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 (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.