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

• Published in: Clinical cancer research 2007-02, Vol.13 (3), p.965-971
• Main Authors: JAVIE, Milind M, SHOUSONG CAO, DURRANI, Farukh A, PENDYALA, Lakshmi, LAWRENCE, David D, SMITH, Patrick F, CREAVEN, Patrick J, NOEL, Diane C, LYER, Renuka V, RUSTUM, Youcef M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; camptothecin; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Celecoxib; Colorectal Neoplasms - drug therapy; cyclooxygenase inhibitors; diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorouracil - administration & dosage; Fluorouracil - therapeutic use; Glucuronates - administration & dosage; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Leucovorin - therapeutic use; Male; Maximum Tolerated Dose; Medical sciences; mucositis; Mucositis - chemically induced; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; Pyrazoles - administration & dosage; Pyrazoles - therapeutic use; Rats; Rats, Inbred F344; stomatitis; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0551

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 × 3 or weekly × 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/m 2 . 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/m 2 .