Bleximenib Dose Optimization and Determination of RP2D from a Phase 1 Study in Relapsed/Refractory Acute Leukemia Patients with KMT2A and NPM1 Alterations

Background: Despite improvements in treatment for acute leukemia (AL), outcomes for patients with relapsed/refractory (R/R) disease remain poor. Novel therapies are needed to treat AL with KMT2A (9-15% of adult acute myeloid leukemia AML, 10% of acute lymphoblastic leukemia ALL) and NPM1 (30% of adult AML) alterations. Bleximenib (JNJ-75276617) is a potent, selective inhibitor of the menin-KMT2A interaction and is being evaluated as monotherapy in R/R AL with KMT2A or NPM1 alterations (NCT04811560). Here we report data that informed the recommended phase 2 dose (RP2D) from the ongoing Phase 1 multicenter dose-finding study of bleximenib monotherapy for KMT2A- or NPM1- altered R/R AL. The aim of this study is to determine the RP2D of bleximenib and establish the safety and tolerability at the RP2D. This study also explores the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of bleximenib at the RP2D. Methods: Participants (pts) in dose-escalation receive bleximenib orally on a 28-day cycle, with step-up dosing to mitigate the risk of differentiation syndrome (DS) and to optimize therapeutic exposures. Adverse events (AEs) are graded using the CTCAE v5.0. The safety dataset comprises pts who have received at least one dose of bleximenib. Efficacy responses are investigator-assessed per modified ELN 2017 in pts with R/R NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AL. Results: As of July 2024, 121 pts with R/R AL (AML, n=108; ALL, n=6; other AL, n=7) received study treatment (median age: 61 years range: 18-85 years; 55% female; 82% White; 36% Eastern Cooperative Oncology Group Performance Status of 0). KMT2A and NPM1 alterations were present in 73 (60%) and 48 (40%) pts, respectively. Median number of prior lines of therapy was 2 (range: 1-7); 25% (30/121) had ≥1 prior allograft. To determine the RP2D, data were evaluated using 3 composite treatment dose subgroups: 45 mg twice daily (BID; n=15), 90/100 mg BID (n=27), and 150 mg BID (n=28). Data from 90/100 mg BID (RP2D) pts were combined, given the similar doses and overlapping PK exposures. Treatment-related AEs (TRAEs) of any grade (G) occurred in 70/121 (58%) pts, most commonly DS (13%), neutropenia (12%), thrombocytopenia (11%), and nausea (9%). Seventeen pts experienced DS (both KMT2A and NPM1), with 8 (7%) DS events ≥G3, including 2 fatal events. One fatal DS AE occurred in a pt with recurrent DS after rapid dose escalation. A single related AE of QTc prolongation (G3, dose-limiting toxicity DLT) was observed in a pt with significant cardiac comorbidities at once daily dosing without step-up. TRAEs ≥G3 were observed in 40/121 (33%) pts, most commonly neutropenia (11%), thrombocytopenia (8%), and DS (7%), with an increased incidence of ≥G3 TRAEs (11 pts 39%) observed at 150 mg BID. G4 TRAEs of thrombocytopenia were more common at 150 mg BID (3 11%) versus 100 mg BID (2 7%) or 45 mg BID (0%), and more G4 neutropenia DLTs were reported at 150 mg BID. Bleximenib-related dose interruptions and reductions were more frequent at 150 mg BID (25% and 14%), compared to 90/100 mg BID (7% and 7%), or 45 mg BID (7% and 7%), respectively. Overall response rate (ORR: ≥PR) was 50% (10/20) at both 90/100 mg BID and 150 mg BID, while the ORR observed at 45 mg BID was 39% (5/13). Composite complete response (cCR; CR/CRh/CRi) rates were identical at 90/100 mg BID and 150 mg BID (8/20 40% each) and lower at 45 mg BID (3/13 23%). The CR/CRh rate was higher at 90/100 mg BID (7/20 35%) and 150 mg BID (6/20 30%) versus 45 mg BID (3/13 23%). Median time to first response at 90/100 mg BID was 30 days (range: 27-85), and median duration of response was 6.4 months (95% CI: 0.1-NE). ORR and cCR were similar between KMT2Ar and NPM1m AML. Bleximenib exposures corresponding to 90/100 mg BID resulted in reduced hematologic toxicity, optimized PD effect with MEIS1 reduction, and maximal efficacy as evidenced by exposure safety and efficacy analyses. Conclusion: When compared to other dose levels explored, the data informed a bleximenib RP2D of 100 mg BID (after a 50 mg BID step-up dose) with optimal safety, PK exposure, and PD response, and promising antileukemic activity as monotherapy in R/R AML harboring KMT2Ar or NPM1m. No cardiac safety signal was observed, and mitigation measures have been implemented 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.