A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination With Venetoclax/Azacitidine, Venetoclax, 7+3, or 7+3+Quizartinib in Patients With AML

Key Inclusion Criteria:

* Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML

1. Those intending treatment with intensive chemotherapy in Arm C should be NPM1-m and FLT3-ITD+ with an allelic ratio ≥0.05 and eligible for FLT3-targeted treatment
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
3. Adequate liver, renal, and cardiac function according to protocol defined criteria
4. A female of childbearing potential must agree to use adequate contraception as well as a double barrier method from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or use a double barrier method of contraception from the time of screening through 180 days following the last dose of study intervention

* Female patients of childbearing potential who receive quizartinib in Arm C should use a highly effective method of contraception during quizartinib treatment and for 7 months after the last dose

Key Exclusion Criteria:

1. Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloid leukemia
2. Known history of BCR-ABL alteration
3. Advanced malignant hepatic tumor
4. Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
5. Active central nervous system (CNS) involvement by AML.
6. Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine if used per institutional SOC for control of leukocytosis are permitted to meet this criterion
7. Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
8. Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
9. For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine per institutional standards to control leukocytosis, or prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia
10. For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
11. Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol
12. Mean QT interval corrected for heart rate by Fredericia's formula (QTcF)

1. Arm A and Arm B: >480 ms on triplicate ECGs
2. Arm C: >450 ms on triplicate ECGs
3. Uncontrolled infection
4. Women who are pregnant or lactating
5. An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing
6. Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increase in immunosuppressants in the prior 2 weeks for GVHD treatment