No Evidence of QTC Interval Prolongation With the Menin Inhibitor Bleximenib When Given as Monotherapy or in Combination With Acute Myeloid Leukemia Aml-Directed Therapies for Kmt2a or Npm1 Altered Aml

Background Corrected QT interval (QTc) prolongation is a known risk for fatal cardiac arrythmias and emerged as a safety signal with currently approved menin inhibitors (all-grade: 12%–36%; high-grade: 8–17%). QTc prolongation may limit dose intensity of available menin inhibitor therapy and complicate management of AML by preventing combination with anti-leukemic therapies and use of critical supportive care medicines. Bleximenib is being evaluated in late stage clinical studies in relapsed/refractory or newly diagnosed KMT2A-rearranged or NPM1-mutated AML. We report cardiac safety analyses from two Phase 1 trials evaluating bleximenib as monotherapy (ALE1001 [NCT04811560]) or in combination with AML-directed therapies (ALE1002 [NCT05453903]). Methods The safety population included 141 participants (pts) in ALE1001 and 193 in ALE1002. Patients were excluded for QTcF ≥450 ms (males) or ≥470 ms (females), or a family history of long QT syndrome. Bleximenib was administered orally in 28-day cycles at doses ranging from 50–100 mg QD or 15–150 mg BID, as monotherapy or combined with venetoclax/azacitidine (VEN/AZA) or intensive chemotherapy (7+3). Cardiac monitoring included triplicate 12-lead ECGs at baseline and Day 1 of each cycle (or as clinically indicated), with central review. AEs were assessed per CTCAE v5.0. Exposure-response analysis using ΔQTcF as the dependent variable and time-matched bleximenib concentrations as the explanatory variable was performed in 139 ALE1001 patients with central ECG data, supported by intensive pharmacokinetic sampling and mean ΔQTcP. Results Of 334 pts receiving bleximenib across both studies, only one (0.3%) high grade (Grade [Gr] 3) event of QTc prolongation was observed in a pt receiving bleximenib 100mg QD as monotherapy with baseline comorbidities of ongoing cardiomyopathy and hypokalemia. At the recommended Phase 2 dose (RP2D) in ALE1001, a single (1.6%) Gr 1 QTcF prolongation treatment emergent AE (TEAE) occurred that resolved without dose reduction or interruption. In ALE1002, minimal QTcF prolongation TEAEs were reported in pts receiving bleximenib 15–150mg BID in combination with VEN, VEN+AZA, or ‘7+3’.; 8 (4.1%) experienced a QTcF prolongation event. All were low-grade (7 Gr1, 1 Gr2) non serious and did not result in bleximenib dose modifications. No dose dependent trend in QTcF interval increases were apparent across analyses in either study. In ALE1001 central ECG data (n=139), time course of mean change in heart rate (HR) was comparable across different doses. No increase of >10 bpm was observed, with no QTc prolongation seen up to the highest dose explored (2-fold higher exposure vs RP2D). Observations from ALE1002 were similar with no dose-dependent effects on QTc prolongation. ALE1001 exposure-response analysis based on time-matched central ECG data indicated no clinically relevant effect of bleximenib on cardiac repolarization following bleximenib monotherapy at all doses explored. Bleximenib had no clinically significant impact on HR. Conclusions Administration of bleximenib as monotherapy or in combination with AML-directed therapies did not prolong QTc interval and no cardiac safety signal was identified.