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2907.2 A Randomized Phase 2 Trial of 28-Day (Arm A) Versus 14-Day (Arm B) Schedule of Venetoclax + Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients ≥ 60 Years

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Uma Borate, MD1, Ying Huang, MS, MA2, Joshua F. Zeidner, MD3, Ronan T. Swords, MD, PhD, FRCP, FRCPath4, Kristin L Koenig, MD5, Eytan M. Stein, MD6, Maria R. Baer, MD7, Wendy Stock, MD8, Yazan F Madanat, MD9, Rebecca Olin, MD10, William Blum, MD11, Gary J. Schiller, MD12, Tara L. Lin, MD13, Emily K Curran, MD14, Molly Martycz1*, Leonard Rosenberg15*, Sonja Gullen Marcus, MPH15*, Timothy Chen, PhD1, Mona Stefanos, MD16, Ross L Levine, MD17, Brian J. Druker, MD4, Ashley Owen Yocum, PhD15, Amy Burd, PhD18, Alice Mims, MD19 and John C. Byrd, MD20

1The Ohio State University, Columbus, OH
2Division of Hematology, Department of Statistics, The Ohio State University Wexner Medical Center, Columbus, OH
3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
4Knight Cancer Institute, Oregon Health & Science University, Portland, OR
5Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
6Department of Medicine; Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY
7University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD
8Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
9Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX
10University of California San Francisco, San Francisco, CA
11Emory University, Winship Cancer Institute, Atlanta, GA
12David Geffen School of Medicine at UCLA, Los Angeles, CA
13Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Westwood, KS
14University of Cincinnati, Cincinnati, OH
15Leukemia and Lymphoma Society, Rye Brook, NY
16The Ohio State University, Lewis Center, OH
17Memorial Sloan Kettering Cancer Center, New York, NY
18Leukemia and Lymphoma Society, White Plains, NY
19The Ohio State University Comprehensive Cancer Center, Columbus, OH
20Department of Internal Medicine, University of Cincinnati, Cincinnati, OH

Background: Treatment options for older, less fit acute myeloid leukemia (AML) patients continue to be challenging, with toxicities and limited efficacy. The combination therapy of azacitidine (Aza) and the bcl-2 inhibitor venetoclax (Ven) showed superior benefit in response rates and overall survival compared to Aza alone, leading to the combination’s FDA approval in newly diagnosed AML patients ≥ 75 years and younger patients ineligible for intensive chemotherapy. While Ven-Aza is a very effective and potent therapy, the 28-day continuous dosing of Ven combined with 7 days of Aza resulted in interrupted dosing or shortened dosing schedules due to persistent cytopenias in more than 50% of treated patients in the VIALE-A trial and subsequent real-world data. Furthermore, investigation of novel agents in combination with Ven-Aza has been challenging due to prolonged cytopenias even when monotherapy with the new agent shows no myelosuppression. Given that Ven-Aza is not curative, successful integration of other agents with this standard of care remains important in AML. The growing knowledge of Ven-Aza toxicities prompted attention to developing a safer dosing regimen while maintaining similar efficacy. Our study will examine the FDA label of 28 days of Ven, versus 14 days, in combination with Aza for newly diagnosed AML patients ≥ 60 years who are not candidates for intensive chemotherapy. The primary objective of this study is to compare complete remission (CR) rates with an abbreviated schedule of Ven (14 days) versus the current package insert approved schedule (28 days). We hypothesize that reducing the dosing duration of Ven would reduce the associated toxicities while maintaining a comparable response rate.

Study Design and Methods: This protocol, supported by the Leukemia and Lymphoma Society, is a sub-study of the Beat AML Master Trial (NCT03013998) in which untreated AML patients age ≥ 60 are assigned an investigational therapy based on cytogenetic and central genomic analysis. Patients are randomized onto Arm A (28-day Ven-Aza schedule) or Arm B (14-day Ven-Aza schedule) stratified by age (60-74 vs. 75+ years). The primary objective is to determine the complete remission (CR) rate of patients treated in each randomized arm for up to 2 cycles. The secondary objectives will include assessments of composite complete remission (CR, CR with hematologic improvement, CR with incomplete count recovery), duration of remission, survival, and incidence of treatment-related and non-related toxicities. Additionally, the overall incidence of febrile neutropenia, grade ≥3 infections, transfusions, days of hospitalization and time to neutrophil recovery will be determined.

In both arms of the study, patients will be assessed for response at day 21-28 of cycles 1 and 2. Patients who have marrow remission (< 5% blasts) will wait for count recovery of absolute neutrophil count ≥ 1.0x109/L and platelets ≥ 100x109/L before initiating the next cycle of therapy. Patients will then be followed for survival. With the exception of the Ven dosing schedule (14 vs. 28 days), the FDA approved package insert for Ven, including dose modifications for concurrent azole therapy, will be followed in both arms.

The intent of the analysis is to demonstrate that the 14-day Ven-Aza regimen is at least as effective as the standard 28-day regimen. A two-part design with total of 166 patients (83 per group) will provide 80% power to detect a 10% non-inferiority margin at the one-sided 5% significance level, assuming that the CR rate is 36% for the 28-day regimen, as observed in VIALE-A, and 25% higher (45%) for the 14-day regimen. In addition to assessing the frequency of adverse events such as cytopenias, safety monitoring will include an assessment of response rates after at least 25% of patients have completed 2 cycles of treatment, with consideration for stopping the study if data suggest the 14-day regimen is inferior to the standard regimen. The study has now expanded and will fully enroll all 166 patients.

Disclosures: Borate: Daiichi Sankyo: Consultancy; Sumitomo: Consultancy; Abbvie: Consultancy; Incyte: Consultancy; Astellas: Consultancy; Rigel: Consultancy; BMS: Consultancy; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: IDMC; Novartis: Consultancy. Zeidner: Sumitomo Pharma: Consultancy, Research Funding; Stemline: Research Funding; Shattuck Labs: Consultancy, Research Funding; Servier: Consultancy; Sellas Life Sciences: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Newave: Research Funding; Merck: Research Funding; Loxo: Research Funding; Jazz: Research Funding; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Foghorn: Consultancy; Faron: Research Funding; Daiichi Sankyo: Consultancy; AstraZeneca: Research Funding; Astex: Research Funding; Arog: Research Funding; Akeso Biopharma: Research Funding; AbbVie: Consultancy, Research Funding; Syndax: Consultancy; Takeda: Research Funding; Zentalis: Research Funding. Swords: Disc Medicine: Consultancy. Stein: Genentech: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees. Stock: Adaptive: Consultancy, Honoraria; Kura: Research Funding; Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Madanat: Blueprint Medicines, MD Education, and Morphosys: Other: travel; Taiho Oncology, Rigel Pharmaceuticals, Novartis: Consultancy; OncLive, MD Education, Sierra Oncology, Stemline, MorphoSys: Consultancy; Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences and Novartis: Other: Advisory Board; BMS, Kura Oncology, BluePrint Medicines, Geron: Consultancy. Olin: Cellectis: Research Funding; Servier: Consultancy; Rigel: Consultancy. Lin: Aptevo; Bio-Path Holdings; Ciclomed; Cleave; Jazz; Jazz Pharmaceuticals; Leukemia & Lymphoma Society; Kura Oncology; Trovagene: Research Funding; Jazz Pharmaceuticals; Servier: Consultancy. Curran: Jazz Pharmaceuticals: Consultancy; Kite Pharmceuticals: Consultancy; Clincal Care Options: Honoraria; Dava Oncology: Honoraria; Pfizer: Consultancy; Servier: Honoraria. Stefanos: Eilean Therapeutics: Consultancy. Levine: Isoplexis: Membership on an entity's Board of Directors or advisory committees; Scorpion: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Anovia: Consultancy; Mana: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Epiphanes: Membership on an entity's Board of Directors or advisory committees; Jubilant: Membership on an entity's Board of Directors or advisory committees; Bridge Bio: Consultancy; Bridge Medicines: Consultancy; Imago: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Burd: Eilean Therapeutics: Current Employment. Mims: Novartis: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society Beat AML Study: Other: Senior Medical Director; Treadwell Therapeutics: Membership on an entity's Board of Directors or advisory committees. Byrd: Abbvie, AstraZeneca, and Syndax: Consultancy; Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company.

OffLabel Disclosure: The trial investigates an alternative schedule of venetoclax that is not per label.

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