A Phase 1/2 study of the menin inhibitor revumenib with the celmod mezigdomide in relapsed/refractory KMT2A-rearanged, NPM1-mutant, and NUP98-rearranged acute leukemias

Abstract

Abstract Background and Significance: Menin complexes with KMT2A and drives leukemic transformation in acute leukemias with aberrant homeobox (HOX) gene expression. Developed based on this knowledge, menin inhibitors (MENINi) are a new class of targeted agents that have shown impressive efficacy in the treatment of relapsed or refractory (R/R) KMT2Ar and NPM1c acute leukemias. Other HOX-high acute leukemias such as NUP98r acute leukemias have also responded to revumenib. Revumenib, the first FDA-approved MENINi, achieved a 63% ORR and 21% CR/CRh rate in R/R KMT2Ar acute leukemias the AUGMENT-101 study (Issa, Nature 2023 and JCO 2024). Despite its compelling efficacy, revumenib treatment can lead to the rapid acquisition of resistance mutations and duration of response is limited. MEN1 mutation emerged in 39% of patients treated with revumenib in AUGMENT-101, sometimes after 2 cycles (Perner, Nature 2023). Data is limited, but outcomes after MENINi failure appear poor and few targeted options exist beyond initial MENINi treatment. IKAROS, a key transcription factor in lymphocyte development and immune regulation, is a critical dependency in KMT2Ar and NPM1c acute leukemias (Aubrey, Nat. Cancer 2022). Mezigdomide, a cereblon E3 ligase modulator (CELMoD) in phase 3 studies for multiple myeloma, degrades IKAROS. Preclinical models show synergy between mezigdomide and MENINi, downregulating HOX genes while preventing and overcoming MEN1 mutations (Bourgeois, Blood 2023). Based on these data, we designed a phase 1/2 clinical trial to evaluate the combination of revumenib and mezigdomide in patients with R/R KMT2Ar, NPM1c, or NUP98r acute leukemias, including those previously treated with MENINi. This is the first clinical study to target both prevention and reversal of MEN1-mediated resistance to menin inhibition, with the goal of extending the therapeutic utility of MENINi. Study Design and Methods: This study will be a phase 1/2, multicenter, investigator-initiated studying the combination of revumenib and mezigdomide in R/R KMT2Ar, NPM1c, or NUP98r acute leukemias. MENINi refractory patients as well as menin inhibitor naïve patients are permitted. Key eligibility criteria include age ≥12 years and KMT2Ar, NPM1c, or NUP98r alterations. Phase 1 permits prior MENINi use though it is not required. Phase 2 will be split into 2 cohorts: cohort 1 will require participants to be MENINi-naïve and cohort 2 will require participants to be MENINi-exposed. Major exclusion criteria include patients actively using strong or moderate CYP3A4 inhibitors while on study due to drug-drug interactions with mezigdomide. The trial will accrue across 4 U.S. centers and enroll 2-18 patients in phase 1. If a RP2D is determined, up to 40 additional patients will be enrolled in phase 2 across 2 cohorts. The phase 1 portion of the study will utilize a 3+3 dose escalation design with 3 dose-levels to determine maximum tolerated dose (MTD) and RP2D of revumenib with mezigdomide and the primary endpoint will be safety and tolerability. Revumenib will be given at 270 mg every 12 hours, the FDA-approved dose. Mezigdomide doses are based on prior myeloma trials, where the RP2D was 1 mg daily days 1-21 with dexamethasone in 28-day cycles. Selected mezigdomide dose levels (0.6 mg daily for 14 out of 28 days, 0.6 mg daily for 21 out of 28 days, and 1 mg daily for 21 out of 28 days) all showed effective degradation of AIOLOS (an IKAROS homolog) in myeloma trials. The phase 2 portion will feature 2 cohorts and a Simon's minimax 2-stage design for each with CR/CRh within 6 cycles as the primary endpoint. Cohort 1 (MENINi-naïve) will test for a CR/CRh rate of 40% vs 20% based on AUGMENT-101. Three responses out of the first 14 and then 8 responses out of 24 total patients are needed for the combination to be promising. Cohort 2 (MENINi-exposed) will test for a CR/CRh rate of 25% vs 5% based on retrospective data on outcomes after MENINi failure. 1 response out of 12 and then 3 or more responses out of 16 total patients are needed for the combination to be promising. Type-1 error is 10% and power is 80% in both cases. A stopping rule will also be used to monitor excess toxicity. Key additional endpoints include depth and duration of response, survival, resistance mutations, and immunomodulatory effects.The study is funded and IRB-approved. First patient accrual is anticipated in fall of 2025.