title: 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.
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/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.
authors.affiliation: Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Rm D3154, Boston, MA, 02215, USA, mark_kieran@dfci.harvard.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Susan
authors.initials: S
authors.lastname: Chi
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Sridhar
authors.initials: S
authors.lastname: Vajapeyam
authors.forename: Frederic
authors.initials: F
authors.lastname: Fahey
authors.forename: Shengjie
authors.initials: S
authors.lastname: Wu
authors.forename: David C
authors.initials: DC
authors.lastname: Turner
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Marsha
authors.initials: M
authors.lastname: Moses
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Regina
authors.initials: R
authors.lastname: Jakacki
authors.forename: Anu
authors.initials: A
authors.lastname: Banerjee
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Larry
authors.initials: L
authors.lastname: Kun
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D001682:Biological Availability; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D013223:Statistics as Topic; D013997:Time Factors; D055815:Young Adult; D007211:Indoles
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C500926:cediranib; D007211:Indoles