A Phase 1 Study Evaluating ASTX727 (decitabine and cedazuridine) and Venetoclax Combination Therapy in Newly Diagnosed AML Patients Unfit for Intensive Induction Chemotherapy
Authors: Mannis Gabriel N. , Griffiths Elizabeth A. , Savona Michael R. , Odenike Olatoyosi , Roboz Gail J. , O'Connell Casey L. , Dillingham Jacqueline , Wason Prieya , Zhu Lixia , Chan Danna , Keer Harold N. , Oganesian Aram , Dao Kim-Hien , DiNardo Courtney D. 
Published: November 2021

Abstract
Introduction: The combination of a DNA methyltransferase inhibitor (DNMTi; parenteral azacitidine or decitabine) with the BCL2 inhibitor venetoclax is a newly established standard-of-care regimen for patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive induction chemotherapy (DiNardo et al, 2020). Replacing the parenteral DNMTi with an oral DNMTi with equivalent exposure may provide the benefit of reducing patient and caregiver burden of chronic parenteral therapy, and may help responding patients stay on treatment longer. ASTX727 (a fixed-dose combination of decitabine 35 mg and cedazuridine 100 mg) is an oral DNMTi that provides equivalent exposure to its parenteral DNMTi at standard dosing (Savona et al, 2020) and is under evaluation in combination with venetoclax as an all-oral regimen.
Methods: This is an ongoing Phase 1 study being conducted at 7 US medical centers (ClinicalTrials.gov NCT04657081). Newly diagnosed AML patients 75 years or older, or with comorbidities that preclude use of intensive induction chemotherapy are eligible. The primary objective is to evaluate the effect of ASTX727 on the PK of venetoclax. Key secondary objectives are to evaluate the effect of venetoclax on the PK of ASTX727, and to determine the safety and efficacy profile for the combination. For Cycle 2 and beyond, ASTX727 is administered orally daily on days 1-5 and venetoclax 400 mg is administered orally daily on days 1-28 of 28-day cycles. For Cycle 1, ASTX727 is given in the same dose schedule while venetoclax is given as a ramp-up on days 1 and 2 according to the venetoclax US prescribing information (USPI); therefore, the PK studies are conducted during Cycle 2. Delay of subsequent cycles and venetoclax dose modifications for hematologic toxicities and anti-fungal concomitant medications follow the venetoclax USPI. Response assessments are evaluated using the 2017 ELN criteria (Döhner et al, 2017) and the CRh criterion (complete response [CR] with partial hematologic recovery) defined as those patients achieving marrow CR criteria but not peripheral blood count criteria and demonstrating an absolute neutrophil count &gt;500/μL and platelet &gt;50,000/μL (Kantarjian et al, 2017).
Results: At the data cut-off date of August 1, 2021, 15 AML patients have enrolled and received study treatment. Median age is 78 years (range 66 - 84) and 9 (60%) are males. Of the 12 patients with data, 2 (17%), 6 (50%), and 4 (33%) patients are in the favorable, intermediate, and adverse risk ELN categories, respectively. Of the 15 dosed patients, 6 (40%) are diagnosed with AML with myelodysplasia-related changes. The median duration of exposure is 2 cycles (range 1-5) and 1.7 months (range 0.8-5.6). The most common adverse events (AEs) of Grade 2 or higher occurring in ≥10% of patients include neutropenia (5, 33%), febrile neutropenia (2, 13%), anemia (2, 13%), thrombocytopenia (2, 13%), vomiting (2, 13%), pneumonia (2, 13%), peripheral edema (2, 13%), hypertension (2, 13%) and vascular access complication (2, 13%). There are 17 serious AEs experienced in 7 patients; a grade 3 pneumonia and a grade 3 dysphagia are the only serious AEs assessed as related to ASTX727 and/or venetoclax and both events occurred in the same patient. Both AEs were part of the patient's medical history. Two deaths have occurred to date: one patient due to rapidly progressive disease during Cycle 2 and one patient who achieved a best response of CRh transitioned to hospice due to progressive multiple myeloma. Of 9 patients with response assessments and evaluable data, 3 (33%) achieved CR and 4 (44%) achieved CRh as the best response for a composite CR+CRh rate of 78%. Preliminary PK data available from 9 patients show venetoclax exposures are not affected by coadministration of ASTX727and are similar to historical data. Exposures of decitabine and cedazuridine are consistent with the range seen in previous studies. Updated PK, safety, and efficacy data will be provided in December 2021.
Conclusions: A preliminary analysis of ASTX727 and venetoclax combination therapy in patients with newly diagnosed AML unfit for intensive induction chemotherapy demonstrate expected PK data, and a similar safety and efficacy profile to the approved combination therapy of a DNMTi and venetoclax. These preliminary data suggest that an all-oral regimen of a DNMTi in combination with venetoclax is feasible and should be investigated further.

Disclosures
Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Griffiths: Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Genentech: Research Funding; Abbvie: Consultancy, Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Savona: Geron: 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; CTI: Consultancy, 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. 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. Roboz: MEI Pharma - IDMC Chair: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Agios: Consultancy; Janssen: Consultancy; Astex: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Research Funding; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Dillingham: Astex Pharmaceuticals, Inc.: Current Employment. Wason: Astex Pharmaceuticals, Inc.: Current Employment. Zhu: Astex Pharmaceuticals, Inc.: Current Employment. Chan: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Oganesian: Astex Pharmaceuticals, Inc.: Current Employment. Dao: Astex Pharmaceuticals, Inc.: Current Employment. DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding.

OffLabel Disclosure:
1. Inqovi (35 mg decitabine and 100 mg cedazuridine) is a prescription medicine approved in the United States to treat adults with myelodysplastic syndromes and chronic myelomonocytic leukemia. In this study, Inqovi is referred as ASTX727 due to the off-label investigational use in combination with venetoclax in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. 2. Venclexta is a prescription medicine approved in the United States for: 1) adults with chronic lymphocytic leukemia or small lymphocytic lymphoma; 2) adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine, or low-dose cytarabine. In this study, Venclexta is referred as venetoclax due to the off-label investigational use in combination with ASTX727 in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.