• Herbert I Hurwitz, Roger B Cohen, J Patrick McGovren, Samit Hirawat, William P Petros, Yutaka Natsumeda, and Tomoko Yoshinari.
• Division of Hematology and Oncology, Duke University Medical Center, P.O. Box 3052, Durham, NC 27710, USA. hurwi004@mc.duke.edu
• Cancer Chemother. Pharmacol. 2007 Jan 1; 59 (1): 139-47.

PurposeTo assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy.Patients And MethodsTwenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m(2) every 21 days (with an additional 1-2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response.ResultsThe most common non-hematologic toxicities were grade 1-2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1-2 thrombocytopenia and grade 3-4 neutropenia, leukopenia, and anemia. No grade 3-4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m(2) dose and one patient at the 13 mg/m(2) dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m(2). One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m(2). There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3-8% of the dose).ConclusionThe recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.

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