Celecoxib and Mucosal Protection: Translation from an Animal Model to a Phase I Clinical Trial of Celecoxib, Irinotecan, and 5-Fluorouracil

Purpose: Chemotherapy-induced diarrheaoccurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study. Experimental Design: In the Ward rat model, irinotecanwas given daily × 3 or weekly × 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecanin the FOLFIRIregimen ( irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecanwas escalated in four dose levels: 180, 200, 220, and 260 mg/m 2 . Celecoxibwas administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3 + 3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography. Results: Celecoxibameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrheawas the cause for discontinuation in one. Grade 2 and 3 diarrheaoccurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxibhad limited influence on the pharmacokinetics of irinotecanin this data set. Conclusions: Maximum tolerated doseof irinotecanin FOLFIRIschedule with celecoxibis 200 mg/m 2 .