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

Mark W. Kieran*, Susan Chi, Stewart Goldman, Arzu Onar-Thomas, Tina Young Poussaint, Sridhar Vajapeyam, Frederic Fahey, Shengjie Wu, David C. Turner, Clinton F. Stewart, Marsha Moses, Roger J. Packer, Regina Jakacki, Anu Banerjee, James M. Boyett, Maryam Fouladi, Larry Kun

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 languageEnglish (US)
Pages (from-to)1433-1445
Number of pages13
JournalChild's Nervous System
Volume31
Issue number9
DOIs
StatePublished - Sep 10 2015

Keywords

  • AZD2171
  • Antiangiogenesis
  • Cediranib
  • Pediatric brain tumor
  • Recentin

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Clinical Neurology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this