Phase I trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies1

Background . Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity. Objectives . Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m 2 ) in a cohort of women with recurrent mullerian malignancies. Methods . Topotecan dose was escalated from 0.5 mg/m 2 /day for 3 days in 0.2 mg/m 2 /day increments with treatment repeated every 21 days. Eligibility criteria required ECOG ≤2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity. Results . Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40–71) years. Patients received a median 1 (1–6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses. Conclusions . Doxil 30 mg/m 2 and topotecan 0.5 mg/m 2 /day by 72-h infusion (total dose 1.5 mg/m 2 ), although a rational combination of cytotoxic therapies, have limited clinical activity.