• Jens Samol, Malcolm Ranson, Edwina Scott, Euan Macpherson, James Carmichael, Anne Thomas, and James Cassidy.
• St George's Hospital, Blackshaw Rd, London, UK.
• Invest New Drugs. 2012 Aug 1;30(4):1493-500.

BackgroundThe aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors.Patients And MethodsPatients aged ≥ 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m(2)/day × 3 days or 1.0 mg/m(2)/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan.ResultsTwenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m(2)/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting.ConclusionsFurther development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

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