Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer

Our objective was to determine the maximum tolerated dose (MTD) of sequential raltitrexed (Tomudex) and 5-fluorouracil (5-FU) by bolus administration every 3 weeks in patients with advanced colorectal cancer (aCRC) and appendiceal adenocarcinoma. This phase I dose-escalation study was carried out in three stages: (1) 5-FU fixed at 900 mg/m², raltitrexed escalated from 0.5 to 3.0 mg/m², (2) raltitrexed fixed at 3.0 mg/m², 5-FU escalated from 900 mg/m² until dose-limiting toxicity (DLT) and (3) 5-FU fixed at the dose level below DLT, raltitrexed escalated from 3.0 mg/m² until MTD. Seventy-one patients with measurable disease were enrolled. No DLTs were observed during stage 1 of treatment. At a fixed dose of raltitrexed 3.0 mg/m², DLT developed when 5-FU was increased to 1350 mg/m² (stage 2). When 5-FU was fixed at 1200 mg/ m² and raltitrexed was increased to 6.0 mg/m² (stage 3), DLT was dose limiting. The recommended doses for further study are 5.5 mg/m² ralitrexed and 1200 mg/m² 5-FU. Of the 69 patients evaluated for efficacy, one had a complete response (8.0 months) and five had partial responses (5.1-11.6 months). Thirty patients had stable disease for 5 or more cycles of therapy (mean time to progression: 3.6 months). Median survival was 11.7 months. We conclude that raltitrexed can be combined with bolus 5-FU, at raltitrexed doses that are higher than the recommended single-agent dose of 3.0 mg/m², with manageable toxicity. This combination shows encouraging activity, and survival appears promising in the pre-treated aCRC patient population. Further clinical trials are warranted.