First in Human Study of SEL24/MEN1703, First in Class, Orally Available Dual PIM/FLT3 Kinase Inhibitor, in Patients with Acute Myeloid Leukemia
Authors: Solomon Scott R. , Nazha Aziz , Strickland Stephen A. , Walter Roland B. , Valimberti Ilaria , Tagliavini Alessia , Mazzei Paolo , Fiesoli Caterina , Scartoni Simona , Bellarosa Daniela , Binaschi Monica , Chrom Pawel , Baldini Simone , Brzózka Krzysztof , Capriati Angela , Pellacani Andrea , Ravandi Farhad 
Published: November 2019

Introduction
SEL24/MEN1703 is a potent dual inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) and FMS-like tyrosine kinase 3 (FLT3) with increased activity in both primary Acute Myeloid Leukemia (AML) cells and AML cell lines, irrespectively of FLT3 mutational status, when compared to either FLT3 or PIM single agent inhibitors. PIM kinases are thought to be major drivers of resistance to FLT3 inhibitors and their inhibition in relapsed samples restores cell sensitivity to these agents. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. In addition, the broader spectrum of activity of SEL24/MEN1703, which goes beyond PIM/FLT3 inhibition, warrants the compound investigation in AML patients regardless of the genetic aberrations of FLT3.
Methods
CLI24-001 is a First-in-Human, single-arm, phase I/II trial with a dose-escalation (DE) part followed by a cohort expansion (CE) part in patients with AML (excluding Acute Promyelocytic Leukemia) -newly diagnosed, relapsed or refractory - that are unsuitable for intensive chemotherapy and meet the main inclusion criterion of white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukapheresis permitted to lower WBC). In both study parts, patients are eligible regardless of mutational status and prior exposure to FLT3 inhibitors; however, prior treatment with PIM inhibitors is not allowed. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle to be repeated until disease progression, or unacceptable toxicity or withdrawal of patient consent. Bayesian modified toxicity probability interval model was implemented in the DE part after achieving 5 incremental dose levels in order to provide the most accurate identification of the Recommended Phase 2 Dose (RP2D). Also, during the DE part, a new oral formulation was introduced and compared to the original one by repeating the 100 mg dose level in order to avoid a subsequent formal bioequivalence study in patients. The primary objective of the study is to identify the RP2D of SEL24/MEN1703 in the DE part that will be further characterized in the CE part for next steps of clinical development. Key secondary objectives include the characterization of pharmacokinetics (PK) and efficacy assessment of SEL24/MEN1703 given as single agent; exploratory objectives include the assessment of relevant biomarkers (e.g. pS6) in peripheral blood and bone marrow, and their correlation with PK at different time points. Correlation of clinical activity and the cell surface antigen CD25 will be also explored.
Study update
Currently, the study is enrolling at 5 US sites and will be extended both in the US and EU. The recruitment started in March 2017 and, as of July 26th, 2019, 24 patients received SEL24/MEN1703 at dose levels ranging from 25 to 150 mg. Patients had a median age of 69 (25-84) years and a median of 3 (0-8) prior treatments for AML. Adverse prognostic factors such as primary refractory AML, unfavorable cytogenetics and prior MDS history accounted for 45.8%, 37.5%, 33.% of study patients, respectively. The most frequently reported mutations were FLT3-ITD (20.8% of patients) and those of DNMT3A and IDH1 (16.7% each).
Conclusions
This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to overcome FLT3 inhibitor resistance, but also to be active in AML regardless of FLT3 mutational status. Ongoing adjustment of the DE design, including the switch to an optimized oral formulation, has been performed to obtain more robust data on the RP2D (ClinicalTrials.gov Identifier: NCT03008187).

Disclosures
Nazha: Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Walter:Boehringer Ingelheim: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy. Valimberti:Menarini Ricerche S.p.A: Employment. Tagliavini:Menarini Ricerche S.p.A: Employment. Mazzei:Menarini Ricerche S.p.A.: Employment. Fiesoli:Menarini Ricerche S.p.A.: Employment. Scartoni:Menarini Ricerche S.p.A.: Employment. Bellarosa:Menarini Ricerche S.p.A.: Employment. Binaschi:Menarini Ricerche S.p.A.: Employment. Chrom:Selvita S.A.: Employment. Baldini:Menarini Ricerche S.p.A.: Employment. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Capriati:Menarini Ricerche S.p.A.: Employment. Pellacani:Menarini Ricerche S.p.A.: Employment; Amgen: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding.