Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from the Ascertain Phase 3 Study

ABSTRACT

text Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%;90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 11 to either Sequence A (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI);Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et a 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017 3754-3762. [Formula presented] Disclosures Savona Geron Consultancy, Membership on an entity's Board of Directors or advisory committees;CTI Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene 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;Ryvu Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics 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, Research Funding;ALX Oncology Research Funding;Astex Research Funding;Incyte Research Funding. McCloskey Pfizer Consultancy;Takeda Consultancy, Speakers Bureau;Incyte Speakers Bureau;Novartis Consultancy;COTA Other Equity Ownership;BMS Honoraria, Speakers Bureau;Amgen Speakers Bureau;Jazz Consultancy, Speakers Bureau. Griffiths Boston Biomedical Consultancy;Celgene/Bristol-Myers Squibb Consultancy, Honoraria, Research Funding;Abbvie Consultancy, Honoraria;Taiho Oncology Consultancy, Honoraria;Genentech Research Funding;Astex Pharmaceuticals Honoraria, Research Funding;Takeda Oncology Consultancy, Honoraria;Novartis Honoraria;Apellis Pharmaceuticals Research Funding;Alexion Pharmaceuticals Consultancy, Research Funding. Yee Novartis Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics Research Funding;Geron Research Funding;Shattuck Labs Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb/Celgene Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie Honoraria;Janssen Research Funding;Onconova Research Funding;Genentech Research Funding;Otsuka Membership on an entity's Board of Directors or advisory committees;MedImmune Research Funding;Jazz Research Funding;Astex Membership on an entity's Board of Directors or advisory committees, Research Funding;Tolero Research Funding;Takeda Membership on an entity's Board of Directors or advisory committees;TaiHo Membership on an entity's Board of Directors or advisory committees;Pfizer Membership on an entity's Board of Directors or advisory committees;Paladin Membership on an entity's Board of Directors or advisory committees. Zeidan BeyondSpring Consultancy;Janssen Consultancy;Boehringer Ingelheim Consultancy, Research Funding;BioCryst Other Clinical Trial Committees;AstraZeneca Consultancy;Pfizer Other Travel support, Research Funding;Kura Consultancy, Other Clinical Trial Committees;Incyte Consultancy, Research Funding;Ionis Consultancy;Daiichi Sankyo Consultancy;Epizyme Consultancy;Novartis Consultancy, Other Clinical Trial Committees, Travel support, Research Funding;Loxo Oncology Consultancy, Other Clinical Trial Committees;Genentech Consultancy;Geron Other Clinical Trial Committees;Cardiff Oncology Consultancy, Other Travel support, Research Funding;BMS Consultancy, Other Clinical Trial Committees, Research Funding;Gilead Consultancy, Other Clinical Trial Committees;Aprea Consultancy, Research Funding;Astellas Consultancy;Astex Research Funding;Jazz Consultancy;Jasper Consu tancy;Amgen Consultancy, Research Funding;Agios Consultancy;ADC Therapeutics Research Funding;Acceleron Consultancy, Research Funding;AbbVie Consultancy, Other Clinical Trial Committees, Research Funding. Al-Kali Novartis Research Funding;Astex Other Research support to institution. Patel Agios Membership on an entity's Board of Directors or advisory committees;Celgene-BMS Membership on an entity's Board of Directors or advisory committees;PVI Honoraria. Sabloff Takeda Membership on an entity's Board of Directors or advisory committees;BMS Membership on an entity's Board of Directors or advisory committees;Astellas Membership on an entity's Board of Directors or advisory committees;Novartis Membership on an entity's Board of Directors or advisory committees;TaiHo Membership on an entity's Board of Directors or advisory committees;Jaxx Membership on an entity's Board of Directors or advisory committees;Abbvie Membership on an entity's Board of Directors or advisory committees;Pfizer Membership on an entity's Board of Directors or advisory committees;ROCHE Membership on an entity's Board of Directors or advisory committees;Celgene Membership on an entity's Board of Directors or advisory committees. Dao Astex Pharmaceuticals, Inc. Current Employment. Fazal Janssen Oncology Consultancy, Honoraria, Speakers Bureau;Taiho Pharmaceuticals Consultancy, Honoraria, Speakers Bureau;Gilead Sciences Consultancy, Honoraria, Speakers Bureau;Novartis Consultancy, Honoraria, Speakers Bureau;Agios Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme Consultancy, Honoraria, Speakers Bureau;Takeda Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline Consultancy, Honoraria, Speakers Bureau;AMGEN Consultancy, Honoraria, Speakers Bureau;Incyte Consultancy, Honoraria, Speakers Bureau;Jazz PharmaceuticalsConsultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals Consultancy, Honoraria, Speakers Bureau. Odenike Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea Research Funding;AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda Consultancy. Kantarjian Ipsen Pharmaceuticals Honoraria;Astra Zeneca Honoraria;Astellas Health Honoraria;Aptitude Health Honoraria;Pfizer Honoraria, Research Funding;Novartis Honoraria, Research Funding;Jazz Research Funding;Immunogen Research Funding;Daiichi-Sankyo Research Funding;BMS Research Funding;Ascentage Research Funding;Amgen Honoraria, Research Funding;AbbVie Honoraria, Research Funding;KAHR Medical Ltd Honoraria;NOVA Research Honoraria;Precision Biosciences Honoraria;Taiho Pharmaceutical Canada Honoraria. DeZern Bristol-Myers Squibb 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;Taiho 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. Roboz Janssen Research Funding;AbbVie Consultancy;Actinium Consultancy;Agios Consultancy;Amgen Consultancy;Astex Consultancy;Astellas Consultancy;AstraZeneca Consultancy;Bayer Consultancy;Blueprint Medicines Consultancy;Bristol Myers Squibb Consultancy;Celgene Consultancy;Daiichi Sankyo Consultancy;Glaxo SmithKline Consultancy;Helsinn Consultancy;Janssen Consultancy;Jasper Therapeutics Consultancy;Jazz Consultancy;MEI Pharma - IDMC Chair Consultancy;Mesoblast Consultancy;Novartis Consultancy;Otsuka Consultancy;Pfizer Consultancy;Roche/Genentech Consultancy. Busque Novartis Consultancy. Leber Novartis Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer Membership on an entity's Board of Directors or advisory committees, peakers Bureau;BMS Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AMGEN Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao Astex Pharmaceuticals, Inc. Current Employment. Keer Astex Pharmaceuticals, Inc. Current Employment. Azab Astex Pharmaceuticals, Inc. Membership on an entity's Board of Directors or advisory committees.