Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations (NPM1-m) or KMT2A-rearrangment (KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A (KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts (NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML (KMT2A-r and NPM1-m) and zifto/ven in R/R AML (NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336.