Sequential topotecan and oral etoposide in recurrent ovarian carcinoma pretreated with platinum-taxane -: Results from a multicenter phase I/II study

BACKGROUND. The objectives of this study were to determine the maximum tolerable dose (MTD), toxicity, efficacy, and feasibility of a sequential regimen of fixed-dose topotecan (1.00 mg/m(2) on Days 1-5) and increasing doses of oral etoposide (50 mg, 75 mg, and 100 mg on Days 6-12 or Days 6-19) in patients with recurrent ovarian carcinoma. METHODS. This multicenter, open-label study was planned as a Phase I-II study that included patients with epithelial ovarian carcinoma who failed or who developed recurrent disease < 12 months after the end of platinum and taxane-containing chemotherapy. Dose-limiting toxicity (DLT) was defined as follows: Grade 4 neutropenia for > 1 week, or neutropenic fever 38.5 degrees C for > 24 hours/sepsis, or Grade 4 thrombocytopenia for > 1 week, or thrombocytopenia with bleeding, or Grade 3-4 nonhematologic toxicity. RESULTS. The MTD, as defined in the protocol, could not be settled because of unpredictable toxicity, because DLT was found at all dose levels except the starting dose level. In 28 patients (Phase I), 155 cycles were evaluable for toxicity. The main DLT was neutropenia Grade 4 for > 1 week or neutropenic fever/sepsis. Overall, neutropenia Grade 4 that lasted > 1 week and sepsis were noticed in 3% and 2% of cycles, respectively. Because no MTD was reached, the planned Phase II trial was not initiated. However, the patients from Phase I were followed until they developed progressive disease and, among them, 9 patients (32%) obtained an objective response (according to Response Evaluation Criteria in Solid Tumors (RECIST) or CA125 response criteria). CONCLUSIONS. Combined topotecan and oral etoposide was inappropriate in patients with recurrent ovarian carcinoma because of unpredictable hematologic toxicity. However, the high objective response rate highlighted the potential additive effect of topoisomerase I and II inhibitors. (c) 2005 American Cancer Society.