title: A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children's Oncology Group study.
abstract: OBJECTIVE
  To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children.
  
  
  METHODS
  ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 microg/m(2) with planned dose escalation of 200 microg/m(2) increments. Pharmacokinetic sampling was done during the first treatment course.
  
  
  RESULTS
  Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 microg/m(2)), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 microg/m(2). Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 +/- 18.4 hours, a total body clearance of 28.2 +/- 10.5 L/h/m(2), and a 959 +/- 807 L/m(2) steady-state apparent volume of distribution.
  
  
  CONCLUSIONS
  ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 microg/m(2).
authors.affiliation: New Agent and Innovative Therapy Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lau
authors.forename: Jeffery G
authors.initials: JG
authors.lastname: Supko
authors.forename: Susan
authors.initials: S
authors.lastname: Blaney
authors.forename: Linda
authors.initials: L
authors.lastname: Hershon
authors.forename: Nita
authors.initials: N
authors.lastname: Seibel
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Wenchun
authors.initials: W
authors.lastname: Qu
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Jose
authors.initials: J
authors.lastname: Jimeno
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004149:Dioxoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D016879:Salvage Therapy; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin