Gefitinib can be safely combined with an intermittent weekly schedule of IFL. 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.

Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. 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. 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. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) and 5-FU to 500 mg/m(2). 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. 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.