Phase l dose escalation and expansion of ziftomenib in combination with quizartinib in AML

Abstract Background and Significance: The menin-KMT2A interaction is a dependency in acute leukemia caused by either rearrangement of the KMT2A (KMT2Ar) or Nucleoporin 98 (NUP98r) genes, or by mutation of NPM1 (NPM1mt). Mutations in FLT3 commonly co-occur with these genotypes susceptible to menin inhibition. FLT3 is a putative transcriptional target of MEIS1, the DNA binding co-factor of HOX genes, and the expression of MEIS1 is dependent on the menin-KMT2A interaction. Menin inhibition leads to a transcriptional suppression of FLT3, and preclinical data in KMT2Ar, NPM1mt or NUP98r leukemia models with FLT3 co-mutation show synergy of combined menin and FLT3 inhibition, leading to a profound antileukemic effect. Quizartinib is a potent FLT3 inhibitor, currently approved in combination with high-intensity chemotherapy, then as maintenance monotherapy for newly diagnosed FLT3-ITD positive AML (Erba, Lancet 2023), and is currently being evaluated in the global phase 3 randomized, placebo-controlled trial QuANTUM-Wild in FLT3-ITD negative AML. Ziftomenib is an investigational menin inhibitor with demonstrated efficacy and safety in relapsed/refractory (R/R) AML (Wang, Lancet Oncology 2024). We designed a study investigating the combination of the menin inhibitor ziftomenib and quizartinib in relapsed/refractory AML (NCT06769490). Study Design and Methods This is a single arm, open label, single center phase 1 study evaluating escalating doses of ziftomenib in combination with quizartinib at 40 mg PO daily. Patients age ≥ 18 years, and NPM1mt, or KMT2Ar, or NUP98r with R/RAML are eligible regardless of FLT3 mutational status. Given the relatively higher occurrence of FLT3 mutations in all the genotypes of interest in this study and given that expression of FLT3 is higher in KMT2Ar leukemia regardless of FLT3 mutational status, we hypothesize that FLT3 inhibition could therapeutically target all these leukemias regardless of FLT3 mutational status. This observation has been bolstered by the activity of quizartinib in FLT3-wildtype AML. Therefore, if escalation of ziftomenib in combination with quizartinib is found to be safe, we plan to explore the combination ziftomenib with quizartinib at 60 mg PO daily as the dose with single-agent activity in FLT3-wildtype AML. Ziftomenib will be escalated up to 600 mg, which is the recommended phase 2 dose as monotherapy. A bone marrow (BM) biopsy is planned on day 14 of cycle 1 in addition to end of cycle assessment and treatment will be held if BM blasts are <5% to improve chances of count recovery. The primary objective of the phase I is to determine safety and the recommended phase II dose (RP2D). Up to 24 pts will be included in the dose escalation portion of the study, and escalation will proceed using the Bayesian optimal interval (BOIN) design with a target dose-limiting toxicity rate <20%. Once we determine the RP2D, two expansion cohorts stratified by FLT3 status and treatment combination with up to 10 patients per separate expansion cohort will be enrolled for additional experience with safety and efficacy. Secondary objectives include assessment of the composite complete remission rate, duration of response, event-free and overall survival and concordance of genetic (NGS, Invivoscribe, USA) and flow MRD. This trial includes longitudinal collection of samples, with exploratory objectives focused on improving MRD detection, and understand of response and resistance using cytometry by time of flight. This study, currently enrolling patients at MD Anderson, could lead to a novel all-oral targeted therapy combination for the largest subset of patients with AML.