Background/Introduction: Effective therapies for FGFR2-driven cholangiocarcinoma (CCA) and other advanced solid tumors remain unmet medical needs. RLY-4008 is a potent, highly selective and irreversible FGFR2 inhibitor designed to target both primary FGFR2 oncogenic alterations and clinically relevant resistance mutations. RLY-4008 is currently being studied in a Phase 1/2 clinical trial to treat patients with FGFR2-driven CCA. To guide RLY-4008 dosing in cancer patients, we report here results from a clinical study to assess the effect of food and proton pump inhibitor (PPI) esomeprazole (ESO) on the pharmacokinetics (PK) of RLY-4008 in healthy subjects (HS).
Methods: This was a randomized, open-label, three-period, fed and fasted two-treatment crossover and fixed sequence, drug-drug interaction study to assess the effect of food and ESO on RLY-4008 PK. Twenty-four HS were enrolled to receive single oral doses of 50 mg RLY-4008 (fasted or fed with a high fat, high calorie meal) or RLY-4008 with ESO (fasted), with ≥7 days washout between each treatment. RLY-4008 PK was assessed up to 120 hours post dose. The effect of food and ESO was assessed using log-transformed RLY-4008 Cmax and AUC by linear mixed-effect modeling and calculating point estimates and associated 90% confidence intervals (CI) of geometric least squares mean ratios (LSGMR). Safety and tolerability were assessed through discharge/end of study.
Results: Twenty-four HS were enrolled and completed the study. The median Tmax of RLY-4008 was similar when administered fasted, with food or with ESO. LSGMRs of Cmax, AUC(0-tlast) and AUC (0-inf) between RLY-4008 administered with food and fasted were 87%, 105%, and 106%, respectively, and the associated 90% CIs were 77-97%, 100-110%, and 100-110%, respectively. The LSGMRs and associated 90% CIs of AUCs were fully contained within 80% to 125%, while the lower bound of 90% confidence of Cmax LSGMR was below 80%. The 13% reduction in RLY-4008 Cmax with food was not considered clinically relevant. LSGMRs of Cmax, AUC(0-tlast) and AUC (0-inf) between RLY-4008 administered with ESO and alone were 110%, 113%, and 113%, respectively, and the associated 90% CIs were 102-119%, 109-117%, and 109-117%, respectively, and were fully contained within 80% to 125%. RLY-4008 was safe and well tolerated in HS when administered fasted, fed or with ESO.
Conclusion: Food and ESO does not have a clinically relevant effect on RLY-4008 PK in HS, indicating that RLY-4008 can be dosed with or without food and can be dosed with PPIs, H2-blockers and anti-acids in cancer patients.
Citation Format: Jinshan Shen, Rishikesh Sawant, Rick Blakesley, Kai Yu Jen, Fabien Ricard, Xiaoyan Li, Cassandra Key, Djuro Karanovic. A food effect and esomeprazole drug-drug interaction study of RLY-4008, a highly selective FGFR2 inhibitor, in healthy subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2795.
