title: Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. o.soepenberg@erasmusmc.nl
authors.forename: Otto
authors.initials: O
authors.lastname: Soepenberg
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruin
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Gerda
authors.initials: G
authors.lastname: de Heus
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Peter
authors.initials: P
authors.lastname: Cheverton
authors.forename: Murray P
authors.initials: MP
authors.lastname: Ducharme
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D012074:Remission Induction; D016879:Salvage Therapy; D013997:Time Factors; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C452060:DE-310 cpd; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin