A phase I trial and PK study of cediranib (AZD2171), an orally bioavailable pan-VEGFR inhibitor, in children with recurrent or refractory primary CNS tumors

摘要: Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics children adolescents with recurrent or refractory primary central nervous system (CNS) tumors. Children <22 years were enrolled into one of two strata: stratum I—those not receiving enzyme-inducing anticonvulsant drugs (EIACD) II—those EIACDs. Dose-level selection based on the continual reassessment method (CRM). Thirty-six eligible patients median age 12.7 years (range, 5.4–21.7 years) (24 males) 12 (7 II 13.4 years 8.9–19.5 years) initially assessed over a 4-week DLT evaluation period, modified 6 weeks during study. An MTD 32 mg/m2/day declared; however, excessive (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) expansion cohort treated at suggested that it might be tolerated longer time period. 20 mg/m2/day also demonstrated poor longer-term tolerability. Diffusion perfusion MRI PET imaging variables as well biomarker analysis performed correlated outcome. At 20 mg/m2/day, plasma area under concentration-time curve steady state lower than observed adults similar dosages. While once daily cediranib progressive CNS tumors defined 32 mg/m2/day, considered tolerable protracted