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.
Childs Nerv Syst
; 31(9): 1433-45, 2015 Sep.
Article
em En
| MEDLINE
| ID: mdl-26188774
ABSTRACT
BACKGROUND:
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 in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors.METHODS:
Children and adolescents <22 years were enrolled into one of two strata stratum Ithose not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum IIthose receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM).RESULTS:
Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages.CONCLUSIONS:
While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.
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Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Neoplasias do Sistema Nervoso Central
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Inibidores de Proteínas Quinases
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Recidiva Local de Neoplasia
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article