A Multi-Site Break through Cancer Trial: Phase II Study Investigating Dual Inhibition of BCL2 and Menin in AML MRD Using the Combination of Venetoclax and Revumenib (Trial In Progress)
Abstract
Background and Significance: Measurable residual disease (MRD) represents the fundamental driver of relapse and mortality in acute myeloid leukemia (AML). However, there are currently no established approaches to address this unmet need. Our central hypothesis is that targeting vulnerabilities associated with specific leukemia genotypes will eradicate MRD and prevent disease relapse. Break Through Cancer is a collaboration between our centers aimed at making progress in the deadliest cancers by stimulating radical clinical and laboratory research collaboration.
The menin-KMT2A interaction is a critical dependency in acute leukemias caused by rearrangement of the Lysine methyl transferase (KMT2Ar) or Nucleoporin 98 (NUP98r) genes, or mutation of the Nucleophosmin 1 gene (NPM1mt). Revumenib (previously SNDX-5613), is a potent, oral, selective inhibitor of this interaction with an established safety and efficacy in refractory leukemias with these genotypes (Issa GC, Nature 2023). Additionally, KMT2Ar or NPM1mt leukemias can undergo BCL2-dependent apoptosis, and dual Bcl-2 and menin inhibition led to synergistic activity in KMT2Ar or NPM1mt leukemia models (Carter BZ, Blood 2021; Fiskus W, BCJ 2022). Therefore, we designed this study investigating the combination of revumenib and venetoclax to eradicate MRD in these AML subtypes (NCT06284486).
Study Design and Methods: This is a single arm, open label, multicenter, phase I/II investigator-initiated study. Patients (pts) age ≥ 12…
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