To see the other types of publications on this topic, follow the link: Directors label.
Journal articles on the topic 'Directors label'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Directors label.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Groves, Bruce W., and Roy H. Olsson. "Response Rates to Surveys with Self-Addressed, Stamped Envelopes versus a Self-Addressed Label." Psychological Reports 86, no. 3_suppl (June 2000): 1226–28. http://dx.doi.org/10.2466/pr0.2000.86.3c.1226.
Full textAbstract:
Return rates were studied for a survey on the perceived professional preparation of therapeutic recreation specialists by directors of college and university recreational therapy programs. Specifically, returns for surveys with self-addressed, stamped return envelopes enclosed were compared to those with self-adhering return address labels. Of the 75 surveys sent with a self-addressed, stamped return envelope, 42 responses (56%) were returned at a cost of $2.58 per respondent. Of the 72 surveys sent with a self-adhering return address label 43 responses (59.7%) were returned at a cost of $1.56 per response. While there was no significant difference in return rates, the self-adhering return address label was more cost effective than the self-addressed, stamped, return envelopes.
2
Groves, Bruce W., and Roy H. Olsson. "Response Rates to Surveys with Self-Addressed, Stamped Envelopes versus a Self-Addressed Label." Psychological Reports 86, no. 3_part_2 (June 2000): 1226–28. http://dx.doi.org/10.1177/003329410008600327.2.
Full textAbstract:
Return rates were studied for a survey on the perceived professional preparation of therapeutic recreation specialists by directors of college and university recreational therapy programs. Specifically, returns for surveys with self-addressed, stamped return envelopes enclosed were compared to those with self-adhering return address labels, Of the 75 surveys sent with a self-addressed, stamped return envelope, 42 responses (56%) were returned at a cost of $2.58 per respondent. Of the 72 surveys sent with a self-adhering return address label 43 responses (59.7%) were returned at a cost of $1,56 per response. While there was no significant difference in return rates, the self-adhering return address label was more cost effective than the self-addressed, stamped, return envelopes.
3
Gupta, Shveta, Joseph R. Stanek, and Sarah H. O'Brien. "Off-Label Utilization Trend for Recombinant Factor VIIa in Children's Hospitals in the United States." Blood 134, Supplement_1 (November 13, 2019): 2177. http://dx.doi.org/10.1182/blood-2019-126294.
Full textAbstract:
Background: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications. Along with uncertainty regarding clinical efficacy, available data suggests that the risk of thromboembolic events is increased when rFVIIa is used in off-label settings. Studies on the off-label use of rFVIIa in children are limited to a few large case series. In a retrospective multicenter cohort study utilizing the Pediatric Health Information System (PHIS) administrative database, Witmer et al demonstrated a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007. The mortality rate in the off-label group was 34% and thrombotic events occurred in 11% of the off-label admissions. We conducted a follow up study to characterize the evolution of the off-label use of rFVIIa in children. Objective: To describe current trends of off-label utilization and adverse effects of rFVIIa in children. Study design: A retrospective multicenter cohort study utilizing the PHIS administrative database was conducted. The PHIS dataset includes 51 children's hospitals in the United States and is representative of tertiary care centers in the nation. In patients, 18 years of age or younger who received rFVIIa between 2012-2018 were included. A label admission was defined as an admission with an International Classification of Diseases (ICD-9 and ICD-10) diagnostic code for hemophilia, Factor VII deficiency or Glanzmann thrombaesthenia; admissions without these codes were classified as off-label. Data were analyzed descriptively. Results: There were 7,738 number of admissions, representing 6,493 unique individual subjects. A total of 78.3 % of the admissions were off-label. The rate of off-label use was stable at approximately 80% of the admissions from 2012-18. The most frequent admitting services for the off-label admissions included cardiology (29.8%), cardiovascular/thoracic surgery (15.7%), critical care (15.0%), neonatal-perinatal medicine (8.7%), and hematology/oncology (6.1%). Over half (54.6%) of off-label administration occurred in children younger than 1 year old. Among the off-label admissions 57 % were male and the median days of use of rFVIIa was 1 day. The mortality rate in the off-label group was 22.3 %. Thrombotic events occurred in 11.4% of the off-label admissions. Among the off-label admissions with thrombotic events, the most common admitting services were cardiology (35.0%) and critical care (21.2%). Conclusion: We have demonstrated that on a per admission basis the predominant use of rFVIIa is off-label. Thrombotic events are common. Although the mortality rate in the pediatric patients who received off-label rFVIIa is high; its lower when compared with the previous review. This may likely reflect, in part, the severity of illness in this patient group. In the absence of clearly supportive data demonstrating safety and efficacy, restraint should be exercised with careful consideration of risk versus benefit for use of rFVIIa in off-label settings. Disclosures Gupta: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. O'Brien:Pfizer: 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, Research Funding. OffLabel Disclosure: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications.
4
Sonneveld, Pieter, Maria-Victoria Mateos, Adrián Alegre, Thierry Facon, Cyrille Hulin, Mahmoud Hashim, Talitha Vincken, Tobias Kampfenkel, Sarah Cote, and Philippe Moreau. "Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison." Blood 134, Supplement_1 (November 13, 2019): 4739. http://dx.doi.org/10.1182/blood-2019-122775.
Full textAbstract:
Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos: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; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.
5
Bussel, James B., Michael D. Tarantino, Victor S. Blanchette, Ashok Raj, Jenny Despotovic, Donald Beam, John Roy, Xuena Wang, Bhakti Mehta, and Melissa Eisen. "Safety and Efficacy of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)." Blood 128, no. 22 (December 2, 2016): 3738. http://dx.doi.org/10.1182/blood.v128.22.3738.3738.
Full textAbstract:
Abstract Background: Children with ITP for ≥6 months who completed a romiplostim phase 1/2 or phase 3 parent study could enroll in an open-label long-term extension study, data from which is presented here. Methods: Patients enrolled at 28 sites in the US, Canada, Spain, and Australia. All patients received SC romiplostim once weekly. The initial dose was the final dose from the parent study or 1 µg/kg for patients previously receiving placebo, adjusted from 1−10 µg/kg to target platelet counts of 50−200×109/L. Incidence of adverse events (AEs) was the primary endpoint. Results: As of 24 Feb 2016, 66 patients entered the extension study; 65 received romiplostim for up to 6.2 years. At baseline, median (min-max) age was 11 (3-18) years; 56% were female; 61% were white, 14% African American, 14% Hispanic/Latino, 9% Asian, and 3% other; 9.1% had prior splenectomy. Median (min-max) baseline platelet count was 27.5 (2-458)×109/L. Median (min-max) treatment duration was 100 (5-321) weeks. Median (min-max) average weekly romiplostim dose was 4.8 (0.1-10.0) µg/kg, which included escalation to a stable dose; 19 patients started on 1 μg/kg. After ~week 200 (n ≤8 patients), the median dose was observed to fluctuate. All 65 patients received their doses per protocol >90% of the time; 18 patients missed ≥1 dose due to noncompliance for a total of 41 times. Reasons for discontinuing treatment (n = 22, 33%) included consent withdrawn (n = 8), required other therapy (n = 4), noncompliance (n = 3), administrative decision (n = 3), treatment no longer needed (n = 1), per protocol (n = 1), and AE (n = 2) (asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other, per investigator, none of the AEs were treatment-related); 43 (65%) patients continued in the study. Fifty-two serious AEs occurred in 17 patients, 3 deemed treatment-related (anemia, epistaxis, and thrombocytopenia). Bleeding AEs occurred in 56 patients; 5 deemed treatment-related (gingival bleeding, petechiae, injection site bruising, injection site hematoma, and epistaxis). Bleeding AEs occurring in ≥10 patients included contusion (n = 30), epistaxis (n = 29), petechiae (n = 19), and gingival bleeding (n = 12). No thrombotic events were reported. There were no peripheral blood abnormalities to warrant a bone marrow examination. After sporadic platelet responses and negative antibody (Ab) results in the parent study, a patient left the extension due to a need for other therapies and was then identified to have anti-romiplostim neutralizing Ab which were not present on retesting 3 and 6 months later. No patients had anti-TPO neutralizing Ab. From week 2 on, median platelet counts remained >50×109/L; platelet counts were >100×109/L at most timepoints, despite an observed decrease in the median dose from 4-5 μg/kg to 2-3 μg/kg around week 160 (Figure). For 15 patients (23%), the first study week was the first week receiving romiplostim (previously these patients received placebo). Nearly all (94%, 61/65) patients had a platelet response (median platelet counts for a month ≥50×109/L); the mean (SD) % of months with a platelet response was 77% (33%). Most (72%, 47/65) patients had a platelet response ≥75% of the time and over half (58%, 38/65) of patients had a platelet response ≥90% of the time. Nine (14%) patients entered remission (Table), defined here as platelet counts ≥50×109/L for 24 weeks with no ITP treatments; these patients, 5 boys and 4 girls, none with prior splenectomy, had ITP for a median (min-max) of 5 (2-10) years and had received romiplostim for a median (min-max) of 1.6 (0.7-6.2) years. Fifty-eight (89%) patients (or caregivers) self-administered romiplostim. Twenty-three (35%) patients received rescue medications. Conclusion: Over 6 years of data from this ongoing open-label extension study of romiplostim in children with ITP show that >90% of children achieved a platelet response with romiplostim, most responding ≥75% of the time. The safety profile was overall tolerable, similar to that in past studies. Some children (9/66) with longstanding ITP entered remission after receiving romiplostim. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Bussel: Symphogen: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Speakers Bureau; Immunomedics: Research Funding; Cangene: Research Funding; UpToDate: Patents & Royalties; Boehringer Ingelheim: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; BiologicTx: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tarantino:Biogen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Blanchette:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data safety monitoring boards , Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data safety monitoring boards . Wang:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.
6
Bose, Prithviraj, David McCue, Nathan P. Wiederhold, Tapan M. Kadia, Gautam Borthakur, Farhad Ravandi, Musa Yilmaz, et al. "Isavuconazole (ISAV) As Primary Anti-Fungal Prophylaxis in Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-Label, Prospective Study." Blood 132, Supplement 1 (November 29, 2018): 2674. http://dx.doi.org/10.1182/blood-2018-99-111727.
Full textAbstract:
Abstract Introduction: Invasive fungal infections (IFIs) are important causes of morbidity and mortality among patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and consensus guidelines recommend the use of mold-active antifungal prophylaxis (ppx), e.g., voriconazole (vori) or posaconazole (posa). Isavuconazole (ISAV), the most recently introduced triazole antifungal, is currently approved for the treatment of invasive aspergillosis and invasive mucormycosis. ISAV is an appealing option for ppx against IFIs in neutropenic pts with AML/MDS because of its extended spectrum, superior tolerability (over vori), fewer drug-drug interactions (than posa), absence of need for therapeutic drug monitoring (TDM) and lack of prolongation of the QT interval (enabling easier administration in pts receiving certain anti-leukemic targeted therapies, 5-HT3 antagonists, quinolones, etc). NCT03019939 is an investigator-initiated, phase 2, single-arm, open-label trial of primary antifungal ppx with ISAV in pts with AML/MDS. Methods: Previously untreated adult pts with AML or MDS who are or are anticipated to become neutropenic as a result of their first therapy for AML/MDS are eligible to participate in this ongoing trial. Accrual of 100 pts is planned. Stopping rules exist for both futility and toxicity, assuming equivalence between ISAV and the current standard of care, posa, in preventing breakthrough IFIs (expected rate, 5%). In pts who have begun definitive anti-leukemic treatment, ISAV must be initiated within 4 days. Use of systemic antifungal therapy for >72 hours during the week prior to ISAV initiation is not allowed. ISAV is administered orally as the pro-drug, isavuconazonium sulfate, and dosed per the US label. ISAV ppx is administered until recovery from neutropenia (absolute neutrophil count (ANC) ≥0.5 x 109/L and attainment of complete remission (CR), with or without complete count recovery, occurrence of a proven or probable IFI (per 2008 EORTC/MSG criteria), development of unacceptable toxicity, pt withdrawal or death, or for a maximum of 12 weeks. The primary endpoint is the incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV). ISAV plasma concentrations are determined immediately pre-dose on days 8 and 15 using a validated assay. Results: A total of 50 pts were enrolled between April 28, 2017 and July 10, 2018. Four pts did not begin ppx with ISAV (1 each could not complete caspofungin washout and screening tests in time, 2 insurance denials). Of the remaining 46 pts (Table 1), 2 remain on study. Reasons for going off study (n = 44) included achievement of CR with neutrophil recovery (n = 26), completion of 12 weeks of therapy (n = 7), possible IFI (n = 5), investigator decision (n = 2), death (n = 2, 1 disease progression, 1 cardiac arrest), probable IFI (n = 1) and transaminitis (n = 1). In these 44 pts, the median duration of ISAV ppx was 30 (10-86) days. Only 1 case of proven breakthrough IFI occurred: a gluteal abscess that later grew Candida glabrata in a pt who had come off study upon achievement of CR. One case of probable IFI (focal mass-like opacity with ground-glass halo on CT; elevated Aspergillus antigen in broncho-alveolar lavage (BAL) fluid) occurred. All 5 cases of possible IFI were based on pulmonary radiologic findings alone: lower respiratory fungal cultures remained negative at 4 weeks in all 5 pts, and galactomannan was not detected in serum or BAL fluid in any pt. Tolerability of ISAV was excellent, with mild transaminitis attributed to ISAV reported in 1 pt (2%). No pt experienced QTc prolongation while on ISAV. Plasma ISAV levels were measured in 62 blood samples from 34 individual pts, including 28 paired samples. Median (range) ISAV concentrations were 3.74 (2.03-7.65) and 4.1 (2.17-9.25) mcg/ml on days 8 and 15, respectively. There was no correlation between plasma ISAV concentrations (available in 4 of the 7 pts) and the occurrence of confirmed, probable or possible IFI. Conclusions: These results demonstrate ISAV to be a safe and effective alternative for antifungal ppx in treatment-naïve pts with AML/MDS undergoing induction therapy with a variety of different regimens. ISAV's weak inhibition of P-glycoprotein and lack of risk of QT prolongation may make ISAV particularly attractive for antifungal ppx in the era of recently approved or emerging AML therapies such as enasidenib, ivosidenib, midostaurin and quizartinib. Disclosures Bose: CTI BioPharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Wiederhold:Astellas Pharmaceuticals: Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Daver:Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Cortes:Arog: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Jain:Verastem: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Cellectis: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologioes: Research Funding; Infinity: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: 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; Cellectis: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Kontoyiannis:Astellas Pharmaceuticals: Research Funding.
7
Tarantino, Michael D., James B. Bussel, Amy Geddis, Michael F. Guerrera, Alan K. Ikeda, Kun Nie, and Melissa Eisen. "Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)." Blood 122, no. 21 (November 15, 2013): 3530. http://dx.doi.org/10.1182/blood.v122.21.3530.3530.
Full textAbstract:
Abstract Background Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim is a peptibody that stimulates platelet production via activation of the thrombopoietin (TPO) receptor. Romiplostim increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 trial. Patients who completed this study or an ongoing phase 3 trial were given the option of rolling over into an open-label long-term extension study. Objectives To evaluate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods Patients received weekly subcutaneous injections of romiplostim; the starting dose was the last dose in the prior study. Patients who had received placebo started at 1 μg/kg. Dose adjustments targeted platelet counts in the range of 50–200 x 109/L. The maximum allowed romiplostim dose was 10 µg/kg. Assessments of adverse events, concomitant medications, and local platelet counts were performed weekly. The primary endpoint was incidence of adverse events. The protocol did not require bone marrow biopsies to be performed, but when performed, specimens were submitted to a central lab for analysis. Patients who were on a stable dose had the option to receive romiplostim at home; patients and their caregivers then recorded dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results Twenty-two patients (N = 12 from the phase 1/2 study and N = 10 from the phase 3 study) were treated with romiplostim for up to 172 weeks (3.3 years). Baseline demographics included a median age of 12.0 years (range 3–16), 50% male, and 18.2% with prior splenectomy. Median romiplostim treatment duration was 89.0 weeks (range 3–172); median total number of doses was 64 (range 3–171); median average weekly romiplostim dose was 4.0 µg/kg (range 1–10), including ramp up to stable dose; and median maximum dose was 8.0 µg/kg (range 1–10). Of the 4 patients who discontinued the study, 3 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 18 continued on study. After the first week of this extension study, which for some patients was the first week of romiplostim, median platelet counts remained above 50 x 109/L throughout the study, and were in the target range of 50–200 x 109/L for all visits but weeks 76 and 156 (Figure). The median romiplostim dose (Q1, Q3) was 6.0 (2.0, 8.0) µg/kg at week 1 and 3.5 (0.0, 7.0) µg/kg at week 168 (Figure). Four patients discontinued romiplostim. Eight patients received rescue medications (defined as medications used for platelet counts < 10 x 109/L, bleeding/wet purpura, or investigator decision) which included immunoglobulins (3 patients), tranexamic acid (3 patients), platelet transfusion (1 patient), aminocaproic acid (1 patient), and prednisone (1 patient). Four patients had serious adverse events (asthma, hemangioma, hypotension, infection, thrombocytopenia, and transfusion reaction) and 1 had life-threatening adverse events (infection and thrombocytopenia). None of the serious adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Twelve patients had bleeding adverse events; 2 of which were deemed treatment-related (gingival bleeding and petechiae). Bleeding adverse events included epistaxis (4 patients); petechiae (3 patients); gingival bleeding (2 patients); hemorrhage (2 patients); and bleeding from the anus, injection site, lip, and mouth (1 patient each). No bone marrow biopsies were performed as part of this study. Conclusion In this open-label extension study, long term treatment with romiplostim maintained platelet counts in pediatric patients with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with ITP. Disclosures: Tarantino: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Octapharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Romiplostim is approved for the treatment of adults with chronic ITP. Romiplostim is not approved for the treatment of pediatric patients with chronic ITP. Bussel:Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.
8
Kruse-Jarres, Rebecca, Michael U. Callaghan, Stacy E. Croteau, Victor Jimenez-Yuste, Liane Khoo, Ri Liesner, Tadashi Matsushita, et al. "Surgical Experience in Two Multicenter, Open-Label Phase 3 Studies of Emicizumab in Persons with Hemophilia A with Inhibitors (HAVEN 1 and HAVEN 2)." Blood 130, Suppl_1 (December 7, 2017): 89. http://dx.doi.org/10.1182/blood.v130.suppl_1.89.89.
Full textAbstract:
Abstract Introduction Emicizumab is a therapeutic bispecific antibody being studied for the the prevention of bleeding in people with hemophilia A. HAVEN 1 and HAVEN 2 are multicenter, open-label phase 3 studies of subcutaneous administration of emicizumab in patients with hemophilia A with inhibitors; HAVEN 1 in adults and adolescents, and HAVEN 2 in children. Patients with planned surgeries, with the exception of minor procedures, were excluded from both studies. However, unplanned emergency surgeries, in addition to minor procedures, were performed in patients receiving emicizumab. Perioperative management was at the discretion of the investigators based on individual clinical assessment, without specific guidance (per protocol) on surgical management provided by the sponsor. Methods We describe the combined surgical experiences from HAVEN 1 and an interim analysis of HAVEN 2, specifically, the frequency of peri-operative bypassing agent (BPA) use and post-operative bleeding events in patients who were treated with emicizumab. Additionally, the type and frequency of surgical procedures and the numbers of surgical procedures associated with and without use of prophylactic BPAs are summarized. Frequency of post-operative bleeding, which were reported in the data as bleeding events resulting from a surgery or procedure, as well as the doses of peri-operative BPAs are also described. Bleeding events were defined as in HAVEN 1 (Oldenburg et al. NEJM 2017; July 10: epub). Results In HAVEN 1 and in the interim analysis of HAVEN 2, there were 22 patients who underwent a total of 29 surgical procedures (24 surgical procedures in 17 patients in HAVEN 1, and 5 surgical procedures in 5 patients in HAVEN 2). Twenty of these procedures (69%) were managed without prophylactic BPAs. Nine procedures (31%) were managed with prophylactic BPAs. Among the 29 surgeries, 6 were tooth extractions and 9 were central venous access device (CVAD)-related procedures (insertion/replacement/removal). Of the remaining 14 surgical procedures, 12 were minor and 2 were major: (1) right knee arthroscopy, synovectomy, debridement of arthrofibrosis, and chondroplasty in HAVEN 1, and (2) a laparoscopic appendectomy in HAVEN 2. Among the 20 surgeries that were not managed with surgical prophylactic BPAs, 14 (70%) did not result in post-operative bleed(s), and 6 (30%) resulted in post-operative bleeds (2 treated with BPAs and 4 not treated with BPAs). The 2 treated post-operative bleeding events occurred with a tooth extraction and with a right knee arthroscopy, synovectomy, debridement of arthrofibrosis, and chondroplasty. Among the 9 surgeries that were managed with surgical prophylactic BPA, 8 were managed with rFVIIa with mean dose (range): 152.81 µg/kg (86.54-254.72 µg/kg) and median number of injections of 1; 1 surgery used prophylactic aPCC (single dose of 49.78 U/kg). Eight (89%) of these surgeries did not result in post-operative bleeding, and 1 (11%) was a tooth extraction that resulted in a single treated post-operative bleeding event. Anti-fibrinolytics were used in 4 of 29 surgical procedures, 3 of which were tooth extractions and 1 of which was a CVAD removal. Among the 7 surgeries that resulted in post-operative bleeding, 3 surgeries were managed with rFVIIa and no surgery was managed with aPCC. BPA doses administered post-operatively in these surgeries are shown in Table 2. Conclusions In HAVEN 1 and an interim analysis of HAVEN 2,management of perioperative BPA use was at the discretion of the investigator. In the two studies combined, the majority (20/29; 69%) of surgeries performed were not managed with prophylactic BPAs, with no post-operative bleeding reported in the majority (14/20; 70%) of these surgeries. Among the 4 tooth extractions that were not managed with prophylactic BPAs, 3 resulted in post-operative bleeding, only 1 of which was treated with BPAs. Among the 5 CVAD-related procedures that were not managed with prophylactic BPAs, only 1 resulted in a post-operative bleed that was not treated with BPAs. In this analysis of patients with hemophilia A with inhibitors who underwent mostly minor surgical procedures while receiving emicizumab prophylaxis, the majority of patients did not receive pre-operative treatment with BPAs. Post-operative bleeding requiring additional BPA treatment seldom occurred. Disclosures Kruse-Jarres: Roche/Genentech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Baxalta: Honoraria. Callaghan: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare; Pfizer Inc.; Roche; Shire: Consultancy; Biogen: Membership on an entity's Board of Directors or advisory committees; Roche; Shire: Speakers Bureau; Global Blood Therapeutics: Other: Site PI; Grifols: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals, Inc: Other: Owns stock, stock options, or bonds ; Novo Nordisk: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Speakers Bureau; Sancillio: Other: Site PI; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees. Croteau: Aptevo, Baxalta/Shire, Bayer, CSL Behring, Genentech, Novo Nordisk, Octapharma, Pfizer: Consultancy; ATHN/Hemophilia of Georgia: Research Funding; Octapharma: Honoraria; Baxalta, Dimension Therapeutics, Genentech, Pfizer: Research Funding. Jimenez-Yuste: Novo Nordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Khoo: Novo Nordisk: Honoraria; Biogen: Honoraria; Baxalta/Shire: Honoraria. Liesner: Bio Products Laboratory: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Octapharma: 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; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI/Bioverativ: Research Funding, Speakers Bureau. Matsushita: Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recht: Biogen: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. Young: Novo Nordisk: Consultancy; CSL Behring: Honoraria. Chang: Genentech: Employment, Equity Ownership. Dhalluin: F. Hoffmann-La Roche Ltd: Employment. Mu: Genentech, Inc.: Employment. Xu: Genentech: Employment. Devenport: Genentech, Inc.: Employment. Ko: Genentech, Inc.: Employment. Solari: Genentech, Inc.: Employment. Oldenburg: 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; CSL: 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; Grifols: 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; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; 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; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
9
Tarantino, Michael D., James B. Bussel, Victor S. Blanchette, Jenny M. Despotovic, Carolyn Bennett, Ashok Raj, Bronwyn Williams, et al. "Safety and Efficacy of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Pediatric Patients with Immune Thrombocytopenia (ITP)." Blood 126, no. 23 (December 3, 2015): 3467. http://dx.doi.org/10.1182/blood.v126.23.3467.3467.
Full textAbstract:
Abstract Background: Chronic ITP in children is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Pediatric patients with chronic ITP that completed a romiplostim phase 1/2 or phase 3 study could enroll in this open-label long-term extension; 5.2 years of data are reported. Methods: All patients received SC romiplostim once weekly. The initial dose was the final dose from the parent study or 1 µg/kg (for patients previously receiving placebo or who had not received romiplostim for >24 weeks), adjusted from 1-10 µg/kg to target platelet counts of 50-200×109/L. The incidence of adverse events (AEs) was the 1° endpoint. If approved by investigators, patients who maintained platelet counts ≥50×109/L for ≥4 consecutive weeks at a stable dose could subsequently administer doses by self or caregiver. Patients who turned 18 years of age could remain on study. Results: A total of 66 patients (phase 1/2, n=12; phase 3, n=54) entered the extension; 65 received romiplostim for ≤269 weeks (5.2 years); 1 patient withdrew consent before treatment. At baseline, median (range) age was 11 (3-18) years; 56% were female; 61% were white, 14% African American, and 14% Hispanic/Latino; 9.1% had prior splenectomy. Median (range) treatment duration was 57.9 (1-269) weeks; median number of doses was 53.0 (1-268). Median (range) average weekly romiplostim dose was 5.5 (0.1-10.0) µg/kg, including escalation to stable dose, median maximum dose was 8.0 (1.0-10.0) µg/kg, and median most frequent dose was 6.0 (0-10) µg/kg. The median dose fell from 6 to 1 µg/kg; after ~week 140 (n≤9), the median dose fluctuated (Fig 1). Thirteen patients discontinued treatment: consent withdrawn (n=6), noncompliance (2), administrative decision (2), nonresponse (2), and per protocol (1). Fifty-two (79%) patients continued in the study; none withdrew due to AEs. After the first study week median platelet counts remained >50×109/L (Fig 2); for 15 patients (23%), the first study week was the first week receiving romiplostim (ie, previously received placebo). Fifty-six (86%) patients (or caregivers) self-administered romiplostim. Twenty-one (32%) patients received rescue medications on 63 occasions (for low platelet counts [n=35], bleeding/bruising [17], pre- or post-procedure [9], and other [2]), including IVIG (n=10), prednisone (9), aminocaproic acid (3), tranexamic acid (2), methylprednisolone (2), and platelet transfusion (1). Patients required rescue treatment during the first 3 months (27/63 instances), >3-6 months (9), >6-9 months (6), >9-12 months (7), and after 1 year (14) in the extension. Five previous placebo recipients received rescue medication, mostly during the first 3 months (10/14 instances). Three patients achieved remission (platelet counts ≥50×109/L for 24 weeks with no ITP treatments): 1) 9-year-old boy with ITP for 9 years, after 4.3 years of romiplostim, entered remission for the last 2.1 years as of this datacut; 2) 13-year-old boy with ITP for 8.5 years, after 3.3 years of romiplostim, entered remission for the last 1.1 years; and 3) 17-year-old girl with ITP for 8.2 years, after 5.9 years of romiplostim, entered remission for the last 44 weeks. Thirty-four serious AEs occurred in 14 patients, including pyrexia (n=3), epistaxis (2), and thrombocytopenia (2); 3 were deemed treatment-related (anemia, epistaxis, and thrombocytopenia), and none led to discontinuation of romiplostim. Five patients had life-threatening AEs, including thrombocytopenia (n=2) and infection, decreased platelet counts, and subcutaneous abscess (1 each); none were fatal or deemed treatment-related. Bleeding AEs occurred in 47 patients; 3 were deemed treatment-related by the investigator (gingival bleeding, petechiae, and epistaxis). Bleeding AEs occurring in ≥4 patients included contusion (n=25), epistaxis (21), petechiae (16), gingival bleeding (9), mouth hemorrhage (6), ecchymosis (5), and hemorrhage, injection-site bruising, and purpura (4 each). No thrombotic events were reported. There were no peripheral blood abnormalities suggestive of malignancy to warrant a bone marrow examination in any patient. There was no development of anti-TPO or anti-romiplostim antibodies. Conclusion: In this ongoing open-label extension of children with chronic ITP, romiplostim for ≤5.2 years maintained platelet counts with a safety profile similar to that seen in past studies. Disclosures Tarantino: BPL: Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties: royalties. Off Label Use: Romiplostim is indicated for use in adults with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in children with ITP is investigational.. Bussel:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Immunomedics: Membership on an entity's Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data Safety Monitoring Board; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morales:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Nie:Amgen Inc.: Employment, Other: Stockholder. Eisen:Amgen Inc: Employment, Other: stock ownership.
10
Namoglu, Esin C., Mitchell E. Hughes, Daniel J. Landsburg, Stephen J. Schuster, Jakub Svoboda, Elise A. Chong, James N. Gerson, Stefan K. Barta, and Sunita Dwivedy Nasta. "Clinical Outcomes of Non-Hodgkin Lymphoma Patients on Acalabrutinib Including Off-Label Utilization." Blood 134, Supplement_1 (November 13, 2019): 5261. http://dx.doi.org/10.1182/blood-2019-130039.
Full textAbstract:
Introduction: Acalabrutinib (acala), a Bruton's Tyrosine Kinase inhibitor (BTKi), received accelerated FDA approval for treatment of mantle cell lymphoma (MCL) in 2017. Since approval, there has been limited "real world" data, especially in the setting of off-label utilization. We performed an analysis of the safety and efficacy of acala in non-Hodgkin lymphoma (NHL) at our institution for both on- and off-label indications. Methods: We performed a retrospective analysis of all patients (pts) who had received acala for NHL at the University of Pennsylvania between 1/2017 and 5/2019. We examined best response to therapy, duration of response, and progression free survival. Response assessments were determined by treating physician using standard, disease-specific criteria. We collected clinical and demographic data such as genetic risk factors, staging, previous and concomitant therapies. We analyzed adverse events (AEs) and toxicities associated with acala. Survival analyses were completed as described by Kaplan and Meier; all other analyses were descriptive in nature. Results: We identified 23 pts treated with acala at our institution. The cohort consisted of 83% males (n=19). Diagnoses were chronic lymphocytic leukemia (CLL) (n=10; 44%), MCL (n=9; 39%), and diffuse large B-cell lymphoma (DLBCL) (n=4; 17%). One DLBCL was GCB subtype and three were ABC subtype; two of four DLBCL pts were transformed from marginal zone lymphoma and two were de novo. The median age at diagnosis was 61 years, median age at acala start was 69 years. Sixteen (70%) of the pts were Ann Arbor or Rai stage III or IV at diagnosis. The median number of therapies prior to acala was 3 (range 0-12). Of note, the GCB-DLBCL patient had previously undergone both allogeneic (alloSCT) and autologous (autoSCT) stem cell transplants and four of the MCL patients (44%) also had prior allo and/or autoSCTs. The majority (65%) of pts received acala 100 mg twice daily, with the rest of the patients receiving 100 mg once daily. The median time to best response was 2 months (mos). All CLL pts (n=10; 100%) had at least a partial response (PR), including 1 complete response (CR) by iwCLL criteria. In the MCL cohort of 9 pts, 8 (88%) had at least a PR (including 1 CR), and one patient (11%) had stable disease (SD). One MCL pt achieved a CR and moved to alloSCT. One (25%) of the DLBCL pts had a PR (pt was ABC subtype), and three (75%) had SD (one GCB and two ABC-DLBCL pts.) At the time of last follow up, two DLBCL pts had SD and remain on acala, one progressed after 10 months on acala and was switched to obinutuzumab, and one died due to disease progression. The 12 mo progression free survival (PFS) was 89% for CLL and 83% for MCL; 12 mo overall survival (OS) was 89% for CLL and 100% for MCL respectively. (Figure 1). Of note, 16 pts (70%) had been on ibrutinib previously and all pts discontinued (d/c) ibrutinib due to intolerance. Acala related toxicities included: 26% (n=6) arthralgias/myalgias, 13% (n=3) infection, 13% (n=3) bruising/ bleeding, 9% (n=2) rashes, and 4% (n=1) diarrhea. Two pts required dose adjustment of acala and one patient had to d/c acala due to fatigue and bleeding/bruising. Ten (43%) of pts tolerated acala without any side effects. Of note, there were 6 pts with a history of atrial fibrillation (afib) or an afib-related toxicity of ibrutinib, and none of our pts experienced new afib while on acala. In total, six pts d/c acala: 1 patient moved to alloSCT, 3 had disease progression, 1 d/c due to toxicity, and 2 pts died. One death was unrelated to lymphoma progression (renal cancer). Conclusion: Our "real world" experience with acala demonstrates its efficacy and tolerability in the setting of NHL, supporting previously published literature (ACE-LY-004 and ACE-CL-001 trials). In our analysis of 23 patients, the response rates in our CLL and MCL cohorts were 100% and 88% respectively and only one patient discontinued acala for intolerance. There is limited information on the off-label utilization of acala in the relapsed/refractory DLBCL setting. However, the response in our cohort may warrant further evaluation of acala as a possible therapeutic agent in this aggressive/refractory patient population. Acala continues to demonstrate a favorable toxicity profile, especially in pts who were unable to tolerate ibrutinib. Our experience with acala supports pilot data showing efficacy and thus further research in other B-cell malignancies, especially DLBCL, is warranted. Figure 1 Disclosures Hughes: Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Chong:Merck: Research Funding; Novartis: Consultancy; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria. Dwivedy Nasta:Rafael: Research Funding; Millenium/Takeda: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding; 47 (Forty Seven): Research Funding; Debiopharm: Research Funding. OffLabel Disclosure: FDA label indication for acalabrutinib is only for patients with CLL. Utilization in DLBCL and CLL populations is beyond the specified indication.
11
Grainger, John, James B. Bussel, Nichola Cooper, Michael Tarantino, Victor Blanchette, Jenny Despotovic, Alexey Maschan, Nancy Carpenter, Melissa Eisen, and Bhakti Mehta. "A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)." Blood 128, no. 22 (December 2, 2016): 869. http://dx.doi.org/10.1182/blood.v128.22.869.869.
Full textAbstract:
Abstract Background: The TPO receptor agonist romiplostim is approved for use in adults with chronic ITP. The use of romiplostim in children with ITP has been evaluated in phase 1/2 and 3 studies. In this study, children with ITP will receive open-label SC romiplostim for up to 3 years (y). Methods: Eligible children, recruited in 16 countries worldwide, had ITP for ≥6 months, ≥1 prior ITP therapy, and platelet (plt) count ≤30×109/L. Weekly SC dosing started at 1 μg/kg and was titrated in 1 μg/kg increments up to 10 μg/kg to target plt counts of 50-200×109/L. In patients in Europe, bone marrow aspirates and biopsies were obtained at baseline and after 1 or 2 y of exposure. The 1º endpoint was the % of time in the first 6 months with a plt response, with response defined as a plt count ≥50×109/L without rescue medication use in the past 4 weeks (wk). Results: As of 15 Mar 2016, 147 patients enrolled; 145 received ≥1 romiplostim dose. At baseline, median (min-max) age was 10 (2-17) y; 51% were female; 4% had prior splenectomy. Median (min-max) ITP duration was 1.9 (0.5-12.3) y and plt count was 13 (2-168)×109/L. The median (Q1, Q3) % of time with a plt response in the first 6 months patients were on study was 50% (0%, 83.3%); that of months 7-12 was 92% (33%, 100%). Over the course of the study, 80% (114/143) of patients had a plt response. The median (Q1, Q3) % of time with an increase in plt counts ≥20×109/L above baseline was 60% (25%, 84%). The median dose increased to 10 μg/kg by wk 32 (Figure). Median (min-max) treatment duration as of data cutoff was 25 (1-67) wk for a total exposure to date of 79 patient-years; 67 (46%) patients (or caregivers) self-administered romiplostim. Median (min-max) average weekly romiplostim dose was 6.1 (0.4-9.0) µg/kg. Thirty-two patients (22%) discontinued treatment for lack of efficacy (n = 17), required other therapy (n = 5), patient request (n = 4), noncompliance (n = 2), adverse event (AE) (n = 2) (interstitial lung disease unrelated to treatment in a 15 y old boy and abdominal pain, vomiting, and headache related to treatment per investigator in a 9 y old girl), administrative decision (n = 1), and investigator decision (n = 1). After wk 12, median plt counts remained ≥50×109/L (Figure). Thirty-four (23%) patients received rescue medications. The most frequently reported AEs were headache (27.6%), epistaxis (22.8%), and nasopharyngitis (23%); 15 (10.3%) patients had serious AEs (SAEs) including epistaxis (n = 4), petechiae (n = 2), decreased plt count (n = 2), and thrombocytopenia (n = 2). A case of abdominal pain was the only SAE deemed treatment-related by the investigator. Bleeding over the course of the study was seen in 52% of patients. CTCAE grade 3 bleeding was seen in 8 patients (6%) and included epistaxis (n = 5), ecchymosis (n = 2), petechiae (n = 2), and 1 case each of hematemesis, hematoma, SC hemorrhage, injection site hemorrhage, and mouth hemorrhage. No grade 4 or 5 bleeding was observed. One event of grade 2 phlebitis/thrombophlebitis in deep veins in the left arm lasting 14 days was reported in a 13 y old girl; plt counts were 40-70×109/L and the dose was 7-8 µg/kg during this time. Per investigator, this event was not serious or related to romiplostim. She was treated with antibiotics (oral amoxicillin/clavulanic acid and transdermal muciprocin) and continued romiplostim treatment as before. No neutralizing antibodies against romiplostim or TPO were identified. Of 30 patients with baseline bone marrow biopsies [50% female, median (min-max) age 10.5 (6-12) y, ITP duration 3.1 (0.6-11) y], all had modified Bauermeister scores of grade 0 (no reticulin) or 1 (fine fibers) and bone marrow typical for ITP. Of these 30 patients, 21 had evaluable on-study biopsies, with no increases in 2 or more grades, findings of collagen, or bone marrow abnormalities. Conclusion: In this year 1 datacut of an ongoing open-label study of romiplostim in children with ITP, the % of time in the first 6 months with a platelet response was 50%, with 80% of children having a platelet response at some point on study. The median romiplostim dose reached 10 μg/kg and there were no new safety signals. No effects of romiplostim were observed in the subset of patients with bone marrow biopsies. Future datacuts for year 2 and 3 in this study, the largest of romiplostim in children with ITP with 79 patient-years of exposure to date, will provide more information on platelet response, dose requirements, and safety. Disclosures Grainger: Baxter: Honoraria, Research Funding; Amgen Inc.: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Honoraria. Bussel:Shionogi: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; BiologicTx: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Genzyme: Research Funding; UpToDate: Patents & Royalties; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; Cangene: Research Funding; Sysmex: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:UK ITP support association: Research Funding; National Organization for Rare Disorders: Research Funding; Imperial College BRC: Research Funding; Eisai: Consultancy, Honoraria, Other: Received honoraria for speaking at educational meetings; GlaxoSmithKline: Consultancy, Honoraria, Other: Received honoraria for speaking at educational meetings ; Amgen Inc.: Consultancy, Honoraria, Other: Received honoraria for speaking at educational meetings . Tarantino:Pfizer: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Blanchette:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data safety monitoring boards , Research Funding; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data safety monitoring boards . Carpenter:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership.
12
Chari, Ajai, Maria-Victoria Mateos, Niels WCJ van de Donk, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, et al. "Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)." Blood 132, Supplement 1 (November 29, 2018): 1995. http://dx.doi.org/10.1182/blood-2018-99-113590.
Full textAbstract:
Abstract Introduction: Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. DARA (16 mg/kg administered intravenously [IV]) is approved in many countries as monotherapy and in combination with standard of care (SOC) treatment regimens for patients with relapsed/refractory (RR) multiple myeloma (MM) and newly diagnosed MM. Three phase 3 studies have now demonstrated that DARA in combination with SOC treatment doubles complete response (CR) rates, triples minimal residual disease-negative rates, and reduces the risk of progression or death by at least 50% vs SOC alone. The median durations of the first, second, and subsequent DARA IV infusions are 7.0, 4.3, and 3.4 hours, respectively. To determine whether the duration of infusion can be shortened without compromising the safety or efficacy of daratumumab, an open-label, multicenter, phase 1b clinical trial (PAVO; NCT02519452) was conducted to evaluate a subcutaneous (SC) formulation of DARA with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) in patients with RRMM. Part 1 of the study revealed that a mix-and-deliver SC administration was well tolerated, with low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV (Usmani et al. ASH 2016; abstract 1149). Here, we present updated safety and efficacy findings from Part 2 of the PAVO study, where a concentrated, pre-mixed SC co-formulation of DARA and rHuPH20 (DARA SC) was evaluated in patients with RRMM. Methods: Eligible RRMM patients had received ≥2 prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). In Part 2 of the study, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial was administered over 3 to 5 minutes by manual SC injection into the abdomen. DARA SC was given QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter in 28-day cycles. Pre- and/or post infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone. Co-primary endpoints were safety and Ctrough of DARA SC at the end of QW dosing. Secondary endpoints included the overall response rate (ORR) and CR rate according to the International Myeloma Working Group response criteria. Results: At the clinical cut-off date of December 13, 2017, 25 patients were enrolled in Part 2 of the study. Patients received a median of 3 (range: 2-9) prior lines of therapy, with 56% double refractory to both PI and IMiD. No treatment discontinuations occurred due to treatment-emergent adverse events (TEAEs). The most common (≥20%) TEAEs included lymphopenia (32%), thrombocytopenia (24%), fatigue, asthenia, back pain, diarrhea, nausea, headache, and viral upper respiratory tract infection (20% each). The incidence (16%) and severity of IRRs (mostly grade 1-2) with DARA SC was low, the majority of which occurred on Cycle 1 Day 1, and no discontinuations due to IRRs were observed. Transient grade 3 hypertension was reported as an IRR in 2 patients. Grade 1 injection-site TEAEs were reported with DARA SC in 3 patients (induration, erythema, injection-site discoloration, and hematoma [n = 1 each]). At 6.5 months of median follow-up, the ORR was 52% (28% very good partial response; 24% partial response). Median progression-free survival (PFS) was not reached among all-treated patients, including among patients who were double refractory. Updated data will be presented at the meeting based on longer follow-up. Conclusions: DARA SC enabled dosing in 3-5 minutes and improves patient convenience. DARA SC was well-tolerated in patients with RRMM with low rates of IRRs and no new safety signals compared with DARA IV. Over 50% of patients responded to treatment and median PFS has not been reached after median follow-up of 6.5 months. These data inform ongoing phase 3 studies of DARA SC in RRMM (including a non-inferiority study of DARA SC vs DARA IV [COLUMBA; NCT03277105]), smoldering multiple myeloma, and AL amyloidosis. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; The Binding Site: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy. Moreau:Amgen: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Takeda: 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; Janssen: 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. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. Tang:Janssen: Employment. Hellemans:Janssen Research & Development: Employment. Tromp:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. San-Miguel:Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.
13
Kulasekararaj, Austin, Antonio M. Risitano, Jaroslaw P. Maciejewski, Rosario Notaro, Peter Browett, Jong-Wook Lee, Mingjun Huang, Michael Geffner, and Robert A. Brodsky. "A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy." Blood 134, Supplement_1 (November 13, 2019): 3514. http://dx.doi.org/10.1182/blood-2019-124748.
Full textAbstract:
Background: PNH is a rare, acquired blood disorder. A somatic mutation in the PIGA gene of one or more hematopoietic stem cells generates a clone of abnormal erythrocytes (RBCs) that lack alternative pathway (AP) regulatory complement proteins CD55 and CD59. This leads to uncontrolled complement activation on affected RBCs and intravascular hemolysis (IVH). Standard of care is C5 inhibition to prevent membrane attack complex (MAC) formation. Despite preventing MAC-mediated IVH, many patients experience extravascular hemolysis (EVH). Despite C5 inhibition, ~ 70% of patients remain anemic and >1/3 were transfused > 1 time in the prior 12 months. Factor D (FD), a serine protease, catalyzes complement factor B cleavage, allowing formation of AP C3 convertase. By inhibiting FD, oral danicopan blocks C3 convertase formation, the control point for AP activation and amplification of all pathways. This leads to inhibition of C3 cleavage, C3 fragment deposition, terminal pathway activation and MAC formation. Thus, danicopan can control both IVH and EVH therefore, making FD a promising target. Aim: Demonstrate that danicopan is a potential treatment for PNH patients with an inadequate response to C5 inhibition. Methods: Data are presented for this Ph 2, dose-finding, proof of concept trial of danicopan in patients with an inadequate response to eculizumab who were transfusion dependent. Additional criteria in Table 1. In addition to the current eculizumab regimen, danicopan starting doses were 100-150 mg TID, with dose escalation up to 200 mg TID, based on clinical and biochemical response, at protocol defined time points (Figure 1). The primary endpoint was change in Hgb at Treatment Week (TW) 24. Secondary efficacy parameters included transfusion needs, effect on lactate dehydrogenase (LDH), and an exploratory an endpoint of Functional Assessment of Chronic Illness Therapy (FACIT) FATIGUE scores. General safety, tolerability, and PK/PD of danicopan were measured. After TW 24, patients entered a long-term extension. Results: Twelve patients received at least one dose of danicopan. One patient discontinued after 2 doses, due to a serious adverse event of worsening of an underlying condition (pulmonary hypertension/edema), considered unlikely related to danicopan. This patient is excluded from this analysis. Eleven patients continue to receive treatment. Dose titrations are shown in Table 2. Benefits were observed in multiple laboratory markers of PNH, shown in Table 3. Hgb improved in all patients, with a mean Hgb gain of 2.6 g/dL at 24 Weeks of treatment (n=4). Meaningful improvement in FACIT Fatigue scores were reported, with a mean increase of 8 points relative to the baseline on eculizumab. A 3-point change is clinically meaningful on this scale. Transfusion needs dramatically reduced, with one patient receiving one transfusion during the trial, as compared to 34 transfusions (58 units) in 10 patients, in the 6 months prior to screening. One patient (who does not accept blood products due to religious objections and also has hereditary elliptocytosis) had a baseline Hgb=5 g/dL with a 3.5 g/dL improvement at TW24 and significant improvement in fatigue. C3 fragment deposition was inhibited; reticulocytes, total/ direct bilirubin and LDH returned to normal range. Baseline C5 inhibition (classical pathway activity) was essentially inhibited (mean=1 [range 60-144]). Three of 11 patients received > 900 mg eculizumab, making PK a less likely reason for inadequate response. Danicopan has been well tolerated; 96% of treatment emergent adverse events (TEAEs) were mild to moderate in severity and no discontinuations due to TEAEs. Two patients had Grade 3 TEAEs which resolved and continued in the trial. Conclusion: Proof of concept is established with danicopan, an oral, small molecule FD inhibitor in the treatment of PNH in combination with eculizumab. Meaningful improvements in Hgb, transfusion needs, FACIT-FATIGUE and other parameters of interest were achieved. These clinically significant improvements demonstrate that further benefit can be achieved by blocking the alternative pathway at FD with danicopan, in combination with C5 inhibition. This benefit is likely due to the prevention of C3-mediated EVH, in addition to control of IVH. Danicopan targets an unmet need in PNH and will be further evaluated in a pivotal trial in combination with standard of care C5 inhibition. Disclosures Kulasekararaj: Achillion: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Achillion: Research Funding; Amyndas: Consultancy; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Achillion: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ra Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Samsung: Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Notaro:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: letture fees. Browett:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Beigene: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding. Huang:Achillion: Employment, Equity Ownership. Geffner:Achillion: Employment, Equity Ownership. Brodsky:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding; Achillion: Research Funding.
14
Carroll, Brigid, Coral Ingley, and Kerr Inkson. "Boardthink: Exploring the discourses and mind-sets of directors." Journal of Management & Organization 23, no. 5 (August 14, 2017): 606–20. http://dx.doi.org/10.1017/jmo.2017.36.
Full textAbstract:
AbstractIn a context of institutionalized regulation and academic framing determined by agency theory, we note paradoxes in board governance literature and practice. These paradoxes concern boards’ conflicting roles of monitoring/control, and innovation/strategy-making. We explore directors’ mind-sets about governance on which their resolution of paradoxes and their decisions and actions will be based. We do this by applying discourse analysis to the transcripts of 60 semistructured interviews conducted with New Zealand directors who described and evaluated their experience of board governance. We identify and discuss their various discourses, which we label discourses of conformance, of deliberation, of enterprise and of bounded innovation. We note the homogeneity of discourses across different organization types, the dominance of conformance, the nonresolution of paradoxes, and the likely effects in inhibiting board strategy-making and contribution to innovation. We recommend attention by boards to their mind-sets and processes, and the development of generativity.
15
Ghobrial, Irene M., Michael R. Savona, Ravi Vij, David S. Siegel, Ashraf Badros, Jonathan L. Kaufman, Noopur Raje, Andrzej Jakubowiak, Mihaela Obreja, and Jesus G. Berdeja. "Final Results from a Multicenter, Open-Label, Dose-Escalation Phase 1b/2 Study of Single-Agent Oprozomib in Patients with Hematologic Malignancies." Blood 128, no. 22 (December 2, 2016): 2110. http://dx.doi.org/10.1182/blood.v128.22.2110.2110.
Full textAbstract:
Abstract Background: Oprozomib (OPZ) is an oral proteasome inhibitor. This phase 1b/2 study (NCT01416428) is evaluating single-agent OPZ in patients with relapsed hematologic malignancies, including those with multiple myeloma (MM) and Waldenström macroglobulinemia (WM). In the phase 1b portion of the study, the maximum tolerated dose (MTD) of single-agent OPZ was 300 mg/day when administered on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or 240 mg/day when administered on days 1-5 of a 14-day cycle (5/14 schedule) (Vij et al. Blood.2014;124:abstr 34). Here, we present final results from the phase 2 portion of the study. Methods: Adults with relapsed MM or WM (≥1 prior therapy) were eligible for the phase 2 portion of the study. The primary objective of the phase 2 portion was to determine the overall response rate (ORR). During phase 2, patients on the 5/14 schedule received OPZ at the MTD of 240 mg/day, or in a step-up dosing scheme where patients received 150 mg/day in cycle 1, and stepped-up to a target dose of 180 mg/day thereafter (ie, 150/180 mg/day). Patients on the 2/7 schedule received OPZ in a step-up dosing scheme of 240/300 mg/day. All patients received premedication with a 5-hydroxytryptamine-3 inhibitor and dexamethasone 4 mg. Results: During phase 2, patients were initially treated on the 5/14 schedule at the MTD of 240 mg/day (MM, n=27; WM, n=17). Three patients with MM died on study: 2 due to treatment-related gastrointestinal (GI) hemorrhage and 1 due to progressive disease. The study protocol was then amended to test alternative regimens and lower doses, and patients were subsequently enrolled on the 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). The phase 2 portion enrolled 56 patients on the 2/7 step-up dosing schedule (MM, n=41; WM, n=15) and 34 patients on the 5/14 step-up dosing schedule (all MM). Median ages in MM patients were 65 years (2/7, 240/300 mg/day), 64.5 years (5/14, 150/180 mg/day), and 63 years (5/14, 240 mg/day); median ages in WM patients were 65 years (2/7, 240/300 mg/day) and 62 years (5/14, 240 mg/day). Median numbers of prior regimens were 4, 3.5, 5, 2, and 3 in these cohorts, respectively. Among MM patients, 68% were bortezomib (BTZ)-refractory, 37% were carfilzomib (CFZ)-refractory, 75% were lenalidomide-refractory, 45% were pomalidomide-refractory, and 71% had received prior transplant. Median treatment durations were 11.4 weeks (MM, 2/7 schedule, 240/300 mg/day), 10.1 weeks (MM, 5/14 schedule, 150/180 mg/day), 5.4 weeks (MM, 5/14 schedule, 240 mg/day), 34.6 weeks (WM, 2/7 schedule, 240/300 mg/day), and 8.1 weeks (WM, 5/14 schedule, 240 mg/day). Across all cohorts, the most common grade ≥3 adverse events (AEs) included diarrhea, anemia, thrombocytopenia, fatigue, nausea, and vomiting (Table 1). Among patients with MM, the proportions of patients who discontinued treatment due to AEs were 44%, 12%, and 48% in the 2/7, 240/300 mg/day; 5/14, 150/180 mg/day; and 5/14, 240 mg/day cohorts, respectively. Among patients with WM, the proportions of patients who discontinued treatment due to AEs were 20% and 47% in the 2/7 and 5/14 schedules, respectively. No on-study deaths occurred in the 2/7 schedule nor in the 5/14 step-up dosing cohorts. Efficacy outcomes are shown in Table 2. Among response-eligible patients with MM, ORRs were 34%, 22%, and 25% in the 2/7, 240/300 mg/day (n=38); 5/14, 150/180 mg/day (n=32); and 5/14, 240 mg/day (n=24) cohorts, respectively. Among BTZ-refractory patients with MM, ORRs were 28% and 17% on the 2/7 (n=29) and 5/14 (n=24) schedules, respectively; among CFZ-refractory patients, ORRs were 8% and 10% on the 2/7 (n=13) and 5/14 (n=21) schedules. For response-eligible patients with WM, ORRs were 71% and 47% on the 2/7 (n=14) and 5/14 (n=17) schedules. Conclusions: Single-agent OPZ appears to have promising activity in patients with relapsed MM or WM, with durable responses overall and responses observed in those refractory to BTZ or CFZ. GI events (primarily diarrhea) were among the most common grade ≥3 AEs with single-agent OPZ. Further exploration of OPZ therapeutic effect is planned with modified formulations and optimized schedule and dosing administration. Disclosures Ghobrial: Noxxon: Honoraria; Novartis: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Vij:Amgen: Honoraria, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Research Funding. Siegel:Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Kaufman:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding. Raje:Amgen: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, 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. Obreja:Amgen: Employment. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.
16
Chari, Ajai, Hareth Nahi, Maria-Victoria Mateos, Henk M. Lokhorst, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, et al. "Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study." Blood 130, Suppl_1 (December 7, 2017): 838. http://dx.doi.org/10.1182/blood.v130.suppl_1.838.838.
Full textAbstract:
Abstract Introduction : Daratumumab (DARA), a CD38-targeted human monoclonal antibody, is approved as monotherapy and in combination with bortezomib (proteasome inhibitor; PI) or immunomodulatory drugs (IMiD; lenalidomide or pomalidomide) in pts with RRMM. DARA is administered intravenously (IV) and is associated with infusion related reactions (IRRs) in 46% of pts. We previously reported data from PAVO (NCT02519452), an open-label, multicenter, phase 1b study in RRMM, showing that subcutaneous (SC) delivery of DARA with recombinant human hyaluronidase enzyme (rHuPH20) by SC infusion of a mix and deliver formulation (DARA-MD) was well tolerated with low rates of IRRs (Usmani SZ, et al. ASH 2016; abstract 1149). DARA + rHuPH20 also demonstrated an efficacy profile consistent with IV DARA. We present updated data, including initial safety and efficacy findings from an additional cohort that received DARA co-formulated with rHuPH20 (DARA SC), which was delivered by manual SC injection. Methods : RRMM pts had an Eastern Cooperative Oncology Group performance status ≤2 and received ≥2 prior lines of therapy including a PI and an IMiD. To determine the recommended SC dose for Part 2 of this 2-part study, DARA-MD was administered via SC infusion through a syringe pump from 20 to 30 min in Part 1. Pts were administered DARA 1200 mg + rHuPH20 30000 U (in 60 mL) or DARA 1800 mg + rHuPH20 45000 U (in 90 mL) in 28-day cycles: weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. The 1,800 mg dose level was selected for Part 2. In Part 2, a concentrated co-formulation of the selected DARA SC (1800 mg in 15 mL) and rHuPH20 (30000 U) dose in a single, pre-mixed vial was administered in 3 to 5 minutes by manual SC injection. In both parts, the primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR), rate of complete response (CR), and time to response. Results : At the clinical cut-off of June 30, 2017, 53 pts were enrolled in Part 1 (DARA-MD 1200 mg, n=8; DARA-MD 1800 mg, n=45) and 25 pts were enrolled in Part 2 (DARA SC 1800 mg). 0/8 (0%), 12/45 (27%), and 25/25 (100%) pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively, remain on treatment; the median duration of treatment was 2.6 (0.7-12.0), 5.4 (0.7-16.6+), and 1.4 (0.5-2.3+) months, respectively. In Part 1, 100% and 73% of pts discontinued treatment in the DARA-MD 1200 mg and DARA-MD 1800 mg dose cohorts, respectively, due to progressive disease (75% and 58%), physician decision (0% and 9%), death (13% and 2%), withdrawal by pt (13% and 2%), and other (0% and 2%); in Part 2 with shorter follow up, none discontinued treatment. One pt receiving DARA-MD 1200 mg died due to adverse event (aspiration pneumonia) and 2 pts receiving DARA-MD 1800 mg died due to disease progression; no deaths occurred in the DARA SC 1800 mg cohort. IRRs were reported in 13%, 24% and 4% pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively. One grade 3 IRR of dyspnea occurred in the DARA-MD 1200 mg cohort; no grade 3/4 IRRs occurred in pts receiving DARA-MD 1800 mg or DARA SC 1800 mg. SC administration was well tolerated in the DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, with 63%, 29%, and 20% of pts experiencing reversible erythema and 50%, 22%, and 0% of pts experiencing reversible induration at the infusion/injection site, respectively. Among DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, treatment-emergent adverse events (TEAEs) occurred in 100%, 98% and 84% pts, respectively; 63%, 49% and 32% were grade 3 or 4 (Table). Serious TEAEs occurred in 50%, 31%, and 4% pts. No pts discontinued treatment due to TEAEs. As of August 1, 2017, in the DARA-MD 1800 mg cohort, ORR was 42%, and the rates of ≥VGPR and ≥CR were 20% and 7%, respectively. In the DARA SC 1800 mg cohort, a preliminary ORR of 42% was observed which requires confirmation at follow up. Updated safety, efficacy and pharmacokinetic data will be presented at the meeting. Conclusions : SC administration of DARA + rHuPH20 was well tolerated, with lower than expected rates of IRRs in all groups, but particularly in those treated with DARA SC 1800 mg administered over only 3-5 minutes. Planned phase 3 studies will use DARA SC at the dose identified in Part 2. Disclosures Chari: Acetylon Pharmaceuticals: Other: Research funding (to AC's institution); Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Onyx: Research Funding; Pharmacyclics: Research Funding; Biotest: Other: Research funding (to AC's institution); Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Mateos: Janssen: Consultancy, Honoraria, 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lokhorst: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman: Amgen, Novartis: Research Funding; Amgen, Roche, BMS, Seattle Genetics, Sutro Biopharma, Pharmacyclics: Consultancy. Moreau: Takeda: Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol: Celgene: Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Plesner: Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Benboubker: Takeda, Celgene, Janssen, Amgen: Consultancy. Hellemans: Janssen: Employment. Masterson: Janssen: Employment. Clemens: Janssen: Employment. Liu: Janssen: Employment. San-Miguel: Takeda, Celgene, Novartis, Amgen, Janssen, Bristol-Myers Squibb: Consultancy. Usmani: Skyline: Honoraria, 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, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.
17
Moreau, Philippe, Maria-Victoria Mateos, Joan Bladé, Lotfi Benboubker, Javier de la Rubia, Thierry Facon, Raymond L. Comenzo, et al. "An Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Backbone Regimens in Patients with Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 176. http://dx.doi.org/10.1182/blood.v124.21.176.176.
Full textAbstract:
Abstract Multiple myeloma (MM) remains an incurable disease due to complex molecular abnormalities, lower sensitivity to chemotherapy of MM cells in the bone marrow microenvironment, and the emergence of drug resistance. Daratumumab (DARA) is a human IgG1κ MAb in clinical development for the treatment of MM. DARA binds to CD38 and elicits signaling cascade and immune effector function engagement leading to multiple direct and indirect mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, and induction of apoptosis. DARA binding to CD38 also modulates vital cellular enzymatic activities associated with calcium mobilization and signaling, independent of its other activities. All of these activities, in concert, lead to elimination of plasma cells from bone marrow in MM patients. DARA has shown single agent efficacy and a manageable safety profile in patients relapsed or refractory (RR) to 2 prior lines of therapy including immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) (Lokhorst HM, et al. J Clin Oncol 2014;32 Suppl 1: 8513). DARA in combination with lenalidomide (LEN) and dexamethasone (D) has also shown encouraging early efficacy and tolerability in relapsed or RR MM (Plesner T, et al. J Clin Oncol2014;32 Suppl 1: 8533). The aim of this ongoing open-label, 4-arm, multicenter, phase 1b study was to evaluate the safety, tolerability and dose regimen of DARA in combination with other MM backbone treatments including bortezomib-dexamethasone (VD), bortezomib- thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Newly diagnosed patients were included in the VD, VTD arms irrespective of transplant eligibility. Patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were RR to ≥2 lines of therapy including 2 consecutive cycles of LEN and V. Initially six patients in each arm were treated with DARA 16 mg/kg and the approved label or standard of care of each backbone treatment as follows. In the VD and VTD arms treatment was for 18 three-week cycles or until transplantation (DARA qw, 2 cycles; q3w, 16 cycles). In the VMP arm treatment was for 9 six-week cycles (DARA qw, 1 cycle; q3w, 8 cycles) and in the POM-D arm four-week cycles until disease progression (DARA qw, 2 cycles; q2w, 4 cycles; q4w remaining cycles). An independent data safety monitoring board will evaluate dose limiting toxicities (DLT) at the end of Cycles 1, 2 and 3. Combinations are considered safe and well-tolerated if a DLT is observed in ≤1 of the initial 6 patients treated with DARA 16 mg/kg for a given combination regimen and a further 6 patients will be enrolled in the VMP, VTD and POM-D cohorts. If ≥2 DLTs are observed the DARA dose is reduced for the remaining treatment cycles and additional patients may be enrolled at the reduced dose. Data from 17 subjects treated in the newly diagnosed cohorts (VD [n=5], VTD [n=6], and VMP [n=6]) are described with a median duration of treatment of 44 days (range 1 to 113 days). All subjects were treated with DARA 16 mg/kg. The median duration of treatment was 44 days (range 1 to 113 days). There was no additional toxicity when DARA was added to bortezomib-containing backbone therapy, other than infusion related reactions (IRR) specific to DARA. There were 4/17 subjects with IRRs and all events occurred on Cycle 1 Day 1, were grade 1 in severity, and resolved with supportive treatment allowing the subject to continue DARA treatment. All other AEs were consistent with those associated with the backbone agents. The most common AEs were hematologic toxicity, likely related to the backbone therapy (bortezomib, melphalan and/or thalidomide). There were three episodes of grade ≥3 neutropenia and one episode of grade 3 anemia. There were no grade ≥3 non-hematologic AEs. The most common (3 or more occurrences) grade 1 and 2 AEs included: peripheral sensory neuropathy, headache, asthenia, pyrexia, and constipation. Two episodes of rash were noted. One episode of bronchospasm, noted in a subject with a history of COPD, was classified as an IRR (VMP arm). In summary, the addition of DARA was well tolerated in all evaluable patients and did not result in significant additional toxicity. Patient enrollment and assessments of safety and efficacy are ongoing. Disclosures Moreau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Comenzo:Takeda Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding. Fay:BMS: Honoraria. Qin:Janssen Pharmaceutical Research & Development: Employment. Masterson:Janssen Pharmaceutical Research & Development: Employment. Schecter:Janssen Pharmaceutical Research & Development: Employment. Ahmadi:Janssen Pharmaceutical Research & Development: Employment. San Miguel:Millenium: Membership on an entity's Board of Directors or advisory committees; 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.
18
Young, Guy, Robert F. Sidonio, Ri Liesner, Johannes Oldenburg, Tiffany Chang, Marianne Uguen, Christophe Dhalluin, et al. "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 (December 7, 2017): 85. http://dx.doi.org/10.1182/blood.v130.suppl_1.85.85.
Full textAbstract:
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.
19
Clemens, Pamela L., Steven Xu, Melody Luo, Ajai Chari, Saad Z. Usmani, Maria-Victoria Mateos, Niels WCJ van de Donk, et al. "Pharmacokinetics (PK) of Subcutaneous Daratumumab in Patients with Relapsed or Refractory (RR) Multiple Myeloma (MM): Primary Clinical Pharmacology Analysis of the Open-Label, Multicenter, Phase 1b Study (PAVO)." Blood 132, Supplement 1 (November 29, 2018): 2006. http://dx.doi.org/10.1182/blood-2018-99-113161.
Full textAbstract:
Abstract Introduction: Subcutaneous (SC) administration offers several potential advantages for patients (pts) and healthcare providers, including shorter administration times, reduced administration volume, and fewer infusion-related reactions. Daratumumab (DARA), a human IgGκ anti-CD38 monoclonal antibody, has direct on-tumor and immunomodulatory effects. DARA is approved for intravenous (IV) administration as monotherapy for RRMM and in combination with standard of care regimens for RR and newly diagnosed MM. Previous analyses demonstrated that maximum DARA trough concentration (Ctrough), which occurs at the end of weekly dosing, was highly correlated with efficacy in MM (Xu XS, et al. Clin Pharmacol Ther 2017. 101[6]:721-724), but no relationship was observed between DARA concentrations and adverse events. SC administration of DARA in combination with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is being evaluated in an open-label, phase 1b trial (PAVO) to identify a fixed SC dose which is safe and achieves a similar or greater maximum Ctrough as compared with the 16 mg/kg IV dose. Here, we present the clinical pharmacology of SC DARA, including the development of a combined IV-SC population PK (PPK) model. Methods: In PAVO, eligible RRMM pts received ≥2 prior lines of therapy. In Part 1, 2 sequential cohorts received fixed dose regimens of a mix and deliver SC formulation of DARA and rHuPH20 (DARA MD) at 1,200 mg (n = 8; 60 mL) and 1,800 mg (n = 45; 90 mL) doses in 20 and 30 minutes, respectively, on the same schedule as the approved DARA monotherapy IV regimen (QW for Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter; 4-week cycles). A dose that was safe and provided similar or greater Ctrough values on Cycle 3 Day 1 (C3D1) compared with the 16 mg/kg IV dose was selected for Part 2. In Part 2, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial (DARA SC) was administered over 3-5 minutes by manual SC injection. Co-primary endpoints were safety and Ctrough at the end of QW dosing. Serial PK sampling was performed after the first and last weekly dose; sparse PK and immunogenicity was collected at additional timepoints. A mixed-effects 2-compartment PK model based on Michaelis-Menten approximation of target-mediated drug disposition was developed, and PK data used in this PPK analysis were from Part 1 of PAVO (n = 53) and from GEN501/MMY2002 (IV DARA monotherapy; n = 223) studies. Model-based simulations were conducted to facilitate dose selection. Results: In Part 1, the mean C3D1 Ctrough following 1,800 mg DARA MD was similar or higher than that observed for 16 mg/kg IV (Table). The PPK model predicted approximately 88% of pts receiving DARA MD 1,800 mg would achieve the effective concentration of 274 μg/mL vs 73% of pts receiving DARA MD 1,200 mg and 80% of pts receiving 16 mg/kg IV. Simulated PK profiles indicated that both DARA MD doses result in smaller peak-to-trough fluctuation compared to IV dosing, and that 1,800 mg provides higher Ctrough throughout the dosing period without increasing Cmax compared to IV dosing (Usmani SZ, et al. ASH 2016. Abs. 1149). Across a range of simulated body weights, exposure following DARA MD 1,800 mg was similar or slightly higher than for 16 mg/kg IV. Based on these data, the 1,800 mg dose was selected for further evaluation in Part 2. The primary PK endpoint of mean C3D1 Ctrough was slightly higher for DARA SC 1,800 mg than the DARA MD 1,800 mg cohort and 16 mg/kg IV dose (Table). The range of Ctrough observations for the SC cohorts were within the range observed with 16 mg/kg IV (Figure). The observed Cmax of DARA SC 1,800 mg after the first and last weekly dose was within the range of that for 16 mg/kg IV; inter-pt variability for SC administered DARA was also similar across all cohorts. One pt (1%) was positive for DARA anti-drug antibodies and 13% of pts were positive for anti-rHuPH20 antibodies in PAVO; all had no apparent clinical complications. Conclusions: The fixed DARA SC 1,800 mg dose provided a similar or higher C3D1 Ctrough when compared to historical data with 16 mg/kg IV. A combined IV-SC PPK model using a concentration- and time-dependent clearance of DARA described the PAVO data well. Immunogenicity of DARA and rHuPH20 was similar to previous experience. These data validated the dose selection of 1,800 mg for ongoing phase 3 clinical trials of DARA SC in MM, smoldering MM, and amyloidosis. Disclosures Clemens: Janssen Research & Development, LLC: Employment. Xu:Janssen Research & Development, LLC: Employment. Luo:Janssen Research & Development, LLC: Employment. Chari:Array Biopharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Abbvie: Consultancy; Roche: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Takeda: 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; Amgen: 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. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. San-Miguel:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Janssen: Honoraria. Sun:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. Masterson:Janssen Research & Development, LLC: Employment. Hellemans:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment.
20
Grainger, John, James B. Bussel, Michael D. Tarantino, Nichola Cooper, Donald Beam, Jenny M. Despotovic, Alexey A. Maschan, Kejia Wang, Melissa Jeanne Eisen, and Charles Bowers. "Updated Results from the Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)." Blood 134, Supplement_1 (November 13, 2019): 1095. http://dx.doi.org/10.1182/blood-2019-131241.
Full textAbstract:
Background: Romiplostim, a thrombopoietin (TPO) receptor agonist approved for children and adults with chronic ITP, was evaluated in children with ITP in a ≤3-year open-label trial. Interim results were previously reported (Grainger et al., Blood 2017 130:2334). Here we present updated results as of 27 Mar 2019. Methods: Eligible children from 17 countries with ITP for ≥6 months and screening platelet count ≤30×109/L (or uncontrolled bleeding) received SC romiplostim (1 μg/kg titrated to 10 μg/kg to maintain platelet counts of 50-200×109/L). In Europe, bone marrow was evaluated at baseline and after 1 (day 365 ± 4 weeks) or 2 (day 730 ± 4 weeks) years. The primary endpoint was % time with a platelet response (platelet count ≥50×109/L, no rescue therapy in preceding 4 weeks) in months 0-6. Results: A total of 203 patients (pts) received ≥1 dose; the median (interquartile range [IQR]) age was 10 (6-13) and median (IQR) platelet count 14 (7-23.5×109/L). The median (IQR) duration of treatment was 145 (39-156) weeks, median (IQR) % of time with a platelet response in months 0-6 was 50% (17-83%), with 88% (179/203) of pts having a platelet response at least once (Fig. 1A). In all pts, the median (IQR) % of time with an increase in platelet counts ≥20×109/L above baseline from week 2 until the end of treatment was 79% (39-92%). Median and lower quartile platelet counts were both consistently >50×109/L from week 12 and 48, respectively, and did not vary by age. Eleven pts maintained platelet counts ≥50×109/L without ITP medications (including romiplostim) for ≥24 weeks; median (IQR) time to onset was 50 (24-80) weeks after starting romiplostim. During the study, 60 (30%) pts received rescue therapy, typically within weeks 1-36, and 3 underwent splenectomy. With a total exposure of 428.7 patient-years, median (IQR) average weekly romiplostim dose over the entire study was 6.9 (4.6-8.9) µg/kg; 8.5 (5.0-10.0) μg/kg at 1 year (n=144) and 6.0 (3.0-10.0) μg/kg at 2 years (n=129; Fig. 1B). Self-administration was initiated in 68% of pts. Ninety-five pts (46.8%) discontinued treatment: reasons included lack of efficacy (n=43 [21.2%]), patient request (n=15 [7.4%]), adverse event (AE; n=9 [4.4%]), and neutralizing antibodies (NAb; n=7 [3.4%]). AEs occurred in 192 pts (94.6%); the most frequent were epistaxis (38.4%), headache (37.9%), and nasopharyngitis (36.9%). Serious AEs (SAEs) occurred in 59 (29.1%) pts, including epistaxis (5.9%), decreased platelet count (4.4%), and thrombocytopenia and NAb (2% each); 8 pts had treatment-related SAEs (NAbs [n=4], headache and abdominal pain [each n=2], and presyncope [n=1]). Bleeding occurred in 69% of pts over the study, decreasing over time, with bleeding in 18% of pts from week 144 to the end of treatment. Bleeding-related AEs occurring in >10% of pts were epistaxis (38.4%), petechiae (23.6%), hematoma (20.7%), contusion (19.2%) and gingival bleeding (10.3%). CTCAE grade ≥3 bleeding events occurred in 20 pts (9.9%) and included epistaxis (n=9 [4.4%]), and persistent ITP (n=3 [1.5%]). In pts with no evidence of NAbs at baseline, there were 7 cases of NAbs to romiplostim (2 were transient) and 1 transient NAbs to TPO; only 1 pt, with NAbs to romiplostim, had a reduced therapeutic effect. Of 75 European pts with evaluable baseline bone marrow biopsies [modified Bauermeister scores: grade 0 (no reticulin, n=16), 1 (fine fibers, n=54), or 2 (fine fiber network, n=5)], 27 had evaluable on-study biopsies after 1 year and 36 after 2 years (Table). Of these, 5 pts developed increased reticulin at year 1 and 17 at year 2. One pt had an increase in modified Bauermeister score from baseline of ≥2 grades (increase from grade 0 to 2), 4 pts had an increase in 1 grade, 1 a decrease in 2 grades, and 3 a decrease in 1 grade in year 1. In year 2, 15 pts had an increase in 1 grade and 3 pts a decrease in 1 grade. No pts developed collagen and no bone marrow abnormalities were detected. Conclusion: Over the course of the study with >30 months of treatment, on a median dose of 6.9 μg/kg, 88% of children had a platelet response, median platelet counts were ≥20×109/L above baseline 79% of the time and >50×109/L from week 12. An important new safety signal over 429 patient-years was the 3.4% of NAbs to romiplostim; children develop NAbs with romiplostim more frequently than adults. Bone marrow findings showed that children, like adults, did not develop clinically important fibrosis. Disclosures Grainger: Amgen: Consultancy, Speakers Bureau; Ono: Consultancy; Alexion: Consultancy; ITP Support Association: Other: medical advisor; Octapharma: Consultancy; Biotest: Consultancy; Novartis: Consultancy, Speakers Bureau. Bussel:Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; 3S Bio: Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tarantino:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator initiated study, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Pfizer: Other: PI for program grant; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI; Grifols: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cooper:Novartis: Honoraria, Other: clinical trial; Principia: Honoraria, Other: clinical trial; UCB: Other: clinical trial; Rigel: Honoraria, Other: clinical trial; Amgen: Honoraria, Other: clinical trial. Despotovic:Novartis: Research Funding; Dova: Honoraria. Wang:Amgen: Employment. Eisen:Amgen: Employment, Other: stock ownership. Bowers:Amgen: Employment, Other: stock ownership.
21
Usmani, Saad Z., Hareth Nahi, Maria-Victoria Mateos, Henk M. Lokhorst, Ajai Chari, Jonathan L. Kaufman, Philippe Moreau, et al. "Open-Label, Multicenter, Dose Escalation Phase 1b Study to Assess the Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (PAVO)." Blood 128, no. 22 (December 2, 2016): 1149. http://dx.doi.org/10.1182/blood.v128.22.1149.1149.
Full textAbstract:
Abstract Introduction : Daratumumab (DARA), a human CD38 IgG1κ monoclonal antibody, has demonstrated single agent efficacy while being highly tolerable as a monotherapy, and significant efficacy in combination with standard-of-care regimens in pts with multiple myeloma (MM) who have received ≥1 prior lines of therapy (Lokhorst HM. NEJM 2015, 373(13):1207-19; Lonial S. Lancet 2016, 387:1551-60;Palumbo A. NEJM 2016, in press; Dimopoulos MA. NEJM 2016, in press). DARA is currently administered as an intravenous (IV) infusion. Subcutaneous (SC) delivery of DARA is being tested in combination with the recombinant human hyaluronidase enzyme (rHuPH20) to facilitate systemic absorption of DARA after SC infusion into the abdominal wall. PAVO is the first study to assess the safety, pharmacokinetics, and efficacy of SC administration of DARA plus rHuPH20 (DARA-PH20) in pts with relapsed or refractory MM (RRMM). Methods : Pts had RRMM with ≥2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Part 1 of the 2 part study enrolled sequential cohorts at 1200 mg and 1800 mg DARA dose levels to determine the recommended SC dose for Part 2. DARA-PH20 was administered in 4-week treatment cycles: QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter. DARA-PH20 was infused in 1200 mg doses in 60 mL over 20 min or 1800 mg in 90 mL over 30 min, via a syringe pump at rotating sites on the abdomen. Pre- and/or post-infusion medications included paracetamol, diphenhydramine, montelukast, and methylprednisolone. In part 2, pts will be randomized 1:1 to receive the recommended phase 2 dose (RP2D) of SC DARA-PH20 or IV DARA (16 mg/kg). The RP2D of DARA-PH20 will be selected based on a cumulative review of the pharmacokinetic and safety data obtained from part 1 and should achieve a maximum serum Ctrough during weekly dosing that is similar to or higher than that observed for the approved 16 mg/kg IV dose. Primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR). Results : To date, 41 pts were treated in part 1 with SC DARA-PH20 at the 1200 mg (n=8) and 1800 mg (n=33) dose levels. Infusion related reactions (IRRs) were reported in 9/41 pts (22%) and were mostly grade 1/2 in severity including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain and wheezing. One pt developed grade 3 dyspnea and 1 pt required hospitalization due to fever and chills (both grade 2) after the first infusion. All IRRs developed during or within 6 hours of the first SC infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. No IRRs were reported with subsequent infusions. Overall, the adverse event profile of DARA-PH20 was consistent with that of IV DARA. Grade 3 or higher drug-related adverse events were reported in 5/41 (12%) pts including fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome. SC administration of DARA-PH20 was well tolerated at the abdominal wall injection site with 3/41 (7%) pts reporting grade 1 erythema, induration, or burning sensation. Analysis showed a higher max Ctrough in the 1800 mg cohort in comparison to the max Ctrough achieved following IV DARA (16 mg/kg). In the 1200 mg cohort of 8 pts (median of 5 lines of prior therapy [range 2-10]; prior ASCT, 63%; PI refractory only, 0%; IMiD refractory only, 13%; double refractory to PI and IMiD, 63%) a 25% ORR was observed including 2 partial responses (PR). Median time to response was 14 (range 8-20) weeks. Among 17 response evaluable pts in the 1800 mg cohort with cycle 3 day 1 assessments (median of 4 prior lines of therapy [range 2-7]; prior ASCT, 76%; PI refractory only, 6%; IMiD refractory only, 12%; double refractory to PI and IMiD, 65%) a 41% ORR was observed consisting of 3 very good partial responses and 4 PRs. Median time to response was 4 (range 4-8) weeks. Conclusions : SC DARA-PH20 was well tolerated and achieved serum trough concentrations similar to or greater than IV DARA with a lower rate of IRRs compared to IV DARA over a significantly shorter infusion time. Preliminary data suggest that in this pt population SC DARA-PH20 may enable similar response rates to IV DARA monotherapy. The 1800 mg dose level of DARA-PH20 was selected as the RP2D for part 2 of the study. These early data support further study of SC DARA in clinical trials. Additional data on pts from part 1 will be presented at the meeting. Disclosures Usmani: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding. Chari:Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding. Kaufman:Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy. Moreau:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hellemans:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment. Clemens:Janssen: Employment. Ahmadi:Janssen: Employment. Liu:Merck: Equity Ownership; Janssen: Employment; J&J: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.
22
Bussel, James B., Michael D. Tarantino, Amy Geddis, Michael F. Guerrera, Alan K. Ikeda, Kun Nie, Janet Franklin, and Melissa Eisen. "Safety and Efficacy of Long-Term Open-Label Dosing of Romiplostim in Thrombocytopenic Pediatric Patients (Pts) with Immune Thrombocytopenia (ITP)." Blood 124, no. 21 (December 6, 2014): 4184. http://dx.doi.org/10.1182/blood.v124.21.4184.4184.
Full textAbstract:
Abstract Background: Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim, a TPO receptor agonist that stimulates platelet production, increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 study. Pts who completed that study or an ongoing phase 3 study could roll over into this open-label long-term extension; data from up to 4.2 years of romiplostim in this extension are described here. Objectives: To describe the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods: All pts received SC romiplostim weekly (QW); the starting dose was the last dose given in the parent study or 1 μg/kg (for those who had previously received only placebo or who had not received romiplostim for >24 wk). Doses could be adjusted up to 10 µg/kg to achieve target platelet counts in the range of 50-200×109/L. The primary endpoint was incidence of adverse events (AEs). Assessments of AEs, concomitant medications, and local platelet counts were performed QW. For pts who maintained platelet counts of ≥50×109/L for ≥4 consecutive wk at a stable romiplostim dose, they or their caregivers, if deemed appropriate by the investigator, could learn to self-administer subsequent romiplostim doses. Pts who self-administered romiplostim had monthly assessments (not QW). Pts and/or their caregivers recorded dosing date, time, volume administered, and any dosing errors. Pts who turned 18 years of age were permitted to remain on study. Results: 40 pts (12 from the phase 1/2 study and 28 from the phase 3 study) entered the extension; 39 received romiplostim for up to 217 wk (4.2 yrs); 1 pt withdrew consent before receiving romiplostim. At extension study baseline, median age was 11 years (range 3-16), 55% were female, and 12.5% had prior splenectomy. Median (range) romiplostim treatment duration was 40 wk (5–217); median total number of doses was 37 (5–216); median average QW romiplostim dose was 6 µg/kg (1–10 µg/kg), including dose escalation to achieve a stable dose; median maximum dose was 8 µg/kg (1–10 µg/kg). 10 pts discontinued the study: consent withdrawn (n=5), noncompliance (2), administrative decision (2), and non-response (1). No pts withdrew due to AEs and 30 continued on study. After the first wk of the extension, which for some pts was their first wk of romiplostim, median platelet counts remained >50×109/L and were in the target range of 50-200×109/L, except for wk 76 and 156, when they were just above 200×109/L (Figure). Q1 platelet counts were >50×109/L from wk 16 on. The median (Q1, Q3) romiplostim dose was 5 (1, 9) µg/kg at wk 1 and 5 (1, 6) µg/kg at wk 216 (Figure). The median dose fell from 6 µg/kg to 3 µg/kg; from Week 172 on (n≤8), it started to rise and fluctuate. 11 pts received rescue medications (for platelet counts <10×109/L, bleeding/wet purpura, or investigator decision), including IV immunoglobulin (n=4), tranexamic acid (2), prednisone (3), platelet transfusion (1), and aminocaproic acid (1). The 21 instances of rescue treatment for 11 pts occurred: in the first 3 months (12 instances), >3–6 months (4), >6–12 months (4), and after 1 year (1) of romiplostim treatment. 7 pts had 13 serious AEs (asthma, epistaxis, gastroenteritis, gastrointestinal infection, hemangioma, infection, mouth hemorrhage, pain, pharyngitis, pyrexia, tachycardia, transfusion reaction, and viral infection) and 3 had life-threatening AEs (infection, n=1, thrombocytopenia, n=2); none were fatal. None of the serious or life-threatening AEs were deemed treatment-related by the investigators. 30 pts had bleeding AEs, which were deemed treatment-related in 2 pts (gingival bleeding and petechiae). Bleeding AEs occurring in ≥2 pts included contusion (n=11), epistaxis (9), petechiae (8), gingival bleeding (7), ecchymosis (3), hemorrhage (3), injection site bruising (3), mouth hemorrhage (3), and injection site hemorrhage (2). No bone marrow biopsies were performed and no thrombotic events were reported. Conclusion: In this open-label extension, long-term treatment with romiplostim (up to 4.2 yrs) maintained platelet counts in pediatric pts with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with chronic ITP. Figure Figure. Disclosures Bussel: Cangene: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Use of romiplostim in pediatric patients is under investigation.. Tarantino:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Nie:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.
23
Jurczak, Wojciech, Pier Luigi Zinzani, Georg Hess, Gianluca Gaidano, Mariano Provencio, Zsolt Nagy, Tadeusz Robak, et al. "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 (November 13, 2019): 4078. http://dx.doi.org/10.1182/blood-2019-124297.
Full textAbstract:
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.
24
Witzig, Thomas E., Lubomir Sokol, Eric D. Jacobsen, Won-Seog Kim, Francine M. Foss, Ranjana H. Advani, Jose Maria Roncero Vidal, et al. "Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study." Blood 132, Supplement 1 (November 29, 2018): 2937. http://dx.doi.org/10.1182/blood-2018-99-116277.
Full textAbstract:
Abstract Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.
25
Keefe, Peter J., Margaret C. Morrissey, Catherine E. McGuinn, and James B. Bussel. "Randomized Double-Blind Study of Increasing Doses of Eltrombopag in Patients with Chronic ITP." Blood 126, no. 23 (December 3, 2015): 1057. http://dx.doi.org/10.1182/blood.v126.23.1057.1057.
Full textAbstract:
Abstract Background: Eltrombopag (Epag) is an oral thrombopoietin receptor agonist used to increase platelet counts in patients with chronic immune thrombocytopenia (cITP). The maximum licensed Epag dose in cITP patients is 75 mg daily, yet some patients do not respond at this dose. Healthy individuals on escalated doses of eltrombopag (100-200 mg) demonstrated a dose dependent platelet response as did patients with thrombocytopenia secondary to chemotherapy. Doses of 100 mg and 150 mg have been approved for use in patients with hepatitis-C induced thrombocytopenia and aplastic anemia respectively. This is the final report of a double-blind, randomized controlled study to determine if Epag, administered at doses up to 150 mg daily, increases platelet counts in cITP patients who failed to respond to 75 mg. Methods: cITP patients³ 1 year old with platelet counts <50,000uL despite >3 weeks of 75mg of Epag daily), stratified by splenectomy status, were enrolled. Patients could continue stable doses of concomitant ITP medications. In the randomized blinded phase (Part 1), patients first received 75 mg daily of active Epag and 25 mg of study drug (Epag or placebo, 2:1). Every two weeks, study drug doses were increased in 25 mg increments to a maximum daily dose of 150 mg. After 8 weeks subjects were unblinded. If on active drug, they entered the open label phase (Part 2); if on placebo, they received open label Epag as per the study protocol escalating to a maximum dose of 150 mg. Two patients entered part 2 before 8 weeks because their counts were >100,000/uL in the blinded phase. Data analysis was descriptive. Mann Whitney U test estimated p-values (α<.05) or platelet count differences between groups. Imputation of platelet counts allowed omitting falsely high or low platelet counts resulting from rescue therapy (e.g. IVIG), or counts in3 patients discontinuing early with good responses after 2, 2, and 4 weeks who thereby did not have counts at weeks 4, 6, and 8. Interim analysis was pre-specified and data is included on 33 of the planned total of 36 patients. Results: As of July 31, 35 patients consented; 26 completed ³8 weeks on study medication. Two patients are in part 1 and 7 dis-enrolled before completing 8 weeks of study drug: 5 failed screening and never received medication; one had bleeding and low counts on placebo; and one had pre-existing reticulin fibrosis 2-3+, discovered after study drug was dispensed but not administered. The most common adverse event (AE) was minor bleeding. Two adults and 2 children developed transaminitis, which was life-threatening in 1 adult on 100mg. The 4 liver AEs occurred between 2 and 20 weeks of Epag dosing with 3/4 subjects on 150 mg daily; 2/4 discontinued Epag. No strokes or thromboembolic events were seen nor did any cataracts develop. Three patients underwent bone marrows: no grade 2-3 fibrosis was seen. Platelet counts for patients on active drug vs placebo separated by week 2 (Figure 1A) and the difference steadily increased until week 8 (p<0.07) reflecting the thrombopoietic effects of increased dose Epag. Increased eltrombopag doses had greater effect in children (avg age 13) than adults (avg age 51) [Figure 1B]. This may reflect more rapid drug metabolism or relative insensitivity to the effects of Epag in children or both; this was first noted in PETIT and PETIT2. Twenty-six patients entered the long-term open-label study. Three discontinued prior to 24 weeks because of transaminase elevation (1) and no response (2); 7 are not yet at 24 weeks; and 6 were also on other treatments, ie IVIG at increased intervals while on Epag, obscuring their responses. Ten patients were on open label medication for >24 weeks past the 8 weeks in part 1 up to 110 weeks. 72% of the long-term counts in these 10 patients were > 50,000/uL while 40% were > 100,000/uL. Six patients took 150 mg daily for >24 weeks while 4 reduced their doses, though not to <75mg daily. Conclusions: The results demonstrate that Eltrombopag at doses of 100-150mg daily can elevate platelet levels in most children and adults with cITP whose platelet counts were <50,000 on 75mg of Epag daily for >3 weeks. Children responded better to increased doses of Epag than did adults and high dose Epag can be used long term without development of cataracts, strokes or other thromboembolic events although an increased frequency of liver events, 12%, occurred. Although the 150 mg dose can be safely continued for many months, monitoring transaminases is essential. Disclosures Off Label Use: Increased doses of eltrombopag. McGuinn:Baxter: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bussel:Momenta: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; BiologicTx: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Amgen: 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; Protalex: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding.
26
Perkins, Andrew Charles, Kate Burbury, Thomas Lehmann, David M. Ross, Andreas Reiter, Vikas Gupta, Claire Harrison, et al. "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 (November 5, 2020): 52–53. http://dx.doi.org/10.1182/blood-2020-140408.
Full textAbstract:
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.
27
Michel, Marc, Marco Ruggeri, Tomás José González-López, Stephane Cheze, Waleed Ghanima, Tor Henrik Anderson Tvedt, Mikael Ebbo, James B. Bussel, and Bertrand Godeau. "Safety and Efficacy of the Off-Label Use of Thrombopoietin Receptor Agonists for Immune Thrombocytopenia in Pregnancy: Results from a Multicentre Observational Study." Blood 134, Supplement_1 (November 13, 2019): 1081. http://dx.doi.org/10.1182/blood-2019-122595.
Full textAbstract:
Introduction: The management of immune thrombocytopenia (ITP) in pregnancy can be challenging as some patients either do not respond to or tolerate corticosteroids and intravenous immunoglobulin and only very few alternative ITP therapies are available during pregnancy. The use of thrombopoietin receptor agonists (Tpo-RA) which are likely to cross the placenta is not recommended during pregnancy but both romiplostim and eltrombopag have been exceptionally used to treat women with severe and refractory ITP during pregnancy. To better assess safety and efficacy of Tpo-RA during pregnancy, we performed an international multicentre observational retrospective study. Methods: To be included, the patients had to fulfill the following criteria: pregnant woman aged of 18 years and above, diagnosis of primary or secondary ITP according to international consensus guidelines, use of either eltrombopag of romiplostim for at least 1 week for treating ITP during pregnancy (before delivery), at least a month of follow-up after Tpo-RA initiation. Women who became pregnant while on Tpo-RA could be included even if the treatment was stopped if enough data on pregnancy outcome were available. Women treated with a Tpo-RA during pregnancy not for ITP were excluded. All clinical and biological data were collected by means of a standardized study form, whenever available, data on the neonates were also collected and analyzed. Data are presented as mean±SD or median (interquartile range [IQR]) for continuous variables, depending on their distribution. Categorical variables are presented as number (%). Results: In total, 12 women (mean age at time of pregnancy was 30.3 ± 5 years) fulfilling the eligibility criteria were included, for a total of 13 pregnancies and 14 neonates (one twin pregnancy) with an exposure to Tpo-RA. Nine of 12 patients had pre-existing chronic primary ITP (mean ITP duration = 11.8 ± 10.1 years) whereas ITP was newly-diagnosed during pregnancy in 3 cases. The median number of treatment-lines before the use of Tpo-RA was 3 [range 2-7] including splenectomy for 5 patients. Patients were treated transiently during pregnancy with either eltrombopag (n = 6; mean daily dose 50mg) or romiplostim (n = 6; mean maximal weekly dose 7.4 microg/kg). Two patients with chronic ITP were already on Tpo-RA when pregnancy was confirmed, and for 8 pregnancies, treatment with Tpo-RA was initiated only within 4 weeks before term in preparation for delivery. The median time of exposure to Tpo-RA during pregnancy was 4.4 weeks [range: 1-12 weeks]. No side-effects and especially no thromboembolic events were observed; none of the patients was on thromboprophylaxis. The mean platelet count at term was 91 x 109/L (median = 94 x 109/L [6-250]). Delivery occurred pre-term in 4 out of 13 pregnancies, mode of delivery was vaginal in 8 out of 13 pregnancies (with an epidural in 4 cases) and a C-section in 5. The platelet count was available at birth in 10 out of 13 neonates and neonatal thrombocytopenia was found in 5 (including 3 from the same mother). No case of neonatal thrombocytosis was observed. No neonatal complications attributable to the exposure to a TpoRA in the mother was observed. One neonate (whom the mother received 1 week of romiplostim in preparation for delivery) was diagnosed with trisomy 8 and died on day 7 and another neonate had a pulmonary artery stenosis diagnosed during fetal life (before the initiation or Tpo-RA in the mother), that was successfully operated at 2 weeks of life. A complete platelet response (CR) was achieved on Tpo-RA during pregnancy in 8/12 patients (66%) (5 of them received concomitant ITP therapy), a response (R) in 2 whereas no response was achieved in 2 patients with refractory ITP (table). Conclusion: Based on this preliminary results on a relatively small number of patients (more cases are expected) and taking into account that Tpo-RA was used only in preparation for delivery in 7/13 pregnancies, a temporary off-label use of a Tpo-RA over a short period of time for ITP during pregnancy seems safe for the mother and the neonate. The pattern and magnitude of response seems comparable to what is observed outside pregnancy but only few patients were treated with Tpo-RA alone. For now, the transient use of Tpo-RA during pregnancy should only be considered exceptionally for women with severe and refractory ITP. Disclosures Michel: Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Ghanima:Amgen: Consultancy, Honoraria; Bayer: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer/BMS: Research Funding. Anderson Tvedt:Alexion: Other: Advisory Board; Ablynx: Other: Advisory Board; Novartis: Other: Advisory Board. Bussel:Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Godeau:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. OffLabel Disclosure: It reports some data about the use of either romiplostim or eltrombopag (thrombopoietin receptor agonists) to treat ITP during pregnancy. Both drugs are licensed for adult' ITP but are not supposed to be used in pregnant women
28
Verstovsek, Srdan, Robert P. Hasserjian, Olga Pozdnyakova, Ivo Veletic, Ruben A. Mesa, Lynda Foltz, John Mascarenhas, et al. "PRM-151 in Myelofibrosis: Efficacy and Safety in an Open Label Extension Study." Blood 132, Supplement 1 (November 29, 2018): 686. http://dx.doi.org/10.1182/blood-2018-99-115362.
Full textAbstract:
Abstract Introduction: PRM-151, a recombinant human pentraxin-2 molecule, has been shown to prevent and reverse fibrosis in animal models of myelofibrosis (MF) by postulated targeting differentiation of fibrocytes (essential cells in fibrotic process) from monocytes. In the first stage of a two-stage trial, 27 patients (pts) with primary myelofibrosis (PMF), post-essential thrombocythemia/polycythemia vera (post-ET/PV) MF, and Grade 2 or 3 bone marrow fibrosis (BMF) received PRM-151 10 mg/kg IV ± ruxolitinib (RUX) for 6 cycles (24 weeks). A reduction in BMF, decrease in symptoms (MPN-SAF Total Symptom Score [TSS]), and a reduction of palpable splenomegaly were observed, along with a favorable safety profile. Pts experiencing clinical benefit were allowed to continue beyond 24 weeks in an open label extension (OLE) study. Here, we report interim efficacy and safety data for 18 pts enrolled in the OLE, who had been treated for up to 35 cycles (140 weeks). Methods: All pts in the OLE received a monthly infusion of PRM-151 10 mg/kg IV. Pts receiving PRM-151 alone or in combination with RUX in the main study continued with their respective drugs. Safety and hematology parameters were assessed monthly, and MPN-SAF TSS Q3 months. BM biopsies were obtained at baseline, end of main study, and at physician discretion in the OLE. These were evaluated centrally by two independent, blinded hematopathologists for the degree of reticulin and collagen fibrosis. Immunostaining for fibrocytes was performed on available biopsies. The primary objective of the OLE was to assess safety and efficacy of long-term administration of PRM-151. Results: Of the 18 pts enrolled in the OLE, 9 received PRM-151 as single agent, and 9 in conjunction with RUX. Baseline characteristics included median age of 66 years (51-78); 8 pts were DIPSS Int-1, 9 Int-2, and 1 high-risk; 6 (33%) had Hgb < 100 g/L, 12 (67%) had PLT < 100 x 109/L; 7 (39%) had PLT <50 x 109/L; 8 pts had PMF, 10 had post-ET/PV MF; 13 pts (72%) had a palpable spleen, and 9 (50%) had Grade 3 BMF. Median time on study for these 18 pts was 30.9 months (15.9-47.2 months). All pts experienced at least 1 adverse event (AE), with 8 pts (44%) reporting a possible study drug-related AE. No unexpected AEs were observed, and no deaths were reported during the study period. The mean best percent change (by palpation) in spleen size from baseline was −37%, with a median percent reduction of −26.1% (Figure). The mean best percent improvement in MPN-SAF TSS was −54%, with a median percent reduction of TSS of −64%. Pts in the PRM-151 monotherapy group showed similar improvements in MPN-SAF TSS and splenomegaly as those receiving PRM-151 + RUX (Figure). Complete data on hematology parameters will be available at the time of presentation. Improvement in BM reticulin grade was observed in 5 of 7 pts (71%) with Grade 2 BMF at baseline, and in 4 of 9 pts (44%) with Grade 3 BMF at baseline. Of the pts with Grade 3 BMF at baseline, 2 of 9 pts (22%) had a 2-grade reduction (Table). In addition, 5 of 6 pts (83%) with Grade 2 collagen fibrosis at baseline had a 1-grade reduction, with 2 of 6 pts (33%) improving to Grade 0. Also, 2 of 7 pts (28%) with Grade 3 collagen fibrosis had a reduction of 1-grade with 1 of 7 (14%) improving to Grade 0 (Table). Eight of 18 pts had BM fibrocyte immunostaining done: mean fibrocyte count in the hematopoietic BM decreased from 378.0 ± 255.3 per mm2 (11.2 ± 7.7% of total cells) at study baseline to 81.3 ± 86.5 per mm2 (2.0 ± 2.1% of total cells; 7 of 8 pts evaluable) at cycle 25, with continuous reduction in fibrocyte numbers observed at interim. Over the same period, improvement in BM reticulin grade was detected in 4 of 7 pts (57%), and collagen fibrosis grade was decreased in 3 of 7 pts (43%). Conclusions: This long-term follow-up study of 18 pts with MF who received PRM-151 for a median of 31 months showed the drug to be well tolerated. An overall improvement in BM reticulin and collagen fibrosis grade, as well as reductions in MPN-SAF TSS and splenomegaly were observed. In a subset of pts for whom bone marrow fibrocyte immunostaining data were available, a mean reduction in fibrocyte counts was observed, as well as improved bone marrow reticulin and collagen fibrosis grade. These data warrant confirmation in a larger controlled study. Figure. Figure. Disclosures Verstovsek: Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Pozdnyakova:Promedior, Inc.: Consultancy. Mesa:Promedior: Research Funding; Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Galena: Consultancy; Gilead: Research Funding; CTI: Research Funding. Foltz:Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Roche: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding. Ritchie:Astellas Pharma: Research Funding; NS Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Palmer:Novartis: Research Funding. Kremyanskaya:Incyte: Research Funding. van den Blink:Promedior, Inc.: Employment. Gupta:Promedior, Inc.: Employment. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
29
Ribrag, Vincent, Julio C. Chavez, Jason B. Kaplan, Umberto Vitolo, Jason C. Chandler, Armando Santoro, Paolo Corradini, et al. "A Phase 1b, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma: CC-122-DLBCL-001." Blood 128, no. 22 (December 2, 2016): 1849. http://dx.doi.org/10.1182/blood.v128.22.1849.1849.
Full textAbstract:
Abstract Background: Relapsed/refractory (R/R) DLBCL remains an unmet medical need with no approved or standard therapy in the third-line setting. Several new promising classes of drugs are being developed based on emerging understanding of the molecular pathology of DLBCL. These include CC-122, a pleiotropic pathway modifier that promotes CRBN-dependent Aiolos and Ikaros degradation, CC-223, a potent selective ATP-competitive inhibitor of mTOR kinase, and CC-292, a highly selective irreversible-inhibitor of Btk. Early phase studies with these compounds indicated single-agent activity in B cell malignancies including DLBCL. CC-122-DLBCL-001 is a Phase 1b dose escalation and expansion study of CC-122, CC-223 and CC-292 administered orally as doublets, and as triplets in combination with rituximab (R), as well as a CC-122 plus R doublet, in subjects with high risk R/R DLBCL. Methods: The dose escalation phase of the study explores combinations of one or more doses for each novel agent using a modified 3+3 dose escalation design with higher dose cohorts including the addition of a fixed dose of rituximab 375 mg/m2 IV Q28 days. CC-122 1mg, 2mg, 3mg, or 4mg is given orally QD or for 5 out of 7 days/week (5/7d). CC-223 15mg, 20mg, or 30mg is given orally QD. CC-292 500mg is given orally BID. Subjects were treated until progression or intolerable side effects. Study endpoints were: safety, tolerability, PK, PD and preliminary efficacy [overall response rate (ORR) and complete response (CR)]. Subjects were considered efficacy evaluable if they received at least one cycle of treatment and had one post-baseline tumor assessment. Peripheral blood PD biomarkers on treatment were compared to baseline levels by flow cytometry for CC-223 mTOR pathway targets p4EBP1 and pAKT and CC-122 target Aiolos. CC-292 500mg BID was previously demonstrated to result in >90% Btk receptor occupancy at 24 hours (Blood 2013 122:4169). Results: As of May 02, 2016, a total of 102 subjects were enrolled into the ongoing dose escalation phase of the study. The median no. of prior anti-lymphoma regimens was 3 (range, 1-10), 30% had prior ASCT and 30% were refractory to any prior therapy. Arm A (CC-122 + CC-223 +/- R) enrolled 31 subjects (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common (> 10%) related grade 3/4 adverse events (AEs) were neutropenia (43%), thrombocytopenia (14%), diarrhea (18%), and rash (11%). Arm B (CC-122 + CC-292 +/- R) enrolled 28 (27 treated) subjects on 5 dose levels. The MTD was determined to be CC-122 1mg 5/7d + CC-292 500mg BID + R. The most common (> 10%) related grade 3/4 AEs were neutropenia (37%), thrombocytopenia (22%), anemia (11%) and febrile neutropenia (15%) Arm C (CC-223 + CC-292) included 14 enrolled (all treated) subjects on 2 dose levels. A tolerable dose demonstrating sufficient PD biomarker inhibition was not established. The most common (> 10%) related grade 3/4 AEs were neutropenia (14%), thrombocytopenia (29%) and diarrhea (14%). Arm D (CC-122 + R) included 29 subjects enrolled (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common (> 10%) related grade 3/4 AEs were neutropenia (32%). Generally, response rates of interest were noted in Arms A, B and D (Table 1). ORR increased at higher dose levels and responses were durable. Preliminary PD data (Table 2) demonstrated differential effects of CC-223 20mg dose on p4EBP1 inhibition between Arms A and C and differential effects of low and high dose CC-122 dosing on Aiolos inhibition between Arms A, B and D. Preliminary PK analysis for drug-drug interactions will be presented. Conclusions: Preliminary data from this ongoing novel-novel dose escalation study indicate that safe and tolerable combinations of CC-122 with CC-223, CC-292, and/or rituximab can be achieved. Combination effects on toxicity, efficacy and PD biomarkers were seen. The observed signals of efficacy are encouraging in this R/R DLBCL population and will be further explored in dose expansion of selected arms at the optimized doses. Disclosures Ribrag: Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Kaplan:Janssen: Research Funding; Seattle Genetics: Research Funding. Vitolo:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria; Celgene: Honoraria. Santoro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ArQule: Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Sanofi: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Takeda: Consultancy, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Cassier:Celgene Corporation: Research Funding; AstraZeneca: Research Funding; MSD: Research Funding; Merck Serono: Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; Amgen: Honoraria. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Advani:Janssen: Research Funding; Celgene: Research Funding; Merck: Research Funding; Kura: Research Funding; Millennium: Research Funding; Infinity: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria; FortySeven: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Sutro: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Stanford University: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding. Sangha:Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Eli-Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Pfizer: Honoraria. Hagner:Celgene Corporation: Employment, Equity Ownership. Trowe:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Kuruvilla:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria.
30
Stewart, A. Keith, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, et al. "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, no. 21 (December 6, 2014): 79. http://dx.doi.org/10.1182/blood.v124.21.79.79.
Full textAbstract:
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.
31
Shapiro, Amy, Giancarlo Castaman, Katarina Cepo, Lone Hvitfeldt Poulsen, Christian Hollensen, Tadashi Matsushita, Guy Young, Silva Zupancic-Salek, and 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 (November 13, 2019): 1139. http://dx.doi.org/10.1182/blood-2019-122809.
Full textAbstract:
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.
32
Petter, Säwen, Pankaj Kumar Mandal, Derrick J. Rossi, and David Bryder. "Hematopoietic Stem Cells Are Active Contributors to Hematopoiesis in Steady State." Blood 128, no. 22 (December 2, 2016): 421. http://dx.doi.org/10.1182/blood.v128.22.421.421.
Full textAbstract:
Abstract Hematopoietic stem cell (HSC) function is typically evaluated using transplantation experiments, which offers quantitative and qualitative information on their self-renewal and multilineage differentiation potential. In this setting, potent long-term multilineage contribution can be observed from even single HSCs. However, emerging data has highlighted fundamental differences between hematopoiesis as seen after transplantation compared to that in steady state, with surprisingly little evidence of robust lymphomyeloid contribution from HSCs in native adult hematopoiesis (Busch et al., 2015; Sun et al., 2014). On the other hand, multilineage capacity has most often been defined as the ability to produce mature B-, T- and myeloid lineage cells, with evaluation of the capacity to generate erythroid cells and thrombocytes often neglected. Thus, the bulk amount of hematopoietic cells in need of continuous regeneration has been omitted from such analyses. Here, we evaluated the kinetics of blood cell generation in adult hematopoiesis using Fgd5-CreERT2 mediated cell tracing (Gazit et al., 2014), a model that can approach close to 100% label of adult HSCs in a highly specific manner. In agreement with that seen using an alternative model for HSC lineage tracing (Busch et al., 2015), HSC derived peripheral B and T lymphoid cells emerged with very slow kinetics (detection beginning at week 5 for B cells and at week 8 for T cells), while HSC derived granulocytes and monocytes emerged earlier (detectable by 3 weeks). NK cells were generated from HSCs with kinetics more resembling the kinetics for the myeloid lineages (detectable by 4 weeks), indicative of an intermediate developmental relationship of NK cells to myeloid and lymphoid cells. Finally, our ability to trace peripheral platelets revealed that this lineage was generated from HSCs not only in a highly robust manner, but also with the fastest kinetics (detectable by 2 weeks). Consistent with the mature blood cell labeling kinetics, detailed kinetic evaluations of defined myeloerythroid progenitors in the bone marrow revealed that megakaryocyte progenitors acquire label earlier than other hematopoietic progenitor subsets while thymocytes acquired label slowly. Evaluation of label progression from HSCs to other subfractions of the immature Lineage negative, c-kit positive and Sca-1 (LSK) positive compartment revealed that a CD150+CD48+ subset acquired label faster than other LSK fractions, pointing to a close temporal relationship of cells with this phenotype and HSCs. The demonstration that HSCs are potent and relatively rapid contributors to the megakaryocytic/platelet lineage in the settings evaluated strongly argues for their physiological importance not only upon transplantation, but also in steady state. Disclosures Rossi: Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Intellia Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Moderna Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
33
Greenbaum, Laurence A., Yahsou Delmas, Fadi Fakhouri, John F. Kincaid, Christoph Licht, Enrico E. Minetti, Chris Mix, et al. "Eculizumab Prevents Thrombotic Microangiopathy: Long-Term Follow-up Study of Patients with Atypical Hemolytic Uremic Syndrome." Blood 126, no. 23 (December 3, 2015): 2252. http://dx.doi.org/10.1182/blood.v126.23.2252.2252.
Full textAbstract:
Abstract Background: Eculizumab was demonstrated to effectively treat and prevent thrombotic microangiopathy (TMA) and to improve renal function and hematologic parameters for up to 2 years in4 previous prospective clinical trials and in 1 retrospective study of patients with atypical hemolytic uremic syndrome (aHUS). Patients in these studies enrolled in a long-term follow-up study, in which rates of TMA were evaluated during eculizumab treatment and during discontinuation from eculizumab. Methods: Data were gathered from an ongoing, observational, multicenter study of aHUS patients treated with eculizumab in 5 prior clinical studies. The primary endpoint was TMA event rate post-parent study during on-treatment (ON; among patients receiving eculizumab) and off-treatment (OFF; among patients who discontinued eculizumab) periods. Results: As of March 28, 2015, 87 patients, including 35 children <18 years of age (40%) and 52 adults ≥18 years of age (60%), enrolled in the study (Table). Of these, 76 patients had ON and 39 patients had OFF treatment periods with median follow-up of 26.1 and 20.1 months, respectively. A reduced dosage of eculizumab was received by 33 of 87 patients (38%). Seventeen of 39 patients (44%) reinitiated eculizumab after therapy discontinuation. The TMA event rates were 7.3 and 19.9 per 100 patient-years for ON and OFF patients, respectively. The rate of TMA in ON patients was greater in those receiving reduced dosing compared with label recommendations (Table). OFF patients had higher estimated glomerular filtration rates at time of discontinuation than ON patients. Age, frequencies of higher-risk complement factor mutations (CFH, C3, or CFB) and kidney transplant status were not different between ON and OFF patients. Factors that independently predicted TMA events included: ON treatment status (compared with OFF; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.07‒0.49; P<0.001), higher-risk mutations (compared with no mutation; HR, 5.51; 95% CI, 1.61‒18.84; P=0.007), and lower-risk mutations (compared with no mutation; HR, 3.70; 95% CI, 1.05‒13.02; P=0.04). Conclusions: The TMA event rate was 2.7-fold higher after eculizumab discontinuation compared with patients receiving ongoing eculizumab therapy. TMA event rates were lowest during on-label dosing, higher during reduced dosing, and highest during off-treatment periods. These findings suggest that patients with aHUS have a progressive increase in the risk of TMA events during periods of reduced dosing and after discontinuation of eculizumab, compared with on-label eculizumab dosing. Disclosures Greenbaum: Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fakhouri:Alexion Pharmaceuticals: Consultancy. Kincaid:Alexion Pharmaceuticals: Employment, Equity Ownership. Licht:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillon: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mix:Alexion Pharmaceuticals: Employment, Equity Ownership. Provôt:Alexion Pharmaceuticals: Honoraria. Rondeau:Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sheerin:Alexion Pharmaceuticals: Honoraria. Wang:Alexion Pharmaceuticals: Employment, Equity Ownership. Menne:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees.
34
Saleh, Mansoor N., James B. Bussel, Abderrahim Khelif, Paul Burgess, Ali El-Ali, Anuja Roy, Victoria Barghout, Mei Sheng Duh, Kelly M. Grotzinger, and Abdulgabar Salama. "Improvements in Patient Health-Related Quality of Life (HRQoL) with Clinical Efficacy in Patients Treated with Eltrombopag: Final Results from the Long-Term, Open-Label Extend Study." Blood 128, no. 22 (December 2, 2016): 3742. http://dx.doi.org/10.1182/blood.v128.22.3742.3742.
Full textAbstract:
Abstract Background: EXTEND (June 2006 to July 2015) was an open-label, dose-adjustment extension study to evaluate the safety and efficacy of eltrombopag for the treatment of patients with chronic immune thrombocytopenia purpura (cITP) who had previously been enrolled in a pivotal eltrombopag trial. CITP may lead to fatigue and interference with daily activities, and affect patient functioning and experience i.e., health-related quality of life (HRQoL). Objective: To investigate the association between platelet response and HRQoL reported by patients in the EXTEND study, employing widely used and well-validated measures. Methods: Four standard HRQoL instruments were used in this study: SF-36v2 including Physical Component Summary (PCS) and Mental Component Summary (MCS) to measure general physical and mental health status; Motivation and Energy Inventory Short Form (MEI-SF) to measure motivation and energy; Fatigue Subscale of FACIT (FACIT-F) to measure symptoms of fatigue; and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6) to measure concerns related to bleeding and bruising and their impact on usual activities. The four instruments were used at baseline (BL) and at a frequency of every 3 months until last on-treatment assessment. Patients were blinded to their current platelet count results before completing the questionnaires. HRQoL scores and mean platelet count based on clinical assessments were calculated during time periods post-baseline (BL) to <3 months, ≥3 to <6 months, and at 6-month periods thereafter. Three definitions of response in the absence of rescue therapy (composite of new cITP medication, increased dose of cITP medication from BL, platelet transfusion, and splenectomy) were considered: 1) platelet count ≥30 Gi/L (109/Liter); 2) platelet count ≥50 Gi/L; and 3) platelet count ≥50 Gi/L and > 2 times BL. Generalized estimating equations were used to assess the association between HRQoL over time and clinical response, accounting for within-patient correlation. Covariates included demographic characteristics and BL clinical characteristics (BMI, BL use of cITP medication, prior splenectomy, prior eltrombopag use, and BL platelet count). Results: 302 patients were enrolled in EXTEND. Between 273 and 292 (depending on instrument) had a BL, at least one on-treatment HRQoL assessment, and platelet count information. Baseline platelet count was <30 Gi/L for 69.9% of patients. Median treatment duration was 2.4 years. During treatment, 86.8% of the patients achieved platelet response of platelet count ≥30 Gi/L, 79.8% achieved ≥50 Gi/L, and 75.2% achieved ≥50 Gi/L and 2x BL at least once during the study. All HRQoL instruments had a positive best mean change from BL greater than a minimally important difference of at least half a standard deviation from BL score or an established threshold. All four HRQoL instruments had positive association with the three platelet response definitions. The adjusted mean score increase (signifying improvement) associated with platelet response compared to no response was 0.9-1.3 for SF-36v2 PCS, 0.8-1.3 for SF-36v2 MCS, 1.3-1.9 for MEI-SF, 1.6-2.0 for FACIT-F, and 1.8-2.3 for FACT-Th6 (most p <0.05; Table 1). Conclusion: These data show positive associations between platelet response and HRQoL measurements, especially with SF-36v2 PCS, FACIT-F, and FACT-Th6. Benefits from eltrombopag therapy in increasing platelet counts may carry forward into alleviating fatigue, concerns about bleeding and bruising, as well as enhancing motivation, energy, general physical and mental health status. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Boehringer Ingelheim: Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Immunomedics: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; BiologicTx: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Burgess:Novartis: Employment. El-Ali:Novartis: Employment. Roy:Novartis: Employment. Barghout:Novartis: Consultancy. Duh:Novartis: Research Funding; Abbvie: Consultancy; Allergan: Consultancy; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding.
35
Moreau, Philippe, Cyrille Hulin, Sonja Zweegman, Yannan Hu, Bart Heeg, Mahmoud Hashim, Carla de Boer, et al. "Comparative Efficacy and Safety of Bortezomib, Thalidomide, and Dexamethasone (VTd) without and with Daratumumab (D-VTd) from Cassiopeia Versus Vtd from Pethema/GEM in Patients with Newly Diagnosed Multiple Myeloma Using Propensity Score Matching (PSM)." Blood 134, Supplement_1 (November 13, 2019): 4740. http://dx.doi.org/10.1182/blood-2019-123491.
Full textAbstract:
Introduction: For patients (pts) with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, VTd with autologous stem-cell transplantation (ASCT) is a standard of care. In the PETHEMA/GEM study, pts in the VTd group received pre-ASCT induction therapy (six 28-day cycles) of bortezomib, thalidomide (ramp up to 200 mg daily, per label), and dexamethasone, followed by post-ASCT maintenance (up to 3 years) of interferon alfa-2b, thalidomide (100 mg daily), or thalidomide (100 mg daily) with bortezomib (1 cycle every 3 months; Rosiñol L, et al. Blood. 2012;120[8]:1589-96). Clinical practice has evolved and a modified thalidomide daily dose of 100 mg instead of 200 mg is now the standard of care (Mohty M, et al., presented at EBMT 2019, abstract OS12-3) and is reflected in treatment guidelines. In the phase 3 CASSIOPEIA study (part 1), pts received pre-ASCT induction (four 28-day cycles) and post-ASCT consolidation therapy (two 28-day cycles) of VTd (thalidomide 100 mg daily; VTd-mod) without or with daratumumab (D-VTd). In CASSIOPEIA part 2 (ongoing), pts with a partial response or better were re-randomized to maintenance therapy of daratumumab or observation (up to 2 years; Moreau P, et al. Lancet. 2019;394[10192]:29-38). Here, we used PSM to estimate the effect of treatments by controlling for differences in baseline covariates. We evaluated efficacy and safety in treatment groups from CASSIOPEIA versus the VTd group from PETHEMA/GEM (VTd-label). Methods: Patient-level data for VTd-label were from PETHEMA/GEM, and VTd-mod and D-VTd were from CASSIOPEIA. Propensity scores were estimated using logistic regression. Pre- and post-match balance between groups was assessed using standardized differences for included covariates. The near neighbor matching procedure was used for matching. Covariates for matching were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) disease stage, creatinine clearance, hemoglobin level, and platelet count. Outcomes observed in the matched sample were compared directly using a suitable measure of treatment effect for different endpoints. Outcomes of interest were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) post-induction and post-ASCT, and rate of grade 3/4 peripheral neuropathy. Results: Pts received VTd-mod (n=542), D-VTd (n=543) and VTd-label (n=130). After matching, 250 pts each for VTd-mod and D-VTd and 125 pts for VTd-label were included in the analyses. Baseline characteristics were similar across groups after matching. For OS and PFS, the comparison on matched samples demonstrated that VTd-mod was non-inferior to VTd-label (OS hazard ratio [HR] 0.573 [95% CI: 0.286-1.146], P=0.115; PFS HR 0.781 [95% CI: 0.522-1.168], P=0.229), and D-VTd was significantly better than VTd-label (OS HR 0.176 [95% CI: 0.065-0.477], P=0.001; PFS HR 0.296 [95% CI: 0.177-0.493], P<0.0001; Figure). Post-induction, the ORR for VTd-mod was non-inferior to VTd-label (odds ratio [OR] 1.314 [95% CI: 0.698-2.426], P=0.387). Post-transplant, VTd-mod demonstrated significantly better ORR versus VTd-label (OR 2.374 [95% CI: 1.316-4.292], P=0.004). D-VTd was significantly better than VTd-label for both post-induction and post-transplant ORRs (post-induction OR, 2.061 [95% CI: 1.050-4.036] P=0.034; post-transplant OR, 3.004 [95% CI: 1.626-5.624], P<0.0001). Compared with VTd-label, rates of grade 3/4 peripheral neuropathy were non-inferior for both VTd-mod (rate difference, 1.2 [95% CI: ⁻3.9-6.3], P=0.655) and D-VTd (rate difference, ⁻2.8 [95% CI: ⁻7.32-1.72]; P=0.186). Conclusion: In this PSM analysis, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, PFS, post-induction ORR, and grade 3/4 peripheral neuropathy; VTd-mod was significantly better for post-transplant ORR. D-VTd was significantly better than VTd-label for OS, PFS, post-induction ORR, and post-transplant ORR, and was non-inferior to VTd-label for rates of grade 3/4 peripheral neuropathy. OS results for VTd-mod and D-VTd should be interpreted with the caveat that CASSIOPEIA OS data remain immature. These findings confirm those of CASSIOPEIA: D-VTd had superior efficacy versus VTd, both of which used a modified thalidomide dose. Potential imitations include unobserved confounding factors, and differences in study design (eg, response criteria and maintenance therapy). Disclosures Moreau: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hu:Ingress-health: Consultancy, Employment, Other: funding from Pfizer. Heeg:Ingress-Health: Employment. Hashim:Ingress-Health: Employment. de Boer:Janssen: Employment, Equity Ownership. Vanquickelberghe:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Lam:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding.
36
Mascarenhas, John O., Moshe Talpaz, Vikas Gupta, Lynda M. Foltz, Michael R. Savona, Ron Paquette, Robert Turner, et al. "Primary Analysis Results from an Open-Label Phase II Study of INCB039110, a Selective JAK1 Inhibitor, in Patients with Myelofibrosis." Blood 124, no. 21 (December 6, 2014): 714. http://dx.doi.org/10.1182/blood.v124.21.714.714.
Full textAbstract:
Abstract Background: Janus kinases (JAKs), including JAK1 and JAK2, mediate the signaling of cytokines and growth factors implicated in the pathogenesis of myelofibrosis (MF). Suppression of JAK2 leads to cytopenias due to its involvement in the signaling pathways of thrombopoietin and erythropoietin. Purpose: The objective of this ongoing study is to evaluate the efficacy and safety of INCB039110, a selective JAK1 inhibitor, in patients with MF with the goal of improving MF-related symptoms with less myelosuppression than seen with JAK1/JAK2 inhibition. Here, we report the 12- and 24-week efficacy and safety of INCB039110 in a phase II trial. Methods: Adults with intermediate-1 or higher (per Dynamic International Prognostic Scoring System [DIPSS]) primary MF (PMF), post–polycythemia vera MF (PPV-MF), or post–essential thrombocythemia MF (PET-MF) were eligible regardless of JAK2V617F mutation status. A platelet count of ≥ 50 × 109/L, hemoglobin ≥ 8.0 g/dL (transfusions permitted), and a palpable spleen or prior splenectomy were required. Patients assessed the severity of 19 disease-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v3.0 electronic diary. Spleen volume (SV) was evaluated by magnetic resonance imaging or computed tomography at baseline, week 12, and week 24. The primary endpoint was the proportion of patients with a ≥ 50% reduction from baseline in total symptom score (TSS, consisting of the sum of 6 individual symptom scores: night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, and bone/muscle pain) at week 12. Other endpoints included the proportion of patients with a ≥ 50% reduction from baseline in TSS at week 24, percentage change from baseline in TSS at week 12 and 24, percentage change from baseline in SV at week 12 and 24, and safety. The study used a Simon 2-stage design to assess 3 separate dose cohorts (100 mg twice daily [BID], 200 mg BID, and 600 mg once daily [QD]). A dose cohort could be expanded if ≥ 3 of the first 10 patients met the primary endpoint (intent-to-treat method). Results: Enrollment is complete and 87 patients have been treated with INCB039110: 10 in the 100 mg BID, 45 in the 200 mg BID, and 32 in the 600 mg QD groups; 10, 42, and 31 patients, respectively, were evaluable for the primary endpoint. The 200 mg BID and 600 mg QD cohorts met criteria for expansion. Enrolled patients (mean age, 64 years) had PMF (55%), PPV-MF (26%), or PET-MF (18%), and most had intermediate-1 (37%) or intermediate-2 (47%) risk by DIPSS. Mean SV at baseline was 2442.7 cm3, mean hemoglobin was 10.2 g/dL, and mean platelet count was 246.7 × 109/L. Reductions in TSS were similar between the 200 mg BID and 600 mg QD groups, and largely maintained through week 24 (Table). Modest reductions in spleen volume were attained in the 200 mg BID and 600 mg QD groups. TableINCB039110 Dose100 mg BID200 mg BID600 mg QD Patients with ≥ 50% improvement in TSS,* n/N (%)Week 122/10 (20)15/42 (36)10/31 (32)Week 242/10 (20)12/42 (29)11/31 (35) Median change from baseline in TSS,† %Week 12−28.5−45.8−37.2Week 24−57.2−48.6−46.7Median change in SV,† %Week 12−0.5−14.1−14.5Week 24−31.1−17.4−17.1 * Patients who discontinued prior to the week 12 or 24 visit were considered nonresponders at that time point. † Only patients with baseline and week 12 or 24 data were included. Negative change = improvement. Mean platelet count is shown in Figure 1. Mean hemoglobin levels in patients who entered the study without transfusion requirements and did not receive post-baseline blood transfusions are shown in Figure 2. In these patients, the mean percent change from baseline in hemoglobin at week 24 increased by 5.6% in the 200 mg BID group and 8.6% in the 600 mg QD group. The most common nonhematologic adverse events (occurring in > 15% of enrolled patients overall regardless of causality) were fatigue (29%), nausea (21%), upper respiratory tract infection (18%), constipation (17%), diarrhea (17%), and cough (16%); most of these events were grade 1 or 2 and did not appear to be dose dependent. New or worsening grade 3 or 4 anemia occurred in 33% and 0% of patients, respectively, and thrombocytopenia in 24% and 5% of patients, respectively. Conclusions: Patients with MF treated with the JAK1 inhibitor INCB039110 (200 mg BID or 600 mg QD) continued to show meaningful improvements in MF-related symptoms and modest decreases in spleen size, while preserving mean hemoglobin levels over time through week 24. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Mascarenhas: Incyte Corporation: Consultancy. Talpaz:ARIAD, BMS, Sanofi. Incyte, Pfizer: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Savona:Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead : Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene : Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte Corporation: Speakers Bureau. Coughlin:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eastern Health: Employment. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hunter:Incyte Corporation: Employment. Assad:Incyte Corporation: Employment. Clark:Incyte Corporation: Employment. O'Neill:Incyte Corporation: Employment. Hoffman:All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding.
37
Kutsch, Nadine, Christian Pallasch, Eugen Tausch, Volkmar Boehme, Matthias Ritgen, Ruediger Liersch, Alexander Wacker, et al. "A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)." Blood 134, Supplement_1 (November 13, 2019): 4297. http://dx.doi.org/10.1182/blood-2019-130912.
Full textAbstract:
Introduction: In CLL, numerous new therapeutic options have been introduced recently, without establishing a definitive standard therapy or cure for most patients (pts). An advantage of targeted therapies is the avoidance of toxicities associated with chemotherapy. However, all new kinase inhibitors used for treatment of CLL have low rates of complete remission (CR). Combinations of targeted agents have the potential to improve outcomes, shorten treatment duration, and reduce toxicity. Tirabrutinib (a BTK inhibitor), and entospletinib (a SYK inhibitor), both show significant single-agent clinical activity in pts with CLL. In this study, we evaluated tirabrutinib and entospletinib as dual therapy (TE), and as triple therapy in combination with obinutuzumab (TEO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02983617) at 15 clinical centers in Germany that recruited pts with relapsed or refractory CLL between April 2017 and September 2018. As of amendment 3, pts who did not progress while on an inhibitor of BTK, SYK, PI3K, BCL-2 or on obinutuzumab were also included. Pts received the TE regimen with tirabrutinib 80 mg once daily (QD) + entospletinib 400 mg QD for up to 104 weeks, or the TEO regimen adding obinutuzumab at standard dosing for a total of 8 doses of 1000 mg over 21 weeks. After the implementation of protocol amendment 3, randomization was discontinued and all subsequently enrolled pts received the TEO regimen. Response was measured by modified iwCLL 2008 criteria. The primary endpoint was the CR rate at week 25. Results: Thirty-six pts were treated, 6 with TE and 30 with TEO. Median (range) age was 68 (45-82) years, with a median of 1 (1-2) and 2 (1-8) prior anticancer therapies in those assigned to TE and TEO, respectively. As of 16 May 2019, 29 of all 36 pts (81%) continue to receive tirabrutinib and entospletinib on study; 2 (6%) pts completed study drug dosing as specified per protocol at week 104. Twenty-eight of 30 pts (93%) in the TEO arm completed obinutuzumab dosing as specified per protocol. Of the 36 pts, 34 (94%) continued the study and 2 (6%) discontinued the study due to adverse events (AEs) or death, both were in the TEO group. Median duration (range) of exposure to tirabrutinib and entospletinib was 99 (90-105) weeks on TE and 50 (4-104) weeks on TEO, including 20 (2-35) weeks for obinutuzumab. At week 25, CR rate was 0% (90% confidence interval [CI] 0-39.3) with TE and 7% (90% CI 1.2-19.5) with TEO (Table 1). Overall response rates at week 25 were 100% (90% CI 60.7-100) and 90% (90% CI 76.1-97.2) for TE and TEO.One pt on the TEO regimen experienced disease progression (per clinical response assessment) after 3.75 months of therapy. Three (10%) pts on TEO were minimal residual disease (MRD) negative in peripheral blood (PB MRD-) at week 25; one (3%) pt was also MRD negative in bone marrow (BM MRD-).No pts showed MRD negativity with TE therapy. Best rate of CR/PB MRD- was 7% (90% CI 1.2-19.5) and for CR/BM MRD- was 3% (90% CI 0.2-14.9) with TEO. Median time to first PB MRD- was 32 weeks on TEO. Median progression-free survival (PFS) and overall survival have not been reached yet, and 24-month PFS rates were not yet estimable in either treatment group. Treatment-emergent AEs (TEAEs) are listed in Table 2. No pt in the TE and 3 pts (10%) in the TEO group discontinued tirabrutinib and entospletinib due to TEAEs, and no pt discontinued obinutuzumab due to TEAEs. Two (7%) pts in the TEO arm died following a TEAE: an 82-year-old male from subdural hematoma (onset within 30 days of last dosing, and death within 68 days) and a 77-year-old male from syncope (onset on the last dosing date, and death at day 35 after last dosing); both deaths were considered unrelated to study treatment by investigators. Conclusion: A triple combination with tirabrutinib, entospletinib, and obinutuzumab (TEO regimen) was tolerable and demonstrated excellent therapeutic activity in pts with relapsed or refractory CLL, but with limited CR rate. Disclosures Kutsch: Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Pallasch:Gilead Sciences, Inc.: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Boehme:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Glenmark Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Helsinn: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; VioPharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; InCyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Wacker:Celgene: Consultancy; Roche: Consultancy; BMS: Consultancy; Incyte: Consultancy; Amgen: Consultancy. Trappe:Celgene, Janssen, Takeda, TEVA: Other: Congress related travel support ; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharma: Consultancy, Honoraria, Other: Congress related travel support , Research Funding; AbbVie: Consultancy, Other: Congress related travel support . Dreger:AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhang:Gilead Sciences, Inc.: Employment, Other: Shareholder. Jürgensmeier:Gilead Sciences, Inc.: Employment, Other: Shareholder. Bhargava:Gilead Sciences, Inc.: Employment, Other: Shareholder; Tioma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dicerna Pharmaceuticals: Consultancy; Sanofi, Aveo Pharma: Patents & Royalties. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Janssen: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, 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.
38
Ghobrial, Irene M., Jean-Luc Harousseau, Steven P. Treon, Brianna Harris, Courtney E. Lin, Zheng Yuan, Karim Benhadji, James E. Wooldridge, and Veronique Leblond. "Enzastaurin in Previously Treated Waldenstrom's Macroglobulinemia: An Open-Label, Multicenter, Phase II Study." Blood 114, no. 22 (November 20, 2009): 3867. http://dx.doi.org/10.1182/blood.v114.22.3867.3867.
Full textAbstract:
Abstract Abstract 3867 Poster Board III-803 Background Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM), and clinical studies suggest encouraging activity and a well-tolerated safety profile in a variety of hematologic cancers. We are conducting a multicenter, two (parallel) cohort, two-stage, phase II trial to determine whether further study of single-agent enzastaurin is warranted in patients with previously treated WM or MM. The primary objective is to assess the response rate (RR); secondary objectives include assessment of time to progression (TTP), safety, biomarkers, and the impact of adding dexamethasone to enzastaurin in patients with progressive disease (PD). Preliminary results for the WM cohort are reported here. Methods Eligible patients with WM and 1-5 prior therapies were enrolled and treated with 250 mg oral enzastaurin twice daily (1125-mg loading dose on day 1) in 28-day cycles. Patients continued for 8 cycles or until PD or unacceptable toxicity occurred. At the investigator's discretion, dexamethasone (20-40 mg po QD, days 1-4, 9-12, and 17-20 for 4 cycles; days 1-4 of each cycle thereafter) was added to enzastaurin in patients with PD. According to the Simon two-stage design, if 2 of the first 10 patients (in stage 1) experienced a minor response (MR) or better, then the study would be expanded to 29 patients (stage 2). Best response was determined according to the response assessment recommendations of the Third International Workshop on WM (IWWM). Adverse events were graded according to CTCAE version 3.0. Results Twenty-nine patients (7 females, 22 males) with WM were enrolled. The median age was 65.6 years (range: 51.7-82.3 years) and 93% of patients had an Eastern Cooperative Oncology Group performance status of 0. Patients had a median of 2 prior systemic therapies and 26 patients (89.7%) had prior rituximab. Patients completed a median of 4 cycles. Six patients received ≥6 cycles of enzastaurin treatment. Twenty patients remain on study. There were no drug-related discontinuations. None of the patients had a complete response (CR). One patient had a partial response (PR) and 7 patients had a minor response (MR), for a RR (CR+PR+MR) of 27.6%. Immunoglobulin M decreased by ≥25% in 11 patients. Three (10.3%) patients had a PD. One patient had a drug-related grade 3 wound complication; there were no other drug-related grade ≥3 toxicities. One patient died on study due to infection unrelated to enzastaurin. Conclusions Although the results are preliminary, enzastaurin appears to have activity and is well tolerated in patients with previously treated WM. The WM cohort was expanded to allow up to 50 patients to be treated on study. Disclosures: Ghobrial: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Research Funding, Speakers Bureau. Lin:Eli Lilly and Company: Employment. Yuan:Eli Lilly and Company: Employment. Benhadji:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Leblond: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; Amgen: Honoraria.
39
Witzig, Thomas E., Lubomir Sokol, Francine M. Foss, Won-Seog Kim, Eric Jacobsen, Maria de Fatima De La Cruz, Dolores Caballero, et al. "Proof of Concept for Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study." Blood 134, Supplement_1 (November 13, 2019): 468. http://dx.doi.org/10.1182/blood-2019-128513.
Full textAbstract:
Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a ligand for CXCR4 that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. We have previously shown that FT inhibition by tipifarnib downregulates CXCL12 secretion. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (wt CXCL12 3'UTR cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Tumor Whole Exon Sequencing (WES) was generated by NGS and gene expression data generated by RNA Seq. Ancillary studies also investigated the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results As of 24 May 2019, 50 PTCL pts (23 AITL, 25 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 31 pts in the ongoing AITL histology and wt CXCL12 3'UTR cohorts. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts (n=48 with available safety data) had at least one treatment-emergent adverse event (TEAE); 42 (88%) had at least 1 study drug-related TEAE and 13 (27%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade >3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (40%), thrombocytopenia (33%), leukopenia (25%), anemia and febrile neutropenia (19% each). There have been 14 deaths on study; one related to study drug (lung infection). Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 5 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable of 16 pts enrolled), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the wt CXCL12 3'UTR cohort (n=12 evaluable pts), a 42% ORR was observed (3 CR, 2 PR), with 2 of the 3 CRs observed in patients of AITL histology (n=4). A total of 23 AITL subjects were enrolled in the overall study of whom 16 had WES data. A strong association with the activity of tipifarnib was observed in 8 of the 16 (50%) carrying KIR3DL2 gene variants C336R/Q386E: 50% CR rate, 75% ORR, 100% clinical benefit rate. These tumors expressed also very low levels of CXCL5, a ligand for CXCR2, that may mediate resistance to tipifarnib. High Allele Frequency of KIR3DL2 variants predicted CR to tipifarnib treatment (ROC AUC=0.94, p<0.0001) and AITL patients carrying KIR3DL2 gene variants experienced a better outcome with tipifarnib treatment than with prior SOC treatment. While AITL tumors expressed high levels of CXCL12 and responded to tipifarnib, a trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR=1.8, p=0.09) was observed in a series of 50 PTCL subjects treated with SOC therapy. Fifty percent of AITL and 35% of non-AITL samples overexpressed CXCL12. Conclusion The AITL and wt CXCL12 3'UTR cohorts met pre-specified statistical hypotheses supporting proof-of-concept for tipifarnib in PTCL. AITL histology, KIR3DL2 and CXCL12 genotype provided robust tools for the selection/stratification of PTCL subjects treated with tipifarnib. Extended enrollment of AITL patients continues and an update on enrollment and outcomes will be provided at the time of the presentation. Disclosures Sokol: EUSA: Consultancy. Foss:Mallinckrodt: Consultancy; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy. Kim:Donga: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding. Jacobsen:Kura Oncology: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Research Funding; Millennium: Research Funding. Roncero:Kura Oncology: Research Funding. Terol:Janssen: Consultancy, Research Funding; Roche: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy; Abbvie: Consultancy. Domingo-Domenech:Bristol-Myers Squibb: Other: Travel expenses; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Rodriguez:Kura Oncology: Research Funding. Bolognese:Kura Oncology: Consultancy. Kessler:Kura Oncology: Employment. Mishra:Kura Oncology: Employment. Curry:Kura Oncology: Employment. Kurman:Kura Oncology: Employment. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Gualberto:Kura Oncology: Employment, Equity Ownership, Patents & Royalties.
40
Spencer, Andrew, Simon Harrison, Jacob P. Laubach, Jeffrey Zonder, Ashraf Z. Badros, Krystal Bergin, Amit Khot, et al. "Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study." Blood 128, no. 22 (December 2, 2016): 3326. http://dx.doi.org/10.1182/blood.v128.22.3326.3326.
Full textAbstract:
Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.
41
Hillmen, Peter, John G. Gribben, George A. Follows, Donald Milligan, Hazem A. Sayala, Paul Moreton, David G. Oscier, et al. "Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study." Blood 116, no. 21 (November 19, 2010): 697. http://dx.doi.org/10.1182/blood.v116.21.697.697.
Full textAbstract:
Abstract Abstract 697 Introduction: Despite the increasing use of combination therapy with rituximab, fludarabine and cyclophosphamide (R-FC) for chronic lymphocytic leukemia (CLL), a significant proportion of patients (pts) are not suitable or eligible for such intensive chemotherapy due to co-morbidity and/or age. In those pts considered unfit for R-FC, chlorambucil (Chl) remains a widely used first-line therapy. However, overall responses rates with Chl are relatively modest with very few complete remissions and therefore more effective treatment options are required for this patient group. In this multi-centre Phase II study we evaluate the feasibility of adding R to Chl and assess response rate compared to single agent Chl. Methods: One hundred previously untreated CLL pts requiring therapy according to iwCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1–7; 10mg/m2/day p.o.) every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in pts with continuing clinical response at 6 cycles. Efficacy data were compared to matched historic data from the UK LRF CLL4 trial, which treated pts between 1999 and 2004 with Chl-monotherapy at the same dose as used in this study. Each patient of this study was matched to 2 pts treated with Chl in the LRF CLL4 study according to Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. It should be noted that the CLL4 data was from 1999–2005, while the Chl-R responses were from 2008. Over this time, any improvements in patient response may be due to better care, improved knowledge, different concomitant medications, etc, rather than treatment used. In addition the median age of patients in LRF CLL4 was significantly lower than those treated with Chl-R (66.5 compared with 70 yrs). Results: A total of 100 pts from 12 centres, who had completed the treatment were included in this analysis; median age was 70 years (range 43–86) and 65% were male. To date, 88 pts remain alive and 12 pts have died. Ninety-two pts (92%) had reported an AE by the end of treatment. The most common AEs were: nausea (47 pts), neutropenia (39 pts), lymphopenia (38 pts), fatigue (26 pts), pyrexia (26 pts), leukopenia (21 pts), diarrhoea (20 pts), vomiting (19 pts), anaemia (18 pts) and thrombocytopenia (18 pts). Most AEs reported were Grade 1–2; Grade 3–4 neutropenia occurred in 39% of pts. Infusion-related reactions occurred in 7 pts. Overall, 37% of pts reported a total of 53 serious AEs (SAEs). The most common SAEs were febrile neutropenia (5 pts) and neutropenic sepsis (4 pts). Overall response rate (ORR) on an intent-to-treat analysis was 82% (95% CI, 73.1–89.0), with 9 pts achieving a complete response (CR), 58 pts showing partial response (PR), 15 pts showing nodular PR (nPR) and 11 pts with stable disease (SD). Median PFS to date is 23.5 months. ORR in this study was 16% higher than in the matched subset of Chl pts from the CLL4 study (95% CI, 6.0–26.0%), suggesting improved responses for Chl-R compared with Chl-alone. Conclusions: With a median age of 70 years, the population in this study was noticeably older than that of pts in CLL4 and other large trials in CLL. This study represents a more typical CLL patient population, as often seen in the clinic. These data confirm that in previously untreated CLL pts who are unable to tolerate a more intensive chemotherapy regimen, the combination of R and Chl is an efficacious therapy with an acceptable tolerability profile resulting in a better ORR than Chl monotherapy. Further evaluation of R-Chl in a randomized Phase III study is warranted. Disclosures: Hillmen: F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is used broadly in this indication at some specific lines of therapy/chemotherapy combinations may be off label in some countries. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kennedy:Roche Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pettitt:Glaxo Smith Kline: Research Funding. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Pocock:F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.
42
Iyer, Swami P., Auris Huen, Bradley Haverkos, Weiyun Z. Ai, Craig Okada, Timothy M. Kuzel, Mary Jo Lechowicz, et al. "A Multi-Center, Open Label, Phase I/II Study to Assess the Safety and Efficacy of Tenalisib Given in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 8–10. http://dx.doi.org/10.1182/blood-2020-136018.
Full textAbstract:
Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.
43
Bussel, James B., George R. Buchanan, David J. Gnarra, Richard H. Ho, Kun Nie, and Melissa Eisen. "Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune Thrombocytopenia (ITP)." Blood 120, no. 21 (November 16, 2012): 621. http://dx.doi.org/10.1182/blood.v120.21.621.621.
Full textAbstract:
Abstract Abstract 621 Background: Treatment options for children with chronic/refractory ITP are not well characterized. In a phase 1/2 16-week randomized double-blind placebo-controlled study of 22 patients (romiplostim n = 17, placebo n = 5), the thrombopoietin (TPO) receptor agonist romiplostim was well tolerated and 15 of 17 romiplostim-treated patients achieved platelet counts ≥50×109/L (Bussel et al, Blood 2011). Twenty-one of 22 patients from this phase 1/2 study subsequently entered an open-label extension study; 1/21 patients discontinued the extension study before receiving romiplostim. For the 20 patients who received romiplostim in the first extension study, the mean duration of treatment was 1.6 years (range, 0.1 to 2.1 years); all 20 achieved platelet counts >50×109/L (Nugent et al, 2011 ASPHO abstracts). Of the 17 patients who completed this extension study, 12 rolled over into a second open-label extension study for up to 2.5 years of further romiplostim treatment. Results from those 12 patients are described here. Objective: To investigate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods: During the second extension study, patients received weekly subcutaneous injections of romiplostim with the initial dose being the same as the last dose in the prior study. Dose adjustment was allowed to maintain platelet counts in the target range of 50–200×109/L. The maximum allowed romiplostim dose was 10 μg/kg. The primary endpoint of this study was incidence of adverse events; platelet response was a secondary endpoint. The protocol did not require bone marrow biopsies to be conducted at pre-defined intervals, but any bone marrow biopsies performed as clinically indicated were to be analyzed. As deemed appropriate by investigators, patients or their caregivers had the option to administer romiplostim at home during this study; those patients who administered romiplostim at home used diary cards to record dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results: Baseline demographics for this second extension study included a median age of 12 years (range 3, 16 years), 67% male, and 33% with a prior splenectomy. Median romiplostim treatment duration in this second extension study was 118.9 weeks (range 100.1, 125.9 weeks); median average weekly romiplostim dose was 5.2 μg/kg (range 1, 10 μg/kg). Of the 3 patients who discontinued the study, 2 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 9 continued on study. Median platelet counts for all 12 patients were above 50×109/L throughout, and were in the target range of 50–200×109/L for all visits but Weeks 3 and 76 (Figure). Interestingly, the median dose decreased over time from a median (Q1, Q3) of 8.0 (5.5, 9.0) μg/kg at Week 1 to 1.0 (0.0, 6.0) μg/kg at Week 116 (last timepoint for which data are available) (Figure). Two patients received rescue medications (defined as medications used for platelet counts <10×109/L, bleeding/wet purpura, or investigator decision); one patient received platelet transfusions and another prednisone. Four patients (33.3%) had serious adverse events (asthma, epistaxis, hemangioma, hypotension, pyrexia, thrombocytopenia, and transfusion reaction) and one had a life-threatening adverse event (thrombocytopenia). None of the adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Eight patients had bleeding adverse events; one of which (gingival bleeding) was deemed treatment-related. These bleeding adverse events included epistaxis (4 patients), petechiae (3 patients), gingival bleeding (2 patients), and (in 1 patient each) bleeding from the anus, injection site, lip, and mouth; 1 patient also had unspecified bleeding. No bone marrow biopsies were reported to have been performed. Conclusion: In this open-label extension study, romiplostim increased platelet counts in pediatric patients with chronic ITP without significant toxicity. Thus, romiplostim has been well tolerated and shown to be of clinical benefit to pediatric patients with refractory severe chronic ITP. As this study is ongoing, future results will provide additional data regarding even longer-term use of TPO receptor agonists in this patient population. Disclosures: Bussel: Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: The use of romiplostim in pediatric patients was examined in this study. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.
44
Gay, Francesca, Valeria Magarotto, Maria Teresa Petrucci, Francesco Di Raimondo, Luděk Pour, Tommaso Caravita, Vlastimil Scudla, et al. "Autologous Transplantation Versus Cyclophosphamide-Lenalidomide-Prednisone Followed By Lenalidomide-Prednisone Versus Lenalidomide Maintenance in Multiple Myeloma: Long-Term Results of a Phase III Trial." Blood 126, no. 23 (December 3, 2015): 392. http://dx.doi.org/10.1182/blood.v126.23.392.392.
Full textAbstract:
Abstract Introduction. High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in newly diagnosed, transplant-eligible myeloma patients. We compared consolidation with high-dose melphalan plus ASCT versus cyclophosphamide-lenalidomide-dexamethasone (CRD), and maintenance with lenalidomide-prednisone (RP) versus lenalidomide alone (R). Methods. This is an open-label, randomized, phase 3 study. We enrolled newly diagnosed, transplant-eligible myeloma patients aged ≤65 years. Using a 2-by-2 factorial design, we randomized patients to consolidation with melphalan 200 mg/m2 (MEL200) followed by ASCT or CRD (cyclophosphamide 300 mg/m2 days 1, 8, 15; dexamethasone 40 mg days 1, 8, 15, 22; lenalidomide 25 mg days 1-21); and to maintenance with RP (lenalidomide 10 mg days 1-21; prednisone 50 mg every other day) or R alone. The primary endpoint was progression-free survival (PFS). Results. 389 patients were enrolled between July 6, 2009 and May 6, 2011. Median follow-up was 54.5 months. MEL200 significantly increased PFS (median PFS from the start of consolidation: 43.3 versus 28.6 months; HR 0.40, P<0.001) and overall survival (OS; 4-year: 86% versus 73%; HR 0.42, P=0.004) compared with CRD. Median PFS from the start of maintenance was 37.5 months with RP versus 28.5 months with R maintenance (HR 0.84, P=0.336); 3-year OS was 83% with RP versus 88% with R maintenance (HR 1.53, P=0.210). Grade 3-4 hematologic toxicities (84% versus 26%, P<0.001), gastrointestinal toxicities (20% versus 5%, P<0.001) and infections (19% versus 6%, P=0.002) were higher with MEL200 than with CRD. No significant difference in adverse events (AEs) between RP and R was noticed. The most frequent grade 3-4 hematologic AEs were neutropenia (8% with RP versus 13% with R; P=0.193), infections (8% with RP versus 5% with R; P=0.417), systemic AEs (6% vs 2%; P=0.174) and vascular AEs (4% with RP versus 2% with R; P=0.449). In the RP arm, lenalidomide dose-reduction for AEs was required in 9% of patients; prednisone dose-reduction was required in 36% of patients (median time to prednisone dose-reduction: 4 months); 5% discontinued treatment for toxicity and 3% stopped treatment after developing a second primary malignancy (SPM). In the R arm, lenalidomide dose-reduction was required in 21% of patients; 8% discontinued lenalidomide for toxicity; 2% stopped treatment after developing a SPM. The median duration of lenalidomide treatment was comparable in the 2 groups. Conclusions. MEL200 significantly prolonged PFS and OS compared with CRD, regardless of maintenance. RP maintenance did not significantly improve PFS and OS compared with R alone. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Ria:Italfarmaco: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Spencer:Celgene: Honoraria. Hajek:Merck Sharp & Dohme: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Boccadoro:Sanofi: 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; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.
45
Gotlib, Jason, Nashat Gabrail, Casey L. O'Connell, Regina Garcia-Delgado, Timothy Sbardellati, Wayne M. Rothbaum, Jesse McGreivy, Claire N. Harrison, and Jean-Jacques Kiladjian. "A Randomized, Open-Label, Multicenter, Phase 2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared with Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera." Blood 134, Supplement_1 (November 13, 2019): 4168. http://dx.doi.org/10.1182/blood-2019-123546.
Full textAbstract:
Background: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by clonal stem cell proliferation of the erythroid, myeloid, and megakaryocytic lines. The predominant clinical characteristic is an increase in red cell mass, resulting in hyperviscosity of the blood, which is responsible for most symptoms during early stages of disease. Disease progression typically results in symptomatic splenomegaly and severe constitutional symptoms, causing significant morbidity and a shortened life expectancy. Patients with PV may develop cardiovascular complications, myelofibrosis (MF), myelodysplasia, or acute myeloid leukemia (AML). Long-term (20-year) survival for PV is 18%, highlighting the poor long-term prognosis and need for additional therapies. Phlebotomy and low-dose aspirin are the standard of care for initial treatment; hydroxyurea (HU) remains the myelosuppressive agent of choice, despite the increased potential for leukemic transformation, estimated at 10% after 13 years of exposure. The Janus kinase (JAK) inhibitor ruxolitinib is approved in the US and Europe for the treatment of patients who have had an inadequate response to or are intolerant of HU. In clinical trials, ruxolitinib produced responses in 23% of patients, compared with <1% in patients receiving best available therapy (Verstovsek, et al. Haematologica. 2016). Despite this significant improvement, there remains a substantial unmet need for patients with PV who are resistant to or intolerant of HU. The tumor suppressor protein p53 is the master regulator of cell-cycle arrest and apoptosis in response to cellular stress or DNA damage. Murine double minute 2 (MDM2) is a key regulator of p53, inhibiting its activity via ubiquitination, nuclear export, and direct inhibition of transcriptional activity. MDM2 is upregulated in PV CD43+ stem/progenitor cells, making the p53-MDM2 axis an attractive target in PV. In PV, TP53 is observed to be wild-type in 94% of patients, suggesting MDM2 inhibition as a potentially successful strategy (Raza, et al. Am. J. Hematol. 2012). KRT-232 is a potent and selective oral small-molecule drug that targets MDM2 and prevents MDM2-mediated p53 inhibition, allowing p53 to mediate tumor cell-cycle arrest and apoptosis. In a phase 1 dose-finding study, clinical responses were observed in 7/12 (58%) of PV patients treated with an alternative MDM2 inhibitor (Mascarenhas, et al. Blood, 2019). KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed in these studies were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue. The majority of TRAEs were grade 1 or 2. Methods: This randomized, open-label study aims to evaluate the efficacy, safety, and pharmacokinetics of KRT-232 compared with ruxolitinib in up to 320 patients with phlebotomy-dependent PV (Figure). The study will be conducted in 2 parts. Part A will identify the recommended dose and schedule by testing 4 treatment cohorts. In Part B, patients will be randomized 1:1 to either KRT-232 or ruxolitinib in order to evaluate safety and efficacy using the recommended dose/schedule for KRT-232 from part A. This study will enroll patients ≥ 18 years of age with PV and an ECOG performance status ≤ 2. In Part A, patients who are phlebotomy dependent with and without splenomegaly are eligible and patients must be resistant to or intolerant of HU or have undergone treatment with interferon. In Part B, only phlebotomy-dependent patients with splenomegaly are eligible, and patients must be resistant or intolerant to HU. The primary endpoint is proportion of patients with splenomegaly achieving a response at Week 32, defined as having achieved both of the following: 1) the absence of phlebotomy eligibility from Week 8 through Week 32, with no more than one phlebotomy eligibility occurring after randomization and before the Week 8 visit and 2) a reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32. Secondary endpoints include response rate, duration of response and improvement in patient-reported outcomes. Exploratory endpoints include molecular and biomarker analysis including TP53 mutational status. This trial is enrolling at multiple sites in the United States and Europe (NCT03669965, EduraCT: 2018-001672-38). Figure Disclosures Gotlib: Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Promedior: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Connell:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Garcia-Delgado:Celgene: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Hospital Virgen De La Victoria Malaga: Employment. Sbardellati:Kartos Therapeutics: Employment, Equity Ownership. Rothbaum:Kartos Therapeutics: Employment, Patents & Royalties: Pending; Quogue Bioventures LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. McGreivy:Kartos Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Harrison:Janssen: Speakers Bureau; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Sierra Oncology: Honoraria; AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Shire: Speakers Bureau; Incyte: Speakers Bureau. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a registered clinical trial that will evaluate the safety and efficacy of KRT-232 for patients with polycythemia vera.
46
Burke, John M., Marc André, Bruce D. Cheson, Johannes Duell, Grzegorz Nowakowski, Andreas Rosenwald, Gilles A. Salles, et al. "A Phase Ib, Open-Label, Randomized Study to Assess Safety and Preliminary Efficacy of Tafasitamab (MOR208) or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: The First-Mind Trial." Blood 134, Supplement_1 (November 13, 2019): 2877. http://dx.doi.org/10.1182/blood-2019-128021.
Full textAbstract:
Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the standard of care for newly diagnosed DLBCL, with cure rates of 60-70%. However, more effective front-line options are needed to further improve outcomes, particularly in high-risk patients (Sehn LH, Gascoyne RD. Blood 2015;125:22). Approximately 15-20% of treatment-naïve patients with DLBCL have CD20-low expressing tumors, while CD19 is expressed in >90% of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. Blood 2009;113:3773; Prevodnik VK, et al. Diagnostic Pathol 2011;6:33). CD19 is a B-lymphocyte lineage-specific surface antigen that is widely expressed in mature B-cell malignancies, including DLBCL. CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation, and is, therefore, an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized anti-CD19 monoclonal antibody with an engineered constant region (Fc) that enhances Fc-γ receptor binding affinity on effector cells, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Preliminary data in DLBCL cell lines suggest that combined targeting of CD19 and CD20 with tafasitamab and rituximab, respectively, could have synergistic cytotoxic effects. Monotherapy with tafasitamab has shown clinical activity and acceptable safety in a Phase I study in relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT01161511) and in a Phase IIa study in R/R NHL (NCT01685008). In patients with R/R DLBCL, treatment with single agent tafasitamab until progression led to a 26% objective response rate (ORR) with several long-term responses (Jurczak W, et al. Ann Oncol 2018; 29:1266). Preclinical in vitro and in vivo data have demonstrated increased combinatorial antitumor effects with tafasitamab and the immunomodulatory agent lenalidomide (LEN). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, treatment with tafasitamab/LEN achieved an ORR of 60%, a complete response (CR) rate of 42.5% and a median progression-free survival (PFS) of 12.1 months (Salles GA, et al. ICML 2019; Abstr 124). This combination received breakthrough therapy designation by the US Food and Drug Administration. Study design and methods First-MIND is a Phase Ib, open-label, multicenter, randomized trial of tafasitamab/R-CHOP or tafasitamab/LEN/R-CHOP in patients with newly diagnosed DLBCL (Figure 1). Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index 2-5). Key exclusion criteria include known double- or triple-hit lymphoma, and transformed or composite lymphoma. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Days [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) and LEN (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). The trial includes a safety run-in phase and a main phase. In the safety run-in phase, 12 patients will be enrolled in each arm. If no unexpected safety signals suspected to be related to the addition of tafasitamab ± LEN to R-CHOP are observed, an additional 18 patients will be enrolled in each arm in the main phase. The primary objective of the trial is to assess safety; secondary objectives include evaluation of efficacy (ORR and PET-assessed CR rate at end of treatment, PFS, overall survival, event-free survival, time to next anti-lymphoma treatment), long-term safety and pharmacokinetics, and immunogenicity of tafasitamab in each arm. Exploratory objectives will include the assessment of biomarkers in peripheral blood (natural killer [NK] cell count, cell-free circulating tumor DNA) and tumor tissue (DLBCL cell of origin, NK cell or macrophage count/gene expression profile, CD19 and CD20 expression) that may be relevant to the mechanism of action and/or response to study treatment. As this is a Phase Ib study to primarily explore safety, no formal statistical hypothesis is considered for the sample size calculation; approximately 60 patients will be recruited across Europe and the US. Disclosures Burke: Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Consultancy, Research Funding; Kite: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Rosenwald:MorphoSys: Consultancy. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Staber:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: 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, Speakers Bureau; MSD: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria. Westin:Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Fingerle-Rowson:MorphoSys AG: Employment. Klanova:MorphoSys AG: Employment. Würth:MorphoSys AG: Employment. Truemper:Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Roche: Research Funding; Mundipharma: Research Funding.
47
Zelenetz, Andrew D., Pier Luigi Luigi Zinzani, Henry Chan, Christian Buske, Vincent Ribrag, David Cunningham, Wojciech Jurczak, et al. "ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5244. http://dx.doi.org/10.1182/blood-2019-124326.
Full textAbstract:
Background: PI3Kδ signaling is at the crossroads of B-cell receptor signaling pathways that are major drivers of survival and proliferation of B-cell malignancies, making it an attractive target for drug development. PI3Kδ inhibitors have proven clinical efficacy in relapsed or refractory non-Hodgkin's lymphoma (NHL); however, the high incidence of immune-related adverse events (irAEs) of early generation PI3Kδ inhibitors has limited their use. Management of toxicities by daily dose reduction may reduce the incidence of toxicities but also can lead to potential loss of efficacy, therefore novel approaches are needed to maximize clinical utility. ME-401 is an oral once-daily selective PI3Kδ with a molecular structure and pharmacodynamic characteristics that are distinct from other PI3Kδ inhibitors, either approved or under development. ME-401's high volume of distribution, long half-life (~30 hours), and intracellular penetration/ retention kinetics predict a significantly higher tumor exposure to drug relative to plasma which has been borne out in pre-clinical mouse lymphoma studies. These properties allow use of an intermittent dosing schedule to minimize immune-related toxicities common to other PI3kδ agents. ME-401 has demonstrated high and objective response rates (ORR) in both FL and CLL/SLL; 80% in 50 patients with relapsed/refractory (R/R) FL and 100% in 14 patients with R/R CLL/SLL (Zelenetz et al 2019). During the Phase 1b dose escalation study of ME-401 administered on a continuous daily dosing schedule (CS, 28-day cycle), no dose limiting toxicities were identified, and the first dose level of 60 mg was selected for further development due to its high response rate. Delayed (≥ cycle 3) grade 3 AEs such as diarrhea and rash occurred in approximately one third of patients (Zelenetz, 2018). These AEs are likely related to on-target effects on T-regulatory cells (T-regs) resulting in immune-mediated toxicity. With the goal of improving tolerability we developed a novel dosing approach for ME-401, reducing dose intensity via intermittent dosing (IS) 7 days on/21 days off, with the goal of allowing Treg repopulation. The IS is introduced after an initial period (2 cycles) of daily dosing for tumor debulking. Preliminary evaluation of this novel schedule resulted in a marked decrease in delayed Grade 3 irAEs compared to the CS. The ME-401-003 (TIDAL) study was designed to further evaluate risk-benefit profiles of these two treatment schedules of this potent PI3Kδ inhibitor in patients with relapsed or refractory FL. Study Design and Methods:ME-401-003 (TIDAL) is a global study of ME-401 in patients with FL after failure of ≥2 prior systemic therapies and will enroll approximately 166 subjects. Subjects must have received prior therapy with an anti-CD20 antibody and chemotherapy with an alkylating agent or purine analogue with adequate organ and bone marrow function; no prior therapy with a PI3Kδ is allowed. Upon meeting eligibility criteria, patients are randomized to the CS or IS dosing group with a 1:1 allocation ratio at baseline and receive open-label ME-401 at 60 mg daily for the first two cycles. The stratification factors for randomization are disease status (relapsed or refractory) and tumor bulk. Patients with stable disease or an objective response after 2 cycles will then continue onto the blinded, placebo-controlled portion of the study and will receive ME-401 either on a CS or an IS. Patients who experience disease progression on IS will be able to receive open-label ME-401 on CS to explore the recapture of response. Subjects who develop grade ≥ 2 adverse of special interest (AESI) will have study drug halted and upon resolution of AE will continue on open label IS to mitigate toxicity. The primary objectives are ORR using Lugano Response Criteria, as determined by an Independent Response Review Committee, and tolerability defined as the rate of AEs requiring dose modification or study drug discontinuation utilizing a sample size of 75 subjects per treatment schedule. A correlative study will evaluate the effects of ME-401 on T-cell subsets, cytokines and chemokines. The study opened to enrollment in December 2018 with sites planned in North America, Europe, Asia, New Zealand and Australia. (NCT03768505) Disclosures Zelenetz: Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: 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; Pharmacyclics/AbbVie: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: 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; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: 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; Bayer: 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; DAVA Oncology: 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, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zinzani: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; 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; EUSAPHARMA: Consultancy, 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; SANOFI: Consultancy. Buske:Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bayer: Research Funding; Celltrion: Honoraria, Speakers Bureau; Hexal: Honoraria, Speakers Bureau. Ribrag:AZ: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Cunningham:Bayer: Research Funding; Amgen: Research Funding; MedImmune: Research Funding; Clovis: Research Funding; Merck: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; Merrimack: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Janssen: Research Funding. Jurczak:Gilead: Research Funding; Takeda: Research Funding; Celtrion: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abrisqueta:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Brown:Kite, a Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy; Pfizer: Consultancy; Juno/Celgene: Consultancy; BeiGene: Consultancy; Loxo: Consultancy, Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Teva: Honoraria; Janssen: Honoraria; Sun Pharmaceuticals: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy.
48
Escobar, Miguel A., Amy Dunn, Doris Quon, Ben Trzaskoma, Lucy Lee, Richard H. Ko, and Shannon L. Carpenter. "A Phase IV, Multicenter, Open-Label Study of Emicizumab Prophylaxis in Persons with Hemophilia a with or without FVIII Inhibitors Undergoing Minor Surgical Procedures." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-134906.
Full textAbstract:
Introduction: Emicizumab is a subcutaneously administered, bispecific, humanized monoclonal antibody that bridges factor (F)IXa and FX to restore the function of missing activated FVIII in persons with hemophilia A (PwHA). This study (NCT03361137) was designed to evaluate the safety and efficacy of emicizumab prophylaxis in PwHA with or without FVIII inhibitors undergoing minor surgical procedures without additional prophylaxis with bypassing agents (BPAs; for patients with FVIII inhibitors) or FVIII (for patients without FVIII inhibitors). Methods: This Phase IV, multicenter, single-arm, open-label study enrolled PwHA of any age, with or without FVIII inhibitors, who were scheduled to undergo minor surgical procedures. Patients were required to have received a minimum of four loading doses of emicizumab (3mg/kg once weekly for 4 weeks) prior to surgical procedure; subsequent maintenance doses of emicizumab were 1.5mg/kg once weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. Patients were required to be adherent to emicizumab prophylaxis. Treatment with emicizumab was scheduled to continue for at least 1 month after surgery. No other prophylactic treatment with coagulation factor was permitted. Outcome measures included incidence of excessive bleeding intra-operatively and until discharge from surgery, use of BPAs or FVIII to control bleeding (intra- and post-operatively), incidence of adverse events (AEs), and the percentage of patients with complications requiring hospitalization or return to surgery. Excessive bleeding was defined as a rating of fair to poor on the hemostatic rating scale and translates to an intra- and/or post-operative blood loss of ≥25% over expectation for a patient without hemophilia prior to discharge from surgery. Patients were followed for 28 days following discharge from surgery. Results: Between June 28, 2018 and March 13, 2020, 14 PwHA undergoing minor surgeries were enrolled (with FVIII inhibitors n=11; without FVIII inhibitors n=3); one PwHA with FVIII inhibitors enrolled but did not have surgery and discontinued prematurely, therefore the surgery analysis population comprised 13 patients (with FVIII inhibitors n=10; without FVIII inhibitors n=3). The majority (78.6%) of those enrolled were <18 years of age and all surgeries were either central venous access device (CVAD) removal (n=11) or dental procedures (n=2; Table 1). Of the 10 patients with FVIII inhibitors, one CVAD removal led to excessive bleeding during surgery with a need for BPA therapy, two patients undergoing CVAD removal received BPA therapy during surgery but had no reported excessive bleeding, three (two CVAD removals, one dental extraction) had post-operative bleeding that required use of a BPA (Table 2). Seven patients with FVIII inhibitors had zero bleeds after discharge from surgery. None of the three PwHA without FVIII inhibitors had excessive bleeding necessitating FVIII treatment during surgery or until discharge; two CVAD removals resulted in zero bleeds post-operatively and one dental extraction led to a post-operative bleed that did not require treatment. No serious AEs, thromboembolic events (TEs), thrombotic microangiopathies (TMAs) or deaths were reported during the study. Overall, 10 AEs occurred in five patients with FVIII inhibitors (headache n=3, limb injury, procedural pain, pyrexia, constipation, device occlusion, adhesiolysis, and hematoma, all n=1); no AEs were reported in patients without FVIII inhibitors. There were no AEs leading to dose modification, interruption or withdrawal of treatment, and no patient in either group had surgical complications requiring hospitalization or a return to surgery. The study was terminated early due to low enrollment and the limited variety of surgery types. Conclusions: In this study of mostly pediatric PwHA with and without FVIII inhibitors receiving emicizumab prophylaxis, minor surgeries were safely performed. The majority of surgeries were performed without additional prophylactic coagulation factor, however the small sample size should be considered here. There were no serious AEs, TEs, TMAs, or deaths. These findings are consistent with results from previous studies of patients undergoing minor surgery while receiving emicizumab prophylaxis. Disclosures Escobar: National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: 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; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunn:Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Spire: Honoraria; ATHN: Research Funding; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy. Quon:Octapharma: Honoraria; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Shire/Takeda: Speakers Bureau; Orthopaedic Institute for Children: Current Employment. Trzaskoma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ko:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Carpenter:Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria.
49
Richardson, Paul G., David Siegel, Rachid Baz, Susan L. Kelley, Nikhil C. Munshi, Daniel Sullivan, Melissa Alsina, et al. "A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or In Combination with Low-Dose Dexamethasone In Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib." Blood 116, no. 21 (November 19, 2010): 864. http://dx.doi.org/10.1182/blood.v116.21.864.864.
Full textAbstract:
Abstract Abstract 864 Background: Pomalidomide (POM) is a distinct immunomodulatory drug (IMiD®) with potent antiproliferative activities in vitro. It has demonstrated clinically significant responses in heavily-pretreated patients (pts) with relapsed and refractory (R/R) multiple myeloma (MM). Phase (Ph) 1b data on POM alone from a single-center, ascending dose, open-label study in heavily pretreated pts with R/R MM (Schey 2004) identified a maximum tolerated dose (MTD) of 2mg orally once daily (QD), and encouraging response rates were observed. Based on these data, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study evaluating MTD, safety and efficacy of POM alone and POM plus 40mg dexamethasone weekly (POM+dex) in pts with R/R MM after at least 2 prior regimens including bortezomib and lenalidomide (Len) was performed. Results from Ph 1 of this study are reported with enrolment to the Ph 2 ongoing. Methods: The Ph 1 portion of the study to determine MTD (n=38) was followed by a Ph 2 open-label segment that randomized pts to receive POM+dex vs POM alone (192 planned). Eligible pts had documented R/R MM. All pts received low-dose prophylactic aspirin QD and were monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of each 28-day cycle. Four dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex 40mg/wk after 4 cycles for lack of response or disease progression (PD). Pts previously enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified EBMT criteria, respectively. Results: As of May 31, 2010, 38 pts have been enrolled in Ph 1. Thirty-two pts have discontinued therapy and 6 pts are ongoing for both safety and efficacy analyses. Median age is 67 yrs with a median number of prior MM regimens of 6 (range 2–17). MTD has been determined to be 4mg/day and validated by Data Monitoring Committee. Neutropenia and anemia were the most common grade 3/4 toxicities. Eighteen (47%) pts had at least one serious adverse event (SAE); POM-related SAEs included infection, retropharyngeal abscess, neutropenia, thrombocytopenia, diarrhea, musculoskeletal chest pain, brain edema, deep vein thrombosis. Dex-related SAEs included infectious arthritis, infection, retropharyngeal abscess, sepsis, lung infection, and musculoskeletal chest pain. During the study, there were 3 deaths all considered related to MM complications (1 due to rapid PD, 1 to pneumonia and 1 GI perforation due to amyloidosis). Thirty-two pts treated with single-agent POM were evaluable for response. Confirmed response (≥PR) was seen in 22% of evaluable pts (1 CR, 6 PR) with an additional 5 pts achieving MR. In addition, 14 (44%) pts had stable disease (SD). Estimated median duration of response was 28.1 wks, and estimated median progression-free survival was 16.1 wks. Of 24 evaluable pts who were refractory to both Len and bortezomib, a response was seen in 25% (1 CR, 5 PR). Importantly, 28% (9/32) of pts were also refractory to carfilzomib. Dex was added to the regimens of 20 pts due to PD or lack of response with POM alone (median POM treatment duration before dex: 11.8 wks); 19/20 pts (15 after progression, 4 after lack of response) were evaluable for response. During treatment with POM+dex, confirmed response (2 PR) was observed in 11% with an additional 7 pts achieving MR. In addition, 37% (7/19) pts achieved SD. Of the 38 pts who received any POM dose during the Ph 1 of the study, 26 (68%) were still alive as of July 27, 2010. Kaplan-Meier estimate of median overall survival for the 38 pts in Ph 1 was 17 months. Enrollment to the Ph 2 portion of the study has since followed and is now fully accrued (n=215). Conclusions: Preliminary results indicate that single-agent POM achieves clinically significant durable responses with a manageable safety profile in heavily pretreated pts with R/R MM. The addition of dex to POM can re-induce response in selected patients. The MTD in this study was 4mg/day. Overall, these data suggest that POM could provide a clinically active therapeutic option, and warrants further investigation in this pt population. Response and safety data from the Ph 2 study will be presented at the meeting. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and Bortezomib for treatment of Multiple Myeloma. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Baz:Celgene: Consultancy, Research Funding; Millennium: Research Funding. Kelley:MMRF/MMRC: Employment. Munshi:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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; Onyx: Membership on an entity's Board of Directors or advisory committees. Sullivan:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Alsina:Celgene: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Ortho Biotech: Research Funding. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Lizza:Celgene: Employment. Yu:Celgene: Employment. Zaki:Celgene: Employment. Jacques:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.
50
Raje, Noopur, Paul Richardson, Parameswaran N. Hari, Anuj Mahindra, Sarah Kaster, Christine Connolly, Linda Rivera, et al. "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, no. 22 (November 20, 2009): 3856. http://dx.doi.org/10.1182/blood.v114.22.3856.3856.
Full textAbstract:
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.