Phase 1/2 study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in patients with IDH1/2-mutated acute myeloid leukemia: The DIAMOND-01 trial.
Authors: Martinelli Giovanni , Santoro Armando , Gambacorti-Passerini Carlo , Vives Polo Susana , Solomon Scott R. , Mukherjee Sudipto , Levy M. Yair , Wierzbowska Agnieszka , Calbacho Maria , Angelosanto Noemi , Galleu Antonio , Baldini Simone , Blotta Simona , Habboubi Nassir , Ravandi Farhad , Montesinos Pau 
Published: June 2022

7024 Background: Mutations in the FLT3 tyrosine kinase are the most frequent ones that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3/8 IDHm patients (pts) responded. Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 pts with R/R IDHm AML. Methods: Pts with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety; adverse events (AEs) were graded according to NCI-CTCAE v4.03. The secondary endpoint was anti-leukemic activity including overall response rates (ORR). Results: As of 10 Jan 2022, 14 pts were enrolled in the IDHm cohort. Median age was 68 years (range 37-79). Four pts had AML secondary to myelodysplastic syndrome and 7 pts had intermediate cytogenetic risk. The median number of prior lines was 2 (range 1-3). Seven pts had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3/ITD were detected in 2 pts. Median duration of treatment was 2 cycles (range 1-8). Safety data (N = 12) showed that serious treatment-emergent AEs (TEAEs; ≥5%) were pneumonia (33%), and skin infection and gastroenteritis clostridial (8% each). These were all unrelated to study drug. Drug-related TEAEs were liver injury, overdose, and hyponatremia (8% each). The drug-related liver injury occurred in a pt who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10%) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 pts who completed ≥1 treatment cycle and had ≥1 post-baseline assessment or clear disease progression, ORR was 28.6%; 1 pt achieved CRi at cycle (C) 3 and underwent hematopoietic stem cell transplant, 1 pt had PR at C4 (confirmed at C7 and still on treatment), 4 had disease progression, 1 discontinued for AE not drug-related. Among the 7 remaining pts, 3 discontinued before completion of C1 without progression or response, while 4 pts were ongoing and have not yet had any post-baseline assessment. Conclusions: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first in class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in pts with R/R IDHm AML. Updated results will be presented at the congress. Clinical trial information: NCT03008187.