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| Ref Type | Abstract | ||||||||||||
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| Authors | Jordi Rodon Ahnert, Juan Manuel Sepulveda Sanchez, Olatunji B. Alese, Georgia Anguera, Chandrikha Chandrasekharan, Sant P. Chawla, Melissa Amber Burgess, Maen Abdelrahim, John L. Villano, Bo Zhang, Yukang Wang, Xiuya Yu, Zeyu Zhong, Xian Luo, Songhua Fan, Michael Shi, Weiguo Su, and Maria Vieito Villar | ||||||||||||
| Title | 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. | ||||||||||||
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| URL | https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2013 | ||||||||||||
| Abstract Text | 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. | ||||||||||||