Phase l dose escalation and expansion of ziftomenib in combination with quizartinib in AML
Abstract
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).
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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 10 participants or records.
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