Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

To determine the maximum recommended dose (RD) and pharmacokinetics of Myocet(A (R)), a non-pegylated liposomal doxorubicin, in children. Eligible patients were children with refractory high-grade glioma who had received prior chemotherapy and radiotherapy but no anthracyclines. Cohorts of at least three patients each received escalating doses of Myocet(A (R)) starting at 60 mg/m(2) at 3-week intervals, administered intravenously over 1 h, and then doses were escalated to 75 mg/m(2) corresponding to the adult RD. Periodic blood samples were collected, and plasma doxorubicin and doxorubicinol concentrations were quantified to characterise the pharmacokinetics of Myocet(A (R)). Between October 2010 and January 2013, 13 children aged 6-17 years were treated. In total, 27 courses were administered, at the 60 mg/m(2) dose level in seven patients without dose-limiting toxicity (DLT), and at 75 mg/m(2) in six patients of whom two experienced DLT (grade 4 neutropenia). The most common grade 3-4 toxicities reported for all courses were neutropenia (35 and 38 %, respectively), thrombocytopenia (12 and 4 %, respectively); and grade 3 vomiting, nausea, mucositis, and fever (4 % each). Mean estimates of central volume of distribution at steady state, clearance, and elimination half-life of doxorubicin were 24.8 L, 15 L/h/m(2), and 34.8 h, respectively, with a large interpatient variability. The RD of Myocet(A (R)) administered every 3 weeks to paediatric patients was 60 mg/m(2). The efficacy of Myocet(A (R)) in paediatric patients with high-grade glioma remains to be determined and should be studied in Phase II trials.