A first-in-human study of the menin inhibitor DS-1594b in patients with acute leukemias was discontinued early due to lack of efficacy as a monotherapy and the occurrence of differentiation syndrome in nearly a third of patients.
Jayastu Senapati, MBBS, of the University of Texas MD Anderson Cancer Center, and colleagues published the findings of the trial in the Journal of Hematology & Oncology.
The authors noted that DS, a potentially life-threatening complication, is an “important class-wide [adverse event] to be recognized in patients treated with menin inhibitors” and “developing novel menin inhibitors with potentially differential efficacy, safety, and resistance profiles remains highly pertinent and important for the field.”
Phase 1 of the planned single-arm, open-label, single-center, phase 1b/2 study included 17 adult patients (median age, 56 years) with relapsed/refractory acute myeloid leukemia (AML; n=15) or acute lymphocytic leukemia (ALL; n=2). Nine patients (53%) had a KMT2A mutation, and patients had received a median of three prior lines of therapy, five of whom (29%) had received a prior menin inhibitor. Nearly half of patients (n=8; 47%) were ≥60 years.
Patients received the oral menin inhibitor DS-1594b at various dose levels (70 mg twice daily, 50 mg twice daily, 20 mg once daily, and two cohorts that included a lead-in dose), and most patients (n=11; 64.7%) received two or more cycles of treatment with DS-1594b.
Phase 2 was planned to be a multicohort phase that included treatment with DS-1594b monotherapy and in combination with other agents in patients with KMT2A– and NPM1-mutated AML or ALL. However, a recommended phase 2 dose was not reached, and the supporting company decided to stop the trial. No patients achieved a protocol-defined response to treatment, though four patients (23%) saw a 25% to 50% (n=3) or >50% (n=1) reduction in bone marrow blasts after one cycle of treatment.
DS occurred in 29.4% of patients (n=5), including one case of grade 4 intensity in the 70 mg cohort. At a point in the study, a lead-in ramp-up dose was instituted to improve tolerability, and no DS occurred with this approach. Other grade ≥3 adverse events reported included infections (41%), pneumonia (41%), febrile neutropenia (41%), and sepsis (35%). No treatment-related deaths were reported, though three patients died during the study.
The median event-free survival was 1.2 months and median overall survival was 4.0 months.
Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in two hours, with total exposure increasing with escalating doses and reaching steady-state by day eight of the first cycle.
“Despite the early termination of our clinical trial, the evidence of DS in [five] patients is likely suggestive of the functional on-target engagement of the drug,” the authors noted.
Reference
Senapati J, Konopleva M, Issa GC, et al. A phase 1/2 study of DS-1594 menin inhibitor in relapsed/refractory acute leukemias. J Hematol Oncol. 2025;18(1):108. doi:10.1186/s13045-025-01757-4
