TY - JOUR
T1 - 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
AU - Kieran, Mark W.
AU - Chi, Susan
AU - Goldman, Stewart
AU - Onar-Thomas, Arzu
AU - Poussaint, Tina Young
AU - Vajapeyam, Sridhar
AU - Fahey, Frederic
AU - Wu, Shengjie
AU - Turner, David C.
AU - Stewart, Clinton F.
AU - Moses, Marsha
AU - Packer, Roger J.
AU - Jakacki, Regina
AU - Banerjee, Anu
AU - Boyett, James M.
AU - Fouladi, Maryam
AU - Kun, Larry
N1 - Funding Information:
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.
Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.
PY - 2015/9/10
Y1 - 2015/9/10
N2 - 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.
AB - 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.
KW - AZD2171
KW - Antiangiogenesis
KW - Cediranib
KW - Pediatric brain tumor
KW - Recentin
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U2 - 10.1007/s00381-015-2812-5
DO - 10.1007/s00381-015-2812-5
M3 - Article
C2 - 26188774
AN - SCOPUS:84941170214
SN - 0256-7040
VL - 31
SP - 1433
EP - 1445
JO - Child's Nervous System
JF - Child's Nervous System
IS - 9
ER -