A Phase 1/2 Dose Escalation Study of the Myeloid Kinase Inhibitor HM43239 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

INTRODUCTION: HM43239 is an oral kinase inhibitor that potently inhibits myeloid kinases including diverse forms of the FLT3, SYK, JAK1/2, and mutant KIT kinases. These kinases and their mutant forms drive aberrant activation of downstream proliferation pathways and are associated with a high risk of relapse in AML. In a preclinical xenograft and orthotopic model of AML, HM43239 exhibited greater antitumor potency than FLT3 inhibitor gilteritinib, SYK inhibitor entospletinib, BCL-2 inhibitor venetoclax, and demethylation agent azacitidine. HM43239 is being evaluated in an international Phase 1/2 trial in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).

AIMS: The primary objectives are to assess the safety and tolerability of HM43239 and determine the recommended phase 2 dose in R/R AML patients. A key secondary objective is to elucidate the pharmacokinetic (PK) profile in dose escalation and expansion cohorts.

METHODS: The study is enrolling R/R AML eligible patients into dose escalation and dose exploration cohorts. HM43239 is administered continuously as oral tablets once daily in 28-day cycles. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated using CTCAE and Revised Recommendation International Working Group criteria, respectively.

RESULTS: As of July 14, 2022, a total of 50 patients, 26 male and 23 female, median age 59.5 (range 18-84) years, 28 FLT3-WT (56%) and 22 FLT3 mutated (44%) (15 FLT3-ITD (30%), 4 FLT3-TKD (8%) and 3 (6%) FLT3-ITD and / TKD), with a median of 2 prior treatments (range 1-6), have been treated with HM43239 at dose levels of 20 mg (n=2), 40 mg (n=1), 80 mg (n=20), 120 mg (n=13), 160 mg (n=10), and 200 mg (n=4). Nine patients (18%) were previously treated with 1 to 2 FLT3 inhibitors. Six patients (12%) had drug related TEAEs of Grade ≥ 3 which include decreased neutrophil count and muscular weakness (n=2; 4% each), and decreased white blood cell count, leukopenia, and nausea (n=1; 2% each). One patient experienced a DLT (grade 3 muscle weakness upper and lower limb) at the 200 mg dose level, without evidence of rhabdomyolysis. No DLTs were reported up through 160 mg. No drug-related adverse events (AEs) of QT prolongation or CK elevation were noted, and no drug-related serious AEs or deaths were reported. Eight of 50 patients achieved clinical response at multiple dose levels including 80 mg, 120 mg, and 160 mg. These include 7 patients with a reported best response of composite complete remission (CRc, including complete remission [CR], complete remission with incomplete platelet recovery [CRp] and complete remission with incomplete hematological recovery [CRi]) and 1 with partial remission (PR). All responses were achieved 1 or 2 cycles after HM43239 was initiated. Among 7 CRc patients, 5 proceeded to hematopoietic stem cell transplantation (HSCT). Of 22 FLT3 mutated patients, 5 (18%) achieved clinical response (4 CRc and 1 PR). Importantly, 3 of 7 (43%) FLT3-mutated patients who received prior FLT3 inhibitor treatment including gilteritinib and/or midostaurin achieved a response (2 CRc and 1 PR). Of 28 WT-FLT3 patients, 3 (11%) achieved a CRc. Notably, patients with clinical responses had a variety of additional adverse resistance mutations of NPM1, MLL-PTD, IDH2, NRAS, KRAS, DNMT3A, RUNX1, PTPN11, TP53 and others, with or without FLT3 mutation. Markedly, a WT-FLT3 patient with a TP53 mutation achieved CR and continued treatment for 14 cycles. The steady-state PK exposure of HM43239 rose from 20 mg to 120 mg, but no further increase was observed at 160 mg. Considering this and the safety profile, 120 mg was chosen as the expansion single agent starting dose with potential adjustments from 80 to 160 mg upon further evaluation of safety, tolerability, and efficacy.

CONCLUSIONS: As of July 14, 2022, HM43239 has delivered CRc at 80 mg, 120mg and 160 mg, and was well tolerated at these dose levels over multiple cycles with no DLTs or drug-related SAEs. Pharmacokinetic data illustrate increasing drug exposures through 120 mg and observed objective responses through 160 mg in both FLT3-WT and FLT3-mutated R/R AML patients even after gilteritinib and midostaurin treatment. An update of this study, including a planned single agent and venetoclax combination expansion, will be presented at the meeting.