http://repub.eur.nl/res/aut/11470/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/10375/ 2005-01-01T00:00:00Z PURPOSE: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0 mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. RESULTS: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor.