OBJECTIVE The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSIONS With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.