A phase I study of HPB-092, a dual FLT3/IRAK4 inhibitor, in relapsed or refractory acute myeloid leukemia.

TPS6599 Background: Fms-like tyrosine kinase 3 (FLT3) is a clinically validated oncogenic driver in acute myeloid leukemia (AML). While FLT3 kinase inhibitors have been approved for AML patients with FLT3 mutations, resistance remains a significant challenge. Interleukin-1 receptor–associated kinase 4 (IRAK4) has emerged as a key signaling node in treatment-induced resistance. Moreover, a subset of AML patient population harbors mutations in RNA splicing factors U2AF1 or SF3B1. These mutations result in expression of an oncogenic long form of IRAK4. Therefore, co-targeting FLT3 and IRAK4 can potentially both address resistance and treat a broader population in AML. HPB-092 is a highly selective dual-target small-molecule kinase inhibitor designed to target mutant FLT3 and IRAK4. HPB-092 demonstrated robust potency against FLT3-ITD ( IC ₅₀ = 0.24 nM), FLT3-D835Y ( IC ₅₀ = 0.18 nM), and IRAK4 ( IC ₅₀ = 3.1 nM). In vivo, HPB-092 elicited dose-dependent regression of the MV4-11 tumor model. HPB-092 received IND clearance in both China and the US, showing a favorable safety profile with no significant genotoxicity or hERG inhibition, supporting its clinical evaluation. Methods: This ongoing, first-in-human, phase 1 study evaluates oral HPB-092 monotherapy in adults with RR-AML. The primary objectives are to evaluate safety, tolerability, pharmacokinetics (PK), and to determine the recommended phase II dose (RP2D). Secondary objectives include preliminary antileukemic activity (ORR, DOR) and exploratory biomarkers analyses. Part A is a dose-escalation phase spanning five dose levels (30–200 mg), utilizing an accelerated titration design followed by a 3+3 scheme in patients with R/R AML, regardless of FLT3, U2AF1 or SF3B1 mutation status. The study initiates with a single-dose administration on cycle 1 day 1 for SAD-PK assessment, followed by multiple ascending doses administered twice daily for MAD-PK and dose-limiting toxicities (DLTs) over a 28-day observation window. Part B is a randomized dose-expansion phase to evaluate selected dose levels in patients with FLT3-mutant AML and those with U2AF1 or SF3B1 mutations. Correlative pharmacodynamic and biomarker analyses are planned. No formal hypothesis testing or sample size calculation was performed. Safety, PK, and efficacy analyses will be descriptive in patients receiving at least one dose of HPB-092. AEs will be graded according to NCI CTCAE v5.0. PK parameters will be derived using noncompartmental methods. Time-to-event endpoints will be estimated using Kaplan–Meier methods, where applicable. Site initiation is complete; enrollment is initiated and ongoing, with the first patient anticipated in Q1 2026. Clinical trial information: NCT07137637 .