KOMET-017

Adults ≥18 with newly diagnosed NPM1-m or KMT2A-r AML (WHO 2022); IC-ineligible (NPM1-m only) for ven+aza arm OR IC-fit with FLT3-WT/ineligible for 7+3 arm; ECOG 0–2; adequate organ function.

1. Age ≥18 years at time of signing the informed consent form (ICF). 2. Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition). 3. Patients with therapy-related AML (t-AML) or secondary AML (prior myelodysplastic syndrome [MDS] or myeloproliferative neoplasm [MPN]) are eligible. Note: Prior MDS eligibility requires that at the time of MDS diagnosis the patient did not have evidence of either NPM1-m or KMT2A-r (now classified as AML by WHO 5th Edition). 4. Patients with prior MDS who have received a single line of treatment with single-agent HMA, lenalidomide, luspatercept, or imetelstat are eligible. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 6. Adequate liver function defined as: • AST <5×upper limit of normal (ULN), and • ALT <5×ULN, and • Total bilirubin <1.5×ULN (except for patients with known Gilbert's syndrome or presumed leukemic involvement). Note: If the patient does not meet this criterion but the liver function abnormalities are presumed to be due to AML, this may be discussed with the Medical Monitor to determine eligibility. 7. Adequate renal function defined by calculated creatinine clearance ≥30 mL/min (according to the 2021 Chronic Kidney Disease Epidemiology-Collaboration [CKD-EPI] creatinine equation). 8. If the patient has comorbid illness, life expectancy attributed to this other condition(s) must be greater than 2 years in the opinion of the Investigator. 9. Female patients of childbearing potential (ie, any premenopausal woman who has begun menstruation and can get pregnant) must agree to use highly effective contraception as well as a double barrier method from Screening until 180 days following the last dose of study intervention. Female patients must also agree not to donate eggs throughout the study and for 180 days after the last dose of study treatment. Male patients capable of having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or use a double barrier method of contraception and have their partner use adequate contraception from Screening until 90 days after the last dose of study intervention. Male patients must also refrain from sperm donation from Screening until 90 days following the last dose of study intervention. See Appendix 2. 10. Patients, or their legally authorized representative, must be able to understand and provide informed consent, understand protocol requirements, and be willing to comply with study requirements, in the opinion of the Investigator. 11. NONINTENSIVE THERAPY STUDY ONLY (VEN+AZA): a. Documented NPM1-m. b. Patients considered ineligible for IC defined by the following i. Age ≥75, OR ii. Age <75 and unfit for IC. Must meet one of these comorbidity exceptions which prevents them from being treated with IC: 1. ECOG performance status of 2, or 2. Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction of ≤50% or chronic stable angina, or 3. Diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%, or 4. Creatinine clearance <45 mL/min and >30 mL/min, or 5. Moderate hepatic impairment with total bilirubin 1.5 to 3.0×ULN, not related to AML involvement or Gilbert's syndrome, or 6. Other comorbidities that, in the opinion of the Investigator, cause the patient to be incompatible with IC (prior approval by the Medical Monitor is required before enrollment). 12. INTENSIVE THERAPY STUDY ONLY (7+3): a. Documented NPM1-m or KMT2A-r (patients with a partial tandem duplication [PTD] are not eligible). b. 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. c. Ejection fraction of >50% by transthoracic echocardiogram (ECHO) or multigated acquisition scan (MUGA). d. Fit for IC per Investigator opinion.

APL/CML-BP/isolated myeloid sarcoma; BCR-ABL; active CNS AML; leukostasis or WBC >25×10⁹/L; prior AML therapy or ven+HMA/IDH1i for MDS; active HIV/HBV/HCV; QTcF >480 ms; pregnancy.

1. Diagnosis of either acute promyelocytic leukemia (APL), blast phase chronic myeloid leukemia, or isolated myeloid sarcoma. Note: Patients with myeloid sarcoma in addition to BM disease are eligible. 2. Known history of BCR-ABL mutation. 3. History of other active concurrent malignancies prior to study entry except: • Basal cell skin cancer or localized squamous cell cancer of the skin • Previous malignancy confined and locally resected (or treated with other modalities) with curative intent • Prostate or breast cancer receiving adjuvant hormonal therapy (see Section 7.5.1 for permitted medications) 4. Active central nervous system (CNS) involvement by AML. Note: Those patients with evidence of CNS AML involvement at baseline/screening now controlled (cerebrospinal fluid [CSF] cleared and no symptoms) with intrathecal chemotherapy or those who are at high risk of developing CNS disease (including KMT2A-r, high white blood cells [WBC], high lactate dehydrogenase [LDH], presence of extramedullary disease [EMD]) may continue to receive intrathecal chemotherapy as treatment or prophylaxis, respectively, as per institutional practice. 5. Clinical signs/symptoms of leukostasis or WBC >25×10^9/L prior to start of ziftomenib/placebo. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion. Cytotoxic therapy in addition to the SOC protocol backbones (7+3 or ven+aza) is not permitted to manage leukocytosis. 6. Prior therapy for AML (except hydroxyurea or leukapheresis for WBC control). Patients may have received ATRA if there is an early suspicion of APL. Patients with a confirmed diagnosis of APL are not eligible. 7. Prior ven+HMA therapy, isocitrate dehydrogenase 1 inhibitor, or intensive chemotherapy for MDS. Note: Prior MDS treatment with either single agent HMA, lenalidomide, luspatercept, or imetelstat is allowed. Any of these agents for prior MDS treatment must have been discontinued ≥14 days prior to Cycle 1 Day 1. 8. Known uncontrolled HIV infection or known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Viral serologies for HIV, HBV, HCV are not required. However, for patients with a known medical history of HIV/HBV/HCV infection, an undetectable viral load must be confirmed. Patients with serologic evidence of prior vaccination to HBV (HBV surface antigen negative and anti-HBV surface antibody positive) may participate. 9. Any other significant ongoing medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient from participating in the study or would confound the interpretation of the results of the study in the opinion of the Investigator. 10. Diagnosis with any of the following per Investigator opinion: uncontrolled intercurrent illness including but not limited: • Symptomatic CHF • Unstable angina pectoris • Serious cardiac arrhythmia • Myocardial infarction with evidence of residual abnormalities within 6 months prior to enrollment (troponin leak alone not included if no residual dysfunction) • New York Heart Association Class III or IV heart failure • Severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia • Mean QTcF >480 ms on triplicate ECGs Note: If a patient has bundle branch block or QRS >120 ms, the QTcF must be either calculated by cardiology, calculated using a QTc calculator (eg, the Mayo Clinic QTc calculator [https://www.mayoclinic.org/medical-professionals/cardiovascular-diseases/calculators/corrected-qt-interval-qtc-calculator/itt-20487211]), or calculated using the Boghossian simplified formula (QTc=QT-0.5*QRS). 11. Diagnosis of an uncontrolled infection. Note: Patients with an active infection may be eligible provided that the infection is controlled by appropriate antimicrobial therapy in the opinion of the Investigator. 12. Known severe hypersensitivity to the product or similar chemical structure and class to the study drugs evaluated in this study or 1 of the active or inactive excipients. 13. Women who are pregnant or breastfeeding.