Skip to main content

The FLT3/SYK Inhibitor HM43239 Shows Activity in Patients with Relapsed or Refractory FLT3-Mutated and Wild-Type AML

Conference Correspondent

Preclinical evidence indicates that the novel FLT3 inhibitor HM43239 was active in both FLT3-mutated and wild-type acute myeloid leukemia (AML) while also inhibiting the SYK protein, which is implicated in resistance to FLT3-targeted therapy. An ongoing phase 1/2 dose-escalation and dose-expansion first-in-human study (NCT03850574; study HM-FLTI-101) evaluated the safety, efficacy, pharmacokinetics, and pharmacodynamics of HM43239 in patients with relapsed/refractory AML.

Between March 2019 and June 2021, the study enrolled patients with relapsed/refractory AML who had received ≥1 prior lines of therapy, including ≥1 prior FLT3 inhibitors at multiple international centers. Eligible patients with or without an FLT3 mutation received HM43239 orally once daily, dosed at 20 to 160 mg until unacceptable toxicity or no clinical benefit. The dose escalation was initiated with an accelerated titration design followed by a 3+3 design (after the first occurrence of a dose-limiting toxicity or moderate toxicity, defined as a grade 2 nonhematologic adverse event investigator-assessed to be at least possibly related to study drug). Based on the safety and efficacy in the dose-escalation cohorts, the dose-expansion cohort was initiated.

A total of 34 patients were enrolled in the study; 34 patients in the 20- to 160-mg dose-escalation cohort, 20 patients in the 80-mg dose-expansion cohort, and 7 in the 120-mg dose-expansion cohort. At enrollment, patients had received a median of 2 prior therapies for AML; 14 (41.2%) patients had an FLT3 mutation, 18 (52.9%) had FLT3 wild-type, and 2 (7%) were FLT3 unknown. Among the 14 FLT3-mutated patients, ITD (26.5%) mutations were the most common, followed by TKD (11.4%) and ITD/TKD (2.9%) mutations.

Moderate toxicity (grade 3 nausea) was reported in the 80-mg dose-escalation cohort; the accelerated titration design was switched to the 3+3 design for doses ≥80 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were diarrhea (11.8%), nausea (11.8%), vomiting (5.9%), and alanine aminotransferase increased (5.9%); 3 grade ≥3 treatment-related TEAEs were reported (nausea, leukopenia, neutrophil count decreased).

In the dose-expansion cohort at 80 mg (n = 20), responses were achieved in both the FLT3 mutated (n = 8) and FLT3 wild-type (n = 12) cohorts, with a composite complete response of 37.5% and 16.7%, respectively. Six of the responding patients, including 1 patient who had received prior FLT3 inhibitors, 4 proceeded to allogeneic stem-cell transplantation and remain in remission. Median time to first response was 29 days; median duration on study was 51 days. The 30- and 60-day mortality rates were 11.4% (n = 4) and 17.6% (n = 6), respectively.

Based on results from this ongoing phase 1/2 study, the authors concluded that HM43239 showed a favorable safety profile and encouraging antileukemic activity in patients with both FLT3-mutated and FLT3 wild-type relapsed/refractory AML. Dose escalation continues to determine the optimal recommended phase 2 dose; at the time of this analysis, the dose-escalation cohort of 160 mg and the dose-expansion cohort of 120 mg are currently enrolling.

Source: Daver N, et al. ASH 2021; abstr 702.

Related Items