Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer Journal Article
| Authors: | Schwartz, G. K.; Bertino, J.; Kemeny, N.; Saltz, L.; Kelsen, D.; Tong, W.; Welch, M.; Endres, S.; Dimery, I. |
| Article 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/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. © 2004 Lippincott Williams & Wilkins. |
| Keywords: | adult; cancer survival; aged; middle aged; survival analysis; major clinical study; clinical trial; fluorouracil; advanced cancer; area under the curve; diarrhea; drug efficacy; colorectal cancer; computer assisted tomography; mucosa inflammation; thrombocytopenia; drug administration schedule; odds ratio; creatinine; hemoglobin; febrile neutropenia; colorectal neoplasms; confidence intervals; aspartate aminotransferase; bilirubin; loperamide; dermatitis; drug blood level; maximum tolerated dose; phase 1 clinical trial; quinazolines; granulocyte colony stimulating factor; appendix tumor; thiophenes; raltitrexed; dose escalation; humans; human; male; female; priority journal; article; 5-flurouracil |
| Journal Title: | Anti-Cancer Drugs |
| Volume: | 15 |
| Issue: | 3 |
| ISSN: | 0959-4973 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2004-03-01 |
| Start Page: | 219 |
| End Page: | 227 |
| Language: | English |
| DOI: | 10.1097/00001813-200403000-00005 |
| PROVIDER: | scopus |
| PUBMED: | 15014354 |
| DOI/URL: | |
| Notes: | Anti-Cancer Drugs -- Cited By (since 1996):7 -- Export Date: 16 June 2014 -- CODEN: ANTDE -- Source: Scopus |
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