A Phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5 FU), we conducted a Phase I study of docetaxel in combination with continuo us i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase IZ studies, and the safety and pharmacokinetic profiles of this combination. Forty-two pat ients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed b y a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoie tic growth factor support. All patients were premedicated with methylpredni solone. Dose levels of docetaxel/5FU studied were (daily dose, in mg/m(2)) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000, Forty-one pat ients were assessable for toxicity. The maximum tolerated dose determined d uring the first cycle was 1000 mg/m(2)/day for 5 days of 5FU with either 75 or 85 mg/m(2) docetaxel, Dose-limiting toxicities at these dose levels wer e reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutro penia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively, Four patients experienced grade 3/4 infection, which led to t oxic death in one of them. There were five early deaths: (a) one was clearl y treatment related; (b) two others were possibly treatment related or remo tely treatment related; and (c) two deaths were not related to the study dr ugs. Partial responses were documented in 5 of 39 evaluable patients. Pharm acokinetic results of both drugs were consistent with those from single-age nt studies. The recommended dose of this combination, which showed acceptab le toxicity and antitumoral activity at various dose levels, is 85 mg/m(2) docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5 -day continuous i.v. infusion of 5FU (750 mg/m(2)/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.