FDA Grants Fast Track Status to HM43239 for R/R FLT3+ AML


The FDA has granted a fast track designation to HM43239 for the treatment of patients with relapsed or refractory acute myeloid leukemia whose tumors harbor a FLT3 mutation.

The FDA has granted a fast track designation to HM43239, an oral, myeloid kinome inhibitor, for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) whose tumors harbor a FLT3 mutation, according to Aptose Biosciences Inc.1

HM43239, a potent, genotype-agnostic small molecule inhibitor consisting of several kinases which are operative in myeloid malignancies, previously received an orphan drug designation from the FDA for the treatment of patients with AML in 2018. It is known to play a role in tumor proliferation, resistance to therapies, and differentiation, and the agent is highly active against FLT3, as well as resistance-conferring D835, and gatekeeper (F691) tyrosine kinase domain mutations.

In vivo murine xenograft models have suggested HM43239 to possibly have stronger antitumor activity and better tolerability than other kinase inhibitors currently used in AML, and to be synergistic with other inhibitors of DNMT, BCL-2, and more. Some of these inhibitors include, such as the FLT3 inhibitor gilteritinib (Xospata) and the SYK inhibitor entospletinib (GS-9973).

“Fast track status acknowledges HM43239’s potential to fill an unmet need for AML patient populations and supports our efforts as we advance it toward a potential registrational study,” stated William G. Rice, PhD, chairman, president, and chief executive officer of Aptose Biosciences, Inc., in the press release. “HM43239, which potently inhibits all tested forms of FLT3 and SYK and JAK driven pathways, already has delivered complete remissions in a broad diversity of relapsed or refractory AML patients in an ongoing phase 1/2 clinical trial, including patients with prior failure of other FLT3 inhibitor agents.”

An open-label, multicenter, first-in-human, phase 1/2 trial (NCT03850574) is currently ongoing in order to examine the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM43239 in patients with relapsed or refractory AML.2,3

Eligibility for enrollment is open to patients aged 18 years or older with primary or secondary AML that was either refractory to at least 1 cycle of previous therapy or relapsed following remission with a prior treatment. Other requirements include to have an ECOG performance status of 0 to 2, a life expectancy of at least 3 months, and the interval from prior treatment to study drug administration needed to be at least 2 weeks for cytotoxic agents or at least 5 half-lives for previous investigative or noncytotoxic drugs.

The trial consisted of 2 parts which included dose-escalation and dose-expansion phases. During the dose-escalation portion of the study, an accelerated titration design was followed with around 50% dose increments and 1 patient per dose level. This accelerated design is set to continue until 1 patient experiences a dose-limiting toxicity (DLT), moderate toxicity, or drug-related grade 2 adverse event, not including hematologic toxicities, at any dose level. After this, a 3 + 3 dose-escalation design will be utilized.

If a patient experiences a clinical response, complete remission, complete remission with low platelets, complete remission with incomplete hematologic recovery, or partial remission at any dose level being evaluated in the escalation cohort, an expansion cohort will be open at that dose level.

Patients received HM43239 at once-daily doses as part of 28-day treatment cycles except for the first 30-day cycle, which included a single pharmacokinetic (PK) sampling period. There would be at least 10 patients with FLT3mutations included in each dose level if chosen for expansion.

The primary end point of the study was to evaluate PK, safety, tolerability, and determine the recommended phase 2 dose of the agent. Secondary end points included best response rate, duration of response (DOR), event-free survival, overall survival, and cumulative incidence of relapse.

The phase 1/2 clinical trial has shown HM43239 to deliver complete remissions in a diverse group of relapsed or refractory AML patients and continues to be a well-tolerated oral agent.

  1. Aptose receives fast track designation for HM43239 in relapsed/refractory AML patients and FLT3 mutation. News release. Aptose Biosciences Inc. May 4, 2022. Accessed May 5, 2022. https://bit.ly/3Fh34ks
  2. Clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of HM43239 in patients with relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated March 2, 2022. Accessed May 5, 2022. https://clinicaltrials.gov/ct2/show/NCT03850574
  3. Daver NG, Lee KH, Yoon S-S, et al. 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. Blood. 2019;134(suppl 1):1331. doi:10.1182/blood-2019-129670
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