A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies with Isocitrate Dehydrogenase (IDH) Mutations

Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can result in tumor formation and/or progression and have been associated with various different tumor types. Selective, single mutant IDH (mIDH) isotype inhibitors (for either mIDH1 or mIDH2) have demonstrated only a modest efficacy benefit and a potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, and potent inhibitor of both mIDH1 and mIDH2, with the potential to provide durable clinical benefit for patients (pts) with hematological malignancies with IDH mutations.

Study Design and Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years of age with advanced relapsed, refractory, or resistant hematological malignancies that harbor IDH mutations (or co-mutation) (NCT04764474). Major exclusion criteria include pts who have undergone hematopoietic stem cell transplantation within 60 days of first dose.

HMPL-306 will be administered orally once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated according to the modified toxicity probability interval-2 design in 4 cohorts in approximately 12 to 15 pts: 50, 100, 150, and 200 mg (oral, once daily) in Part 1. The primary objectives are to evaluate the safety, dose limiting toxicities, tolerability, maximum tolerated dose, and the recommended phase 2 dose (RP2D) of HMPL-306.

Pts in Part 2 will be enrolled at the RP2D to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306 in approximately 60 pts. Part 2 will include 4 dose expansion cohorts with approximately 15 pts each who have received at least 2 prior lines of therapy: acute myeloid leukemia, myelodysplastic syndrome/myeloproliferative neoplasm, angio-immunoblastic T-cell lymphoma, and other mIDH-positive hematological malignancies.

All pts who receive any study treatment will be included in the safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses, and objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data, such as progression-free survival and duration of response. No statistical hypothesis testing is planned.

Safety endpoints will include dose limiting toxicities, treatment emergent adverse event and serious adverse events. Efficacy endpoints will include objective response rate, time to response, and duration of response.