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

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 mg were within effective ranges from preclinical models and were well below severely toxic levels in GLP toxicology studies. Biopsy pairs were collected from patients in 10 (n = 2), 20 (n = 1), 40 (n = 1), 75/40 (1 cycle/dose, n = 1), and 75 mg (n = 1) cohorts. Consistent with preclinical effects, IHC showed pathway engagement through asparagine synthetase induction in 6/6 biopsy pairs (avg positive: pre = 3.6%, post = 26.4%) and reduced nuclear HIF1α in both tumor cells (5/6, 85-99% reduction) and in myeloid cells (6/6, 53-99% reduction). Serum PD markers showed a transient reduction of EPO by day 8 in the 75 mg (21%) and 125 mg (53%) cohorts, which may be due to inhibition of HIF2α at higher doses as observed preclinically. HC-7366 also induced changes in metabolic proteins relevant to anti-tumor effects, including increased adiponectin after 3 weeks (40 mg: 25%, 75 mg: 43%, 125 mg: 70%), decreased chemerin after 1 week (40 mg: 28%, 75 mg: 26%, 125 mg: 46%), and decreased IGF-1 after 3 weeks (40 mg: 28%, 75 mg: 55%, 125 mg: 72%). Conclusions: PK/PD evaluation of HC-7366 showed a favorable PK profile, with dose-proportional exposure and a half-life suitable for QD dosing. Drug exposure, pathway engagement, and mechanistic biomarkers suggested 40-75 mg as the optimal dose range. Importantly, the metabolic effects suggest suitability for development in metabolically rewired cancers, including renal cell carcinoma (NCT06234605). Clinical trial information: NCT05121948 .