The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged > or =18 to < or =75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m(2) per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m(2) and further dose escalations were planned by increments of 12.5 mg/m(2) up to 125 mg/m(2). Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m(2), and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.