Phase I trial of oral topotecan with intravenous carboplatin in patients with advanced cancer

Abstract

3184 Background: Topotecan is an active agent, approved for second line treatment of ovarian and small cell lung cancer. Its use has been limited by leukopenia and its schedule of drug administration requiring 5 daily intravenous infusions. Synergy and schedule dependence has been reported with platinum compounds in some preclinical models. We sought to develop an oral five-day regimen that could be safely administered with carboplatin. Methods: Patients eligible for this trial included those with advanced solid tumors who had disease progression on standard chemotherapy, ECOG performance status < 2, calculated creatinine clearance > 60, prior radiotherapy to less than 20% bone marrow, WBC > 3.5, platelet count > 100, and signed informed consent. The population studied had received 1–3 (median 2) prior chemotherapy regimens. A total of 12 patients received 24 cycles of therapy. Six patients in the first cohort received oral topotecan 1.0 mg/m2 daily x 5. The second cohort of six patients received the same schedule of oral topotecan at 1.4 mg/m2 daily x5. The initial three patients of both cohorts received carboplatin AUC 5 on day 1 and the second three patients of both cohorts received carboplatin AUC 5 on day 5. Results: Dose-limiting toxicity was reached in the second cohort with 3/6 patients experiencing grade 4 dose-limiting thrombocytopenia. All grade 3–4 toxicity (per patient) observed in these 12 patients included anemia (3), granulocytopenia (6), thrombocytopenia (6), diarrhea (1) and febrile neutropenia (1). No patient developed thrombocytopenic bleeding. No responses were observed. The median time to progression was 8 weeks in this population of pre-treated patients. Conclusion: The maximally tolerated dose of oral topotecan given on this schedule is 1.4 mg/m2 daily x 5 plus carboplatin AUC 5. The day of administration of carboplatin (day 1 vs. day 5) made little impact on toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis