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

Gary K. Schwartz, Joseph Bertino, Nancy Kemeny, Leonard Saltz, David K. Kelsen, William Tong, Mary Welch, Sandra Endres, Isaiah Dimery

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)219-227
Number of pages9
JournalAnti-Cancer Drugs
Volume15
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

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Fluorouracil
Colorectal Neoplasms
Maximum Tolerated Dose
raltitrexed
Survival
Adenocarcinoma
Clinical Trials
Therapeutics
Population

Keywords

  • 5-flurouracil
  • Colorectal cancer
  • Dose escalation
  • Raltitrexed

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Schwartz, G. K., Bertino, J., Kemeny, N., Saltz, L., Kelsen, D. K., Tong, W., ... Dimery, I. (2004). Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer. Anti-Cancer Drugs, 15(3), 219-227. https://doi.org/10.1097/00001813-200403000-00005

Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer. / Schwartz, Gary K.; Bertino, Joseph; Kemeny, Nancy; Saltz, Leonard; Kelsen, David K.; Tong, William; Welch, Mary; Endres, Sandra; Dimery, Isaiah.

In: Anti-Cancer Drugs, Vol. 15, No. 3, 03.2004, p. 219-227.

Research output: Contribution to journalArticle

Schwartz, GK, Bertino, J, Kemeny, N, Saltz, L, Kelsen, DK, Tong, W, Welch, M, Endres, S & Dimery, I 2004, 'Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer', Anti-Cancer Drugs, vol. 15, no. 3, pp. 219-227. https://doi.org/10.1097/00001813-200403000-00005
Schwartz, Gary K. ; Bertino, Joseph ; Kemeny, Nancy ; Saltz, Leonard ; Kelsen, David K. ; Tong, William ; Welch, Mary ; Endres, Sandra ; Dimery, Isaiah. / Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer. In: Anti-Cancer Drugs. 2004 ; Vol. 15, No. 3. pp. 219-227.
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