A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-Epileptic Drugs
I. To determine the safety profile and optimal dose of AZD2171 (cediranib) (15mg or 20mg or
30mg) in combination with temozolomide and radiation in patients with newly diagnosed
glioblastoma (Phase Ib) II. To determine median progression-free survival of patients with
newly diagnosed glioblastoma treated with AZD2171 in combination with temozolomide and
radiation (Phase II)
I. To determine the radiographic response proportion in newly diagnosed glioblastoma
patients with measurable disease. (Phase II) II. To determine the median overall survival.
(Phase II) III. To determine the "vascular normalization" window in newly diagnosed
glioblastoma patients by the application of serial, non-invasive, MRI parameters. (Phase II)
IV. To measure the glucose metabolism changes in a subset of newly diagnosed glioblastoma
patients by performing FDG PET studies. (Phase II) V. Measurement of circulating endothelial
and progenitor cells and plasma levels of VEGF-A; VEGF-B; VEGF-C; VEGF-D; sVEGFR1, sVEGFR2,
bFGF, PlGF, PDGF-AA; PDGF-AB; PDGF-BB; SDF1α; tumstatin; thrombospondin-1; interleukin-8;
collagen IV sICAM1, sVCAM1 as markers for response to AZD2171 in newly diagnosed
glioblastoma patients. (Phase II) VI. Correlation of treatment outcomes with pre-AZD2171
tumor specimens with respect to cell proliferation, apoptosis, microvascular density (MVD),
basement membrane and pericyte coverage, angiopoietin-1 and -2 expression to determine
whether these immunohistochemical analyses can be predictive of the response to AZD2171.
OUTLINE: This is a phase I, dose-escalation study of cediranib followed by a phase II study.
Patients begin study treatment within 21-42 days after craniotomy or 14-21 days after
CHEMORADIOTHERAPY: Patients receive cediranib orally (PO) once daily and oral temozolomide
once daily for 6 weeks. Within 2-6 hours of dosing, patients undergo concurrent
intensity-modulated radiotherapy (IMRT) once daily, 5 days a week for 6 weeks. Cediranib
monotherapy: Patients receive cediranib PO once daily for 4 weeks (weeks 7-10). Cediranib
and temozolomide monthly therapy: Patients receive cediranib PO once daily for 24 weeks
(weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and
31. Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24
weeks (weeks 35-58).
CHEMORADIOTHERAPY: Patients receive cediranib PO at the recommended phase II dose determined
in phase Ib, temozolomide PO, and undergo concurrent IMRT as in phase Ib (weeks 1-6).
Cediranib monotherapy: Patients receive cediranib PO (at the recommended phase II dose
determined in phase Ib) once daily for 4 weeks (weeks 7-10). Cediranib and temozolomide
monthly therapy: Patients receive cediranib PO (at the recommended phase II dose determined
in phase Ib) once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a
week in weeks 11, 15, 19, 23, 27, and 31. Cediranib monotherapy: Patients receive a
fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).
Patients undergo blood and urine sample collection at baseline and periodically during
study. Blood samples are measured for tumstatin, as well as other well established
biomarkers, including VEGF-A, -D, sVEGFR1, sVEGFR2, sICAM1, sVCAM1, PlGF, PDGF-AA, PDGF-AB,
PDGF-BB, thrombospondin-1, and IL-8 by electrochemiluminescence detection. Circulating
endothelial cell (CEC) assays are evaluated to assess the kinetics of CECs and progenitor
cells prior to and during antiangiogenic therapy with cediranib and chemoradiotherapy. Urine
samples are collected for proteomic analyses to evaluate serial change of growth factors
such as VEGF and PlGF and of matrix metalloproteinases in response to treatment with
cediranib. Archival tumor tissue is collected for analysis of tumor microvascular density,
basement membrane and pericyte coverage, angiopoietin-1 and -2 expression, tumor cell
proliferation, and apoptosis by immunostaining methods and immunoenzyme techniques.
Patients also undergo dynamic contrast enhanced (DCE)-MRI and T2-weighted or
perfusion-weighted MRI at baseline and periodically during study to monitor antiangiogenic
effect on tumor vasculature through parameters reflecting both tumor perfusion and
permeability; and diffusion tensor imaging to measure degree of water diffusion and
fractional anisotropy. A subset of patients undergo fludeoxyglucose F 18 positron emission
tomography (FDG-PET) periodically to monitor antiangiogenic effects on glucose utilization.
After completion of study treatment, patients are followed periodically for 1 year.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety profile and optimal dose of cediranib during chemoradiotherapy (Phase I)
A dose-limiting toxicity of cediranib is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/temozolomide and occurs following the first dose of cediranib in the chemoradiation.
Up to 30 days after the last dose
Massachusetts General Hospital
United States: Food and Drug Administration
|Beth Israel Deaconess Medical Center||Boston, Massachusetts 02215|
|Massachusetts General Hospital Cancer Center||Boston, Massachusetts 02114|
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|