Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML)

Inclusion Criteria:

1. Participant must be 18 years of age or older.

2. Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria.

3. Projected life expectancy of at least 3 months.

4. Participants must be considered ineligible for intensive induction chemotherapydefined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with atleast one of the following comorbidities: i) Severe cardiac disorder (eg, congestiveheart failure requiring treatment, ejection fraction ≤50%, or chronic stableangina), ii) Severe pulmonary disorder (eg, diffusing lung capacity for carbonmonoxide 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 withtotal bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN), v) Phase 1: EasternCooperative Oncology Group (ECOG) Performance Status of 2 (participants with ECOG ≥3are not eligible); Phase 2, Parts A and B: ECOG Performance Status of 2 or 3 (participants with ECOG 4 are not eligible).

5. Phase 1: ECOG Performance Status of 0-2; Phase 2, Parts A and B: ECOG 0-3.

6. Women of child-bearing potential (according to recommendations of the Clinical TrialFacilitation Group [CTFG]) must not be pregnant or breastfeeding and must have anegative pregnancy test at screening.

7. Participants and their partners with reproductive potential must agree to use ahighly effective contraceptive measure during the study and for 3 months after thelast dose of study treatment, including refraining from sperm donation. Effectivecontraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).

8. Capable of giving legally effective informed consent, which includes compliance withthe requirements and restrictions listed in the informed consent form and protocol,and willing to participate in the study.

Exclusion Criteria:

1. History of myeloproliferative neoplasm including myelofibrosis, essentialthrombocythemia, polycythemia vera, chronic myeloid leukemia with or withoutBCR-ABL1 translocation and AML with BCR-ABL1 translocation.

2. The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acutepromyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.

3. Known active central nervous system involvement from AML.

4. Known human immunodeficiency virus (HIV) infection (due to potential drug-druginteractions between antiretroviral medications and venetoclax). Humanimmunodeficiency virus testing will be performed at Screening, only if indicated perlocal guidelines or institutional standards.

5. Known active hepatitis B or C infection (detectable viral load). Hepatitis B or Ctesting will be performed at Screening, only if indicated per local guidelines orinstitutional standards.

6. Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) forparticipants ≥75 years or >3×ULN for participants <75 years; or aspartateaminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanineaminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unlessconsidered to be due to leukemic organ involvement).

7. Severe renal impairment defined as: calculated creatinine clearance or glomerularfiltration rate <30 mL/min.

8. A malabsorption syndrome or other condition that precludes enteral route ofadministration.

9. Cardiovascular disability status of New York Heart Association Class >2. Class 2 isdefined as cardiac disease in which patients are comfortable at rest but ordinaryphysical activity results in fatigue, palpitations, dyspnea, or anginal pain.

10. Chronic respiratory disease that requires continuous oxygen, or significant historyof renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic,cardiovascular disease, any other medical condition or known hypersensitivity to anyof the study medications that in the opinion of the investigator would adverselyaffect his/her participating in this study.

11. Clinically significant uncontrolled systemic infection requiring therapy (viral,bacterial, or fungal).

12. History of other malignancies prior to study entry, with the exception of adequatelytreated in situ carcinoma of the breast or cervix uteri; localized basal cellcarcinoma or squamous cell carcinoma of the skin; previous malignancy confined andsurgically resected (or adequately treated and controlled with other modalities);and any early stage malignancy for which no definitive therapy is required.

13. White blood cell (WBC) count >25,000/μL (Hydroxyurea treatment is permitted to meetthis criterion).

14. Treatment with the following: a) A hypomethylating agent (azacitidine ordecitabine), or venetoclax including prior treatment for myelodysplastic syndrome (MDS), b) Chimeric Antigen Receptor (CAR)-T cell therapy, c) Investigationaltherapies for MDS or AML.

15. Participants who cannot discontinue concomitant prophylactic antifungal therapy withCYP3A inhibitor activity or other concomitant medications with moderate or strongCYP3A inhibitor activity ≥7 days or 5 half-lives, whichever is greater, prior tocycle 1 day 1 (C1D1).

16. Participants who cannot discontinue concomitant drugs that are strong CYP3A or P-gpinhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.

17. Participants who cannot avoid concomitant drugs known as moderate or strong CYP3Ainducers.

18. Current participation in another research study requiring interventions such as drugtherapy or study procedures.

19. Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or anyof their excipients.

20. Known significant mental illness or other condition such as active alcohol or othersubstance abuse or addiction that, in the opinion of the investigator, predisposesthe participant to high risk of noncompliance with the protocol.

21. Participants who consume grapefruit, grapefruit products, Seville oranges (includingmarmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.