A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study)

Eligibility Criteria

• * 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:
• 1. 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:
• 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• 3. Participants with adequate organ function.
• 4. For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
• 5. Participants with no major surgery within 3 weeks before first study treatment.
• 6. Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
• 7. 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.
• 8. Participants with projected life expectancy of at least 12 weeks.
• * Phase 1 Combination Therapy:
• 1. Has histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2022 criteria.
• 2. Participants with projected life expectancy of at least 12 weeks.
• 3. Must be considered ineligible for intensive induction chemotherapy defined by the following:
• 4. 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.
• * All Monotherapy Phases:
• 1. Has an active uncontrolled gastric or duodenal ulcer.
• 2. Has poor medical risk because of other conditions.
• 3. Has known human immunodeficiency virus (HIV) infection.
• 4. Is known to be positive for Hepatitis B or C infection.
• 5. Has a life-threatening illness.
• 6. Has a history of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected or adequately treated and controlled with other modalities; and any early stage malignancy for which no definitive therapy is required.
• 7. Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
• 8. Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
• 9. Has been treated with any investigational drug or therapy within 2 weeks, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant adverse events from previous treatment with investigational drug or therapy.
• 10. Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
• 11. Cannot discontinue treatment with any drugs that delay gastric emptying such as glucagon-like peptide-1 (GLP-1) and/or gastric inhibitory polypeptide (GIP) agonists in Cycles 1 and 2 of the study.
• 12. Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
• * Phase 1 Combination Therapy:
• 1. Has a history of MPN including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, or AML with BCR-ABL1 translocation.
• 2. Has the following karyotype abnormalities: t(15;17) or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.
• 3. Has known active central nervous system involvement from AML.
• 4. Has known human immunodeficiency virus (HIV) infection.
• 5. Is known to be positive for Hepatitis B or C infection.
• 6. Has severe hepatic impairment
• 7. Has severe renal impairment
• 8. Has a malabsorption syndrome or other condition that precludes enteral route of administration.
• 9. Has a cardiovascular disability status of New York Heart Association Class \>2.
• 10. Has significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular, or pulmonary disease; or any other medical condition that in the opinion of the investigator would adversely affect his/her participation in this study.
• 11. Has clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
• 12. Has a history of other malignancies prior to study entry with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.
• 13. Has a WBC count \>25,000/ microliters (μL) (hydroxyurea treatment is permitted to meet this criterion).
• 14. Has received treatment with any of the following:
• 1. A hypomethylating agent (azacitidine or decitabine) or venetoclax, including prior treatment for MDS.
• 2. Chimeric Antigen Receptor (CAR)-T cell therapy.
• 3. Investigational therapies for MDS or AML.
• 15. Cannot discontinue treatment with any of the following:
• 1. Prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 halflives, whichever is greater, prior to Cycle 1 Day 1 (C1D1).
• 2. Drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
• 16. Cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.
• 17. Cannot discontinue treatment with any drugs that delay gastric emptying such as GLP-1 and/or GIP agonists in Cycles 1 and 2 of the study.
• 18. Is participating in another research study requiring interventions such as drug therapy or study procedures.
• 19. Has a known or suspected hypersensitivity to cedazuridine, azacitidine, venetoclax, or any of their excipients.
• 20. Has known significant mental illness or other conditions such as alcohol or other substance abuse or addictions
• 21. Consumes grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.