-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

LBA-3 The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
survivorship, AML, Diseases, Biological Processes, epigenetics, Clinically relevant, Myeloid Malignancies, hematopoiesis
Tuesday, December 10, 2019, 7:30 AM-9:00 AM
Hall D, Level 2 (Orange County Convention Center)

Andrew H. Wei, MBBS, FRACP, FRCPA, PhD1,2*, Hartmut Döhner, MD3, Christopher Pocock, MBBS4, Pau Montesinos, MD, PhD5,6*, Boris Afanasyev, MD, DSci7*, Hervé Dombret, MD8,9,10, Farhad Ravandi, MD11, Hamid Sayar, MD, MSc12, Jun Ho Jang, MD, PhD13, Kimmo Porkka, MD14, Dominik Selleslag, MD15, Irwindeep Sandhu, MD16*, Mehmet Turgut, MD17*, Valentina Giai, MD18*, Yishai Ofran, MD19,20, Merih Kizil Cakar, MD21*, Aida Botelho de Sousa, MD22*, Justyna Rybka, MD, PhD23*, Chiara Frairia, MD24*, Lorenza Borin, MD25*, Germana Beltrami, MD26*, Jaroslav Cermak, MD, PhD27*, Gert J. Ossenkoppele, MD, PhD28, Ignazia La Torre, MD29*, Barry Skikne, MD29*, Keshava Kumar, PhD29*, Qian Dong, DrPH29*, CL Beach, PharmD29 and Gail J. Roboz, MD30,31

1The Alfred Hospital, Melbourne, AUS
2Monash University, Melbourne, Australia
3Ulm University Hospital, Ulm, Germany
4Kent & Canterbury Hospital, Canterbury, United Kingdom
5CIBERONC, Instituto Carlos III, Madrid, Spain
6Hospital Universitari i Politècnic La Fe, Valenica, Spain
7Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Ru, Russian Federation
8Hematology, Hôpital Saint-Louis, Paris, France
9Institut de Recherche Saint Louis, Paris, France
10Université de Paris, Paris, France
11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
12Indiana University Cancer Center, Indianapolis, IN
13Samsung Medical Centre, Seoul, Korea, Republic of (South)
14Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
15AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium
16University of Alberta Hospital, Edmonton, Canada
17Ondokuz Mayis University, Samsun, Turkey
18Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy
19Rambam Medical Center, Haifa, Israel
20Faculty of Medicine Technion, Haifa, Israel
21Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
22Hospital dos Capuchos (CHLC), Lisboa, Portugal
23Wroclaw Medical University, Wroclaw, Poland
24Città della Salute e della Scienza, Torino, Italy
25Ospedale San Gerardo Monza, Monza, Italy
26Ospedale Policlinico San Martino, Genoa, Italy
27Ústav Hematologie a Krevní Transfuze, Prague, Czech Republic
28Amsterdam UMC, Location VUMC, Amsterdam, Netherlands
29Celgene Corporation, Summit, NJ
30Weill Cornell Medicine, New York, NY
31New York Presbyterian Hospital, New York, NY

Introduction: Many older patients (pts) with AML respond to intensive induction chemotherapy (IC), but responses are often short-lived and overall survival (OS) is poor. The benefit of post-remission maintenance treatment (Tx) for pts with AML is unclear, as no therapy has shown to significantly improve OS. CC-486 is an oral hypomethylating agent that allows for prolonged drug exposure during each Tx cycle to sustain therapeutic activity. We hypothesized that prolonged Tx with CC-486 could be effective as post-remission maintenance in AML.

Herein, we report the primary results of QUAZAR AML-001 (NCT01757535), a phase III international, randomized, double-blind, placebo (PBO)-controlled study evaluating CC-486 as maintenance therapy in pts aged ≥55 years with AML in first remission following IC.

Methods: Eligible pts had de novo or secondary AML, intermediate- or poor-risk cytogenetics, and Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≤3; had achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy; and were not candidates for hematopoietic stem-cell transplant (HSCT). Within 4 months of attaining CR/CRi, pts were randomized 1:1 to receive CC-486 300 mg or PBO once-daily on days 1–14 of repeated 28-day Tx cycles. A 21-day dosing schedule was permitted for pts who experienced AML relapse with 5–15% blasts in blood or bone marrow while on-study. Tx could continue indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. The primary endpoint was OS. Secondary endpoints included relapse-free survival (RFS), health-related quality of life (HRQoL), and safety. Samples were collected for exploratory translational endpoints, including measurable residual disease (MRD). Kaplan-Meier estimates of OS and RFS were compared for CC-486 vs. PBO by stratified log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a stratified Cox proportional hazards model.

Results: Between May 2013 and October 2017, 472 pts were randomized to receive CC-486 (n=238) or PBO (n=234). Baseline characteristics were balanced between Tx arms. Median age was 68 years (range 55–86), 91% of pts had de novo AML, and 86% and 14% of pts, respectively, had intermediate-risk or poor-risk cytogenetics. Following induction, 81% of pts achieved a CR and 19% achieved CRi; 80% of pts had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles).

At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]) (Figure A). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]) (Figure B). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx.

CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1–80) and to PBO was 6 cycles (1–73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3–4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%).

Conclusions: CC-486 is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both OS and RFS in pts with AML in remission following induction chemotherapy, with or without consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for pts with AML in remission.

Disclosures: Wei: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy, 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding; Celgene, Novartis, Sunesis: Honoraria, Research Funding. Montesinos: Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Ravandi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orsenix: 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; Astellas: 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; Xencor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Porkka: Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Selleslag: Celyad: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Daichii Sankyo: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Astex Otsuka: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Sandhu: Takeda: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bioverativ: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Janssen: Consultancy. Giai: BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Beltrami: Ospedale Policlinico San Martino: Employment. Ossenkoppele: Celgene Corporation: Consultancy, Honoraria, Research Funding. La Torre: Celgene Corporation: Employment, Equity Ownership. Skikne: Celgene Corporation: Employment, Equity Ownership. Kumar: Celgene Corporation: Employment, Equity Ownership. Dong: Celgene Corporation: Employment, Equity Ownership. Beach: Celgene Corporation: Employment, Equity Ownership. Roboz: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: 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; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: 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; Bayer: 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; Celltrion: 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; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Otsuka: 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; Roche/Genentech: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees.