Celecoxib and mucosal protection: translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil.
Clin Cancer Res
; 13(3): 965-71, 2007 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-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. EXPERIMENTALDESIGN:
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Sulfonamidas
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Camptotecina
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Neoplasias Colorretais
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Protocolos de Quimioterapia Combinada Antineoplásica
/
Mucosite
/
Fluoruracila
/
Mucosa Intestinal
/
Neoplasias Experimentais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article