HM43239, a Novel Small Molecule Inhibitor of FLT3, in Acute Myeloid Leukemia (AML) with and without FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1/2 Study

Background: FLT3 mutations, found in ~30% of patients with AML, and are associated with a poor prognosis. HM43239 is a novel FLT3 inhibitor that potently inhibits not only FLT3 mutants, including ITD and TKD mutants and FLT3 wild type but also spleen tyrosine kinase (SYK). Its dual inhibition of both FLT3 and SYK may activity in AML.

In preclinical studies, HM43239 showed more potent activity than Gilteritinib in FLT3-WT/ITD heterozygous MOLM-13/-14 AML cell models. Furthermore, HM43239 showed potent antileukemia activity in xenograft models of FLT3-ITD/F691L cell lines harboring double mutations of ITD/TKD, without any body weight loss or significant toxicity. These results indicate that HM43239 may be useful in the treatment of AML patients with FLT3-ITD and/or -TKD mutation, including patients with gilteritinib resistant mutations such as F691L.

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) is in clinical development in the United States and Korea to access the overall safety and efficacy of HM43239 in AML.

Trial Design: This is an ongoing, open-label, multicenter, first in human phase I/II trial enrolling adult FLT3 mutated and FLT3 wild-type patients with AML who have relapsed or refractory disease after at least one prior line of therapy, what can include prior FLT3 inhibitors such as gilteritinib, midostaurin. Patients are treated with HM43239 once daily (QD) in 28-day cycles, except for the first 30-day cycle, which includes a single PK sampling period. This trial comprises two parts: dose-escalation (Part A) and dose expansion (Part B).

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 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 at any dose level in the escalation cohort, 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 the expansion cohort at each dose level selected for expansion. If no CRc is achieved in 6 subjects or less than 2 composite CRs are achieved in 12 subjects who complete 2 treatment cycles that dose level will stop further enrollment. Subjects with FLT3 wild-type will be enrolled to both escalation and expansion cohorts, however, at least 10 subjects with FLT3 mutations (ITD or activating point mutations such as D835Y, D835V, I836) should 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 a supportive reference for dose-escalation procedure and safety monitoring.

The primary endpoint is the assessment of safety, tolerability and PK to determine the recommended phase 2 dose (RP2D). Secondary endpoints include best response rate, duration of response, event free survival, overall survival, cumulative incidence of relapse. PK-PD relationships and PD evaluated by plasma inhibitory assay are exploratory endpoints.

The trial was initiated in Jan 2019 and patients have been evaluated since May 2019. Dose level 1 (20 mg) and 2 (40mg) were completed without any DLTs. In Dose level 3 (80mg), one patient experienced MT, the design was changed from accelerated titration design to 3+3 design. Three patients (one FLT3 mutated) were enrolled, including an ongoing FLT3 wild-type patient (currently in cycle 5) with relapsed AML post-stem cell transplant who had prior chemotherapy and achieved CRi and maintains 0% marrow blasts. The enrollment to next dose level 4 (120mg) initiated in June 2020 and subjects have been enrolled. This study is currently recruiting patients at multiple sites in the Republic of Korea and the USA.

Clinical trial information: NCT03850574.