FDA Grants Fast Track Status to HM43239 for FLT3-Mutated, Relapsed/Refractory AML

The FDA has granted a fast track designation to the myeloid kinome inhibitor, HM43239, for use as a potential therapeutic option in patients with relapsed or refractory acute myeloid leukemia whose tumors harbor a FLT3 mutation.

The FDA has granted a fast track designation to the myeloid kinome inhibitor, HM43239, for use as a potential therapeutic option in patients with relapsed or refractory acute myeloid leukemia (AML) whose tumors harbor a FLT3 mutation.1

HM43239 is an oral genotype-agnostic small molecule inhibitor of several kinases that are operative in myeloid malignancies and are known to play a key role in tumor proliferation, the development of resistance to available therapies, and differentiation. The agent directly inhibits the kinase activity of FLT3 as a reversible type I inhibitor and moderates downstream p-STAT5 and p-ERK; it has also been shown to inhibit SKY, JAK1/2 and TAK1.

Research done with in vivo murine xenograft models suggested that HM43239 may have stronger antitumor activity and better tolerability than other kinase inhibitors that are currently leveraged in AML, such as the FLT3 inhibitor gilteritinib (Xospata) and the SYK inhibitor entospletinib (GS-9973). Findings from in vivo xenograft models that have also suggested that HM43239 is synergistic with other inhibitors of DNMT, BCL-2, and other targets.

“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,” William G. Rice, PhD, chairman, president, and chief executive officer of Aptose Biosciences, Inc., stated in a 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 ongoing, open-label, multicenter, first-in-human, phase 1/2 trial (NCT03850574) was launched to examine the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM43239 in patients with relapsed or refractory AML.2,3 To be eligible for enrollment, patients needed to have primary or secondary AML that was either refractory to at least 1 cycle of previous therapy or relapsed following remission with a prior treatment.

Patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, and a minimum life expectancy of 3 months. 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.

If patients had a diagnosis of acute promyelocytic leukemia, BCR-ABL–positive leukemia, active malignant tumors other than AML or myelodysplastic syndrome, had symptomatic central nervous system involvement of leukemia, disseminated intravascular coagulation abnormality, among other criteria, they were excluded.

The trial is composed of 2 parts: dose-escalation and dose-expansion. The first portion of the trial follows an accelerated titration design, with approximately 50% dose increments and 1 patient per dose level. This titration continued until 1 patient reports a dose-limiting toxicity (DLT) or experiences moderate toxicity, a drug-related grade 2 event, at any dose level.

Once this happens, the trial uses a 3+3 dose-escalation design. Moreover, if a participant experiences clinical response, complete remission with low platelets, complete remission with incomplete hematologic recovery or partial remission at any dose level examined in the escalation cohort, then that dose level will be further explored as part of an expansion cohort.

At least 10 patients with FLT3 mutations will be included in each dose level that is chosen for expansion.

Study participants 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.

The primary end point was to evaluate PK, safety, and tolerability, so that the recommended phase 2 dose of the agent could be identified. Key secondary end points comprised best response rate, duration of response (DOR), event-free survival, overall survival, and cumulative incidence of relapse.

At the time of the 2021 ASH Annual Meeting, 34 patients with relapsed or refractory AML had been enrolled to the trial. These patients received escalating doses of HM43239 that ranged from 20 mg to 160 mg.

Data showed that when HM43239 was administered at 80 mg in a subset of patients whose tumors harbored FLT3 mutations (n = 8), 37.5% achieved a durable composite complete response to treatment.

With the 80-mg dose, a composite CR rate of 25% was noted in those with FLT3-mutated and FLT3 wild-type disease; this included 1 patient who previously experienced failure with gilteritinib. One of these patients, who had TP53-mutated AML who was not fit for hematopoietic stem cell transplant, was able to experience a DOR that was longer than 1 year. Notably, at this dose, 4 of 5 responders were able to advance to transplant.

At the 120-mg dose, 1 patient who previously experienced failure with gilteritinib managed to achieve a partial response to treatment with HM43239 after 1 cycle.

Regarding safety, the agent was noted to have a favorable toxicity profile. No DLTs were observed in the cohorts of patients who received the agent up to 160 mg daily. Moreover, no patients discontinued treatment because of HM43239-related adverse effects.

The trial is ongoing, and at the time of the 2021 ASH Annual Meeting, it was reported that the dose-escalation cohort of 200 mg and the dose-expansion cohorts of 120 mg and 160 mg were enrolling patients.

Previously, in 2018, HM43239 received an orphan drug designation from the FDA for the treatment of patient with AML.


  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 4, 2022. https://bit.ly/3LO4oOc
  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 4, 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