Phase 1 Study of Safety and PK With A Combination of Omeprazole and Trimetazidine for Fatty Acid Oxidation Inhibition in Patients With Advanced Solid Tumors

Fatty acid oxidation (FAO) is a metabolic vulnerability in cancer cells, making pharmacologic FAO inhibition a promising therapeutic strategy. This Phase I, open-label, 3 + 3 dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of two oral FAO inhibitors-omeprazole (KN510), a carnitine-acylcarnitine translocase inhibitor, and trimetazidine (KN713), an acetyl-CoA acyltransferase inhibitor-given once daily in combination to patients with advanced solid tumors. Twelve patients were enrolled across four dose cohorts (omeprazole and trimetazidine, each 60-120 mg/day). The maximum tolerated dose was not reached; the recommended Phase 2 dose was set at 120 mg once daily for each agent. Treatment was generally well tolerated, with most adverse events Grade 1-2; the most common were flu-like symptoms (25.0%), constipation (16.7%), nausea (16.7%), and dizziness (16.7%). Omeprazole showed time-dependent pharmacokinetics consistent with auto-inhibition of its own metabolism, whereas trimetazidine showed dose-proportional pharmacokinetics across the studied range. The best response was stable disease in five patients (disease control rate 41.7%). Median progression-free survival was 1.66 months (95% CI, 1.18-3.55) and median overall survival was 9.13 months (95% CI, 3.29-not reached). Dual pharmacologic FAO inhibition with oral omeprazole and trimetazidine was feasible and well tolerated, supporting the mechanistic rationale for combination dosing. Disease stabilization observed in this heavily pretreated population warrants further clinical evaluation, particularly in combination with standard chemotherapy regimens. Trial Registration: ClinicalTrials.gov, NCT06012708; registered August 25, 2023.