Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer

Purpose: Paclitaxel has shown significant activity in advanced ovarian cancer. In vitro studies with paclitaxel have suggested that fractionated brief infusion schedules may be more effective than the standard 24-hour infusion. We commenced a phase I evaluation of escalating-dose paclitaxel (40, 50, 60, 80, 100 mg/m²) administered weekly as a 1-hour infusion in patients with recurrent ovarian cancer. All patients had received prior paclitaxel and cisplatin therapy. All patients received standard premeditation. Patients and Methods: Eighteen patients are assessable on this phase I study. The mean age was 54 years (range, 48 to 74). The median number of prior chemotherapy regimens was three (range, two to five). The mean paclitaxel-free interval was 10.1 months (range, 1 to 24). Results: A total of 194 cycles of therapy were administered, with a mean of 10 (range, one to 12) per patient. No mucositis or grade III neuropathy was seen. Alopecia occurred in one out of 18 assessable patients. The mean neutrophil nadir was 4.0 x 10⁹/L. At the top dose level (100 mg/m²) delivered, dose-intensity was 90.75% of that planned and greater than two fold the standard dose- intensity. Partial responses were seen in four of 13 assessable patients (30%). Two patients with progression of disease on standard three-week paclitaxel schedules switched to a weekly schedule with demonstrated response. Increasing paclitaxel dose correlated with measured area under the curve (AUC) (R² = .614). Dose-limiting toxicity was reached at 100 mg/m² with two of three patients experiencing a treatment delay, thus defining a maximum-tolerated dose of 80 mg/m² in this group of heavily pretreated patients on this weekly schedule. Conclusion: (1) Paclitaxel administered as a 1-hour infusion is well tolerated; (2) this schedule of administration does not result in cumulative myelosuppression; and (3) this schedule of administration results in dose-intensive paclitaxel delivery with a favorable toxicity profile.