Pharmacokinetics and pharmacodynamics of the GCN2 activator HC-7366 in a phase 1a study in patients with advanced solid tumors.

作者：Meredith Pelster, K. Raghav, Jordan Berlin, Daniel Morgensztern, Sunnie S. Kim, Philip J. Gold, Peter Vu, Jeremy Drees, Eric Lightcap, Ben Harrison, Weiyu Zhang, Anissa SH Chan, Crissy Dudgeon, Ashley LaCayo, Dhamina Karim, Michele Gargano, Nandita Bose · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.e15103 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Endoplasmic Reticulum Stress and Disease、Cancer, Hypoxia, and Metabolism

e15103 Background: HC-7366 is a novel, selective and potent activator of general control nonderepressible 2 (GCN2), a core kinase in the integrated stress response (ISR). GCN2-driven ISR hyperactivation broadly affects metabolic pathways important for tumor progression. HC-7366 has shown preclinical anti-tumor activity alone and in combination with varied standard of care therapies across diverse cancer types. HC-7366 was evaluated in a Ph1a study to determine its maximum tolerated dose and safety in patients with advanced solid tumors. Herein, we describe the pharmacokinetic (PK) and pharmacodynamic (PD) effects of HC-7366 in this study. Methods: The Ph1a first-in-human, open-label study (NCT05121948) enrolled 34 US patients across five QD HC-7366 dose cohorts: 10 mg (3), 20 mg (3), 40 mg (12), 75 mg (10) and 125 mg (6). Most patients had advanced colorectal cancer, with other tumor types also included. Blood samples for PK/PD analyses were collected at baseline and throughout treatment, and paired tumor biopsies were collected at screening and after treatment. Results: In PK analyses, HC-7366 exposures were dose-proportional across 10–75 mg cohorts after single and multiple doses. Steady state was reached within 7–14 days, with a median T MAX of 2 hours, a geometric mean T 1/2 of ~13.5 hours, and an accumulation ratio at steady state of 1.68. HC-7366 showed no substantial time dependence, with observed linearity ratios near 1 across cohorts. Free-drug exposures at 40 and 75...