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 eithernewly diagnosed or relapsed/refractory AML

• Those intending treatment with intensive chemotherapy in Arm C should be NPM1-mand FLT3-ITD+ with an allelic ratio ≥0.05 and eligible for FLT3-targetedtreatment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Adequate liver, renal, and cardiac function according to protocol defined criteria

• A female of childbearing potential must agree to use adequate contraception as wellas a double barrier method from the time of screening through 180 days following thelast dose of study intervention. A male of childbearing potential must agree to useabstinence or use a double barrier method of contraception from the time ofscreening through 180 days following the last dose of study intervention

• Female patients of childbearing potential who receive quizartinib in Arm Cshould use a highly effective method of contraception during quizartinibtreatment and for 7 months after the last dose

Key Exclusion Criteria:

• Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloidleukemia

• Known history of BCR-ABL alteration

• Advanced malignant hepatic tumor

• Administration of live attenuated vaccines within 14 days prior to, during, or aftertreatment until B-cell recovery

• Active central nervous system (CNS) involvement by AML.

• Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyureaand/or leukapheresis and/or up to 2 doses of cytarabine if used per institutionalSOC for control of leukocytosis are permitted to meet this criterion

• Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicitiesexcept for alopecia

• Known clinically active human immunodeficiency virus, active hepatitis B or activehepatitis C infection

• For newly diagnosed cohorts: received prior chemotherapy for leukemia, excepthydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine perinstitutional standards to control leukocytosis, or prior treatment withall-transretinoic acid for initially suspected acute promyelocytic leukemia

• For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy,or any ancillary therapy that is considered to be investigational < 14 days prior tothe first dose of ziftomenib or within 5 drug half-lives prior to the first dose ofstudy drug

• Uncontrolled intercurrent illness including, but not limited to, cardiac illness asdefined in the protocol

• Mean QT interval corrected for heart rate by Fredericia's formula (QTcF)

• Arm A and Arm B: >480 ms on triplicate ECGs

• Arm C: >450 ms on triplicate ECGs

• Uncontrolled infection

• Women who are pregnant or lactating

• An active malignancy and currently receiving chemotherapy for that malignancy ordisease that is uncontrolled/progressing

• Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increasein immunosuppressants in the prior 2 weeks for GVHD treatment