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

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. 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 (816) years received trabectedin at 1.1 (n?=?3), 1.5 (n?=?6), or 1.7 (n?=?3) mg/m2. At the 1.5?mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7?mg/m2, 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/m2 IV over 24?hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required. Pediatr Blood Cancer 2012; 59: 865869. (C) 2012 Wiley Periodicals, Inc.