Faculty, Staff and Student Publications

Language

English

Publication Date

11-27-2025

Journal

Journal of Hematology & Oncology

DOI

10.1186/s13045-025-01757-4

PMID

41310838

PMCID

PMC12661886

PubMedCentral® Posted Date

11-17-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and 2 (12%) had R/R B-ALL; 9 (53%) had a KMT2A-r but none had an NPM1 mutation. The median prior lines of therapy was 3 (range 1-8) and 5 patients (29%) had received prior menin inhibitors. Five dose escalation cohorts were evaluated; no RP2D was established, and the trial was stopped at phase 1 due to a decision by supporting company due to lack of efficacy at studied dose levels and portfolio realignment. Differentiation syndrome (DS) was seen in 5 patients (29%); 2 in cohort 1 (70 mg twice daily, n = 4) 1 each had grade 1 and grade 4 DS, 3 patients in cohort 2 (50 mg twice daily/100 mg daily, n = 4) of whom 2 had grade 2 and 1 patient had grade 3 DS (considered as dose limiting toxicity). No DS was noted at cohort 3 (20 mg/day), and in subsequent dose-escalation cohorts (cohorts 4 and 5) a lead-in ramp-up dosing starting at 20 mg/day was instituted to improve tolerability. Other relevant treatment emergent adverse events of grade ≥ 3 included infections; pneumonia and febrile neutropenia in 7 patients each (41%), and sepsis in 6 patients (35%). No study drug related deaths were noted. No patient achieved a response, however 4 patients (23%) had > 25% bone marrow blast reduction. Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.

Keywords

Humans, Middle Aged, Aged, Adult, Nucleophosmin, Male, Female, Aged, 80 and over, Proto-Oncogene Proteins, Leukemia, Myeloid, Acute, Young Adult, Antineoplastic Agents, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Acute myeloid leukemia, Menin inhibitor, KMT2A, NPM1, Differentiation syndrome

Published Open-Access

yes

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