Aim: Topotecan and gemcitabine have demonstrated mono-activity against recurrent ovarian cancer. Both drugs affect DNA replication; in addition, topotecan inhibits DNA repair. Based on the efficacy profiles and different mechanisms of action, a phase-I study was conducted to determine the maximum tolerated dose (MTD) of topotecan (day 1-5) and the dose-limiting toxicities (DLT) in combination with gemcitabine (day 1 + 8) every 21 days.
Methods: Three to six patients were treated per dose-level. Patients with ovarian cancer who had failed a platinum and paclitaxel-containing therapy were enrolled. No individual dose escalation or use of cytokines were allowed.
Results: Twenty-three patients were recruited. Fifty percent of all patients were pretreated with at least two platinum-containing therapies. Eighty courses were assessable for toxicity. The MTD was reached at a dosage of 0.75 mg/m2 topotecan in combination with 800/600 mg/m2 gemcitabine. Thrombocytopenia and leucopenia were the major DLTs. The dose for phase-II trials is 0.50 mg/m2 topotecan given with 800/600 mg/m2 gemcitabine. In this dose-level only one related non-haematological adverse event > grade 2 was observed (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in six patients and stable disease in four out of 12 assessable patients. Median survival time was 15.3 (95% CI: 13.21-28.64) months.
Conclusion: The results demonstrate feasibility and the tolerability of topotecan in combination with gemcitabine in recurrent ovarian cancer patients. Based on these results a phase-II study was conducted to evaluate the efficacy of this new combination.