Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced...

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250-350 mg/m(2) as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3-4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m(2)) and raltitrexed (3 mg/m(2)) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.