Background: Patients with relapsed/refractory acute myeloid leukemia (R/R AML) have poor outcomes and limited therapeutic options. We previously conducted a phase II trial of 10-day IV decitabine and venetoclax with encouraging results in venetoclax-naïve R/R AML (DiNardo et al. Lancet Haematol 2020). We hypothesized that a total oral regimen with ASTX727 (decitabine/cedazuridine) and venetoclax may offer similar outcomes while offering convenience of an oral regimen.

Methods: This phase II trial enrolled adults with R/R AML with ECOG PS ≤2, WBC ≤10 x10 3/uL, and adequate organ function (NCT04975919). Pts with prior BCL2 inhibitor therapy were eligible. Pts with t(15;17) or active graft-vs-host disease were excluded. Pts received ASTX727 containing decitabine/cedazuridine 100/35 mg for 10 days with venetoclax 400 mg (or equivalent based on CYP interactions) for 21-28 days for induction followed by ASTX727 for 5 days with venetoclax daily in subsequent cycles.The primary objective was to determine overall responses rate (ORR) and secondary objectives were to determine duration of response (DOR), overall survival (OS), and safety of the combination.

Results: Between December 2021 and April 2023 we enrolled 18 pts with R/R AML. The median age was 65 yrs (range 39-76), median bone marrow blasts was 40% (range 6-93), median no. of prior therapies was 2 (range 1-4) including 11 pts (61%) who had received prior venetoclax-based regimens. 94% pts had ELN2022 adverse risk AML, including 6 pts (33%) with TP53 mutations and 11 pts (61%) with complex cytogenetics.

The ORR was 28% (n=5/18) including CR in 2 pts and MLFS in 3 pts. Negative MRD by flow cytometry was achieved in 2/5 responding pts. After a median follow up of 15.3 months (mo), 5 pts are alive, and the median OS was 9.1 mos (Fig 1). 2 pts (11%) who achieved CR proceeded to allogeneic stem cell transplantation remain in remission for 15.3 and 2.4 mos. CR/MLFS response occurred in 4/7 pts who were venetoclax naïve vs 1/11 pts with prior venetoclax exposure (p=0.03). CR/MLFS response occurred in 1/6 pts who were TP53 mutated vs 4/12 pts who were TP53 wild type (p=0.45).

Pts received a median of 1 cycle of treatment (range 1-6). The 30-day and 60-day mortality were 17% and 28%. Most common treatment-related grade 3/4 adverse events included infections in 50% pts, febrile neutropenia in 29% pts, and respiratory failure in 17% pts. Trial continues to accrue and updated results will be presented.

Conclusion: An oral regimen of 10-day ASTX727 with venetoclax showed safety profile comparable to other venetoclax-based regimens in R/R AML and responses occurred in ELN adverse risk venetoclax-naïve pts. Novel therapies are needed for patients progressing on prior BCL2 inhibitor-based regimens.

Maiti:Lin BioScience: Research Funding; Celgene: Research Funding. DiNardo:ImmuniOnc: Honoraria; BMS: Honoraria; Notable Labs: Honoraria; Servier: Honoraria; Novartis: Honoraria; Schrödinger: Consultancy; Fogham: Honoraria; Takeda: Honoraria; AbbVie/Genentech: Honoraria; Astellas: Honoraria. Daver:Trillium: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Shattuck Labs: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; Agios: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Syndax: Consultancy; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; AROG: Consultancy; Glycomimetics: Research Funding; Novimmune: Research Funding; FATE: Research Funding; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; Celgene: Consultancy; Kronos Bio: Research Funding. Borthakur:Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Chien:Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Issa:Kura Oncology: Consultancy, Research Funding; NuProbe: Consultancy; Novartis: Consultancy, Research Funding; Merck: Research Funding; Celgene: Research Funding; Syndax: Research Funding. Masarova:MorphoSys US: Membership on an entity's Board of Directors or advisory committees. Alvarado Valero:MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; Jazz: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Wierda:AbbVie: Consultancy, Research Funding; Gilead Sciences: Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech Inc: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Nurix THerapeutics: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; GSK/Novartis: Research Funding; Numab THerapeutics: Research Funding; Juno Therapeutics: Research Funding; Janssens Biotech: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Accutar Biotechnology: Research Funding; Cyclacel: Consultancy, Research Funding; Oncternal Therapeutics, Inc.: Research Funding. Short:Stemline therapeutics: Research Funding; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Astellas: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Honoraria. Kadia:Delta-Fly Pharma, Inc.: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; Janssen Research and Development: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy; GenFleet Therapeutics: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Iterion: Research Funding; Glycomimetics: Research Funding; Celgene: Research Funding; Amgen, Inc.: Research Funding; Cyclacel: Research Funding; Liberum: Consultancy; Ascentage Pharma Group: Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Genzyme: Honoraria; Genentech: Consultancy, Research Funding; Servier: Consultancy; Hikma Pharmaceuticals: Speakers Bureau; Astellas Pharma Global Development: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Biomea fusion: Honoraria, Research Funding. Kantarjian:Bristol-Myers Squibb (Inst): Research Funding; Amgen (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Abbvie (Inst): Research Funding; Taiho Pharmaceutical: Honoraria; Shenzhen Target Rx: Honoraria; Precision Biosciences: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; KAHR Medical: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Novartis (Inst): Research Funding. Garcia-Manero:Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Konopleva:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trials Support, Research Funding.

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2023
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