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

Authors' Affiliations: ¹ Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Institute, Houston, Texas and ² Departments of Cancer Biology, ³ Medicine, and ⁴ Biostatistics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Milind Javle, Department of Gastrointestinal Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-5434; Fax: 713-563-0543; E-mail: mjavle{at}mdanderson.org.

Purpose: Chemotherapy-induced diarrhea occurs 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, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m². Celecoxib was 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: Celecoxib ameliorated 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). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred 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). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set.

Conclusions: Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m².

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