Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors

Alex A. Adjei, Charles Erlichman, Jeff A. Sloan, Joel M. Reid, Henry C. Pitot, Richard M. Goldberg, Prema Peethambaram, Pamela Atherton, Lorelei J. Hanson, Steven R. Alberts, James Jett

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Purpose: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase 1 trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. Patients and Methods: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m2 on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m2, given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). Results: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum- tolerated dose was gemcitabine/MTA 1,000/500 mg/m2 for group I and 1,250/500 mg/m2 for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. Conclusion: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated arid is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m2. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)1748-1757
Number of pages10
JournalJournal of Clinical Oncology
Volume18
Issue number8
DOIs
StatePublished - Apr 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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