A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605).

TPS609 Background: HC-7366 is a novel, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Prolonged or hyper-activation of GCN2 suppresses general protein synthesis and induces cell cycle arrest, ultimately leading to apoptosis. HC-7366 decreases HIF expression in tumor and immunosuppressive myeloid cells and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function in tumor cells. In CDX RCC xenografts, HC-7366 combined with belzutifan (BELZ) exhibited combination benefit, and in belzutifan-resistant PDX models, HC-7366 drove significant monotherapy antitumor activity. These preclinical effects of HC-7366 suggest potential therapeutic benefit in clear cell renal cell carcinoma (ccRCC) and rationale for combinations with HIF2a antagonists. Mechanism of action studies have identified several biomarkers of pathway engagement some of which may predict efficacy (Stokes, AACR 2024, Abstract 4615). HC-7366 75 mg was determined to be the maximum tolerated dose (MTD) in a previous phase 1a study in patients (pts) with solid tumors which did not include ccRCC histology. Methods: This is a multicenter, open-label, phase 1b dose escalation and expansion study to establish MTD, recommended phase 2 dose, and safety and tolerability of HC-7366 + BELZ (combo) in pts with advanced or metastatic RCC with predominantly clear cell histology. HC-7366 60 mg monotherapy will also be assessed. In combo dose escalation, three doses of HC-7366 (20, 40, 60 mg po qd) will be evaluated with a fixed dose of BELZ (120 mg po qd) using a modified Toxicity Probability Interval design. Up to 20 pts will be enrolled in combo dose escalation. Dose expansion of the combo (N=30) will follow, evaluating up to two dose levels of HC-7366 (15 pts/dose level) with BELZ. In parallel, ≤20 pts will be enrolled into the monotherapy cohort. Response will be assessed by CT scan every 8 wks (RECIST v1.1). Secondary endpoints include ORR, DOR, TTR, DCR, PFS, and OS. PK data will be profiled; exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Key inclusion criteria include prior therapies (combo cohort: 1 to 3 prior lines naïve to BELZ and other HIF-2α inhibitors; monotherapy: 1 to 4 prior lines which may include BELZ or other HIF-2α inhibitors), >1 measurable lesion, and willingness to provide biopsy or archival tumor samples at two timepoints. Enrollment into dose level 2 of escalation and the monotherapy cohorts is ongoing at 20 US sites. The trial is sponsored by HiberCell, Inc. in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson [email protected] , 651.312.5831. Clinical trial information: NCT06234605 .