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

Abstract

Paclitaxel, cisplatin, and vinorelbine are three important antineoplastic drugs with different mechanisms of cell kill. A combination of these 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 cycles repeated every 28 days. The Phase I design utilized a dose de-escalation schema in which the maximum tolerated dose was defined by a patient's ability to complete 6 doses (a full cycle) without interruption for hematologic Grade 3 or 4 toxicity. Twenty-seven patients received a total of 42 evaluable courses of the 3-drug regimen. The cisplatin dose was fixed at 15 mg/M2/fraction. The paclitaxel dose was first fixed at 50 mg/M2/fraction, and venorelbine was delivered at 3 dose levels per fraction: 10, 7.5, and 5 mg/M2. Paclitaxel then was de-escalated to 40 mg/M2/fraction, and the same 3 dose levels of vinorelbine were evaluated. The dose-limiting toxicity was neutropenia. Using fixed doses of paclitaxel at 40 mg/ M2/fraction and cisplatin at 15 mg/M2, the optimal dose fraction for vinorelbine was 7.5 mg/M2, defined as the dose that allowed > 67% of patients to complete 3 weeks (6 consecutive doses) of therapy. Using paclitaxel at 50 mg/M2/fraction (cisplatin at 15 mg/M2/fraction), the optimal dose of vinorelbine was 5 mg/M2/fraction. Tumor responses were observed in 13 patients: 2 with unknown primary, 1 with esophageal carcinoma, 6 with nonsmall cell lung carcinoma, and 3 with breast carcinoma. Grade 2 neurologic (sensory) toxicity was observed in 5 patients. TPN administered according to a twice-weekly dosing scheme can be delivered with acceptable toxicity. The dose intensity for paclitaxel (60-75 mg/M2/week), cisplatin (22 mg/M2/week), and vinorelbine (15 mg/M2/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 paclitaxel, cisplatin, and vinorelbine at either 50, 15, and 5 mg/M2/fraction or 40, 15, and 7.5 mg/M2/fraction in this twice-weekly, multifractionated dose schedule.