HMPL-306 in relapsed or refractory IDH1- and/or IDH2-mutated acute myeloid leukemia: A phase 1 study.

Background: HMPL-306 has equally high inhibitory activity against mutated isocitrate dehydrogenases 1 and 2 (mIDH1/2).
Methods: This first-in-human, phase 1 dose-escalation/dose-expansion study (this study was registered at ClinicalTrials.gov: NCT04272957) enrolled patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring mIDH1 and/or mIDH2. Patients received 25-250 mg of HMPL-306 orally once daily (QD) in a 28-day treatment cycle. Primary objectives were safety, tolerability, and recommended phase 2 dose (RP2D), and the secondary objective was preliminary efficacy.
Findings: A total of 76 patients were enrolled. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. RP2D was 250 mg QD for cycle 1 and 150 mg QD from cycle 2 onward. Common (≥10%) grade ≥3 treatment-related adverse events included platelet count decreased, anemia, neutrophil count decreased, and white blood cell count decreased. In patients who received 150 mg, 250 mg, or the RP2D (N = 59), rates of complete remission (CR)+CR with partial hematologic recovery were 34.6% and 36.4% in the mIDH1 (n = 26) and mIDH2 (n = 33) subgroups, respectively, and among these, CR with minimal residual disease negative rates were 77.8% and 50.0%, respectively. The median overall survival was 13.4 months in patients with mIDH1 and 13.1 months in patients with mIDH2.
Conclusions: HMPL-306 showed an acceptable safety profile and promising preliminary efficacy. A phase 3, randomized study of HMPL-306 in R/R AML (this study was registered at ClinicalTrials.gov: NCT06387069) has been initiated.
Funding: HUTCHMED Limited, National Key Research and Development Program of China, National Natural Science Foundation of China, and Peking University Medicine Fund for world's leading discipline or discipline cluster development.
Competing Interests: Declaration of interests J.C., S.Y., H.Y., J.W., Z.Z., L.W., S.F., M.S., and W.S. are employees of HUTCHMED Limited.
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