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

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 500mg/m(2) 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/m(2) and it was escalated in successive cohorts of three patients by 0.5 to 2 g/m(2), Results: Thirty-five chemotherapy-naive metastatic: colorectal cancer patients were entered onto the study, and AZT doses ranged from 0.5 to 10 g/m(2), The peak AZT plasma concentration increased from 21.9 to 995.6 mu mol/L. The area under the concentration/time curve (AUG) also showed a progressive, but not linear increase from 40.34 to 3,108 h x mu mol/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 greater than or equal to 7 g/m(2) and became dose-limiting for AZT 10 g/m(2), 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 greater than or equal to 6 g/m(2) administered IV over 90 to 20 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/m(2). The recommended AZT dose for further studies is 8 g/m(2). The combination of 5-FU plus leucovorin plus AZT is feasible with acceptable toxicities, and has promising activity in metastatic colorectal cancer. (C) 1996 by American Society of Clinical Oncology.