title: Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer.
abstract: 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/m, raltitrexed escalated from 0.5 to 3.0 mg/m, (2) raltitrexed fixed at 3.0 mg/m, 5-FU escalated from 900 mg/m until dose-limiting toxicity (DLT) and (3) 5-FU fixed at the dose level below DLT, raltitrexed escalated from 3.0 mg/m 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/m, DLT developed when 5-FU was increased to 1350 mg/m (stage 2). When 5-FU was fixed at 1200 mg/m and raltitrexed was increased to 6.0 mg/m (stage 3), DLT was dose limiting. The recommended doses for further study are 5.5 mg/m ralitrexed and 1200 mg/m 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/m, with manageable toxicity. This combination shows encouraging activity, and survival appears promising in the pre-treated aCRC patient population. Further clinical trials are warranted.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, NY 10021, USA. Schwartg@mskcc.org
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: Joseph
authors.initials: J
authors.lastname: Bertino
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.forename: David K
authors.initials: DK
authors.lastname: Kelsen
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Mary
authors.initials: M
authors.lastname: Welch
authors.forename: Sandra
authors.initials: S
authors.lastname: Endres
authors.forename: Isaiah
authors.initials: I
authors.lastname: Dimery
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016001:Confidence Intervals; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011799:Quinazolines / Q000008:administration & dosage*; D016019:Survival Analysis; D013876:Thiophenes / Q000008:administration & dosage*
chemical_list: D011799:Quinazolines; D013876:Thiophenes; C068874:raltitrexed; D005472:Fluorouracil