title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors: Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, USA. meredith.chuk@chp.edu
authors: Meredith K
authors: MK
authors: Chuk
authors: Alberta
authors: A
authors: Aikin
authors: Trish
authors: T
authors: Whitcomb
authors: Brigitte C
authors: BC
authors: Widemann
authors: Peter
authors: P
authors: Zannikos
authors: Eliel
authors: E
authors: Bayever
authors: Frank M
authors: FM
authors: Balis
authors: Elizabeth
authors: E
authors: Fox
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D012008:Recurrence; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018931:Antineoplastic Agents, Hormonal; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003907:Dexamethasone; D000077606:Trabectedin