PF281 CLI24–001: FIRST IN HUMAN STUDY OF SEL24/MEN1703, AN ORAL DUAL PIM/FLT3 KINASE INHIBITOR, IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Abstract

Background:PIM kinases are oncogenic FLT3 targets expressed in acute myeloid leukemia (AML) cells. Increased PIM expression is found in samples of relapsed AML patients exposed to FLT3 inhibitors (FLT3i). There is preclinical evidence that PIM inhibition restores cell sensitivity to FLT3i, and that dual FLT3/PIM inhibition eradicates FLT3‐ITD+ primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, showed a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status compared to FLT3 or PIM inhibitors aloneAims:To determine the recommended phase 2 dose (RP2D), the PK profile and the single agent activity of SEL24/MEN1703 in relapsed/refractory or newly diagnosed AML patients (excluding APL) unsuitable to chemotherapyMethods:First in Human, open label, non‐randomized, multi‐center, dose‐escalation (DE) and cohort expansion (CE) study of oral SEL24/MEN1703. SEL24/MEN1703 is given orally, QD, FOR 14 days in a 21‐day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the RP2D; CE at RP2D is planned to confirm the safety profile and assess single agent activity. Patients are eligible for the study regardless of mutations and/or prior FLT3i treatment; prior PIM inhibitors are not allowed. White blood count (WBC) of ≤30 x 109/L is required at baseline. Key secondary objectives include PK profile and single agent anti‐leukemic activity; exploratory objectives include assessment of clinical activity in relevant AML subsets of patients (eg FLT3 mutated)Results:As of January 8th, 2019 (data cutoff), n = 17 patients were treated and the study is enrolling. In the RP2D expansion phase, the study (currently running in 5 US sites) will be expanded to approximately 40 sites in the US and EUSummary/Conclusion:SEL24/MEN1703, a first in class, oral dual PIM/FLT3‐ITD inhibitor, is completing the DE part of a two‐part FIH study in patients with relapsed/refractory or unfit newly diagnosed AML unsuitable to chemotherapy. The RP2D expansion phase is planned to involve either US and EU investigational sites. This is the first clinical trial testing a dual PIM/FLT3‐ITD inhibitor, potentially active in AML regardless of FLT3 status and able to overcome FLT3i resistance