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 preliminarily evaluate the antitumor activity of this combination in metastatic colorectal cancer.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.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 micromol/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 micromol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17\%). Toxicities were not AZT-dose-related, except fpr hypotension, which occurred in patients treated at AZT doses > or = 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.AZT doses > or = 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentration 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.

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. D., Tacca; A. B., Nethersell; Conte, Pierfranco. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - STAMPA. - 14:(1996), pp. 729-736.

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

CONTE, Pierfranco
1996

Abstract

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 preliminarily evaluate the antitumor activity of this combination in metastatic colorectal cancer.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.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 micromol/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 micromol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17\%). Toxicities were not AZT-dose-related, except fpr hypotension, which occurred in patients treated at AZT doses > or = 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.AZT doses > or = 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentration 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.
1996
14
729
736
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. D., Tacca; A. B., Nethersell; Conte, Pierfranco. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - STAMPA. - 14:(1996), pp. 729-736.
A., Falcone; R., Danesi; F., Dargenio; E., Pfanner; I., Brunetti; M. D., Tacca; A. B., Nethersell; Conte, Pierfranco
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