Background: To survive harsh tumor microenvironments, cancer cells actively utilize ISR as an adaptive stress response and survival mechanism. General control nonderepressible 2 (GCN2), a serine-threonine kinase is essential for maintaining cellular homeostasis in amino acid stress conditions. HC-7366 is a novel, highly selective, and potent GCN2 kinase modulator. Single agent HC-7366 has demonstrated potent anti-tumor activity resulting in regression and complete responses in several pre-clinical tumor models. Methods: This is a first in human, multicenter, open label, Phase 1a/b dose escalation and expansion study to establish the maximum tolerated dose, evaluate safety and tolerability, and determine the recommended Phase 2 dose of daily oral dosing of HC-7366 in patients (pts) with advanced solid tumors. Up to 36 pts with squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or transitional cell carcinoma of the bladder (TCC) will be enrolled into Phase 1a; other solid tumors are eligible if selection criteria are met (capped at 50%). A 3+3 design will be employed and dose escalation determined by occurrence of dose limiting toxicities (DLT) within Cycle 1 (21 days). A Safety Monitoring Committee will review each cohort when the planned number of pts complete the DLT period. Six dose levels (10, 20, 40, 75, 125, 150 mg) of HC-7366 will be evaluated. Phase 1b will be an expansion of up to two Phase 1a dose levels and enroll 15 pts per cohort. Secondary endpoints include ORR, DOR, TTF, PFS, and OS. Pharmacokinetic data will be profiled. Exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Main inclusion criteria include: SCCHN, CRC, NSCLC, TCC or other solid tumors; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; no immune checkpoint inhibitor within 4 weeks (wks) of 1^st dose; ECOG 0 or 1; <10% body weight loss in 4 wks before 1^st dose & serum albumin >3 g/dL; and normal/adequately controlled pan-endocrine function. Main exclusion criteria include: autoimmune disease, organ transplant, retinitis or photosensitive skin disorders; history of interstitial lung disease or pneumonitis within 1yr; and overt or latent disorders of the exocrine pancreas. Formal hypothesis testing will not be performed. Descriptive statistics of parameters of interest will be presented by dose level and safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. Approximately 9 US sites will participate. Clinical trial information: NCT05121948.