Abstract B273: A phase I trial of topotecan and sorafenib for patients with recurrent, platinum-resistant epithelial ovarian cancer

Abstract

Abstract Background: The objectives of the study were to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and objective response rate to combination therapy with sorafenib and topotecan in patients with platinum resistant epithelial ovarian cancer (EOC). Methods: This multi-institutional phase I trial used a fixed dose of weekly topotecan and escalating doses of sorafenib. Eligible patients had recurrent platinum-resistant EOC, measurable or detectable disease, and up to three prior cytotoxic treatments. Prior anti-angiogenic therapy was not allowed. Sorafenib was administered orally daily and topotecan was given iv weekly at a fixed dose of 4 mg/m2, 3 weeks on and 1 week off. Each treatment cycle was 28 days. A standard 3 + 3 dose escalation design was used, testing two sorafenib dose levels: 400 mg daily (level 1) and 800 mg daily (level 2). The topotecan dose was de-escalated to dose level −1 (3.5mg/m2 weekly). The primary endpoints of the phase I study were to determine the MTD and the toxicity profile of this combination. Results: 16 patients were enrolled between 12/12/07 and 11/13/08. Median number of prior regimens was 2 (range 1–7), median age was 52.5 (range 41–66), and all 16 patients had EOC. Distribution of patients per dose level and DLTs encountered are summarized in the table below. Five patients were inevaluable because of intercurrent illness or withdrawal of consent. Grade 3–4 toxicities during cycle 1 included: thrombocytopenia (3), neutropenia (2), febrile neutropenia (1), nausea and vomiting (2), rash (2), abdominal pain (1) and abnormal liver function tests (1). Grade 3–4 toxicities occurring after cycle 1 included: neutropenia (2), thrombocytopenia (1), anemia (2), nausea and vomiting (1), anorexia (1), and insomnia (1). Clinical activity was an exploratory endpoint. There was 1 partial response by RECIST lasting for over 12 months, but no complete responses. Six patients had stable disease. Conclusions: Sorafenib can be safely combined with topotecan in EOC patients. The dose recommended for phase II investigation is sorafenib 400mg daily with topotecan 3.5 mg/m2 weekly. Toxicities during dose escalation Topotecan dose (mg/m2) Sorafenic dose (mg) No patients No patients DLT/Decision DLT/Decision 4 400 6 2; not tolerated 3.5 400 4 0, tolerated, phase 2 3.5 800 6 2, not tolerated Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B273.