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111 Escalated Dosing Schedules of CC-486 Are Effective and Well Tolerated for Patients Experiencing First Acute Myeloid Leukemia (AML) Relapse: Results from the Phase III QUAZAR AML-001 Maintenance Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Novel promising therapies for relapsed/refractory AML
Hematology Disease Topics & Pathways:
AML, Diseases, Elderly, Study Population, Myeloid Malignancies
Saturday, December 5, 2020: 9:30 AM

Hartmut Döhner1, Andrew H Wei, MBBS, PhD2,3, Pau Montesinos, MD, PhD4,5*, Hervé Dombret, MD6,7, Farhad Ravandi, MBBS8, Hamid Sayar, MD, MSc9, Kimmo Porkka10,11, Irwindeep Sandhu, MD12*, Francesco Passamonti13*, Fabrizio Pane, MD14, Tadeusz Robak, MD PhD15, José F. Falantes16*, Andre C. Schuh17, Gert Ossenkoppele, MD, PhD18*, Ignazia La Torre19*, Barry Skikne, MD20,21*, Keshava Kumar, PhD21*, Qian Dong, DrPH21*, C.L. Beach, PharmD21* and Gail J. Roboz, MD22

1Ulm University Hospital, Ulm, Germany
2The Alfred Hospital, Melbourne, Australia
3Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
4CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
5Hematology Department, Hospital Universitario La Fe de Valencia,, Valencia, Spain, Spain
6Institut de Recherche Saint Louis, Université de Paris, Paris, France
7Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, France
8Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
9Indiana University Cancer Center, Indianapolis, IN
10iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
11Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
12University of Alberta Hospital, Edmonton, Canada
13Department of Medicine and Surgery, University of Insubria, Varese, Italy
14Azienda Ospedaliera Universitaria Federico II, Naples, Italy
15Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
16Hospital Virgen del Rocío. Hematología, Seville, Spain
17Princess Margaret Cancer Centre, Toronto, ON, Canada
18Amsterdam UMC, Location VU University Medical Center, Amsterdam, Netherlands
19Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland
20Kansas University Medical Center, Kansas City, KS
21Bristol Myers Squibb, Princeton, NJ
22Weill Medical College of Cornell University New York-Presbyterian Hospital, New York, NY

INTRODUCTION: Standard intensive induction chemotherapy (IC) for AML leads to complete remission (CR) in 60%–80% of patients aged ≤ 60 years and in 40%–60% of patients aged > 60 years. However, about two-thirds of patients relapse after frontline therapy, and most relapses occur within the first 18 months (Yilmaz, Blood Cancer J, 2019).

Effective post-induction AML maintenance treatment should decrease the risk of relapse by suppressing growth of residual leukemic cells. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules (> 7 days per 28-day treatment cycle) to sustain therapeutic activity. In the phase III international, randomized, double-blind QUAZAR AML-001 trial (NCT01757535), CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients with AML in first remission following IC, who were not candidates for hematopoietic stem cell transplant (HSCT) (Wei, ASH 2019, LBA-3). Patients initially received CC-486 or placebo for 14 days per 28-day cycle, but patients identified as having early AML relapse with 5–15% blasts in peripheral blood or bone marrow could receive an escalated 21-day/cycle dosing schedule at investigators’ discretion.

OBJECTIVE: Evaluate clinical outcomes in patients in QUAZAR AML-001 who relapsed with 5–15% blasts on-study who then received escalated 21-day dosing of study drug.

METHODS: Eligible patients were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤ 3, and had achieved a first CR or CR with incomplete blood count recovery (CRi) after IC ± consolidation. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to receive CC-486 300 mg or placebo once-daily on days 1–14 of repeated 28-day treatment cycles. CR/CRi status was assessed centrally every 3 cycles; patients who exhibited signs of relapse in hematology parameters at routine clinic visits (conducted every 2 weeks) could have an unscheduled bone marrow test to confirm AML relapse. Patients who developed 5%–15% blasts in blood or bone marrow could receive study drug for 21 days/cycle at the investigator’s discretion. Treatment could continue until >15% blasts, unacceptable toxicity, or HSCT.

RESULTS: In all, 472 patients were randomized to CC-486 (N=238) or placebo (N=234). During the course of the study, 91 patients (CC-486, n=51 [21%]; placebo, n=40 [17%]) were identified as having early AML relapse with 5–15% blasts and were assigned to receive a 21-day/cycle dosing schedule. Median time to dose escalation of CC-486 was 9.2 months (range 1.0–52.7) and of placebo was 6.0 months (0.5–19.3). Median number of 21-day dosing cycles was 2.0 in both the CC-486 (range 1–45) and placebo (1–16) arms, but proportionally more patients in the CC-486 arm received > 3 escalated dosing cycles (CC-486, 43%; placebo, 18%). Among 78 evaluable patients with ≥ 5% blasts in the most recent bone marrow on or before day 1 of 21-day dosing, 23% (10/43) of patients in the CC-486 arm and 11% (4/35) of patients in the placebo arm regained CR/CRi (< 5% blasts in bone marrow; central review) while receiving an escalated dosing regimen. Among all patients who received escalated dosing schedules, median OS from the time of randomization was 22.8 months in the CC-486 arm vs. 14.6 months in the placebo arm (hazard ratio [HR] 0.66 [95% CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5%, respectively (+20.9% [2.1, 39.7]).

The most common adverse events first reported during 21-day dosing were febrile neutropenia (CC-486, 24%; placebo, 3%), thrombocytopenia (22% and 23%), anemia (22% and 20%), and neutropenia (20% and 10%) (Table). A similar proportion of patients in each arm (CC-486, 31%; placebo, 35%) first experienced a grade 3 or grade 4 adverse event while receiving escalated dosing. CC-486 dose-escalation did not lead to detrimental effects on patient-reported quality of life measures (as assessed by the FACIT-Fatigue and EQ-5D-3L instruments) vs. placebo.

CONCLUSIONS: An escalated 21-day CC-486 dosing regimen was well tolerated and resulted in restoration of remission in approximately one-fourth of patients. Hematologic adverse events first reported during escalated dosing in both treatment arms may be due in part to disease relapse. A 21-day CC-486 dosing schedule could be considered for patients who experience AML relapse with ≤ 15% blasts.

Disclosures: Döhner: Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Oxford Biomedicals: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Roche: Consultancy, Honoraria. Wei: Servier: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria, Research Funding, Speakers Bureau; Macrogenics: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Roche: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Dombret: Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Janssen: Consultancy; Menarini: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ravandi: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Sayar: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Porkka: BMS/Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sandhu: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi/Bioverativ: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Passamonti: Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau. Pane: Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: 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. Robak: GSK: Research Funding; Sandoz: Consultancy, Honoraria; UTX-TGR: Research Funding; Momenta: Consultancy; Takeda: Consultancy; Acerta: Research Funding; BioGene: Honoraria, Research Funding; Octapharma: Honoraria; AstraZeneca: Honoraria, Research Funding; Medical University of Lodz: Current Employment; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Morphosys: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Research Funding; Pfizer: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UCB: Honoraria, Research Funding. Falantes: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ossenkoppele: Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Daiichi Sayko: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Research Funding; Roche: Consultancy; J&J: Consultancy, Research Funding; Agios: Consultancy. La Torre: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne: Bristol Myers Squibb: Current Employment. Kumar: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Roboz: Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Mesoblast: Consultancy; Agios: Consultancy; Orsenix: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Amphivena: Consultancy; Celgene: Consultancy; Astex: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy.

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