Phase 1 study of HMPL-306, an inhibitor of mutant IDH1/IDH2 (mIDH1/2), in western patients (pts) with advanced mIDH solid tumor, including glioma.

2013 Background: Isocitrate dehydrogenase (IDH) 1 or IDH2 mutations or co-mutations have been associated with various tumors, including glioma. HMPL-306 (’306) is a novel, small-molecule, orally available, highly selective, and potent dual inhibitor of both mIDH1 and mIDH2. This is a phase 1 study of ’306 in pts with locally advanced or metastatic solid tumors with mIDH. Here, we report the results of the dose escalation stage. Methods: Pts with locally advanced or metastatic solid tumors with any mIDH were enrolled to receive ’306 once daily (QD) for 28-day cycles. The mTPI-2 design was used for dose escalation, having explored in 8 successive cohorts (50-400 mg). The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), evaluate safety, tolerability, preliminary efficacy and pharmacokinetics/ pharmacodynamics (PK/PD). Results: As of Aug 9, 2024, 42 pts were administered ’306 across 8 doses (n = 3, 3, 5, 12, 6, 4, 4, 5 in 50, 100, 150, 200, 250, 300, 350, 400 mg QD cohorts, respectively), with 17 (40.5%) lower-grade glioma (LGG, grade 2 and grade 3 glioma) pts, 3 (7.1%) grade 4 glioma pts and 22 (52.4%) non glioma pts. The median age was 55 years, and 25 (59.5%) pts were male. During the dose escalation from 50 mg to 400 mg QD cohort, 1 pt given 250 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 lipase increased. MTD was not reached. 12 (28.6%) pts reported grade ≥3 adverse events (AEs), which reported in ≥ 2 pts was abdominal pain. Efficacy signals were observed especially in LGG pts, in the efficacy evaluated set (N = 14), objective response rate (ORR) was 7.1%, disease control rate was 100%; in the safety analysis set (N = 17), median progression-free survival (PFS) was 20.5 months (95% confidence interval [CI]; 5.5-not estimable). One grade 2 glioma pt with multiple previous treatment on the 200 mg QD achieved minor response lasting 16.8 months. The ORR of grade 4 glioma pts and non glioma pts were not reached, the disease control rate were 33.3% and 25%, respectively. Drug exposures were dose-proportional from 50 mg to 400 mg. Steady-state with ~5-fold accumulation was reached after ~28 days of repeated daily dosing. In non-glioma pts, 2-HG inhibition plateaued after ~28 days, increasing with dose, reaching ~90% at ≥150 mg at C2D1. Conclusions: ’306 was well-tolerated in pts with mIDH1/2 solid tumors, showing target inhibition and durable responses in LGG. Clinical trial information: NCT04762602 .