HM43239, a Novel Potent Small Molecule FLT3 Inhibitor, in Acute Myeloid Leukemia (AML) with FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1 /2 Study

Background: HM43239 is an orally active small molecule inhibitor of FLT3 that selectively inhibits not only FLT3 wild type, ITD mutants or TKD mutations, but also FLT3 ITD/TKD double mutations. HM43239 directly inhibits the kinase activity of FLT3 as a reversible Type I inhibitor and effectively modulates downstream p-STAT5 and p-ERK. HM43239 also demonstrated inhibition of SYK, JAK1/2 and TAK1, known to be involved in tumor cell proliferation and/or differentiation HM43239 monotherapy induced dose-dependent regression of tumor growth in FLT3 wild-type and FLT3 mutated leukemia cancer cell lines (Poster presented at AACR 2018; Abst.804 and also prolonged survival in a FLT3 ITD/TKD double mutated xenograft mouse model (Poster presented at AACR 2019; Abst.1293). The anti-leukemic activity of HM43239 monotherapy was evaluated in in vivo studies that suggested the ability of this agent to potentially target LSCs (Poster presented at AACR 2019; Abst.1293). Preclinical studies suggest that HM43239 may be an effective agent in patients with hematologic malignancies including AML, to target various mutant types of FLT3. Herein, we present a clinical trial design to assess the potential clinical activity and safety of HM43239 in patients with AML. This phase I/II clinical trial (NCT03850574) consists of dose escalation (Part A) and dose expansion (Part B) stages to access the overall safety and efficacy findings.

Trial Design: This is an ongoing, open-label, multicenter, first in human, phase I/II trial enrolling adult patient with AML who relapsed or have refractory disease after at least one prior line of therapy. Patients were treated with HM43239 once daily (QD) in 28-day cycle except for the first 30-day cycle including a single PK sampling period. This trial comprises two parts: dose escalation and dose expansion. During dose escalation, the study follows an accelerated titration design, with around 50% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or moderate toxicity (MT), drug-related grade 2 adverse event (except for hematologic toxicities), at any dose level, after which, a 3 + 3 dose escalation design will be used. If a patient achieves a clinical response [complete remission (CR), complete remission with low platelets (CRp), complete remission with incomplete hematologic recovery (CRi) or partial remission (PR)] at any dose level in escalation cohort, then an expansion cohort will be open at that dose level. Based on the evaluation of DLTs and composite complete remissions (CRc) from the dose escalation cohorts, additional subjects may be recruited in expansion cohorts at each dose level selected for expansion. At least 10 subjects with FLT3 mutations (ITD or activating point mutations such as D835Y, D835V, I836) will be enrolled to each dose level selected for expansion (including the subjects from the dose escalation cohort). Blood samples are collected for pharmacokinetics (PK) & pharmacodynamics (PD) evaluation and for exploratory biomarker analysis in both cohorts. A 2-parameter Bayesian logistic regression will be used to model the dose-toxicity relationship on DLT in dose escalation and expansion parts and the estimated DLT rate will be provided as supportive reference for dose escalation procedure and safety monitoring.

The primary endpoint is the assessment of pharmacokinetics, safety and tolerability in order to determine the recommended phase 2 dose (RP2D). Secondary endpoints include best response rate [CRc (CRc=CR+CRp=CRi)+ PR], duration of response, event free survival, overall survival, cumulative incidence of relapse of HM43239. PK-PD relationships and PD evaluated by plasma inhibitory assay (PIA) are exploratory endpoints. At first, this trial was initiated in Jan 2019 and an enrolled patient has been evaluated since May 2019. Dose level 1 (20 mg) was completed without any DLTs; enrollment to next dose level (40 mg) was initiated in June 2019 . This new cohort is currently recruiting patients in the Republic of Korea and the USA.

Clinical trial information: NCT03850574.

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