A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

Introduction Hypomethylating agents (HMAs), azacitidine (Aza) or decitabine, are standard treatment (Tx) for patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) not candidates for immediate allogeneic hematopoietic stem cell transplantation (HSCT). However, complete remission was only reported for 17% receiving Aza, and only half the pts are alive after 2 yrs (Fenaux et. al., 2009). Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, has been shown to synergize with HMAs in preclinical studies in HR-MDS (Jilg et. al., 2016) and clinical studies in AML (DiNardo et. al., 2016), suggesting that the combination of Ven+Aza may be a promising approach for HR-MDS Tx. This ongoing, open-label, Phase 1b, dose-escalation study is evaluating the safety and preliminary efficacy of Ven+Aza for Tx-naive HR-MDS. Methods The study (NCT02942290) initially included a 3-arm randomized cohort. Data from this cohort included 10 pts treated with Ven (400 mg or 800 mg for 28 days) + Aza and 2 pts treated with Aza alone. Following two deaths (Ven 400 mg=1/5 and Ven 800 mg=1/5), the study was amended to a dose-escalation and safety expansion design to determine the recommended Phase 2 dose (RP2D) of Ven+Aza. Key inclusion criteria were age ≥18 yrs, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts Results As of April 9, 2019, 59 pts have been treated and dose-escalation is complete. These included 12 pts in the initial randomized cohort. The dose-escalation cohort included 25 pts (Ven 100 mg=8, Ven 200 mg=9, Ven 400 mg=8) and the safety expansion included 22 pts. Results are presented for all 59 pts [75% male, median age 71 yrs (range 26-85)]. At baseline, 15 (25%) pts had an overall IPSS score of 1.5, 29 (49%) had a score of 2, 8 (14%) had a score of 2.5, 6 (10%) had a score of 3.0, and 1 (2%) pt had a score of 3.5. Eleven (19%) pts had intermediate and 24 (41%) pts had poor baseline cytogenetic risk. In treated pts, the most common treatment-emergent adverse events (TEAE's) were anemia, neutropenia, and thrombocytopenia (Table). Common gastrointestinal symptoms were constipation, nausea, diarrhea, and vomiting. Infection was predominantly febrile neutropenia. Predominant Grade 3 or 4 AEs included neutropenia (61%), thrombocytopenia (39%), leukopenia (31%), and anemia (20%). Major SAEs were febrile neutropenia (31%). There were 10 deaths of which 4 were due to infections (pneumonia-2, neutropenic sepsis-1 and septic shock- 1). Other causes of death were multiorgan failure (n=1), respiratory failure (n=1), progressive disease (n=3), and unexplained death (n=1). Twenty pts discontinued the study including 10 who underwent transplantation. Among 57 pts evaluable for response, the ORR with (CR) was documented in 18, mCR in 22 , and stable disease (SD) in 11. Disease progression was observed in 2 pts. Median TTR for ORR was 1.0 mos (range 0.7-3.5 mos). At this data cut, the median time to FU was 4.3 mos (range 3.3-6.5 months). Median DOR, PFS and OS were not reached. With this short follow up, the 12-mo estimates for DOR for ORR was 74% (95% CI: 34%, 92%) and PFS was 59% (95% CI: 31%, 79%). The 18-mo estimate for OS was 74% (95% CI: 50%, 87%). Among 56 pts eligible for hematological improvement (HI), 28 (50%) patients achieved HI as either HI-erythroid, HI-platelet, or HI-neutrophil. Conclusion The combination therapy of Ven+Aza demonstrated a tolerable safety profile and promising efficacy in pts with HR-MDS. The maximum tolerated dose of Ven without dose-limiting toxicities was determined to be 400 mg in this HR-MDS population. Disclosures Wei: Pfizer: Honoraria; Astellas: former employee, Honoraria; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax; Macrogenics: Honoraria; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Borate:Pfizer: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy. Fong:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy. Baer:Al Therapeutics: Research Funding; Kite: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Incyte: Research Funding. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Jurcic:Incyte: Consultancy; AbbVie Inc: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Odenike:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Tanwani:AbbVie Inc: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.