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)

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 years with weight ≥ 45Kg, and known history of NPM1mt, or KMT2Ar, or NUP98r AML with MRD ≥ 0.1% identified by multiparameter flow cytometry (MFC) using central testing would be eligible; no morphologic evidence of AML (blasts <5%) in first remission following high intensity therapy or at least 2 cycles of low intensity therapy, or in second remission following any therapy. Up to 12 pts will be enrolled on the phase I, using 3+3, with escalating doses of revumenib and a target dose of 163 mg PO Q12h (with strong CYP3A inhibitor) or 276 mg PO Q12h (without strong CYP3A inhibitor) days 1-28, with venetoclax 400 mg (target dose) PO daily, days 1-14.

The primary objective of the phase I is to determine safety, and the recommended phase II dose. The primary objective of the phase II is to assess the efficacy of venetoclax and revumenib in clearance of MRD (conversion to undetectable by central MFC) within 8 cycles. Up to 14 pts will be included on the phase II portion of the study. With a sample size of 20 pts (Phase II + RP2D in Phase I), the power is 76% assuming an MRD clearance of 30% (based on QUAZAR trial, Roboz et al. Blood 2022) against a null rate of 8%, by a two-sided Fisher's exact test at a significance level of 0.05. We plan to monitor futility and toxicity where enrollment will be stopped early if >95% probability that the MRD conversion rate is < 30% or there is >90% probability that the unacceptable toxicity rate >20%.

Secondary objectives include assessment of duration of response, event-free and overall survival and concordance of genetic and flow MRD. This trial includes longitudinal collection of samples, with exploratory objectives focused on improving MRD detection using cell-free DNA, single-cell mutation analysis and cytometry by time of flight. In addition, we aim to use various models in addition to patient samples to improve understanding of MRD biology and identify novel susceptibilities.

Accrual is planned at MD Anderson, Dana Farber, Memorial Sloan Kettering, and Johns Hopkins. This study may identify a novel strategy to eradicate MRD using combination targeted therapies which may decrease recurrence and improve remission duration. In addition, this study could improve detection of MRD, and our understanding of MRD biology.

Issa:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Astex: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Merck: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Celgene: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Ambinder:Astellas: Honoraria. Shalek:Honeycomb Biotechnologies, Cellarity, Ochre Bio, Bio-Rad Laboratories, Relation Therapeutics, IntrECate biotherapeutics, Fog Pharma, Passkey Therapeutics, and Dahlia Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kentsis:Novartis: Consultancy; Blueprint Medicines: Consultancy; Syndax Pharmaceuticals, Inc.: Consultancy; Rgenta Therapeutics: Consultancy. Short:NextCure: Research Funding; Sanofi: Honoraria; Amgen: Honoraria; Autolus: Honoraria; Novartis: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Pfizer Inc.: Honoraria; Adaptive Biotechnologies: Honoraria; GSK: Consultancy, Research Funding; Xencor: Research Funding; Takeda Oncology: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; BeiGene: Honoraria. Daver:Trillium: Consultancy, Research Funding; KITE: Research Funding; Hanmi: Research Funding; Trovagene: Research Funding; Gilead: Consultancy, Research Funding; Syndax: Consultancy; Menarini Group: Consultancy; Jazz: Consultancy; Shattuck Labs: Consultancy; Celgene: Consultancy; Novimmune: Research Funding; Arog: Consultancy; Astellas: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novartis: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Agios: Consultancy. Bachireddy:BioNTech: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; Exelixis: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Allogene Therapeutics: Research Funding; Agenus: Current equity holder in publicly-traded company. Lane:Menarini Group: Other: Steering Committee, Research Funding; AbbVie: Research Funding; Cimeio Therapeutics: Consultancy; IDRx: Consultancy; Jnana Therapeutics: Consultancy; ProteinQure: Consultancy; Qiagen: Consultancy; Stelexis BioSciences: Consultancy; Medzown: Current equity holder in private company. Konopleva:Reata Pharmaceutical: Other: IP; Precision Biosciences: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Rafael Pharmaceutical: Research Funding; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer: Consultancy; Sellas: Consultancy; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Cellectis: Other: Clinical Trials; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Other: clinical trials; Redona: Consultancy; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Legend Biotech: Consultancy; ImmunoGen: Research Funding; Allogene: Research Funding; Pfizer: Other: clinical trials; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding. Abdel-Wahab:Nurix Therapeutics: Research Funding; Minovia Therapeutics: Consultancy, Research Funding; Codify Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Levine:Anovia: Consultancy; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Bridge Medicines: Consultancy; Bridge Bio: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Ajax: Membership on an entity's Board of Directors or advisory committees; Scorpion: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Jubilant: Membership on an entity's Board of Directors or advisory committees; Epiphanes: Membership on an entity's Board of Directors or advisory committees. Levis:Bristol Myers Squibb: Consultancy; Astellas: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Stone:Takeda: Consultancy, Other: DSMB; Lava Therapeutics: Consultancy; Ligand: Consultancy; Redona: Consultancy; Rigel: Consultancy; ENSEM: Consultancy; Epizyme: Consultancy; Glaxo Smith Kline: Consultancy; Glycomimetrics: Consultancy; Hermavant: Consultancy; Janssen: Other: Research Funding to my Institution; Jazz: Consultancy; Kura Oncology: Consultancy; Syndax: Other: Research Funding to my institution; Syntrix/ACI: Consultancy, Other: DSMB; Daiichi Sankyo: Consultancy; Curis Oncology: Consultancy; CTI BioPharma: Consultancy; Cellarity: Consultancy; Bristol Meyers Squibb: Consultancy; BerGen Bio: Consultancy; AvenCell: Consultancy; Aptevo: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy, Other: Research funding to my institution. Andreeff:Kintor Pharmaceutical: Research Funding; Ona: Honoraria; Paraza: Honoraria; Chimerix: Current holder of stock options in a privately-held company; Roivant: Honoraria; Glycomimetics: Honoraria; Oxford Biomedical: Research Funding; Syndax: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Sellas: Honoraria, Research Funding; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Oncolyze: Current holder of stock options in a privately-held company; Ellipses: Research Funding; Aptose: Honoraria; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding. Ravandi:Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Astyex/Taiho: Research Funding. Goldberg:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ikena Oncology: Consultancy; Aprea: Research Funding; Aptose: Research Funding; AROG: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celularity: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura Oncology: Honoraria, Research Funding; Molecular Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Honoraria; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Garcia:Taiho: Research Funding; Servier: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Newave: Research Funding.