The multifractionated, twice-weekly dose schedule for a three-drug chemotherapy regimen - A phase I-II study of paclitaxel, cisplatin, and vinorelbine

BACKGROUND. Paclitaxel, cisplatin, and vinorelbine are three important anti neoplastic drugs with different mechanisms of cell kill. A combination of t hese three drugs potentially could have additive therapeutic effects. METHODS. The three-drug combination (designated TPN) was administered on a twice-weekly (Monday/Thursday; Tuesday/Friday) schedule for 3 weeks, with c ycles repeated every 28 days. The Phase I design utilized a dose de-escalat ion schema in which the maximum tolerated dose was defined by a patient's a bility to complete 6 doses (a full cycle) without interruption for hematolo gic Grade 3 or 4 toxicity. RESULTS. Twenty-seven patients received a total of 42 evaluable courses of the 3-drug regimen. The cisplatin dose was fixed at 15 mg/M-2/fraction. The paclitaxel dose was first fixed at 50 mg/M-2/fraction, and venorelbine was delivered at 3 dose levels per fraction: 10, 7.5, and 5 mg/M-2. Paclitaxel then was de-escalated to 40 mg/M-2/fraction, and the same 3 dose levels of vinorelbine were evaluated. The dose-limiting toxicity was neutropenia. Us ing fixed doses of paclitaxel at 40 mg/M-2/fraction and cisplatin at 15 mg/ M-2, the optimal dose fraction for vinorelbine was 7.5 mg/M-2, defined as t he dose that allowed > 67% of patients to complete 3 weeks (6 consecutive d oses) of therapy. Using paclitaxel at 50 mg/M-2/fraction (cisplatin at 15 m g/M-2/fraction), the optimal dose of vinorelbine was 5 mg/M-2/fraction. Tum or responses were observed in 13 patients: 2 with unknown primary, 1 with e sophageal carcinoma, 6 with nonsmall cell lung carcinoma, and 3 with breast carcinoma. Grade 2 neurologic (sensory) toxicity was observed in 5 patient s. CONCLUSIONS. TPN administered according to a twice-weekly dosing scheme can be delivered with acceptable toxicity. The dose intensity for paclitaxel ( 60-75 mg/M-2/week), cisplatin (22 mg/M-2/week), and vinorelbine (15 mg/M-2/ week) is > 50% of the single agent dose intensity for the component agent. Recommended Phase II or Phase III trials could utilize dose fractions of pa clitaxel, cisplatin, and vinorelbine at either 50, 15, and 5 mg/M-2/fractio n or 40, 15, and 7.5 mg/M-2/fraction in this twice-weekly, multifractionate d dose schedule. (C) 1999 American Cancer Society.