Phase I trial of multiple cycles of high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell support as front-line therapy

Purpose: To determine the safely and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. Patients and Methods: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphomide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m²), and topotecan (10-15 mg/m²), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. Results: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m² when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m². The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. Conclusion: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m², and topotecan 10 mg/m². Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.