A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children's Oncology Group study

Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):672-7.


Purpose: 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.

Experimental design: 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.

Conclusion: 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).

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / pharmacokinetics*
  • Child
  • Child, Preschool
  • Dioxoles / administration & dosage
  • Dioxoles / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Infusions, Intravenous
  • Isoquinolines / administration & dosage
  • Isoquinolines / pharmacokinetics*
  • Male
  • Maximum Tolerated Dose
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Salvage Therapy
  • Tetrahydroisoquinolines
  • Time Factors
  • Trabectedin


  • Antineoplastic Agents, Alkylating
  • Dioxoles
  • Isoquinolines
  • Tetrahydroisoquinolines
  • Trabectedin