UK Center for Clinical and Translational Science

The following criteria apply to both the Nonintensive Therapy Study and the Intensive Therapy Study unless otherwise noted: - Age ≥18 years at time of signing the informed consent form. - Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition). - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. - Adequate liver and kidney function according to protocol requirements. - A 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 with a female partner 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 intervention. - NONINTENSIVE THERAPY STUDY ONLY (VEN+AZA): 1. Documented NPM1-m. 2. Patients considered ineligible for Intensive Therapy defined by the following: - i. Age ≥75, OR - ii. Age <75 with an ECOG performance status of 2 or cardiac, renal, or kidney impairment per protocol criteria. - INTENSIVE THERAPY STUDY ONLY (7+3): 1. Documented NPM1-m or KMT2A-r (KMT2A-r patients with a partial tandem duplication are not eligible). 2. Documented FLT3 wild-type or ITD ratio <0.05 OR ineligible to receive FLT3-targeted therapy (medically ineligible or mutation in which FLT3 inhibition is not SOC). Lack of access to an FLT3 inhibitor is not considered "ineligible" for FLT3-targeted therapy. 3. Ejection fraction of ≥50%. 4. Fit for Intensive Therapy per Investigator opinion.

• Prior therapy for AML (except hydroxyurea or leukapheresis for WBC control). - Diagnosis of acute promyelocytic leukemia (APL), blast phase chronic myeloid leukemia, or isolated myeloid sarcoma. - Known history of BCR-ABL mutation. - History of other active concurrent malignancies prior to study entry except: 1. Basal cell skin cancer or localized squamous cell cancer of the skin 2. Previous malignancy confined and locally resected (or treated with other modalities) with curative intent 3. Prostate or breast cancer receiving adjuvant hormonal therapy. - Active central nervous system (CNS) involvement by AML. - Clinical signs/symptoms of leukostasis or white blood cells (WBC) >25×10^9/L prior to start of ziftomenib/placebo. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion. - Known uncontrolled HIV infection or known active hepatitis B virus, hepatitis C virus infection, or other uncontrolled infection. - Uncontrolled intercurrent illness including but not limited to, cardiac illness as defined in the protocol. - Women who are pregnant or lactating.