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/m(2) as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) bolus i.v. and leucovorin 20 mg/m(2) 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/m(2) and 5-FU to 500 mg/m(2). 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.