Intravenous azidothymidine with fluorouracil and leucovorin: A phase I-II study in previously untreated metastatic colorectal cancer patients

A. Falcone, R. Danesi, F. Dargenio, E. Pfanner, I. Brunetti, M. Del Tacca, A. B. Nethersell, P. F. Conte

Research output: Contribution to journalArticlepeer-review


Purpose: To determine the plasma pharmacokinetics and the maximum- tolerated dose (MTD) of intravenous (IV) azidothymidine (AZT) administered 90 to 120 minutes after fluorouracil (5-FU) and leucovorin and to preliminarly evaluate the antitumor activity of this combination in metastatic colorectal cancer. Patients and Methods: 5-FU 500 mg/m2 IV bolus was administered once a week in the middle of a 2-hour infusion of leucovorin; AZT was given as a 90 to 120-minute IV infusion 60 minutes after 5-FU. Initial AZT dose was 0.5 g/m2, and it was escalated in successive cohorts of three patients by 0.5 to 2 g/m2. Results: Thirty-five chemotherapy-naive metastatic colorectal cancer patients were entered onto the study, and AZT doses ranged from 0.5 to 10 g/m2. The peak AZT plasma concentration increased from 21.9 to 995.6 μmol/L. The area under the concentration/time curve (AUC) also showed a progressive, but not linear increase from 40.34 to 3,108 h x μmol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17%). Toxicities were not AZT-dose-related, except for hypotension, which occurred in patients treated at AZT doses ≥ 7 g/m2 and became dose-limiting for AZT 10 g/m2. Among 34 assessable patients, 15 objective responses were observed (44%; 95% confidence interval 27 to 62), lasting a median of 44 weeks; five (15%) were complete. Conclusion: AZT doses ≥ 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentrations and AUC similar to those previously reached in murine tumor models. Dose-limiting toxicity is hypotension, which occurs at AZT 10 g/m2. The recommended AZT dose for further studies is 8 g/m2. The combination of 5-FU plus leucovorin plus AZT is feasible with acceptable toxicities, and has promising activity in metastatic colorectal cancer.

Original languageEnglish
Pages (from-to)729-736
Number of pages8
JournalJournal of Clinical Oncology
Issue number3
Publication statusPublished - Mar 1996

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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