A Phase I Trial and Pharmacokinetic Study of Trabectedin (YONDELIS [R], ET-743) in Children and Adolescents With Relapsed or Refractory Solid Tumors
Trabectedin (ET-743) is a natural product derived from the marine tunicate Ecteinascidia
turbinata. It binds to the minor groove of DNA and interacts with various transcription
factors resulting in cell cycle arrest. It also inhibits transcription coupled nucleotide
excision repair system inducing lethal DNA strand breaks.
In preclinical and clinical studies, trabectedin has been found to be active in many soft
tissue sarcomas including leiomyosarcoma, synovial cell sarcoma, neuroblastoma,
rhabdomyosarcoma, melanoma, breast, ovarian, non-small cell lung, renal and prostate
In adult phase I and phase II studies, trabectedin has been well-tolerated up to dose levels
of 1.9mg/m(2)/dose with the most common toxicities being fatigue, neutropenia, and
reversible transaminase elevations. Objective responses were seen at doses equal to or
greater than 1.5mg/m(2)/dose. Trabectedin 1.5mg/m(2) administered as a 24-hour continuous
intravenous infusion is the recommended dose and schedule in adults.
A pediatric phase I study of trabectedin administered as a 3-hour infusion has been
completed in the Children's Oncology Group. The maximum tolerated dose was 1.1 mg/m(2).
Dose limiting toxicity was reversible elevation of hepatic transaminases.
Determine the maximum tolerated dose (MTD) of trabectedin administered as a 24-hour
continuous infusion in children and adolescents with relapsed or refractory solid tumors.
Define the toxicity profile of trabectedin administered as a 24-hr infusion in children and
Describe the pharmacokinetics of trabectedin administered as a 24-hr infusion in children
Quantify double strand DNA breaks in peripheral blood mononuclear cells of patients
Evaluate archival formalin fixed paraffin embedded tumor tissue, when available from prior
biopsies or surgical procedures, for the expression of the nucleotide excision repair
proteins and genomic instability markers (histone gamma-H2AX, phospho-ATM, phospho-Chk2) by
Molecular characterization of DNA repair genes and correlation to outcome using mRNA
isolated from microdissected archival formalin fixed, paraffin embedded tumor sections.
Study the pharmacogenetics of host DNA repair proteins and drug metabolizing enzymes to
explore the impact of host factors on trabectedin toxicity.
Children greater than or equal to 4 years and less than 17 years of age with relapsed or
refractory solid tumors.
Patients will receive trabectedin as a 24-hour continuous infusion repeated every 21 days.
The starting dose level is 1.1mg/m(2)/dose with escalations to 1.5mg/m(2)/dose and
All patients will receive dexamethasone pretreatment and growth factor support with
filgrastim or pegfilgrastim.
The definition of dose-limiting hepatic toxicity will be identical to the definition used in
phase I trials in adults on the same dosing schedule.
Pharmacokinetic analysis will be performed on days 1, 2, 3, 4, 5 and 7 of the first
Three to six patients will be enrolled at the first dose level and up to 6 patients will be
enrolled on subsequent dose levels. Dose escalation will be based on tolerability of
trabectedin at the prior dose level. For patients enrolled at dose level 1 (1.1mg/m(2)),
intrapatient dose escalation to dose level 2 (1.5mg/m(2)) will be allowed with subsequent
cycles if no dose limiting toxicities occurred at the lower dose level. Total accrual will
be up to 24 patients.
Primary Purpose: Treatment
Howard A Fine, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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