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 I—those not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum II—those 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/m2/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/m2/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/m2/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/m2/day, this dose and 20 mg/m2/day were not considered tolerable over a protracted time period.
Original language | English (US) |
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Pages (from-to) | 1433-1445 |
Number of pages | 13 |
Journal | Child's Nervous System |
Volume | 31 |
Issue number | 9 |
DOIs | |
State | Published - Sep 10 2015 |
Funding
This work was supported in part by NIH grant U01 CA81457 for the Pediatric Brain Tumor Consortium, American Lebanese Syrian Associated Charities, and the Stop & Shop Pediatric Brain Tumor Program at the Dana-Farber Cancer Institute and Boston Children’s Hospital.
Keywords
- AZD2171
- Antiangiogenesis
- Cediranib
- Pediatric brain tumor
- Recentin
ASJC Scopus subject areas
- Clinical Neurology
- Pediatrics, Perinatology, and Child Health