Inclusion 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:

     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).

  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:

     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.

  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.

Exclusion Criteria:

• 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.