was 10.2 months (1.5-25.9) overall and 7.6 months (1.5-25.9) for DG. ORR (95% confidence interval [CI]) and CRR were 28.3% (16.0-43.5) and 2.2%, respectively in all evaluable pts, and 35.3% (19.7-53.5) and 2.9%, respectively in DG. Median time to complete or partial response was 7.6 weeks. Median DOR (95% CI) was 7.3 months (0.2-not estimable) among all responders and 3.7 months (0.2-7.3) for DG. Median PFS (95% CI) was 3.65 months (1.9-3.9) overall and 3.65 months (1.9-5.5) for DG. Among 47 safety-evaluable pts, most common treatment-emergent adverse events (TEAEs) occurring in >10% of pts were anemia (19.1%), diarrhea (19.1%), neutropenia (14.9%), asthenia and cough (12.8% each), decreased appetite, dyspnea, fatigue, pyrexia and rash (10.6% each). Most common grade ≥3 TEAEs reported in ≥5% of pts included anemia (12.8%), neutropenia (10.6%), thrombocytopenia and rash (6.4% each). TEAEs leading to dose interruption or reduction occurred in 31.9% and 2.1% of pts, respectively. TEAEs leading to treatment discontinuation occurred in 2 (4.3%) pts (diarrhea and colitis). Serious TEAEs reported in ≥2 pts were diarrhea, dyspnea, peripheral swelling and pneumonia (4.3% each). Two pts experienced fatal TEAEs (one pt had general physical health deterioration and respiratory tract infection, deemed not related to treatment; one pt had pneumonia, neutropenia, and septic shock, deemed related to treatment and disease progression). New or worsening grade ≥3 laboratory test values of clinical interest occurring in ≥5% of pts included decreased neutrophils (14.9%), platelets (10.6%), and hemoglobin (8.5%); there were no grade ≥3 increases in alanine/aspartate aminotransferase. Conclusion: Preliminary efficacy data indicate that parsaclisib monotherapy is clinically active in this difficult-to-treat patient population. Treatment with parsaclisib had an acceptable safety profile and was generally well tolerated. Updated study results will be presented. Disclosures Zinzani: EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eusapharma: Consultancy, Speakers Bureau. Delwail:Amgen: Consultancy. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Rule:AstraZeneca: Consultancy; Celgene: Consultancy; Celltrion: Consultancy; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; Roche Pharma AG: Consultancy, Research Funding. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. Salles:Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Servier: Consultancy, Honoraria; Acerta Pharma: Consultancy; Kite Pharma: Consultancy; Merck: Consultancy, Research Funding; Novimmune: Consultancy; Pfizer: Consultancy; Sanofi: Other. Sancho:Sandoz: Consultancy; Celltrion: Consultancy; Roche: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Kern-Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mehta:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gelgene/BMS: Research Funding; Affimed: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding; Juno Parmaceuticals/BMS: Research Funding; Innate Pharmaceuticals: Research Funding; Oncotartis: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding.
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Álvarez Roman, Teresa, Elena Monzón Manzano, Ihosvany Fernandez-Bello, Mónica Martín, María Isabel Rivas Pollmar, Raul Justo Sanz, Sara García Barcenilla i in. "Real Life Experience in Clinical Practice with Recombinant Coagulation FVIII-Fc Fusion Protein". Blood 134, Supplement_1 (13.11.2019): 4929. http://dx.doi.org/10.1182/blood-2019-127878.
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Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.
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Mehta, Amitkumar, Marek Trněný, Jan Walewski, Vincent Ribrag, Caroline Dartigeas, Jacob Haaber Christensen, Fabrizio Pane i in. "Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205)". Blood 136, Supplement 1 (5.11.2020): 22–23. http://dx.doi.org/10.1182/blood-2020-134872.
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Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). A number of therapies are used for second- and later-line treatment including Bruton's tyrosine kinase inhibitors (BTKi). However, treatment failure and intolerance are common and alternative therapies are needed. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor that demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for a cohort of BTK inhibitor-naïve pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments. Prior treatment with BTKi and PI3Ki were prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 104 pts were treated (WG, n = 31; DG, n = 73). Enrollment was ongoing (target:100 pts). At cut-off, a total of 50 (48%) pts had discontinued treatment, including 31 (30%) pts for disease progression. The median exposure (range) was 4.0 months (0.1-19.1). The median age was 72 years and 80% of pts were men. The median time since initial diagnosis was 3.6 years. The majority of pts (92%) had ECOG PS ≤1, and 57% had high-risk MCL International Prognostic Index. The median number of previous systemic therapies was 1; 31% of pts had prior hematopoietic stem cell transplant, and 44% were refractory to their most recent systemic therapy. At the data cut-off, 92 pts were evaluable for efficacy including 31 in WG and 61 in DG (Table). The median follow-up duration (range) for this population was 11.8 months (1.9-24.0) overall and 9.1 (1.9-24.0) for DG. The ORR (95% confidence interval CI) and CRR were 66.3% (55.7-75.8) and 15.2%, respectively in all evaluable pts, and were 65.6% (52.3-77.3) and 11.5% for DG. The median time to response for pts with a complete or partial response was 7.9 weeks. The median DOR (95% CI) was 11.0 months (6.6-14.7) for all responders and 9.0 months (7.7-14.7) for DG. The median PFS (95% CI) was 11.1 (5.8-16.6) months overall, and 11.1 (5.6-16.6) months for DG. Among 104 safety-evaluable pts, most common treatment-emergent AEs (TEAEs) occurring in >10% of pts were diarrhea (25.0%), pyrexia (16.3%), constipation (11.5%), and neutropenia (10.6%). Most common grade ≥3 TEAEs reported in ≥5% of pts were neutropenia (8.7%) and diarrhea (7.7%). TEAEs leading to dose interruption or dose reduction occurred in 31.7% and 1.9% of pts, respectively. TEAEs leading to discontinuation occurred in 16.3% of pts including diarrhea (5.8%) and colitis (2.9%). Serious TEAEs reported in ≥2 pts included diarrhea (5.8%), colitis (2.9%), pyrexia (2.9%) and cytomegalovirus infection (1.9%). Four pts experienced fatal TEAEs. The fatal TEAEs in one pt (monocytic acute myeloid leukemia, leukocytosis, and acute kidney injury) were considered related to treatment. TEAEs of clinical interest included neutropenia (10.6%), rash (8.7%), colitis (4.8%), pneumonia (1.9%), PJP and pneumonitis (1% each). New or worsening grade ≥3 laboratory test values of clinical interest included decreased neutrophils (8.7%), platelets (7.7%), and hemoglobin (1.9%), and increases in alanine/aspartate aminotransferase (2.9%/1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safely profile and was generally well tolerated. These preliminary results suggest that parsaclisib represents a potentially new drug class and treatment option for BTKi-naïve, R/R MCL. Updated study results will be presented. Disclosures Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.