Journal article
Celecoxib and mucosal protection : Translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil
Clinical cancer research, Vol.13(3), pp.965-971
2007
DOI: 10.1158/1078-0432.CCR-06-0551
PMID: 17289892
Abstract
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. © 2007 American Association for Cancer Research.
Details
- Title: Subtitle
- Celecoxib and mucosal protection : Translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil
- Creators
- Milind M Javie - Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Institute, Houston, Texas, United StatesSHOUSONG Cao - Roswell Park Cancer InstituteFarukh A Durrani - Roswell Park Cancer InstituteLakshmi Pendyala - Roswell Park Cancer InstituteDavid D Lawrence - Roswell Park Cancer InstitutePatrick F Smith - Roswell Park Cancer InstitutePatrick J Creaven - Roswell Park Cancer InstituteDiane C Noel - Roswell Park Cancer InstituteRenuka V Lyer - Roswell Park Cancer InstituteYoucef M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.13(3), pp.965-971
- Publisher
- American Association for Cancer Research
- DOI
- 10.1158/1078-0432.CCR-06-0551
- PMID
- 17289892
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 2007
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359847602771
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