Jayastu Senapati, Marina Konopleva, Ghayas C. Issa, Elias Jabbour, Tapan Kadia, Courtney D. DiNardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J. Short, Musa Yılmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A. Abbas, Michael Andreeff, Kapil N. Bhalla, Narasimha M. Midde, N. Ait Said, Amy Noyalis, Derek E. Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia‐Manero, Hagop M. Kantarjian, Naval Daver
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.