e15118 Background: Tumor cells have been shown to adapt to the endoplasmic reticulum (ER) stress resulting from activated oncogenes, nutrient stress, and hypoxia by activating one of the kinases in the Unfolded Protein Response (UPR) pathway, Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK). This adaptation enables them to survive these stresses and develop resistance to standard of care. Targeting PERK in cancer cells could disrupt their ability to thrive under adverse conditions, potentially leading to apoptosis. HC-5404 is a novel, highly selective and potent PERK inhibitor that demonstrates bioavailability and target engagement at efficacious doses across preclinical tumor models. Herein, we report clinical data from the Ph1a study evaluating HC-5404 in patients with advanced solid tumors. Methods: In this first-in-human trial, HC-5404 was administered orally in 21-day cycles to patients ≥18 years old with advanced solid tumors. A Bayesian Optimal Interval (BOIN) design was employed to escalate through 7 dose levels (25 mg to 600 mg BID). Dose Limiting Toxicity (DLT) was assessed during the first cycle. The primary objectives were to establish the Maximum Tolerated Dose (MTD) and evaluate the safety and tolerability of HC-5404. The secondary objectives included evaluating PK/PD and antitumor activity (response rate and survival outcomes). Results: 23 patients received HC-5404 across various dose levels. Of these, 47.8% were ≥ 65 years old, 52.2% were male, and 82.6% had received ≥3 prior therapies. Overall, 1 partial response (PR) with a duration of 130 weeks was observed in a renal cell carcinoma (RCC) patient who started at the 25 mg dose and was escalated to 50 mg, while 8 patients had stable disease (SD) as best overall response. Three DLTs were observed, including hyperglycemia (300 mg), increased AST, ALP, GGT (200 mg) and decreased ejection fraction (EF) (100 mg). Hyperglycemia was observed only at higher doses (≥300 mg) above clinically relevant exposures of 25-100 mg. The MTD was not established. Treatment-related adverse events (TRAEs) of any grade occurred in 69.6% of patients with common events (≥ 20%) including nausea, fatigue, diarrhea, and dry mouth. Grade ≥3 TRAEs occurred in 17.4% of patients and included hyperglycemia, acute myocardial infarction, decreased EF, increased troponin, AST, GGT, ALP, and lipase. HC-5404 PK analysis showed rough dose-proportionality across 25-600mg doses and PK/PD analyses demonstrated the human dose range of 25-100 to be functionally equivalent to the pre-clinical efficacious doses. Final analysis of safety and clinical response are ongoing. Conclusions: HC-5404 showed a favorable safety profile and encouraging preliminary efficacy in heavily pretreated patients with advanced solid tumors. Safety and exposure-response analyses support further exploration of the 25-100 mg dose level of HC-5404, as monotherapy and in novel combinations. Clinical trial information: NCT04834778 .