Phase 1 Results: First-in-Human Phase 1/2 Study of the Menin-MLL Inhibitor Enzomenib (DSP-5336) in Patients with Relapsed or Refractory Acute Leukemia

Introduction: Menin inhibitors are an important new class of agents in development for acute leukemia. Over expression of HOXA9 and MEIS1 driven by the menin and KMT2A/MLL interaction occurs in leukemias with KMT2A rearrangement (KMT2Ar), NPM1 mutations (NPM1m), as well as other abnormalities. Enzomenib (DSP-5336) is an investigational, oral small molecule designed to inhibit the menin and KMT2A protein interaction. Herein, we report updated results of a Phase1/2 study of enzomenib in patients (pts) with relapsed/refractory (R/R) acute leukemia. Methods: We conducted a Phase 1/2 study of enzomenib monotherapy in adult pts with R/R acute leukemia characterized by KMT2Ar, NPM1m, and other HOXA9/MEIS1 driven leukemia subsets. Other eligibility criteria included ECOG PS ≤ 2, QTcF interval ≤ 450 and 470 msec for male and female, adequate hepatic and renal function, & no active CNS leukemia. Dose escalation and optimization occurs in two parallel arms: Arm A (without strong CYP3A4 inhibitor azole antifungals) and Arm B (with strong CYP3A4 inhibitor azoles). The primary endpoints of this study were safety and tolerability (Phase 1) and preliminary efficacy (Phase 2) defined as CR+CRh rate. This study was IRB approved at 55 medical centers around the globe as of June 24, 2024 and registered at NIH ClinicalTrials.gov (NCT04988555). Results: As of June 24, 2024, 81 pts were enrolled; 31 in Arm A and 50 in Arm B. The median age was 60.0 years (range 20 - 89) and 56.8% were female; 76 (93.8%) had AML. The median number of prior lines of therapy was 3 (range 1 to 9); 23 pts (28.4 %) had prior allogeneic stem cell transplant, 63 pts (77.8%) had prior venetoclax, and 6 pts (7.4%) had received a prior menin inhibitor. Documented KMT2Ar was reported in 41 pts (50.6%) and NPM1m in 20 (24.7%). In the phase 1 portion, the enzomenib dose was escalated from 40 mg BID to 300 mg BID (n=81) with no dose limiting toxicities (DLTs) observed. Treatment emergent adverse events (TEAEs) assessed as related to enzomenib in ≥10% of pts was vomiting (14.8%), nausea (13.6%); grade 3 nausea and vomiting were reported in 1 pt. TEAE in ≥ 20% of pts regardless of relationship included nausea (39.5%), vomiting (29.6%), febrile neutropenia, diarrhea, hypokalaemia (22.2% each), decreased appetite, and headache (21.0% each). There were no reports of grade > 3 QTc prolongation related to enzomenib; grade 1 QTc prolongation was reported in 2 pts (2.5%) and grade 2 in 2 pts (2.5%). Possible differentiation syndrome (DS) was reported in 9 patients (11.1%) with no deaths from DS, and no treatment-related deaths. A total of 35 pts with KMT2Ar or NPM1m had not received a prior menin inhibitor and were treated with active doses of enzomenib (≥ 140 mg BID in Arm A or Arm B). Among the 22 pts with KMT2Ar (20 AML, 2 ALL), the objective response rate (ORR) by ELN 2017 (CR+CRi+MLFS) was 59.1% (13/22) with CR + CRh achieved in 22.7% (5/22). Among the 13 pts with NPM1m AML, the ORR was 53.8% (7/13) and CR + CRh achieved in 23.1% (3/13). Among pts with other menin-sensitizing genetics, 1 pt (AML) with a CALM-AF10 fusion also achieved a CR. Overall, the median time to objective response and to CR+CRh was 1.0 and 1.0 months, respectively. Dose-dependent increases in exposure were observed, particularly at doses > 140 mg BID. Little to no drug accumulation was observed with repeat dosing in both arms and data to date suggest that azoles do not have a significant impact on enzomenib exposure. Pharmacodynamic changes potentially indicative of leukemic differentiation were noted in pts with KMT2Ar or NPM1m, including rapid decreases in stemness markers HOXA9, MEIS1, and PBX3 by qPCR and, conversely, increase in the differentiation marker CD11b by qPCR compared to baseline. Conclusion: Enzomenib has been well tolerated with no DLT in 81 pts with R/R acute leukemia. No therapy-related discontinuations or deaths have been observed, and pharmacokinetic (PK) studies have not identified significant drug-drug interaction with strong CYP3A4 inhibitor azoles. Promising single agent activity has been observed in pts with R/R KMT2Ar and NPM1m acute leukemia across a wide therapeutic range of 140 mg to 300 mg BID. Dose optimization continues with the goal of identifying the RP2D for monotherapy. Updated clinical and translational data will be presented.

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