Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: Rapid development of neurotoxicity is dose-limiting

Purpose: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosupression. Patients and Methods: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m(2)) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 mu g/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/mu L). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m(2) (n = 6). Results: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m(2)), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m(2), n = 1; 275 mg/m(2), n = 2), neutropenia (225 mg/m(2), n = 2), diarrhea (275 mg/m(2), n = 2), and nephrotoxicity (225 mg/m(2), n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m(2), n = 1 each), physician request (275 mg/m(2), n = 1), and death (275 mg/m(2), n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/mu L. Conclusion: The MTD of paclitaxel was determined to be 225 mg/m(2) when administered as a 3-hour infusion and combined with cisplatin (75 mg/m(2)). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels. (C) 1997 by American Society of Clinical Oncology.