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A phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis®, ET-743) in children and adolescents with relapsed or refractory solid tumors.

AbstractBACKGROUND:
The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.
PROCEDURE:
Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1.
RESULTS:
Patients (n = 12) median (range) age 14.5 (8-16) years received trabectedin at 1.1 (n = 3), 1.5 (n = 6), or 1.7 (n = 3) mg/m(2). At the 1.5 mg/m(2) dose level, one patient had dose limiting anorexia and fatigue. At 1.7 mg/m(2), two patients experienced dose limiting toxicity, dehydration, and gamma-glutamyl transpeptidase elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis, and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response was observed in a patient with neuroendocrine carcinoma. Stable disease (≥6 cycles) was achieved in three patients (osteosarcoma n = 2, desmoplastic small round cell tumor n = 1).
CONCLUSIONS:
The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5 mg/m(2) IV over 24 hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required.
AuthorsMeredith K Chuk, Alberta Aikin, Trish Whitcomb, Brigitte C Widemann, Peter Zannikos, Eliel Bayever, Frank M Balis, Elizabeth Fox
JournalPediatric blood & cancer (Pediatr Blood Cancer) Vol. 59 Issue 5 Pg. 865-9 (Nov 2012) ISSN: 1545-5017 [Electronic] United States
PMID22847981 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural)
CopyrightCopyright © 2012 Wiley Periodicals, Inc.
Chemical References
  • Antineoplastic Agents, Alkylating
  • Antineoplastic Agents, Hormonal
  • Dioxoles
  • Tetrahydroisoquinolines
  • Dexamethasone
  • Trabectedin
Topics
  • Adolescent
  • Antineoplastic Agents, Alkylating (administration & dosage, adverse effects, pharmacokinetics)
  • Antineoplastic Agents, Hormonal (administration & dosage, adverse effects)
  • Child
  • Dexamethasone (administration & dosage, adverse effects)
  • Dioxoles (administration & dosage, adverse effects, pharmacokinetics)
  • Female
  • Humans
  • Male
  • Neoplasm Recurrence, Local (drug therapy)
  • Neoplasms (drug therapy)
  • Recurrence
  • Tetrahydroisoquinolines (administration & dosage, adverse effects, pharmacokinetics)
  • Time Factors
  • Trabectedin

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