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01-10-2007 | Original Article

Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer

Authors: Jeffrey A. Meyerhardt, Jeffrey W. Clark, Jeffrey G. Supko, Joseph P. Eder, Shuji Ogino, Clinton F. Stewart, Ferdinando D’Amato, Janet Dancey, Peter C. Enzinger, Andrew X. Zhu, David P. Ryan, Craig C. Earle, Robert J. Mayer, Ann Michelini, Kate Kinsella, Charles S. Fuchs

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2007

Abstract

Purpose

To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer.

Experimental Design

Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m² as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m² bolus i.v. and leucovorin 20 mg/m² i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m² and 5-FU to 500 mg/m².

Results

Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3–4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU.

Conclusions

Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.

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Title: Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer
Authors: Jeffrey A. Meyerhardt
Jeffrey W. Clark
Jeffrey G. Supko
Joseph P. Eder
Shuji Ogino
Clinton F. Stewart
Ferdinando D’Amato
Janet Dancey
Peter C. Enzinger
Andrew X. Zhu
David P. Ryan
Craig C. Earle
Robert J. Mayer
Ann Michelini
Kate Kinsella
Charles S. Fuchs
Publication date: 01-10-2007
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2007
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-006-0411-6

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