A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax As Monotherapy or in Combination with Azacitidine for the Treatment of Relapsed/Refractory Myelodysplastic Syndrome
Authors: Zeidan Amer M. , Pollyea Daniel A , Garcia Jacqueline S , Brunner Andrew , Roncolato Fernando , Borate Uma , Odenike Olatoyosi , Bajel Ashish R. , Watson Anne Marie , Götze Katharina , Nolte Florian , Tan Peter T. , Hong Wan-Jen , Dunbar Martin , Zhou Ying , Gressick Lori , Ainsworth William , Harb Jason , Salem Ahmed Hamed , Hayslip John , Swords Ronan , Garcia-Manero Guillermo 
Published: February 2020

Introduction
Over-expression of the anti-apoptotic protein BCL-2 in MDS has been implicated in progression and drug resistance in MDS. Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, was recently approved in combination with HMAs or low dose cytarabine for the frontline management of older unfit pts with AML. In this study, we sought to evaluate the safety and efficacy of Ven in pts with R/R MDS.
Methods
This is an ongoing phase 1b, open-label, multicenter study in R/R MDS (NCT02966782). Key eligibility criteria include age ≥18 years, failure of HMA after receiving at least 4 cycles of Aza or 4 cycles of decitabine within the previous 5 years, marrow blasts &lt;20%, and ECOG Performance status of ≤2. Cohort 1 (C1) pts received Ven monotherapy, either 400 mg (Arm A) or 800 mg (Arm B) per cycle (28 days) and Cohort 2 (C2) pts received Aza combined with escalating doses of Ven: 100, 200 and 400 mg daily for 14 of 28-day cycles. Aza was administered at the standard dose (75 mg/m2/day) for the first 7 days of each cycle.
The primary objectives were to evaluate the safety profiles and the recommended Phase 2 dose (RP2D) of Ven monotherapy and Ven+Aza. Key secondary objectives included a preliminary assessment of overall response rate (ORR, defined as complete remission [CR]+marrow complete remission [mCR]+partial response [PR]) , time to first response (TTR), progression-free survival (PFS), and overall survival (OS). We used the modified International Working Group 2006 criteria for response assessment (Cheson et. al., Blood, 2006).
Results
As of April 9, 2019, 46 pts [87% male, median age 76 years (range 44-91)] were enrolled. C1 (Ven monotherapy) included 22 pts, C2 (combination therapy) included 24 pts. At baseline, 37 (80%) pts received at least one prior therapy, 2 (15%) pts received 2, and 1 (2%) patient received &gt;3 therapies prior to enrollment in the study. Baseline bone marrow blasts were: ≤5% was observed in 16 (35%) pts, &gt;5% and ≤10% in 23 (50%), and &gt;10% in 7 (15%) pts respectively. Cytogenetics risk was evaluated in 27/46 pts and were as follows: Good 12 (44%), Intermediate 9 (33%), and Poor 6 (22%).
Overall, 9 pts discontinued study therapy (8 deaths, 1 withdrew consent). The most frequent treatment-emergent adverse events (TEAEs) included neutropenia, thrombocytopenia, nausea, and diarrhea (Table ). Infectious TEAEs included febrile neutropenia and pneumonia. Predominant Grade 3 and 4 TEAEs were hematological and included neutropenia (41%), thrombocytopenia (30%), leukopenia (24%), and anemia (15%). Serious TEAEs occurring in ≥2 pts were febrile neutropenia (n=8), pneumonia (n=6), thrombocytopenia (n=2), and epistaxis (n=2). Death on study occurred in 8 (17%) pts, of whom 6 died of progressive disease. Other causes of death were septic shock (n=1) and pneumonia (n=1).
Forty of 46 pts were response evaluable. Median follow-up time was 4.7 mos (range: 3.7-6.3 mos). In C1, ORR was 7% (1/16). Stable disease was observed in 75% (12/16) pts. Median TTR was 1.6 mos (range: 1.6-1.6 mos). Median PFS was 3.4 mos (95% CI: 1.9-5.2 mos) and 6-mos estimate for OS was 57% (95% CI: 22%, 81%).
In C2, ORR was 50% (12/24 pts). Of those, 13% (3/24) had CR and 38% (9/24) had mCR. Stable disease was observed in 31% (10/24) pts. Median PFS, and OS were not reached. The 6-mos estimate for PFS was 76% (95% CI: 50%, 89%) and estimated OS at 9-mos was 83% (95% CI: 55%, 95%). Finally, 4 pts came off study to receive allogeneic stem cell transplantation.
Conclusion
Ven monotherapy and combination Ven+Aza were well tolerated in pts with R/R MDS and most AEs were manageable. Although the study is still ongoing, the 6-mos OS estimate of 57% in monotherapy pts compares favorably to historical controls. In addition, the ORR observed with combination therapy, and the observed 9-mos OS rate of 83% also compare favorably with historical data. Updated data on safety and efficacy, including data on RP2D, will be presented at the meeting.

Disclosures
Zeidan: Ariad: Honoraria; Agios: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: 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, Research Funding; Janssen: 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; Takeda: 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; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Roncolato:St. George Hospital: Employment. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Odenike:Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Agios: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding; Oncotherapy: Research Funding. Bajel:Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria. Watson:Amgen: Other: Travel grant; Roche: Other: Travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tan:AbbVie Inc: Other: Investigator in AbbVie funded trial. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Gressick:AbbVie Inc: Employment, Other: Stock/stock options. Ainsworth:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Hayslip:AbbVie Inc: Employment, Other: Stock/stock options. Swords:AbbVie Inc: Employment, Other: Stock/stock options. 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.

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.