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

This Phase 1 study will assess the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with venetoclax and azacitidine (ven/aza), ven, and 7+3 for two different molecularly-defined arms, NPM1-m and KMT2A-r.

Key Inclusion Criteria:Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AMLEastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2Adequate liver, renal, and cardiac function according to protocol defined criteriaA female of childbearing potential must agree to use adequate contraception 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 adequate contraception from the time of screening through 90 days following the last dose of study interventionKey Exclusion Criteria:Diagnosis of either acute promyelocytic leukemia or blast chronic myelomonocytic leukemiaKnown history of BCR-ABL alterationAdvanced malignant hepatic tumor [for patients receiving ven/aza combination]Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recoveryActive central nervous system (CNS) involvement by AML.Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis are permitted to meet this criterionNot recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopeciaKnown clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infectionFor newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis to control leukocytosis, prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia, or non-HMA therapy for prior myelodysplastic syndromeFor 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 drugUncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocolMean corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 ms on triplicate ECGsUncontrolled infectionWomen who are pregnant or lactatingAn active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing