Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors

Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m². Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m² dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C_max values of 103 ± 17 ng/ml at the 13 mg/m² dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression ≥50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m². The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m². The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.