Phase I Trial of Autologous Hematopoietic Stem Cell Transplantation with Escalating Doses of Topotecan Combined with Cyclophosphamide and Carboplatin in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma

We designed a phase I clinical trial of escalating doses of topotecan with cyclophosphamide and carboplatin in combination with autologous hematopoietic stem cell transplantation (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, sixteen patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/day combined with cyclophosphamide 1.5 grams/m(2)/day and carboplatin 200 mg/m(2) /day, all by four-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pretreatment biopsies were examined for expression of topoisomerase I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/day and two of three patients at 6.0 mg/m(2)/day had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. Because topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topoisomerase expression (p = 0.04). Topotecan can be safely dose escalated to 4.5 mg/m(2) per day in combination with cyclophosphamide, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.