A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors.

To 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. Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m² every 21 days (with an additional 1–2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response. The 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/m² dose and one patient at the 13 mg/m² 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/m². One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m². 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). The recommended Phase II dose of edotecarin is 13 mg/m² 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. [ABSTRACT FROM AUTHOR]