Updated results from DIAMOND-01 (CLI24-001) trial: A phase I/II study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in acute myeloid leukemia.
Authors: Solomon Scott R. , Montesinos Pau , Nazha Aziz , Strickland Stephen Anthony , Martinelli Giovanni , Santoro Armando , Walter Roland B. , Cook Rachel J. , Calbacho Maria , Vives Susana , Fazal Salman , Brzózka Krzysztof , Shamsili Setareh , Baldini Simone , Laurent Dirk , Pellacani Andrea Ugo Enrico , Ravandi Farhad 
Published: June 2021

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Background: SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor, in the dose escalation (DE) DIAMOND-01 trial (CLI24-001, NCT03008187), showed an acceptable safety profile up to the recommended dose (RD) of 125 mg along with initial evidence of single agent activity and meaningful target engagement in heavily pre-treated patients (pts) with AML (Solomon et al, EHA 2020; Tomirotti et al, ASH 2020). Here we present updated data including pts enrolled in the Phase II, cohort expansion (CE) of the study. Methods: DIAMOND-01 trial enrolled pts unsuitable for chemotherapy having relapsed or refractory (R/R) (DE and CE) or previously untreated (DE) AML. Previous targeted therapies – except PIM inhibitors – were allowed. SEL24/MEN1703 was given orally, QD, 14 days ON / 7 days OFF until progression/unacceptable toxicity. The DE tested MEN1703 escalating doses from 25 to 150 mg, whereas in the CE the RP2D (125 mg) was administered. The key objectives of the CE were the confirmation of the safety profile determined in the DE along with further investigation of single agent activity. Adverse events (AEs) were graded according to NCI-CTCAE v.4.03; responses assessed as per ELN 2017 criteria. Results: As of January 21, 2021 (cut-off date), n = 48 pts were treated across DE (n = 25) and CE (n = 23). Median age was 69 (25-84) years. Overall, 20 (43%) and 15 (32%) pts had non de novo AML and primary refractory AML, respectively. Adverse karyotype was reported in 7 (15%) pts. Most frequently reported mutations were FLT3/ITD (23%, n = 11), DNMT3A (15% n = 7), NPM1 (15%, n = 7), IDH1 (13%, n = 6) and IDH2 (4%, n = 2), CEBPA (4%, n = 2), FLT3/TKD (2%, n = 1). Median number of cycles was 2 (1-8). At the RD (n = 30), most frequent serious treatment-emergent AEs (serious TEAEs) were pneumonia (23%), sepsis and febrile neutropenia (13%) and pulmonary mycosis (10%) whereas most frequent G≥3 TEAEs were febrile neutropenia and pneumonia (23%), leukocytosis (20%) and neutrophil count decrease, platelet count decrease, lymphocyte count decrease and sepsis (13%). Responses occurred in 2 pts in the CE, both with IDH1 mutant disease (naïve to IDH inhibitors) who achieved complete remission with incomplete hematologic recovery (CRi). Both responses occurred by Cycle 3, with a duration of 79 (ongoing at cut-off date) and 43 days, respectively. Across DE and CE, 4 CR/CRi occurred, three of which in pts with IDH mutations. A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib. Conclusions: SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset. Clinical trial information: NCT03008187.