A Multi-phase, Pharmacokinetics, Safety, and Efficacy Study of ASTX030 (Azacitidine and Cedazuridine) as Monotherapy in Subjects With Myeloid Neoplasm or in Combination With Venetoclax in Subjects With AML (AZTOUND Study)
Study ASTX030-01 is a multi-phase study comprising of Phases 1-3 Monotherapy arms and a Phase 1 Combination Therapy arm Phase 1 Monotherapy consists of an open-label Dose Escalation Stage (Stage A) using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine (only one study drug will be escalated at a time) followed by a Dose Expansion Stage (Stage B). Phase 2 Monotherapy is a randomized, open-label, crossover study to compare oral ASTX030 to subcutaneous (SC) azacitidine. Phase 3 Monotherapy is a randomized open-label crossover study comparing the final fixed dose of oral ASTX030 to SC azacitidine. Phase 1 Combination Therapy is an open-label, multicenter, randomized, exploratory study comparing ASTX030 and SC azacitidine in combination with venetoclax in participants with AML. The duration of this multi-phase study is approximately 7 years.
• Phase 2 Monotherapy:
• 1\. Has Confirmed MDS, CMML, or other MDS/MPN diagnosis who are candidates to receive and benefit from single agent azacitidine and as applicable according to local country approvals and/or local institution standard practice.
• Phase 3 Monotherapy:
‣ Has confirmed MDS or CMML and is a candidate to receive and benefit from single agent azacitidine as applicable according to local country approvals and/or local institution standard practice:
‣ a) French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and CMML or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS).
⁃ Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
⁃ Participants with adequate organ function.
⁃ For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
⁃ Participants with no major surgery within 3 weeks before first study treatment.
⁃ Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
⁃ Is able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting.
⁃ Participants with projected life expectancy of at least 12 weeks.
• Phase 1 Combination Therapy:
‣ Has histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2022 criteria.
⁃ Participants with projected life expectancy of at least 12 weeks.
⁃ Must be considered ineligible for intensive induction chemotherapy defined by the following:
‣ a. Aged 75 years or older, or b. Aged 18 to 74 years with at least one of the following comorbidities: i. Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
‣ ii. Severe pulmonary disorder (e.g., diffusing capacity of the lung for carbon monoxide (DLCO) ≤65% or forced expiratory volume in 1 second \[FEV1\] ≤65%). iii. Creatinine clearance ≥30 mL/min to \<45 mL/min. iv. Moderate hepatic impairment with total bilirubin \>1.5 to ≤3.0 × upper limit of normal (ULN).
‣ v. ECOG Performance Status of 2 or 3.
⁃ Has an ECOG Performance Status of 0-2 for participants ≥75 years of age or 0-3 for participants 18 to 74 years of age.