AML-412: Bleximenib Dose Optimization and Determination of the Recommended Phase 2 Dose (RP2D) From a Phase 1 Study in Patients With Relapsed/Refractory Acute Leukemia (AL) With KMT2A and NPM1 Alterations.

Abstract

Novel therapies are needed to treat AL with KMT2A and NPM1 alterations. Bleximenib (JNJ-75276617) is a potent, selective inhibitor of the menin-KMT2A interaction being evaluated as monotherapy for relapsed/refractory (R/R) AL (NCT04811560). Objective(s): To determine RP2D, evaluate safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of bleximenib at RP2D. Design(s): A dose-escalation design where participants received bleximenib orally (28-day cycle), with step-up dosing to mitigate differentiation syndrome (DS) risk and optimize therapeutic exposures. Patient(s): Adults with R/R NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AL. Main Outcome Measure(s): Safety was evaluated in participants who received >=1 dose of bleximenib. Efficacy was investigator-assessed per modified ELN 2017. Result(s): As of July 2024, 121 participants with R/R AL (acute myeloid leukemia [AML], n = 108; acute lymphoblastic leukemia [ALL], n = 6; other AL, n = 7) received study treatment (median age, 61 years [range, 18-85]; 55% female). KMT2A and NPM1 alterations were present in 73 (60%) and 48 (40%) participants, respectively. RP2D was determined in 3 dosing subgroups: 45 mg BID (n = 15), 90/100 mg BID (n = 27), and 150 mg BID (n = 28). Treatment-related adverse events (AEs) of any grade (G) occurred in 70/121 (58%) participants, most commonly DS (13%), neutropenia (12%), thrombocytopenia (11%), and nausea (9%). Seventeen participants experienced DS (both KMT2A and NPM1), with 8 (7%) DS events >=G3, including 2 fatal events. Overall response rate was 50% (10/20) at both 90/100 mg BID and 150 mg BID, and 39% (5/13) at 45 mg BID. Median time to first response at 90/100 mg BID was 30 days (range, 27-85); median duration of response was 6.4 months (95% CI, 0.1-NE). Conclusion(s): Bleximenib RP2D was determined at 100 mg BID (after a 50-mg BID step-up dose) with optimal safety, pharmacokinetic exposure, pharmacodynamic response, and promising antileukemic activity. No cardiac safety signals were observed; mitigation measures were used for DS. Phase 2 clinical trial activation is ongoing to further evaluate bleximenib monotherapy at the RP2D in R/R AML with KMT2Ar or NPM1m.Copyright © 2025 Elsevier Inc. All rights reserved.