Journal articles on the topic 'Drug and Therapeutics Committees (DTCs)'

Background: As a key partner of Ministry of Health (MOH) Ethiopia, The Clinton Health Access Initiative (CHAI) had been implementing the Child Survival Project (CSP) since October 2015. Strengthening DTC was one of its focuses to improve overall supply chain management (SCM). The objectives of this study are to review the evolution of DTCs in Ethiopia from their early years to current practice and identify the major hindering factors for their functionality. Methods: A descriptive study design was employed with mainly qualitative data collection methods and analysis. The assessment made use of both qualitative and quantitative data, generated from primary sources through key informant interviews and from secondary sources through desk review methods. Results: DTCs were introduced in Ethiopia in the early 1980’s. The mandate of DTCs has been given to four different government organizations since this time. As a result, its implementation was lagging. Recently, the government and its partners have given attention to DTCs. More than 5847 professionals underwent DTC training from 2016 onwards. DTC establishment in health facilities (HFs) improved from 85% to 98% between 2015 and 2019 during baseline and endline assessments carried out by CHAI/CSP. Similarly, DTC functionality in HFs improved from 20% to 63%. The CHAI/CSP regular supervision data analysis revealed that DTC establishment improved from 83% to 100% of HFs, while its functionality improved from 5% to 72% between 2016 and 2019, respectively. A chi-square test of independence examining the relationship between facility and pharmacy head training on DTCs and functionality of DTC in the same facility revealed significant association between the two variables at p<0.0001. Conclusions: Providing consistent capacity building and availing strong monitoring and evaluation system improves functionality of DTCs. Moreover, national coordinating bodies for DTCs and similar structures at Regional Health Bureaus and woreda health offices should be established.

INTRODUCTION:The socioeconomic burden of diseases is increasing in Africa. For instance in 2011, 70 percent of the world's human immunodeficiency virus (HIV) population resided in sub-Sahara Africa. There are also growing rates of Antimicrobial Resistance (AMR), which necessitates newer more expensive antibiotics adding to costs. There is also a growing burden of non-communicable diseases (NCDs), three out of four patients with hypertension currently live in low and middle income countries (LMICs), with prevalence rates up to 30 to 45 percent among adults in Africa. Alongside this, up to 70 percent of total healthcare expenditure is spent on medicines in LMICs; much of this out-of-pocket. Consequently, there is an urgent need to strengthen collaborative research to improve medicine use.METHODS:Summary of groups working together in Africa including the Medicines Utilisation Research in Africa (MURIA) group.RESULTS:African Strategies for Health identifies and advocates best practices, as well as works with others to develop sustainable solutions. Pharmacology for Africa (PharfA) organises and promotes pharmacology on the African continent, including research in clinical pharmacology, alongside the International Union of Basic and Clinical Pharmacology (IUPHAR) sub-division. International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Africa co-ordinates activities from the different African country chapters. The South African Health Technology Assessment Society (SAHTAS) is a scientific and professional society for all those who produce, use, or encounter Health Technology Assessment (HTA) in Southern Africa, and the World Health Organization (WHO) International and Regional groups are improving antibiotic drug utilization capabilities in Africa. The MURIA group was established in 2015 (1). Ongoing collaborative research includes (i) initiatives to optimize antibiotic use; (ii) methods to enhance adherence to anti-infective prescribing guidance, (iii) approaches to improve adherence to HIV and NCDs; (iv) researching current anti-hypertensive utilization patterns and knowledge; (v) approaches to enhance Drugs and Therapeutic Committees (DTC) activities, and (vi) strengthening medicine utilization capabilities (2,3). These activities have already strengthened research ties across Africa.CONCLUSIONS:A number of groups are already working across Africa to enhance appropriate medicine use, and should continue. Ongoing MURIA activities include antibiotic point-prevalence studies, ongoing research into infectious diseases, NCDs and DTCs including adherence as well as the third workshop and symposium in Namibia in 2017.

Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.

Introduction Allogeneic hematopoietic stem cell transplant (Allo-HSCT) is a potentially curative treatment for malignant and non-malignant blood disorders. However, current conditioning regimens limit the use of this curative procedure in many eligible patients due to regimen-related mortality and morbidities, including organ toxicity, infertility, and secondary malignancies. We are developing novel antibody drug conjugates (ADC) as conditioning agents that can achieve full myeloablation as a single agent that may reduce toxicity associated with current conditioning regimens. We have generated an anti-murine ADC targeting CD45 and assessed its effectiveness as single agent conditioning regimen in a fully allogeneic murine HSCT model. Methods Our tool CD45 ADC is engineered for rapid clearance (t1/2=1.7hr) to enable HSCT after conditioning. A single dose of 3 mg/kg is fully myeloablative in C57BL/6 mice. To determine if the tool CD45-ADC could successfully condition recipients for fully mismatched allo-HSCT, we evaluated the ability of a single dose of 5 mg/kg of the tool CD45-ADC to condition C57BL/6 hosts (H-2b, CD45.2+) for transplant with cells from CByJ.SJL(B6) donors (H-2d, CD45.1+). A matched dose of an isotype ADC (Iso-ADC) was used as a negative control, while 9 Gy TBI was used as a conventional conditioning positive control. Conditioned mice were transplanted with 4x107 whole BM cells, and peripheral blood chimerism was assessed over 22 weeks. At 22 weeks, donor hematopoietic cell chimerism was evaluated in the spleen, bone marrow, and thymus of recipients. Results In the fully mismatched Balb/c → C57Bl/6 allo-HSCT model, conditioning with a single dose of 5 mg/kg of CD45-ADC as a single agent was well tolerated and enabled full allogeneic donor chimerism (n=2 separate experiments). Peripheral blood chimerism was observed in mice conditioned with CD45-ADC at week 4 and maintained through week 22 (Figure 1). Multilineage reconstitution was observed in the T-, B-, and myeloid cell compartments with &gt;90% donor chimerism seen in each compartment, indicative of HSC engraftment. These results were comparable to chimerism seen in the 9 Gy TBI positive control. Treatment with a non-targeting isotype ADC at a matched dose was not effective (Figure 1). For all groups, stem cell chimerism in the bone marrow matched that in the periphery. Splenic and thymic donor immune cell reconstitution was similar between CD45-ADC and TBI conditioning at week 22 (Figure 1), demonstrating that CD45-ADC efficiently depletes host lymphocytes in secondary lymphoid organs while preserving the capacity of the host thymus to support de novo generation of donor-derived T cells after transplantation. Conclusion Conditioning with CD45-ADC was well-tolerated, fully myeloablative, and enabled complete chimerism in a full mismatch allo-HSCT model as a single agent. This targeted, readily translatable approach for safer conditioning could improve the risk-benefit profile for allogenic and haploidentical HSCT and may extend the curative potential of HSCT to more patients suffering from blood cancers and other diseases that may benefit from HSCT. Disclosures Hyzy: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Proctor:Magenta Therapeutics: Current Employment. Gillard:Magenta Therapeutics: Current Employment. Hammond:Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sarma:Magenta Therapeutics: Ended employment in the past 24 months. Clark:Magenta Therapeutics: Current Employment. Bhat:Magenta Therapeutics: Current Employment. Lamothe:Magenta Therapeutics: Current Employment. Palchaudhuri:Magenta Therapeutics: Current Employment. Pearse:Magenta Therapeutics: Ended employment in the past 24 months. McDonagh:Magenta Therapeutics: Ended employment in the past 24 months. Kiem:Magenta Therapeutics: Consultancy; CSL: Consultancy; Homology Medicines: Membership on an entity's Board of Directors or advisory committees; Rocket Pharma: Membership on an entity's Board of Directors or advisory committees; Umoja: Membership on an entity's Board of Directors or advisory committees; Enochian: Membership on an entity's Board of Directors or advisory committees; Vor Biopharma: Membership on an entity's Board of Directors or advisory committees. Wagner:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Blazar:Magenta Therapeutics: Consultancy; Fate Therapeutics Inc.: Research Funding; BlueRock Therapeutics: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder; BlueRock Therapeuetic: Consultancy. Boitano:Magenta Therapeutics: Ended employment in the past 24 months, Patents & Royalties. Cooke:Magenta Therapeutics: Ended employment in the past 24 months, Patents & Royalties. Davis:Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Introduction: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after hematopoietic cell transplant or chimeric antigen receptor T-cell therapy, or those who are ineligible for such therapies, need more treatment options. Loncastuximab tesirine (ADCT-402; Lonca) is an antibody-drug conjugate (ADC) comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. Its target, the human CD19 antigen, is a classic B-cell marker expressed at normal-to-high levels on the majority of malignant B-cells. Preliminary data from a Phase 1 dose-escalation and dose-expansion trial of Lonca in R/R B-cell non-Hodgkin lymphoma showed significant clinical activity in DLBCL, with an acceptable safety profile, and the recommended Phase 2 dose of 150 μg/kg was identified. Here, we present the planned interim analysis for futility on the first 52 pts with R/R DLBCL treated with Lonca in Phase 2. Methods: This single-arm, multi-center, open-label, two-stage, Phase 2 trial is currently enrolling pts ≥18 years of age with R/R DLBCL following ≥2 multi-agent systemic treatment regimens and without bulky disease (tumor ≥10 cm). The primary objective is to evaluate the efficacy of single-agent Lonca by overall response rate (ORR). The secondary objectives are to further evaluate efficacy (including duration of response [DOR], progression-free survival [PFS], and overall survival [OS]), to characterize the safety, pharmacokinetics and immunogenicity profile of Lonca, and to evaluate the impact of Lonca on health-related quality-of-life. Pts received 30-minute intravenous infusions of Lonca once every 3 weeks (1 cycle) at a dose of 150 μg/kg for the first 2 cycles, then 75 μg/kg for subsequent cycles, for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. A preplanned interim analysis for futility was conducted when the 52nd pt would have had 2 tumor assessments (approximately 12 weeks after the start of study drug), with the study planned to proceed to full enrollment if ≥10 of the first 52 pts responded to Lonca. ORR (complete response [CR] + partial response [PR]) was determined by an independent reviewer. Results: 52 pts with DLBCL were included in the interim analysis. Pts had a median age of 62.5 years [range 24-84] and had received a median of 3 previous therapies (range 2-7; Table 1). As of the data cut-off of May 01, 2019, pts had received a median of 2.5 (range 1-9) cycles of Lonca. ORR among the futility analysis population (52) was 44.2%, meeting futility requirements. A total of 10/52 (19.2%) and 13/52 (25.0%) pts attained CR and PR, respectively. In addition, 11 pts (21.2%) had stable disease (Figure 1). All (100%) pts had at least 1 treatment-emergent adverse event (TEAE), and 37 (71.2%) pts had grade ≥3 TEAEs. The most common all-grade non-hematological TEAEs, regardless of relationship to study treatment, were gamma-glutamyltransferase (GGT) increase (24 [46.2%]), pyrexia (18 [34.6%]) and hypokalemia (15 [28.8%]); pleural effusions and peripheral edema were reported in 5/52 pts (9.6%) and 6/52 pts (11.5%), respectively; 1 of these pts had a grade ≥3 event (pleural effusion). The most common grade ≥3 TEAEs were GGT increase (11 [21.2%]), hypercalcemia (4 [7.7%]) and hypokalemia (3 [5.8%]). No grade ≥3 skin-related TEAEs have been reported. The most common all-grade hematological abnormalities were platelet count decreased* (34 [65.4%]), neutrophil count decreased* (27 [51.9%]) and anemia (14 [26.9%]), and the most common grade ≥3 hematological abnormalities were neutrophil count decreased* (15 [28.8%]), platelet count decreased* (10 [19.2%]) and anemia (6 [11.5%]). Overall, 26 (50%) pts had TEAEs leading to dose reductions/delays and 10 (19.2%) pts had TEAEs leading to treatment discontinuation. Conclusions: Lonca has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in pts with R/R DLBCL. Futility requirements were met and pts are now enrolling in stage 2 of the trial. Updated efficacy results will be presented at the meeting. *Laboratory abnormality data are reported for platelet count decreased and neutrophil count decreased to avoid under-reporting of these events. Study sponsored by ADC Therapeutics SA. http://clinicaltrials.gov/show/NCT03589469 Disclosures Carlo-Stella: Amgen: Honoraria; Boehringer Ingelheim: Consultancy; AstraZeneca: Honoraria; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Other: Travel, accommodations; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Genenta Science srl: Consultancy; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Janssen: Other: Travel, accommodations; Janssen Oncology: Honoraria; BMS: Honoraria; MSD: Honoraria. Zinzani:VERASTEM: Consultancy, 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; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; IMMUNE DESIGN: 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; CELGENE: 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. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Caimi:ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Townsend:Roche: Consultancy, Honoraria. Stathis:PharmaMar: Other: Renumeration; Roche: Other: Institutional research funding; Pfizer: Other: Institutional research funding; MEI-Pharma: Other: Institutional research funding; Novartis: Other: Institutional research funding; Merck: Other: Institutional research funding; Bayer: Other: Institutional research funding; Abbvie: Other: Renumeration; ADC Therapeutics: Other: Institutional research funding. Cull:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Takeda: Research Funding; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Merck: Research Funding. Spira:Novartis: Research Funding; Roche: Research Funding; Boehringer Ingelheim: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Newlink Genetics: Research Funding; BMS: Consultancy; Virginia Cancer Specialists: Employment; MedImmune: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. He:ADC Therapeutics: Employment, Other: Potential equity interest. Qin:ADC Therapeutics: Consultancy, Other: Potential equity interest. Radford:AstraZeneca: Equity Ownership, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; GSK: Equity Ownership; Seattle Genetics: Consultancy, Honoraria.

Abstract Introduction: CD25 is expressed on the cell surface of many lymphomas, including classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma. ADCT-301 (camidanlumab tesirine [Cami-T]) is an antibody drug conjugate comprising a human monoclonal antibody against CD25 conjugated to a potent pyrrolobenzodiazepine dimer (PBD) toxin. We report here a first-in-human clinical trial of Cami-T, focusing on patients (pts) with relapsed/refractory (R/R) cHL treated in dose-escalation and subtype-specific dose-expansion cohorts. Methods: This was a Phase 1, open-label, dose-escalation and dose-expansion multicenter study in pts with R/R cHL. The objectives of the study were to assess the safety and tolerability, determine the recommended dose(s) for expansion, and evaluate pharmacokinetics and pharmacodynamics. The clinical activity of Cami-T was measured by overall response rate (ORR; per 2014 Lugano Classification), duration of response (DoR), progression-free survival (PFS), and overall survival. Pts received Cami-T intravenously every 3 weeks (Q3W; 1 Cycle). Dose escalation was performed according to a continual reassessment method. Results: As of June 15, 2018, 60 pts with cHL have been enrolled. Baseline characteristics include median age: 38.5 years (range 19-80); median number of prior therapies: 5 (range 2-15). Cami-T doses ranged from 5 to 300 µg/kg (median number of cycles: 3 [range 1-15], with a median treatment duration of 43 days [range 1-354]). Treatment-emergent adverse events (TEAEs) were reported in 57/60 (95%) pts; most common TEAEs (≥20%) were fatigue (25, 41.7%), maculopapular rash (20, 33.3%), increased gamma-glutamyltransferase (GGT; 18, 30%), pyrexia (18, 30%); increased alanine aminotransferase (ALT; 14, 23.3%), dyspnea (13, 21.7%), nausea (13, 21.7%), increased aspartate aminotransferase (AST; 12, 20.0%), increased blood alkaline phosphatase (ALP; 12, 20.0%), and cough (12, 20.0%). As part of immune-related AEs, there were 2 (3.3%) cases of Guillain-Barré syndrome (1 each at dose 45 and 60 µg/kg) and 1 (1.7%) case of thyroiditis. Also, there were 16 (26.7%) cases of peripheral edema or effusion, which are AEs thought to be associated with PBDs. Grade ≥3 TEAEs occurred in 37/60 (61.7%) pts; the most common Grade ≥3 TEAEs (≥5% of pts) were liver function abnormalities (increased GGT [16.7%], ALT [10.0%] AST [5.0%], and ALP [5.0%]), maculopapular rash (13.3%), anemia (8.3%), and decreased platelet count (5.0%). TEAEs leading to treatment discontinuation occurred in 17/60 (28.3%) pts. Most pts (72%) tolerated at least 3 cycles before an AE leading to a dose reduction/delay occurred. Exposure to the conjugated antibody was dose-related and at a ≥45 µg/kg dose was sustainable throughout the dosage interval at a mean concentration of 0.0826 µg/mL (coefficient of variation [CV] 49.9%) and mean minimum concentration of 0.0092 µg/mL (CV=81.7%; n=25). The maximum tolerated dose was not reached; however, the recommended dose for expansion was identified as 45 µg/kg Q3W. Response data for 55 evaluable pts with cHL are shown in the Table. The ORR was 69.1% (38/55 pts) and the complete response (CR) rate was 43.6% (24/55 pts). In the 45 µg/kg dose group (dose escalation + expansion), the ORR was 80.8% (21/26 pts) and the CR rate was 50% (13/26 pts) (Table). ORRs by prior treatment were 80.8% (21/26) in pts who previously received brentuximab vedotin (BV), 80.0% (12/15) in those who previously received both a checkpoint inhibitor (CHPi) and BV, 81.8% (9/11) in those who had a prior hematopoietic cell transplant (HCT), and 85.7% (6/7) in those who had a prior CHPi, BV, and HCT. Median DoR and PFS were 7.7 and 6.7 months, respectively (Figure). Conclusions: In pts with R/R cHL, therapy with Cami-T provided impressive ORRs and CR rates in a heavily pretreated pt population. A 45 µg/kg dose of Cami-T was identified as having optimal activity with an acceptable safety profile. Enrollment of pts with HL is now complete and initial response data for all pts with HL will be available later this year. This data supports further investigation in a planned Phase 2 study. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02432235. Disclosures Hamadani: Celgene Corporation: Consultancy; Cellerant: Consultancy; Janssen: Consultancy; ADC Therapeutics: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau. Collins:BMS: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; Amgen: Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Samaniego:ADC Therapeutics: Research Funding. Spira:AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; Roche: Consultancy; ADC Therapeutics: Research Funding. Davies:GSK: Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy. Radford:ADC Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau. Caimi:Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Menne:ADC Therapeutics: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Boni:ADC Therapeutics: Employment, Equity Ownership. Cruz:ADC Therapeutics: Employment, Equity Ownership. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Wuerthner:ADC Therapeutics: Employment, Equity Ownership. Horwitz:Portola: Consultancy; Corvus: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding.

Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p<0.0001). The most common treatment-emergent adverse events (TEAEs) of any cause or grade reported in patients randomized to moga were: infusion-related reaction (33.2%), drug eruption (ie, skin rash attributed to moga [23.9%]), diarrhea (23.4%), and fatigue (23.4%). This report provides the final safety results of MAVORIC as of the data available on January 3, 2019. Methods: Patients were randomized 1:1 to moga 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or vori 400 mg administered orally once daily. Patients randomized to vori were allowed to cross over to moga upon progression or intolerable toxicity. Safety was assessed by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms, and laboratory analyses. Results: In total, 372 patients were randomized (moga, 186; vori, 186), of whom 370 received study drug and were included in the safety analysis (moga, 184; vori, 186). For the final safety analysis, median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. Median treatment exposure was 170 days (range, 1-1813) for moga and 84 days (4-1230) for vori, which represent the same median values but broader ranges compared to the primary analysis (primary analysis, 170 days [1-1379] for moga and 84 days [4-1058] for vori). The type and frequency of AEs in either the moga or vori treatment groups (Table) were consistent with those reported in the primary analysis. TEAEs, regardless of causality, that were reported at similar rates in the two treatment groups included constipation, peripheral edema, headache, and anemia. TEAEs (all causality) that occurred at higher frequency in the moga vs vori arm included infusion-related reaction (33.2% vs 0.5%) and drug eruption (25.0% vs 1.1%); the majority of these events were grade 1 or 2 (Table). The types and frequencies of AEs attributable to moga (per Investigator assessment) included infusion-related reaction (33.2% [61/184]), drug eruption (23.9% [44/184]), and fatigue (18.5% [34/184]), and for vori, diarrhea (55.4% [103/186]), nausea (38.2% [71/186]), and fatigue (33.3% [62/186]). In patients who crossed over from the vori to moga arm and received study drug (n=135), the most frequently reported AEs attributable to moga were infusion-related reaction (37.8% [51/135]), drug eruption (24.4% [33/135]), fatigue (7.4% [10/135]), increased alanine aminotransferase (7.4% [10/135]), and increased aspartate aminotransferase (7.4% [10/135]). Discontinuation rates due to AEs were similar between treatment arms and in crossover patients (moga, 21.7% [40/184]; vori, 23.7% [44/186]; crossover, 25.9% [35/135]). The most common AEs leading to discontinuation were drug eruption in the moga arm (7.1% [13/184]) and fatigue in the vori arm (4.3% [8/186]). Overall, the rates of drug-related serious TEAEs were similar between treatment arms and in crossover patients (moga, 19.6% [36/184]; vori, 16.7% [31/186]; crossover, 11.9% [16/135]). After the data cutoff for the primary analysis, 1 additional patient randomized to moga (decreased appetite, general physical health deterioration, hypoalbuminemia) and 1 crossover patient (cerebral hemorrhage) experienced TEAEs with an outcome of death, all considered unrelated to study treatment per Investigator. Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrates that moga was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. The type and incidence of treatment-related AEs among patients receiving moga after crossover were similar to those observed for patients initially randomized to moga. Disclosures Kim: Merck: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Neumedicine: Research Funding; miRagen: Research Funding. Bagot:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani: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; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duvic:Seattle Genetics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Shape: Research Funding; UT MD Anderson Cancer Center: Employment; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Spatz Foundation: Research Funding; Tetralogic: Research Funding; Millennium (formerly Takeda): Research Funding; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; PleXus Communications: Speakers Bureau; Guidepoint Global: Consultancy; Evidera, Inc.: Consultancy; Cell Medica Inc.: Consultancy; Allos: Research Funding; Rhizen Pharma: Research Funding; Oncoceuticals: Research Funding; Soligenetics: Research Funding; Cell Medica Ltd.: Honoraria; Therakos: Speakers Bureau; Jonathan Wood & Assoc.: Speakers Bureau; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau. Morris:Guys Hospital: Employment. Kim:Medimmune: Research Funding; Soligenix: Research Funding; Kyowa Kirin: Research Funding; Galderma: Consultancy, Research Funding; Actelion: Consultancy, Research Funding. Musiek:Menlo: Other: Investigator; Helsinn: Membership on an entity's Board of Directors or advisory committees; Soligenix: Other: Investigator; Pfizer: Other: Investigator; Elorac: Other: Investigator; Kyowa: Honoraria, Other: Above honoraria: for Ad Board; miRagen: Other: Investigator. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; miRagen: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees. Eradat:Kyowa: Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding. Magnolo:University Hospital of Muenster, Center of Innovative Dermatology: Employment. Scarisbrick:Kyowa Kirin: 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; Recordat: Consultancy; 4SC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa: Other: Principal Investigator in clinical trials promoted by Kyowa. Fisher:Kyowa Kirin: Consultancy. Poligone:Stemline Therapeutics: Consultancy, Speakers Bureau; Regeneron: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Research Funding; Bioniz: Research Funding; Celgene: Consultancy; Helsinn: Research Funding, Speakers Bureau; Innate Pharma: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria, Research Funding, Speakers Bureau; miRagen: Research Funding; Soligenix: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Quaglino:Actelion: Honoraria, Other: Advisory Board; Innate Pharma: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Kyowa Kirin: Honoraria, Other: Advisory Board; Helsinn: Honoraria, Other: Advisory Board; Therakos: Honoraria, Other: Advisory Board. Reddy:AbbVie: Honoraria; Janssen: Honoraria; KITE: Honoraria; Merck: Research Funding; Celgene: Honoraria, Speakers Bureau. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Actelion: Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Medscape: Speakers Bureau; Medivir: Consultancy, Honoraria. Halwani:Amgen: Other: Investigator; Takeda: Other: PI; Seattle Genetics: Other: PI; Pharmacyclics: Other: Investigator; miRagen: Other: PI; Kyowa Hakko Kirin: Other: PI; Immune Design: Other: PI; Genentech, Inc.: Other: Investigator; Bristol-Myers Squibb: Other: PI; AbbVie: Other: PI. Khot:Peter MacCallum Cancer Centre: Employment; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dermira: Research Funding; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: 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; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Horwitz:Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Astex: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding. Lamar:Seattle Genetics: Consultancy; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding. Wells:Takeda Pharmaceuticals Australia Pty Limited: Membership on an entity's Board of Directors or advisory committees; MSD Australia: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Akilov:Trillium Therapeutics: Consultancy, Other: PI on the clinical trials, Research Funding; Pfizer: Research Funding. Cowan:Kyowa Kirin: Consultancy. Dummer:Merck Sharp & Dohme: Other: Intermittent, project focused consulting and/or advisory relationships; Novartis: Other: Intermittent, project focused consulting and/or advisory relationships; Bristol-Myers Squibb: Other: Intermittent, project focused consulting and/or advisory relationships; Roche: Other: Intermittent, project focused consulting and/or advisory relationships; Amgen: Other: Intermittent, project focused consulting and/or advisory relationships; Takeda: Other: Intermittent, project focused consulting and/or advisory relationships; Pierre Fabre: Other: Intermittent, project focused consulting and/or advisory relationships; Sun Pharma: Other: Intermittent, project focused consulting and/or advisory relationships; Sanofi: Other: Intermittent, project focused consulting and/or advisory relationships; Catalym: Other: Intermittent, project focused consulting and/or advisory relationships; Second Genome: Other: Intermittent, project focused consulting and/or advisory relationships. Lechowicz:Kyowa Kirin Inc: Consultancy; Spectrum: Consultancy. Foss:Eisai: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy; Acrotech: Consultancy; Mallinckrodt: Consultancy; Spectrum: Other: fees for non-CME/CE services . Wilcox:University of Michigan: Employment. Porcu:Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Viracta: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Vermeer:Kyowa: 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, Research Funding. Abhyankar:Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Pacheco:University of Colorado: Employment. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Fukuhara:Kyowa-Hakko Kirin: Honoraria; Bayer: Research Funding; Mundi: Honoraria; Janssen Pharma: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy. Querfeld:Elorac: Other: Investigator, Research Funding; Trillium: Consultancy, Other: Investigator, Research Funding; Medivir: Consultancy; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment; Celgene: Other: Investigator, Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Uhara:Kyowa Kirin Co., Ltd: Honoraria, Research Funding. Huen:Innate Pharmaceuticals: Research Funding; Galderma Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Glaxo Smith Kline Inc: Research Funding. Tobinai:Meiji Seika: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; AbbVie: Research Funding; Verastem: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; Solasia: Honoraria. Tokura:Kyowa Kirin Pharmaceutical Development, Inc.: Honoraria. Boh:Actelion: Other: Principal Investigator; Tulane University School of Medicine: Employment; Celgene: Other: Principal Investigator, Speaker, Grants; Sun: Other: Speaker; Janssen: Other: Principal Investigator, Speaker, Grants; Novartis: Other: Principal Investigator, Speaker, Grants; Soligenix: Other: Principal Investigator; Incyte: Other: Principal Investigator; Regeneron: Other: Principal Investigator, Grants; Ortho Dermatologics: Other: Speaker, Grants; Pfizer: Other: Principal Investigator; UCB: Other: Speaker, Grants; Elorac: Other: Principal Investigator; Abbvie: Other: Principal Investigator. Nicolay:Teva Pharmaceutical Industries: Honoraria, Other: Conference participation fees; Novartis AG: Consultancy, Honoraria; Biogen GmbH: Consultancy, Honoraria; Almirall Hermal AG: Consultancy, Honoraria; Actelion Pharmaceuticals: Consultancy, Honoraria; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Herr:Kyowa Kirin, Inc.: Employment. Sokol:EUSA: Consultancy.

Abstract Introduction: CD19, a B-cell surface antigen, is overexpressed in neoplastic lymphoid cells. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized monoclonal antibody directed against human CD19 conjugated through a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage non-Hodgkin lymphoma. In the United States, follicular lymphoma (FL) is the most common indolent lymphoma and constitutes approximately 20% of all lymphomas, while mantle cell lymphoma (MCL) is rare and represents approximately 5% of all lymphomas. Here we present interim results in a subgroup of pts with FL and MCL; interim safety and efficacy of Lonca-T in pts with diffuse large B-cell lymphoma is presented in a separate abstract. Methods: Pts (≥18 years of age) with R/R FL and MCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, and single-arm study including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts received 1-hour intravenous infusions of Lonca-T every 3 weeks (Q3W; 1 cycle), with a 3+3 dose-escalation study design. No intra-pt dose-escalation is allowed. Results: As of June 20, 2018, 15 pts with FL (12 male, 3 female) and 15 with MCL (4 male, 11 female) had been enrolled in the study. The median ages of pts with FL and MCL were 58 years [range 40-75] and 64 years [range 51-87], respectively. Pts with FL had received a median 4 previous therapies (range 1-9), and those with MCL had received a median 4 prior therapies (range 1-13; Table), including prior ibrutinib therapy in 2/15 (13.3%) and 10/15 (66.7%) pts, respectively. Pts received doses of Lonca-T ranging from 15 to 200 µg/kg Q3W (FL, median cycles: 3 [range 2-11] and MCL, median cycles: 2 [range 1-11]). Of all pts with FL or MCL, treatment-emergent adverse events (TEAEs) were reported in 29/30 (96.7%) pts, and grade ≥3 TEAEs in 20 (66.7%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (13 [43.3%]), increased gamma-glutamyltransferase (GGT) (13 [43.3%]), anemia (10 [33.3%]), myalgia (9 [30.0%]), increased alkaline phosphatase (8 [26.7%]), dyspnea (8 [26.7%]), nausea (8 [26.7%]), peripheral edema (8 [26.7%]), pleural effusion (8 [26.7%]), abdominal pain (7 [23.3%]), erythema (7 [23.3%]), decreased neutrophil count (7 [23.3%]), increased alanine transferase (6 [20.0]), increased aspartate aminotransferase (6 [20]), constipation (6 [20.0]), decreased appetite (6 [20.0]), and headache (6 [20.0]). The most common grade ≥3 TEAEs (>10% pts) were increased GGT (8 [26.7%]), decreased neutrophil count (6 [20.0%]), and anemia (4 [13.3%] pts). The figure depicts tumor response data for pts with FL and MCL. For the 15 evaluable pts with FL, the ORR was 80% (12/15 pts), comprising 8/15 (53.3%) complete responses (CRs) and 4/15 (26.7%) partial responses (PRs). The median DoR and PFS (responders and non-responders) were not reached in pts with FL after a median follow-up time of 7.56 months. Out of 15 evaluable pts with MCL, the ORR was 7/15 (46.7%), comprising 4/15 (26.7%) CRs and 3/15 (20.0%) PRs. In pts with MCL, median DoR was 5.3 months and PFS was 4.8 months after a median follow-up time of 5.78 months. Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging single-agent antitumor activity and manageable toxicity in pts with R/R FL and MCL. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017. Figure. Figure. Disclosures Caimi: Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Kahl:Genentech: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Research Funding. Hamadani:Merck: Research Funding; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Janssen: Consultancy; Takeda: Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; MedImmune: Consultancy, Research Funding; Ostuka: Research Funding. Carlo-Stella:Rhizen Pharmaceuticals: Research Funding; Sanofi: Consultancy; Boehringher Ingelheim Italia: Consultancy; MSD Italia: Speakers Bureau; Genenta Science: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. He:ADC Therapeutics: Employment, Equity Ownership. Ungar:ADC Therapeutics: Employment, Equity Ownership. Feingold:ADC Therapeutics: Employment, Equity Ownership. Ardeshna:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Radford:ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding. Solh:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding; Amgen: Speakers Bureau. Heffner:Kite Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. O'Connor:ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

BACKGROUND: BPDCN is a rare, aggressive hematologic malignancy characterized by poor overall survival and limited therapeutic options. Overexpression of CD123 (IL-3Rα) is present in all BPDCN cases, therefore establishing this marker as a rational target for therapeutic intervention. Despite the recent approval of tagraxofusp-erzs (Pemmaraju NEJM 2019), outcomes remain poor in the setting of R/R BPDCN. IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN class. Preclinically, BPDCN patient-derived xenografts demonstrated high sensitivity to IMGN632 (Zhang 2018, Kovtun 2018), establishing a rationale for the clinical evaluation of IMGN632 in this patient population. AIMS: Safety and efficacy of single agent IMGN632 in patients with R/R BPDCN. METHODS: Adult patients with R/R BPDCN with no more than three prior lines of therapy were eligible. IMGN632 was administered IV at 0.045 mg/kg on day 1 of a 21-day cycle. RESULTS: 23 patients with R/R BPDCN; median age of 73 years [19-82]; 74% male. Fifty-two percent of patients had at least 2 prior therapies, 52% had received prior intensive therapies (eg HyperCVAD, FLAG, CHOP), 22% had prior allogeneic stem cell transplant, and importantly 43% had prior exposure to tagraxofusp-erzs (n=10). At enrollment, 70% had skin involvement, 61% had bone marrow involvement, and 48% had lymph node involvement. The most common treatment emergent adverse events (TEAEs) include: nausea (35% all grade; 0% grade 3+), peripheral edema (26% all grade; 0% grade 3+), and infusion related reactions (22% all grade; 4% grade 3+). There were no Grade 3+ treatment-related AEs observed in &gt;1 patient. No capillary leak syndrome (CLS) was reported; grade 3+ LFT elevations, neutropenia, and thrombocytopenia were all noted in 1 patient each, and there were no deaths within 30-days after last IMGN632 dose. Seven of 23 patients had an objective response (2 CR, 2 CRc, 1 CRi and 2 PR) for an ORR of 30% (95% CI 13-53%) and a composite complete remission rate of 22%. The duration of response (DOR including time from PR) for the four CR/CRc patients were 9.2, 6.8+, 3.1 and 3+ months without transplantation (Figure 1A). Examples of responses are shown in Figure 1B-D. Of note, among the 10 patients with prior exposure to tagraxofusp (none had achieved a CR with tagraxofusp), 30% (n=3) achieved an objective response to IMGN632 (1 CR, 1 CRi, 1 PR). Two remarkable responders had received 3 prior regimens including tagraxofusp followed by intense and other therapies (CLAG-M/CLAG; or CHOP/allogeneic transplant/decitabine with venetoclax) and presented with diffuse disease involvement with skin, nodal, and bone marrow infiltration. After 1 and 2 doses respectively, both patients cleared all three disease compartments (CR/CRi) with one remaining in CR for 9.2 months. Additionally, among 12 patients who had bone marrow involvement and response assessment, 75% (9 of 12) had a reduction in bone marrow blasts, and 50% (6 of 12) achieved a bone marrow complete remission (&lt;5% blasts, grey bars), including 3 patients with prior tagraxofusp. (Figure 1E). CONCLUSION: The current available therapy for patients with R/R BPDCN has limited efficacy and significant safety and tolerability concerns that underscore the high unmet need for this patient population. In heavily pretreated R/R BPDCN patients, including patients who had progressed following tagraxofusp, intense chemotherapies and transplant, IMGN632 demonstrated a 30% (n=7) ORR, with 4 CR/CRc responses with notable DORs. In addition, IMGN632 demonstrated a favorable safety profile that included limited grade 3+ TEAEs/SAEs, no cases of CLS, and no deaths. In addition, IMGN632 is given once every 3 weeks, without the need for hospitalization. This clinical trial represents the largest-to-date prospective group of uniformly treated patients with R/R BPDCN and demonstrates promising activity and favorable tolerability in a cohort of heavily pretreated patients, including nearly half with prior anti-CD123 targeted therapy. FIGURE: A) Swimmers plot for all responders (CR, CRc, CRi, and PR); ^ = HSCT, arrows indicate patients in ongoing remission. Examples of resolution of B) PET and C) skin lesions from one patient, and D) PET lesions from another patient. E) Waterfall graph demonstrating best bone marrow response, gray bars = blasts &lt;5%, arrows indicate prior exposure to tagraxofusp. Disclosures Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Stemline Therapeutics: Honoraria, Research Funding; Plexxikon: Research Funding; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; MustangBio: Honoraria. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Lane:Stemline Therapeutics: Research Funding; Abbvie: Research Funding; Qiagen: Consultancy. Deconinck:ImmunoGen: Consultancy, Research Funding; Stemline: Consultancy. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Astellas: Consultancy; Macrogenics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; PTC Therapeutics: Consultancy. Sweet:Stemline: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees. Mazzarella:Tethis: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Agios: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Shire: Consultancy; Takeda: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy; Forty-Seven: Consultancy. Montesinos:Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding. Tarella:TG-therapeutics: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding. Konopleva:Stemline Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Agios: Research Funding. Kantarjian:BMS: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Immunogen: Research Funding; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Sloss:ImmunoGen, Inc.: Current Employment. Malcolm:ImmunoGen, Inc.: Current Employment. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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. OffLabel Disclosure: Results from a Phase 1/2 clinical trial using a non-approved experimental therapy

Aggressive B-cell lymphomas are genetically and clinically heterogeneous. Standard clinical trial designs do not efficiently evaluate the safety and efficacy of multiple drug combinations within the context of underlying molecular biology. The rapid identification of oncogenic driver pathways and development of multiple targeted drugs in lymphomas create many potential combinations. To address this need, we developed a Phase 1 master protocol termed PRISM (NCT03527147) to evaluate multiple targeted therapies alone or in combination for the treatment of relapsed/refractory (R/R) aggressive B-cell lymphoma. Each study arm is conducted in a predefined disease subset with the aim of addressing clinical and translational questions within an overarching protocol. All study arms are open label and not randomized. Enrolment of subjects into a given study arm is based on meeting inclusion/exclusion criteria and available slots. Pertinent inclusion criteria for the master protocol are: (a) a diagnosis of R/R non-Hodgkin lymphoma based on established World Health Organization criteria; (b) ≥1 prior line of therapy for the treatment of current histology, no known curative treatment options available, or the subject is ineligible for potential curative options; (c) the presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy and; (d) an ECOG performance status ≤2. Exclusion criteria for the master protocol include: (a) a history of prior malignancy, severe or uncontrolled disease or conditions; (b) use of anti-lymphoma therapy within 14 days of the first dose of study drug and; (c) a requirement for ongoing immunosuppressive therapy. Treatment-specific inclusion/exclusion criteria are also provided (see www.clinicaltrials.gov). As PRISM has multiple study arms, subjects can be simultaneously screened for multiple arms. In each arm, a safety review for dose-limiting toxicity (DLT) is performed after 6 subjects have completed the protocol-defined DLT window. Further enrolment will only proceed in that arm if ≤1 subject experiences a DLT (Figure 1). The sample size for each respective arm is determined based on prior clinical/experimental data on anticipated/clinically meaningful activity of each drug combination. This determines a minimally acceptable response and a desirable response. For each arm, a futility analysis occurs after approximately 10 sequentially enrolled subjects. An arm is considered futile if there is <10% probability for the overall response rate (ORR) to be above the desirable response. A final analysis after approximately 21 enrolled subjects will determine whether the treatment should be studied further. The primary criterion for success is set as having >80% chance for the response rate to be above the minimally acceptable response. The study endpoints include safety, ORR, duration of response, progression-free survival, overall survival, and standard pharmacokinetic parameters. Exploratory analyses include in depth translational studies employing peripheral blood and tumor tissue collected at screening and during treatment. These investigations aim to discover predictive biomarkers, identify the molecular correlates of response based on known genetic subtypes, investigate pharmacodynamic and pathway changes and define the depth of response using assays for measurable residual disease (MRD). Exploratory translational endpoints may inform additional biomarker selection strategies for future arms of the PRISM study. All study arms within PRISM to date have combined acalabrutinib, a highly selective BTK inhibitor, with additional targeted agents in subjects with R/R diffuse large B-cell lymphoma. The mechanism of action of the drugs combined with acalabrutinib are as follows: 1. AZD9150 is a 16-nucleotide antisense oligonucleotide designed to target and down-regulate expression of human STAT3 mRNA; administered intravenously. 2. AZD6738 is an inhibitor of ATR; administered orally. 3. Hu5F9-G4 is an anti-CD47 antibody and rituximab is an anti-CD20 antibody; both administered intravenously. 4. AZD5153 is a BRD4 inhibitor; administered orally. In summary, PRISM is a unique platform protocol designed to efficiently evaluate targeted agents in R/R aggressive B-cell lymphoma with an emphasis on comprehensive translational and molecular investigations. Disclosures Izumi: AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Hamdy:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Arkenau:Acerta Pharma: Research Funding. de Vos:Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Zinzani:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; 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; Kyowa Kirin: 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; Portola: 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; TG Therapeutics: Honoraria, Speakers Bureau. Davies:BioInvent: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Pharmacyclics, Inc.: Consultancy. Vose:Legend Pharmaceuticals: Honoraria; Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Bitman:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Brock:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Clark:AstraZeneca: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Ware:Acerta Pharma: Employment; Astrazeneca: Employment, Equity Ownership. Yang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Staudt:Nanostring: Patents & Royalties. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. OffLabel Disclosure: acalabrutinib in DLBCL

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS). However, the expression of PD-1 and PD-L1 was found to be increased in CD34 positive cells from patients with MDS (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with its ligands PD-L1 and PD-L2. A phase 1b, multicohort study of pembrolizumab in advanced hematologic malignancies revealed that a small number of patients with higher-risk MDS had long-term survival and no immune-mediated adverse events (Garcia-Manero G, Blood 2016). We report updated results from a phase II clinical trial evaluating the safety and clinical activity of the combination of azacitidine and pembrolizumab in previously-untreated patients with higher-risk MDS. Methods: Adult patients with untreated intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) &lt; 20%, incidence of grade 3-4 adverse events (AEs) &gt; 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2020), 17 therapy-naïve patients have been enrolled and treated with frontline combination azacitidine and pembrolizumab with a median follow-up time of 13.8 months and 5 patients continuing on treatment in cycles 4-28. The median age of patients treated is 71 years (range 36-82), and additional patient characteristics are depicted in Figure A. The overall response rate is 80%, with 3 patients reaching complete remission (CR), 4 patients attaining marrow CR (mCR), 4 patients exhibiting mCR with either hematologic improvement of platelets (HI-P) or erythrocytes (HI-E), and 1 patient demonstrating HI-E. Out of the 12 responders, 7 patients have normal cytogenetics, 1 has del(7q), 1 has del(5q), and 1 has complex karyotype. The most frequently observed mutations in these individuals are TET2 in 5 patients, ASXL1 and SRSF2 in 4 patients each, and RUNX1 and TP53 in 3 patients each. Overall survival was not reached in the frontline HMA + immunotherapy cohort (Figure B). Treatment was overall well-tolerated. The most common treatment-related adverse events (all grades) observed were arthralgias (40%), pneumonia (33%), nausea (27%), and skin rash (27%). One patient died in the first 60 days while receiving treatment from the unrelated cause of ventricular fibrillation. Conclusions: In this phase II trial, preliminary data suggest that combining azacitidine and pembrolizumab was relatively safe and well-tolerated in patients who had never received prior therapy. Though overall survival was not yet reached with the current follow-up time, combination therapy may have antitumor activity in these patients. Figure 1 Disclosures Borthakur: Abbvie: Research Funding; Jannsen: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Treadwell Therapeutics: Consultancy; Cyclacel: Research Funding; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Research Funding; Polaris: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; GSK: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cortes:Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding. DiNardo:MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Alvarado:BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Jain:Pfizer: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: 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, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Immunogen: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS), but the survival of patients after failure of HMA therapy is poor at approximately 4 to 6 months. Expression of PD-1 and PD-L1 was increased in CD34 positive cells from patients with MDS with further upregulation following HMA therapy and HMA failure (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2. A phase 1b, multicohort study of pembrolizumab in advanced hematologic malignancies showed a small number of patients with long-term survival and no immune-mediated adverse events in the higher-risk MDS cohort (Garcia-Manero G, Blood 2016). We report final results from a phase II clinical trial evaluating the safety and clinical activity of azacitidine and pembrolizumab in patients with higher-risk MDS after failure of hypomethylating agent therapy. Methods: Adult patients with intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. For this HMA failure cohort, patients had to not respond to, progress on, or relapse after at least 6 cycles of HMA therapy. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) &lt; 20%, incidence of grade 3-4 adverse events (AEs) &gt; 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2020), 20 patients with HMA failure have been enrolled and treated with combination azacitidine and pembrolizumab with 2 patients continuing on treatment in cycles 30 and 33. The median age of patients treated is 74.5 years, and additional patient characteristics are shown in Figure A. The overall response rate is 25%, with 1 patient achieving complete remission (CR), 2 patients attaining marrow CR (mCR), and 2 patients showing hematological improvement of platelets (HI-P). One of the responders has normal cytogenetics, 1 has del(20q), 1 has del(5q), and 1 has complex karyotype. The most frequently observed mutations in the 5 responding patients are ASXL1 and SETBP1 in 2 patients each. Interestingly, the patient on treatment in cycle 33 has 2 separate TP53 mutations and continues to have stable disease with sustained transfusion independence. With a median follow-up time of 27.9 months, the overall survival is 6.1 months (Figure B). Treatment is overall well-tolerated. The most common treatment-related adverse events (all grades) observed are neutropenia (40%), pneumonia (35%), constipation (30%), and febrile neutropenia (25%). Two patients died in the first 60 days while receiving treatment from the unrelated causes of septic shock and fungal pneumonia. Conclusions: This phase II trial suggests that the combination of azacitidine and pembrolizumab was relatively safe and well-tolerated in patients who had previously failed HMA therapy. Though no significant improvement in overall survival was observed, combination therapy may have antitumor activity in certain HMA failure patients, resulting in sustained responses in some high-risk individuals. Figure Disclosures Borthakur: PTC Therapeutics: Consultancy; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Incyte: Research Funding; AstraZeneca: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Novartis: Research Funding; PTC Therapeutics: Research Funding. Daver:Jazz: 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; Agios: 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; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Immunogen: Research Funding; Merus: Research Funding; Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding. DiNardo:MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Calithera: Research Funding; Novartis: Consultancy; Jazz: Honoraria; Takeda: Honoraria. Jabbour:Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding. Alvarado:FibroGen: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

Abstract Abstract 326 The key nuclear export protein CRM1 (chromosome region maintenance 1, Exportin 1, XPO1) may directly contribute to the pathophysiology of human multiple myeloma (MM). Here, we characterized the role of CRM1 in MM biology and defined molecular mechanisms whereby novel oral, irreversible, selective inhibitors of nuclear export (SINE) targeting CRM1 mediate anti-MM activity. CRM1 gene expression is increased with disease progression, since it is significantly elevated in active MM and plasma cell leukemia (PCL) vs. normal/MGUS/SMM patients (p< 0.02). CRM1 downregulation by shCRM1 lentiviruses significantly decreases MM cell viability regardless of drug sensitivity and p53 status. Importantly, SINE (KPT-185, KPT-251, KPT-276, and KPT-330) specifically blocked proliferation and decreased survival of MM cell lines (n=14) and patient MM cells (n=17) (LD50 < 200 nM), cultured alone and with bone marrow stromal cells (BMSCs) or osteoclasts. Caspases 3, 8, and 9 were not induced by any SINE in BMSCs derived from MM patients, cultured either alone or with MM cells, under conditions inducing marked apoptosis of MM cells (>2-log differences). These agents potently enhanced nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins p53, IκB, FOXO1A, FOXO3A, p27, and PP2A in MM cells. Transcripts of p53 and its downstream targets p21, PUMA, BAX were also induced by KPT-185, thereby inducing strong growth arrest and apoptosis. KPT-185 decreased MM oncogenes (c-myc, c-maf), anti-apoptosis molecules Mcl-1 and BCL-xL; increased pro-apoptotic protein BAX; as well as inhibited HSP70 and pIkBa. KPT-185 further blocked baseline and APRIL-induced NFkB p65 DNA-binding activity in MM cells. It triggered proteasome-dependent reduction of CRM1 protein; concurrently, KPT-185 and KPT-330 upregulated CRM1 mRNA. Furthermore, KPT-185 induced a number of tumor suppressing, regulatory, apoptotic and anti-inflammatory genes, i.e., p53, p21, PUMA, BAX, CHOP, C10orf10, MIC1, IκBα in MM1S cells in a dose-dependent manner, regardless of the presence of BMSCs. Cleavage of caspase 3 and PARP was markedly increased in MM1R cells treated with KPT-185 and bortezomib vs. either drug alone, validating that the combination of these agents triggered stronger cytotoxicity against MM cells. Combined treatment with dex and KPT-185 (or KPT-276) induced synergistic cytotoxicity against MM cells. Moreover, KPT-185 and KPT-330 impaired osteoclastogenesis and bone resorption via blockade of RANKL-induced NFκB activation in osteoclast precursor cells, without impacting osteoblasts and BMSCs (Abstract#48190). Importantly, SINEs (KPT-251 and KPT-276) suppressed MM cell growth (p< 0.01), diminished MM cell-induced osteolysis, and prolonged survival of SCID mice with diffuse human MM bone lesions (p=0.0004). Together, these results identify CRM1 as a promising novel target in MM, strongly supporting clinical development of SINE CRM1 antagonists to inhibit both MM cell growth and related bone disease. Disclosures: Landesman: Karyopharm Therapeutics Inc: Employment. Senapedis:Karyopharm Therapeutics Inc: Employment. Saint-Martin:Karyopharm Therapeutics Inc: Employment. Kashyap:Karyopharm Therapeutics Inc: Employment. Ying:Karyopharm Therapeutics Inc: Employment. McCauley:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics Inc: Employment. Munshi:Celgene: Consultancy; Millenium: Consultancy; Merck: Consultancy; Onyx: Consultancy. Richardson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: 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. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder, Scientific Founder Other.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) represents 33% of the non-Hodgkin lymphomas (NHL) and expresses CD19, a classic B-cell marker found on B lymphocytes. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage NHL. Here we present interim results in the subgroup of pts with DLBCL. Interim efficacy and safety of Lonca-T in pts with follicular lymphoma and mantle cell lymphoma are presented in a separate abstract. Methods: Pts ≥18 years of age with R/R DLBCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, single-arm study, including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival [OS]), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle), with a 3+3 dose-escalation design for the dose-escalation part of the study. No intra-pt dose escalation is allowed. Results: As of June 20, 2018, 183 pts had been enrolled on the study, including 137 with DLBCL (79 male, 58 female). Pts with DLBCL had a median age of 63 years [range 20-86], and had received a median of 3 previous therapies (range 1-10; Table). Pts received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1-13]). Treatment-emergent adverse events (TEAEs) were reported in 136/137 (99.3%) pts, and grade ≥3 TEAEs in 100/137 (73.0%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (57 [41.6%]), nausea (44 [32.1%], peripheral edema (44 [32.1%]), anemia (39 [28.5%]), rash (35 [25.5%]), gamma-glutamyltransferase (GGT) increased (33 [24.1%]), constipation (30 [21.9%]), dyspnea (29 [21.2%]), and thrombocytopenia (28 [20.4%]). The most common grade ≥3 TEAEs (>10% pts) were GGT increased (21 [15.3%]), neutropenia (20 [14.6%]), neutrophil count decreased (19 [13.9%]), anemia (15 [10.9]), thrombocytopenia (15 [10.9%]) and platelet count decreased (14 [10.2%]. Approximately 66% and 72% of pts in the 120 and 150 µg/kg groups, respectively, tolerated at least 2 cycles before any AE leading to dose reduction/delay occurred. The figure depicts tumor response data. Out of 132 evaluable pts with DLBCL, the ORR was 40.2% (53/132 pts), comprising 29/132 (22.0%) complete responses (CRs) and 24/132 (18.2%) partial responses (PRs). Median DoR was 4.17 months and PFS was 2.79 months after a median follow-up of 5.13 months. Median DoR was not reached in pts achieving a CR and was 2.76 months in pts with a PR. In pts with non-bulky disease, the ORR was 44.2% (50/113 pts); 28/113 (24.8%) pts attained a CR and 22/113 (19.5%) pts attained a PR. The majority of pts (122/132) received doses ≥120 µg/kg; in these pts, the ORR was 41.8% (51/122 pts), with 28/122 (23.0%) pts attaining a CR and 23/122 (18.9%) pts attaining a PR. Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity in pts with R/R DLBCL at doses ≥120 µg/kg. Updated safety, tolerability, and efficacy results will be presented at the meeting. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017. Disclosures Radford: Pfizer: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Research Funding. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Research Funding; Cellerant: Consultancy; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy; Merck: Research Funding. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Genenta Science: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: 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. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Reid:AbbVie: Research Funding; Millenium Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding. Solh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chung:ADC Therapeutics: Research Funding. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Ungar:ADC Therapeutics: Employment, Equity Ownership. O'Connor:ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding.

Background MAVORIC was a phase 3, open-label, multi-center, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab compared with vorinostat in patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) (NCT01728805). Mogamulizumab-associated rash was the second most common TEAE of any cause or grade in the mogamulizumab treatment arm and the most common TEAE leading to treatment discontinuation, resulting in a discontinuation rate of 7% (13/184). Grade 1-2 and 3 drug rashes occurred in 20% (36/184) and 4% (8/184) of mogamulizumab-treated patients, respectively. The objectives of this analysis were to describe histopathological and other characteristics of drug rash in patients who received mogamulizumab in MAVORIC. Methods In MAVORIC, 372 patients were randomized 1:1 to receive either intravenous mogamulizumab at 1.0 mg/kg once weekly for Cycle 1 (28 days) and then on days 1 and 15 of subsequent cycles or oral vorinostat at 400 mg daily. Confirmed overall response rate (ORR; complete response + partial response) was based on a global composite response involving all four disease compartments and verified at two consecutive visits. Guidance to investigators was provided in the protocol for evaluation and management of new drug rash on mogamulizumab treatment. Patients with an initial Grade 1 drug rash were allowed to continue treatment with use of topical steroids as needed. For patients with Grade ≥2 drug rash, mogamulizumab was temporarily stopped, and treatment of the drug rash with topical steroids was advised. Use of systemic steroids was prohibited during the study. Treatment could resume if the drug rash resolved to Grade ≤1 within 2 weeks. Biopsies were evaluated by an on-site pathologist, and a central blinded review was also conducted. Results This analysis included 44 patients who were treated with mogamulizumab and experienced drug rash during MAVORIC. Pathologically, central review assessed rashes as granulomatous, histiocytic spongiotic, lichenoid, eosinophilic, psoriasiform, or a combination of these patterns with no clear predominant histological pattern. Among the 44 patients with drug rash, 59.1% (26/44) were ≥65 years of age, and more patients with SS [56.8 (25/44)] than MF [43.2% (19/44]) experienced drug rash. Median (Q1, Q3) exposure among patients with drug rash was 344 days (162, 652) in patients with SS and 185 days (85, 463) in patients with MF. Mogamulizumab did not result in any cases of anaphylaxis or SJS/toxic epidermal necrolysis (TEN). Concomitant or immediate prior CTCL therapies that may make patients prone to drug rash were examined, and no trend toward increased incidence of drug rash was observed with any particular agent or class. The proportion of SS responders with drug rash was significantly higher than responders without rash (P=0.02; Figure 1); the proportion of MF responders with drug rash did not differ from responders without rash (P=0.21). Overall, the median (Q1, Q3) time to onset of drug rash was 106 days (36, 254). Initial drug rash occurred after response to mogamulizumab in 70% (14/20) of patients who experienced both. Thirty-five patients (80%) in the drug rash cohort resumed treatment with mogamulizumab upon resolution of initial drug rash per-protocol. After these patients resumed treatment, the median (Q1, Q3) duration of exposure to mogamulizumab was 183 days (58, 332). Conclusions Mogamulizumab-associated rashes displayed heterogeneous histopathology without one predominant feature; therefore, close correlation of suspected drug rash with clinical features is advised to differentiate it from disease progression. A trend toward higher rate of drug rash was observed in patients with SS, the group more likely to respond to mogamulizumab. Therefore, drug rash may be attributable to increased exposure, but rash may also involve underlying disease characteristics or treatment-induced immune alterations; further investigations are warranted. Nevertheless, the observation that 80% of patients on trial were able to continue mogamulizumab for &gt;6 months following resolution of their initial rash suggests that appropriate evaluation, identification, and management of these reactions may prevent premature discontinuation. Disclosures Musiek: Kyowa Kirin: Honoraria; Helsinn: Honoraria; miRagen: Other: Investigator; Elorac: Other: Investigator; Soligenix: Other: Investigator. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Bagot:Helsinn/Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huen:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Other: Travel expense reimbursement, Research Funding; miRagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Research Funding; Rhizen: Consultancy, Research Funding. Fisher:Dana-Farber Cancer Institute: Current Employment; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Haun:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Karger, Inc.: Patents & Royalties: Textbook royalties. Vermeer:Kyowa Kirin: Consultancy, Research Funding; Takeda: Research Funding; PIQUR: Research Funding; Innate Pharma: Consultancy. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Herr:Kyowa Kirin, Inc.: Current Employment. Kim:Elorac: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin Pharma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; miRagen: Research Funding; Merck: Research Funding; Solingenix: Research Funding; Trillium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy with a historical overall survival (OS) of ~8-14 months from diagnosis and no approved therapies or standard of care. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on BPDCN and other malignancies. Tagraxofusp was granted Breakthrough Therapy Designation for the treatment of patients with BPDCN, and a rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) was completed in June 2018. Detailed results from the pivotal trial of tagraxofusp in BPDCN will be presented. Methods: This pivotal Phase 2 clinical trial is a multicenter, open label, non-randomized, single-arm trial designed to determine safety and efficacy of tagraxofusp in patients with BPDCN. In Stage 1 (lead-in), first line (1L) and relapsed/refractory (r/r) patients with BPDCN received tagraxofusp as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received tagraxofusp at the dose determined in Stage 1 (12 mcg/kg). Stage 2 (expansion) enrolled 1L and r/r patients, and Stage 3 (pivotal, confirmatory) enrolled only 1L patients. Results: 45 patients with BPDCN (Stages 1 and 2, n=32; Stage 3, n=13) were enrolled at 7 sites in the US, including 32 (71%) patients as 1L. Median age was 70 years (range, 22-84); 82% male. Median follow-up for all 1L patients treated at 12 mcg/kg (n=29) was 13.8 months (range 0.2-37.4+). The most common treatment-related adverse events (TRAEs) at 12 mcg/kg in 148 patients treated in four clinical trials with tagraxofusp were transaminitis (44%), hypoalbuminemia (44%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), all grades, occurred in 17% of patients across all indications at 12 mcg/kg; 0.7% (1/148) and 1.6% (3/182) of cases resulted in death across all indications at 12 mcg/kg and all doses, respectively. The Stage 3 pivotal cohort met its primary endpoint with a 54% (7/13) rate of CR+CRc (95% CI: 25.1, 80.8). Across Stages 1, 2 and 3, in 1L patients dosed at 12 mcg/kg (n=29), ORR was 90% (26/29) with a 72% (21/29) rate of CR+CRc+CRi (ORR=overall response rate; CR=complete response; CRc=clinical CR: absence of gross disease with minimal residual skin abnormality; CRi=CR with incomplete hematologic recovery). 45% (13/29) of first-line patients treated with 12 mcg/kg were bridged to stem cell transplant (SCT) (10 allo+3 auto). In r/r patients, ORR was 69% (9/13) with a 38% (5/13) rate of CR+CRc+CRi. Additional patient follow-up will be provided. Conclusions: The pivotal trial of tagraxofusp was the largest prospectively designed, multi-center trial specifically dedicated to patients with BPDCN. This study has met its primary endpoint, and also demonstrated high response rates that were generally achieved early in the course of treatment and maintained over multiple cycles of therapy. Safety profile demonstrated most common toxicities of transaminitis, hypoalbuminemia, and thrombocytopenia; occurrence of CLS was the most serious TRAE, which was overall manageable in this population. Patients with BPDCN are being enrolled in an additional cohort, Stage 4, to ensure ongoing access. Tagraxofusp is also being evaluated in other trials including in patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF). Disclosures Pemmaraju: celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Blum:Tolero: Research Funding; Forma: Research Funding; Astellas: Consultancy; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Consultancy. Rizzieri:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: 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; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: 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. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Duvic:Guidepoint Global: Consultancy; Eisai: Research Funding; Allos: Research Funding; Clinical Care Options: Consultancy; Array Biopharma: Consultancy, Honoraria; Spatz Foundation: Research Funding; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; MEDACorp: Consultancy; Taiwan Liposome Company LTD: Consultancy; Medscape: Other: Speaker/Preceptor; Concert Pharmaceuticals, Inc.: Consultancy; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya Bioscience Int'l: Consultancy; Shape: Research Funding; Kiniksa Pharmaceuticals: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Huron Consulting Group: Consultancy; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; UT MD Anderson Cancer Center: Employment; The Lynx Group: Consultancy; Evidera, Inc.: Consultancy; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Oncoceuticals: Research Funding; Jonathan Wood & Associates: Other: Speaker; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen Pharma: Research Funding. Spence:Stemline Therapeutics: Consultancy. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Sloan:Stemline Therapeutics: Consultancy. Konopleva:Stemline Therapeutics: Research Funding.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The November 2017 monograph topics are Ertugliflozin, Glecaprevir / pibrentasvir, Neratinib, Sofosbuvir, velpatasvir, voxilaprevir and SQ C1 esterase inhibitor. The MUE is on glecaprevir, pibrentasvir.

Background: Sickle cell disease (SCD) is a chronic, debilitating disorder caused by a mutation in beta globin, which leads to the production of sickle hemoglobin (HbS). Deoxygenated HbS polymerization results in red blood cell (RBC) sickling, which leads to anemia, hemolysis, vaso-occlusion, and organ damage. Voxelotor a first-in-class therapy in development for the treatment of SCD, stabilizes HbS in the oxygenated state and has been shown to reduce anemia and hemolysis. Hydroxyurea induces fetal hemoglobin (HbF) and is an FDA- and EMA-approved treatment for SCD. Because both voxelotor and hydroxyurea can affect anemia and hemolysis, and potentially have additive mechanisms of protection against HbS polymerization, the effects of concomitant hydroxyurea in the setting of voxelotor treatment were investigated. The objective of this analysis was to evaluate RBC parameters, such as hemoglobin (Hb), mean corpuscular volume (MCV), %HbF, absolute reticulocyte count (ARC), and red cell distribution width (RDW), as well as the absolute neutrophil count (ANC) to examine the potential impact of concomitant hydroxyurea use on the effects of voxelotor and on medication adherence during the treatment period. Serum erythropoietin (EPO) levels were also monitored to investigate the effects of increased Hb concentrations on oxygen delivery. Methods: The HOPE study is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo in participants aged 12 to 65 years with SCD. A per-protocol analysis was performed using available data for all participants at the interim data cutoff on October 31,2018. Concomitant hydroxyurea treatment was permitted per protocol if the dose was stable at enrollment and maintained, unless dose adjustments were required due to toxicities. Laboratory parameters were compared in participants with or without concomitant hydroxyurea use. Results: From the HOPE study, 274 participants with lab values for the specified parameters (Hb, MCV, %HbF, ARC, RDW, ANC, EPO) available through week 24 were analyzed. A total of 179 of 274 (65%) participants were receiving hydroxyurea at study enrollment, and they were evenly distributed across the 3 treatment arms. Baseline lab values documented the effects of current hydroxyurea treatment, with higher average Hb, MCV, and %HbF but slightly lower average ARC and ANC compared with those not receiving hydroxyurea. Voxelotor treatment led to significant dose-dependent Hb increases, regardless of concomitant hydroxyurea therapy (Table 1), but the average MCV, %HbF, ANC, and RDW were unchanged. A lower average ARC was noted, which was attributed to the increased Hb level, whereas EPO levels showed wide variability but no significant changes from baseline. Conclusions: The HOPE study demonstrated that voxelotor treatment increased Hb levels in study participants with SCD, irrespective of hydroxyurea use. Significant voxelotor-associated Hb increases were observed for participants on stable-dose hydroxyurea and were equivalent to those observed in participants not taking hydroxyurea. The lack of observed changes in MCV and ANC was consistent with stable hydroxyurea exposure throughout the treatment period, thus addressing questions about potential changes in hydroxyurea compliance during the study. The additive treatment effects on anemia and hemolysis by voxelotor suggest that combination therapy with hydroxyurea may be safe and effective for optimal disease modification. Disclosures Ware: Addmedica: Other: Research Drug Donation; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation. Brown:Novartis, Inc: Research Funding; Imara, Inc: Consultancy, Research Funding; Global Blood Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. de Montalembert:bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: 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. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Novartis: Consultancy; Bioverativ: Consultancy; Global Blood Therapeutics: Employment, Equity Ownership; Imara: Consultancy. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Abboud:Novartis: Consultancy, Honoraria, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Research Funding; Amgen: Other: Travel support; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Background: Chromosomal rearrangements involving the 11q23 locus, resulting in fusions of the Mixed Lineage Leukemia (MLL) gene, are found in 5-10% of adult patients with acute myeloid leukemia and can represent a poor prognostic feature. Patients with this subtype of AML often respond well to standard induction chemotherapy but frequently relapse, even after allogeneic hematopoietic stem cell transplantation. Effective therapy options in the relapsed / refractory setting for this high-risk group represent an urgent unmet clinical need. In MLL-rearranged AML, recruitment of disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, and subsequent changes in methylation of downstream targets HOXA9 and Meis1 is central to leukemogenesis. DOT1L-mediated expression of MLL target genes is critical to developing leukemia in a murine model and inhibition of DOT1L suppressed downstream expression of MLL target genes. Pinometostat is a potent and selective small molecule inhibitor of DOT1L methyltransferase activity. Use of pinometostat in a continuous IV infusion in a rat xenograft model of MLL-rearranged leukemia showed complete, sustained tumor regressions without significant appreciable toxicities. A recent single-agent, phase I trial evaluated pinometostat in R/R patients with MLL-R myeloid malignancies. This study included 43 patients with MLL-R AML and observed that the drug was generally well-tolerated. Responses to pinometostat included one patient with morphologic CR, one with cytogenetic CR, three with resolution of leukemia cutis, and nine with signs of differentiation / leukocytosis. Promoter hypermethylation contributes to the dysregulation of MLL-R target genes HOXA9 and Meis1, and this effect was reversed upon treatment with the hypomethylating agent azacitidine. As such, this combination may lead to a more robust response in this patient population. We now seek to combine the novel, targeted agent pinometostat with azacitidine in R/R MLL-R AML. Study design & methods: We are conducting an open-label, single-arm, phase Ib / II study that will enroll 36-48 patients with R/R MLL-R AML to evaluate the tolerability and preliminary efficacy of pinometostat in combination with azacitidine. Since MLL-R AML is a rare disease and is seen in only 5-10% of patients with AML, we are looking to collaborate with other centers through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) to meet our accrual target. The study is active nationally and enrolling patients (NCT03701295). The presence of the MLL-R will be confirmed locally by FISH or cytogenetics. Adult patients who are refractory to two courses of induction, relapse after CR, or elect not to pursue induction therapy are considered eligible. Patients who have previously undergone HSCT or who have well-controlled HIV are also candidates. Pinometostat will be given by continuous IV infusion via portable pump. Azacitidine will be administered at 75mg/m2 daily over 7 days at the start of each 28-day cycle. Patients will be followed on trial for a total of 6 cycles, with bone marrow biopsies done for assessment after cycles 1, 3, and 6. The dose of pinometostat will be escalated following a standard 3+3 design, and the primary endpoint for the phase Ib portion will be safety and tolerability. The primary endpoint for the phase II will be response to combination therapy as defined by the 2017 European Leukemia Network guidelines. Accrual will proceed as per a Simon two-stage minimax design. Integrative correlative analyses will include genomics, changes in DOT1L-mediated methylation by H3K79 ELISA, and qPCR of HOXA9 and Meis1. PK studies and azacitidine incorporation and DNA methylation studies will also be performed. Disclosures Cai: Imago Biosciences, Inc.: Consultancy. Armstrong:AstraZeneca: Research Funding; Epizyme, Inc.: Consultancy, Equity Ownership; Imago Biosciences, Inc.: Consultancy, Equity Ownership; Cyteir Therapeutics: Consultancy, Equity Ownership; C4 Therapeutics: Consultancy, Equity Ownership; Syros Pharmaceuticals: Consultancy, Equity Ownership; OxStem Oncology: Consultancy, Equity Ownership; Accent Therapeutics: Consultancy, Equity Ownership; Mana Therapeutics: Consultancy, Equity Ownership; Novartis: Research Funding; Janssen: Research Funding. Rudek:RenovoRX: Research Funding; Taiho: Research Funding; Celgene: Research Funding; Cullinan Apollo: Research Funding. Tallman:Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Cellerant: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: 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, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Biosight: Research Funding; Biosight: Research Funding; Biosight: Research Funding; Cellerant: Research Funding; Cellerant: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: The identification of effective therapies based on targeted interventions for human cancers faces the challenges of genetic and epigenetic heterogeneity underlying the disease. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. Methods: We used a functional ex vivo screening assay to identify small-molecule targeted inhibitors and inhibitor combinations demonstrating selective efficacy across broad categories of leukemia. Primary mononuclear cells isolated from leukemia patients (n=588) were plated in the presence of a panel of graded concentrations of over 120 single-agent inhibitors or combinations spanning multiple drug classes. Leukemia specimens from 5 diagnosis subgroups included acute myeloid leukemia (AML; n=293), acute lymphoblastic leukemia (ALL; n=83), chronic lymphocytic leukemia (CLL; n=140), chronic myeloid leukemia (CML; n=26) and myeloproliferative neoplasms/myelodysplastic syndrome (MPN or MDS/MPN; n=46) patients. The combinations were designed as drug pairs that target non-overlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. IC50 and AUC values were derived from probit-based regression for each response curve. Mutational status for FLT3-ITD and NPM1 were compiled from clinical labs or by capillary electrophoresis using a QiaXcel instrument. Disease status was obtained from clinical chart review. Single and combination drug treatment IC50 and AUC values were compared within groups by Friedman test, across groups by Kruskal-Wallis test, and with continuous variables by Spearman rank correlation. Results: Among 588 unique leukemia patients evaluated, we observed that the combination of venetoclax (a BCL2 inhibitor) with ibrutinib(a BTK inhibitor) showed enhanced benefit above that for either single agent in both myeloid and lymphoid malignancies, including AML, ALL, and CLL. Expanded analyses of combination sensitivity in AML patients showed no significant associations with age, gender, or ELN prognostic risk. Comparison of AML samples by disease treatment status indicated a slightly greater sensitivity in relapsed/refractory (n=42) versus newly diagnosed (n=115) AML samples by both AUC and IC50 (p=0.028 and 0.026, respectively). Among AML samples, FLT3-ITD and NPM1 mutation status was available for 204 and 188 patients, respectively. Venetoclax + ibrutinib was significantly more effective in patient samples harboring FLT3-ITD or NPM1 mutations by both AUC (p=0.0002 and p=0.0032, respectively) and IC50 (p=0.0002 and p=0.021, respectively). Furthermore, among 112 AML samples with RNAseq data available, sensitivity to the combination (AUC) was significantly correlated with gene expression for BCL2 and BTK (Spearman r: -0.48 and -0.21, respectively). Evaluation of the combination using an expanded 7x7 concentration matrix on AML cell lines revealed synergy for the majority of drug-pair concentrations by the Bliss independence model. Analysis to align additional clinical and genetic features for leukemia patient samples with drug sensitivities is in progress and results with be presented at the meeting. Conclusion: Both myeloid and lymphoid-derived primary leukemia cells show sensitivity to combined inhibition of BCL2 and BTK with the combination of venetoclax and ibrutinib, suggesting this drug pair may have broad therapeutic indications. Disclosures Tyner: Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Constellation: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Array: Research Funding; Aptose: Research Funding. Danilov:TG Therapeutics: Consultancy; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Genentech: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Druker:Aileron Therapeutics: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Oregon Health & Science University: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract Although recent advances in the development of multiple myeloma (MM) therapies such as proteasome inhibitors and immunomodulatory agents have improved patient outcomes, MM remains incurable. Additional therapeutic agents with high efficacy, low toxicity and the convenience of oral administration are in high demand. BET inhibitors, such as JQ-1, have been considered as potential therapeutic agents for MM. In the present study, we report that TTI-281, an orally bioavailable BET inhibitor, displays anti-MM activity with a low toxicity profile in preclinical studies. First, TTI-281 was tested for binding and anti-tumor activity in vitro. BROMOscan and AlphaScreen assays demonstrated that TTI-281 bound to bromodomains of BRD2/BRD3/BRD4 with Kd values less than 10 nM. In MTS assays, TTI-281 inhibited the growth of MM cell lines (MM.1s, NCIH929, and RPMI-8826) with cell growth-inhibition (IC50) values less than 300 nM. Next, in vitro ADME screening and in vivo PK studies were conducted. Permeability assays using murine gastrointestinal epithelial cells indicated that TTI-281 had good permeability with little efflux liability (efflux ratio <1), suggesting favorable properties for oral absorption. Indeed, TTI-281 displayed excellent oral bioavailability in both mice and rats (93.1% and 91.8%, respectively). In addition, TTI-281 did not interfere with the metabolism of representative CYP isozyme substrates at concentrations up to 50 μM in pooled human liver microsomes. Data also suggested minimal potential for drug-drug interactions, allowing for the possible combination with first-line therapy to improve therapeutic and survival outcomes. Finally, TTI-281 was tested for anti-myeloma efficacy and tolerability in vivo. NOD-SCID mice (n=10/group) subcutaneously engrafted with the human myeloma cell line MM.1S were treated orally once daily for 21 days with different doses of TTI-281, vehicle control or the benchmark drug carfilzomib. TTI-281 reduced tumor growth in a dose-dependent manner in this MM xenograft model. At 30 mg/kg/day, TTI-281 led to a statistically significant decrease in tumor growth compared with the vehicle control and carfilzomib (reduced tumor volume: 67% after TTI-281 treatment vs 33% after carfilzomib treatment, p<0.0003). Furthermore, TTI-281 treatment was well tolerated, with no effect on body weight or other obvious toxicity. In summary, our preclinical data suggest that the orally available BET inhibitor TTI-281 has an excellent efficacy and safety profile, highlighting its potential as a promising drug candidate for myeloma therapy. Disclosures Wang: Trillium Therapeutics: Employment, Patents & Royalties. Choi:Trillium Therapeutics: Employment. Dove:Trillium Therapeutics: Employment, Patents & Royalties. Wang:Trillium Therapeutics: Employment. Schimmer:Novartis: Honoraria. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Slassi:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Abstract Introduction & Objectives: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL. The goals of this first-in-human study are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methods: This Ph 1 trial employs a dose-escalation design to evaluate the administration of MRG-106 via subcutaneous (SC) injection, 2-hour intravenous (IV) infusion, or IV rapid bolus injection (≤ 900 mg/dose). An additional cohort received intralesional injections (75 mg/dose) to evaluate tolerability and efficacy with local delivery. Subjects were required to have biopsy-proven MF stage I-III with plaque and/or tumor lesions. Subjects were permitted to remain on concurrent stable CTCL therapy. Subjects received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses in patients who continued beyond the first cycle. Safety was monitored by physical exams, clinical laboratory tests, and assessment of adverse events (AEs). Immunophenotyping of peripheral blood was performed to measure the impact of MRG-106 on normal immune cell subsets. The PK properties of MRG-106 were compared between different routes of administration. The effect of MRG-106 on individual skin lesions or total skin disease was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score or the modified Severity Weighted Assessment Tool (mSWAT), respectively. Biopsies were collected from all subjects treated by intralesional injection and from a subset of subjects in the SC/IV cohorts to assess molecular and cellular responses to MRG-106. Baseline miR-155 expression and changes in gene expression and T cell repertoire (T cell receptor sequencing) in response to MRG-106 treatment were assessed. Results: 24 subjects (18M/6F, median age 62 yrs) have been in the study for up to 10 months (as of 7/31/2017). 4 subjects received only intralesional doses; 2 subjects were enrolled into both the intralesional and SC cohorts. 18 subjects received only SC injections or IV infusions/bolus injections of MRG-106. 22/26 subjects completed the first treatment cycle per protocol; 2 subjects are on-going. 2 subjects discontinued: one due to progressive disease found shortly after enrollment, and one due to an AE of worsening pruritus (Grade 3), judged as a dose-limiting toxicity at 900 mg SC. The drug was otherwise well-tolerated: of the other 48 drug-related AEs, all were Grade 1 or 2. The MTD has not been reached. 23/24 subjects (95%) showed improvement in either the individually treated lesion (intralesional cohort) or total skin disease (SC/IV cohorts) as measured by maximal change in CAILS or mSWAT. In the SC/IV-infusion cohorts, 17/18 subjects had an improvement in mSWAT score; 9/18 subjects (50%) reached a PR defined as ≥ 50% reduction in mSWAT score. Of the 9 subjects who received MRG-106 for &gt; 1 cycle, 78% reached a PR, suggesting that longer treatment may provide greater benefit. Improvements in mSWAT scores were observed as early as Study Day 19 (the 1st post-treatment assessment), and for all but one subject, improvements from baseline were maintained through the treatment period. Based on immunophenotyping of peripheral blood, absolute numbers and proportions of subjects' leukocyte subpopulations were not significantly altered with MRG-106 treatment, with the exception of transient increases in NK and NK T cells observed only at the highest dose. TCR sequencing of pre- and post-treatment biopsies showed that T cell clonality decreased with intralesional injection of MRG-106. miR-155 was elevated in the lesions of most subjects, drug accumulation was observed with all routes of administration, and gene expression changes were associated with inactivation of the STAT, NFκB, and PI3K/AKT pathways. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated and has clinical activity as indicated by meaningful reductions in CAILS and mSWAT assessments. Exploratory analyses of lesion biopsies support the clinical activity of MRG-106 with reductions in T cell clonality and gene expression changes consistent with the known mechanism of miR-155. These encouraging data support the continued investigation of MRG-106 in MF patients and expansion of the study to include additional hematological malignancies in which miR-155 is known to be elevated and relevant. Disclosures Querfeld: Medivir: Honoraria; Actelion: Honoraria, Research Funding; MiRagen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa: Research Funding; Trillium Therapeutics: Research Funding; City of Hope: Employment; Mallinckrodt: Honoraria; Mindera: Consultancy. Foss: seattle genetics: Speakers Bureau; Eisai: Honoraria; spectrum: Honoraria, Speakers Bureau; immune design: Research Funding; celgene: Honoraria. Porcu: Tetralogic: Research Funding; Celgene: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding; Innate Pharma: Research Funding; Miragen: Research Funding; Kiowa: Research Funding. Kim: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: 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; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Halwani: Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Seto: miRagen Therapeutics: Employment, Equity Ownership, Patents & Royalties: Inventor on patents. Pestano: Sanofi: Equity Ownership; Cascadian Therapeutics: Equity Ownership; miRagen Therapeutics: Employment, Equity Ownership. Jackson: miRagen Therapeutics: Employment, Equity Ownership. Williams: miRagen Therapeutics: Employment, Equity Ownership. Dickinson: miRagen Therapeutics: Employment, Equity Ownership. Ruckman: miRagen Therapeutics: Employment, Equity Ownership. Gordon: Syndax: Consultancy; Taiho: Consultancy; Pre-cell: Consultancy; Bayer: Consultancy; ElevenP15: Consultancy; Clinipace: Consultancy; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Heron Therapeutics: Consultancy; Themis: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees; GLPI: Consultancy, Equity Ownership; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; Globavir: Consultancy; miRagen Therapeutics: Consultancy; IGM: Consultancy; Cleave Pharmaceuticals: Consultancy; Flugen: Consultancy; Inovio: Consultancy. Rubin: miRagen Therapeutics: Employment, Equity Ownership. Marshall: Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy; AmideBio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fluorofinder: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on various patents.

Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 weeks (wks) or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on rux for ≥6 months with a stable dose for ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, and an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must have received ≥5 cycles of sotatercept to be response-evaluable. Results A total of 53 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty one pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Sixteen TD and 15 non-TD pts received sotatercept alone for a median of 5 (1-67) cycles. Thirteen pts received 0.75 mg/kg and 18, 1 mg/kg. Seven of 24 (29%) evaluable pts responded. Of these, 4 were anemia responses; 3 TD pts achieved TI. Five responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 21 (1-22) days and median duration of response (DOR) 13 (3.9-56.4) months. Seven pts (22.6%) received &lt;5 cycles and were not response-evaluable: 2 proceeded to stem cell transplant (SCT), 2 had logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Three pts continue on study. Reasons for d/c included no response (11), progressive MF (6), SCT (3), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. The median number of cycles was 8 (2-43). Five of 17 (29%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (7-147) days and median DOR 34.6 (3.1-47.9) months. Four pts (19%) received &lt;5 cycles and were not response-evaluable, 1 each due to MF progression, loss of insurance, SCT and pt decision. Five pts remain on study. Reasons for d/c included no response (6), SCT (4), progressive MF (2), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 wks because of early d/c of sotatercept. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7), limb (bone/muscle/joint) pain (n=3) and headache (1). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 29% both when used alone and in conjunction with a stable dose of rux. A total of 60 pts are planned to be treated on this trial (NCT01712308). Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria. Daver:Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Kadia:Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Cortes:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Novartis: Consultancy, Research Funding. Jain:BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding. Huynh-Lu:Incyte Corporation: Speakers Bureau. Nguyen-Cao:Incyte Corporation: Speakers Bureau. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding. Kantarjian:Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding.

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic anemia and hemolysis as well as episodic vaso-occlusive crises (VOC). These manifestations of SCD contribute to the cumulative organ damage that leads to disability, reduced quality of life, and accelerated mortality. In particular, VOCs and their associated episodic pain are a hallmark symptom of SCD and frequently require emergency medical attention. Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor in development for the treatment of SCD. It has demonstrated robust, rapid, and sustained improvements in patient Hb levels with numerically fewer VOCs compared with placebo, which suggests that viscosity was not increased with voxelotor treatment. The objective of this study was to further explore this observation by examining the association between absolute Hb achieved by voxelotor treatment and VOC incidence rate. In addition, to inform on the potential for symptom exacerbation after drug discontinuation, rates of VOCs after voxelotor discontinuation were analyzed. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients with SCD aged 12 to 65 years. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints included the annualized incidence rate of VOC. This abstract reports a post hoc analysis of VOC incidence in the per-protocol population stratified by Hb level at 24 weeks of treatment. In addition, VOCs in patients who discontinued voxelotor and completed a 28-day follow-up are reported here (data cutoff October 31, 2018). Results: The proportion of patients with ≥1 VOC was 67.0% (59/88) in the voxelotor 1500 mg group, 66.3% (61/92) in the voxelotor 900 mg group, and 69.2% (63/91) in the placebo group. Overall, the annualized adjusted incidence rate of VOCs (the number of crises per person-year) was 2.77 in the voxelotor 1500 mg group, 2.76 in the voxelotor 900 mg group, and 3.19 in the placebo group. When stratified by Hb level after 24 weeks of treatment, the incidence of VOCs was generally lower in patients who achieved higher absolute Hb levels on voxelotor treatment compared with placebo (Figure 1). Patients who discontinued voxelotor were also observed for 28 days post-treatment. At the time of data cutoff, 55 patients (n=21, voxelotor 1500 mg; n=17, voxelotor 900 mg; n=17, placebo) had discontinued treatment and had post-treatment follow-up. During the 28-day period after treatment discontinuation, 5 patients in the voxelotor 1500 mg group reported 6 VOCs; 3 patients in the voxelotor 900 mg group reported 3 VOCs; and 5 patients in the placebo group reported 8 VOCs. The estimated incidence rates of post-treatment VOCs were 4.63, 4.30, and 7.01 in the voxelotor 1500 mg, voxelotor 900 mg, and placebo groups, respectively. Conclusions: Patients who achieved the greatest absolute Hb level after 24 weeks of treatment with voxelotor had numerically fewer VOCs, suggesting that increasing Hb levels resulting from voxelotor treatment did not lead to a viscosity-related increase in risk of vaso-occlusion. Following drug discontinuation, there was a numerically lower incidence of VOCs in the voxelotor arms compared with placebo. Altogether, these results suggest that voxelotor treatment safely raises Hb without causing a viscosity-related increased risk of VOC and that treatment discontinuation did not increase risk for VOC. Disclosures Vichinsky: GBT: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Telfer:ApoPharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker activities, clinical trial activities; Terumo: Honoraria, Other: Speaker activity; Pfizer: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activity; Kyowa Kirin Limited: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activities; Napp Pharma: Other: clinical trial involvement; Celgene: Other: clinical trial involvement; Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: 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. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Ataga:Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Bioverativ: 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.

Abstract Background: New prognostic factors have been recently identified in AML patient population that include frequent mutations of receptor tyrosine kinases (RTK) including KIT, PDGFR, FLT3, that are associated with higher risk of relapse. Thus, targeting RTKs could improve the therapeutic outcome in AML patients. Aim: To create a digital drug model for dasatinib and validate the predicted response in AML patient samples with ex vivo drug sensitivity testing. Methods: The Beat AML project (supported by the Leukemia & Lymphoma Society) collects clinical data and bone marrow specimens from AML patients. Bone marrow samples are analyzed by conventional cytogenetics, whole-exome sequencing, RNA-seq, and an ex vivo drug sensitivity assay. For 50 randomly chosen patients, every available genomic abnormality was inputted into a computational biology program (Cell Works Group Inc.) that uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated pathways. Digital drug simulations with dasatinib were conducted by quantitatively measuring drug effect on a composite AML disease inhibition score (DIS) (i.e., cell proliferation, viability, and apoptosis). Drug response was determined based on a DIS threshold reduction of > 65%. Computational predictions of drug response were compared to dasatinib IC50 values from the Beat AML ex vivo testing. Results: 23/50 (46%) AML patients had somatic mutations in an RTK gene (KIT, PDGFR, FLT3 (ITD (n=15) & TKD (n=4)), while 27/50 (54%) were wild type (WT) for the RTK genes. Dasatinib showed ex vivo cytotoxicity in 9/50 (18%) AML patients and was predicted by CBM to remit AML in 9/50 AML patients with 4 true responders and 5 false positive. Ex vivo dasatinib responses were correctly matched to the CBM prediction in 40/50 (80%) of patients (Table1), with 10 mismatches due to lack of sufficient genomic information resulting in profile creation issues and absence of sensitive loops in the profile. Only 4/23 (17%) RTK-mutant patients and 5/27(19%) RTK-WT patients were sensitive to dasatinib ex vivo, indicating that presence of somatic RTK gene mutations may not be essential for leukemia regression in response to dasatinib. Co-occurrence of mutations in NRAS, KRAS and NF1 seemed to associate with resistance as seen in 10 of the 14 profiles harboring these mutations. Conclusion: Computational biology modeling can be used to simulate dasatinib drug response in AML with high accuracy to ex vivo chemosensitivity. DNA mutations in RTK genes may not be required for dasatinib response in AML. Co-occurrence of NRAS, KRAS and NF1gene mutations may be important co-factors in modulating response to dasatinib. Disclosures Tyner: Leap Oncology: Equity Ownership; Syros: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Aptose: Research Funding; Takeda: Research Funding; Agios: Research Funding. Druker:Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Millipore: Patents & Royalties; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Celgene: Consultancy; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Patient True Talk: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy. Sahu:Cellworks Research India Private Limited: Employment. Vidva:Cellworks Research India Private Limited: Employment. Kapoor:Cellworks Research India Private Limited: Employment. Azam:Cellworks Research India Private Limited: Employment. Kumar:Cellworks Research India Private Limited: Employment. Chickdipatti:Cellworks Research India Private Limited: Employment. Raveendaran:Cellworks Research India Private Limited: Employment. Gopi:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment. Cogle:Celgene: Other: Steering Committee Member of Connect MDS/AML Registry.

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .