A Phase I Clinical Trial of AZD2171 in Children With Recurrent or Progressive Central Nervous System (CNS) Tumors
I. Determine the maximum tolerated dose of AZD2171 in pediatric patients with recurrent,
progressive, or refractory primary CNS tumors.
II. Describe the toxicity profile and dose-limiting toxicities of AZD2171 in these patients.
I. Characterize inter-patient variability in the pharmacokinetics of AZD2171 in these
II. Describe changes in circulating endothelial cells (CECs) and circulating endothelial
cell precursors (CEPs) in patients treated with AZD2171 at different dose levels.
III. Correlate changes in CECs, CEPs, plasma, serum, and urine levels of proteins with
angiogenesis, including vascular endothelial growth factor (VEGF) and VEGF receptor, in
patients treated with AZD2171 at different dose levels.
IV. Correlate changes in CECs, CEPs, and angiogenic modulators with changes in magnetic
resonance (MR) perfusion.
V. Obtain preliminary evidence of biologic activity of AZD2171 by evaluating alterations in
tissue perfusion, tumor blood flow, and metabolic activity using MR perfusion and diffusion
imaging, and positron-emission tomography, and correlating these findings with changes in
tumor size by standard MRI.
OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to
concurrent enzyme-inducing anticonvulsant drugs (yes vs no).
Patients receive oral AZD2171 once daily on days 1-28. Treatment repeats every 28 days for
up to 13 courses in the absence of disease progression or unacceptable toxicity.
For each stratum, cohorts of 2-6 patients receive escalating doses of AZD2171 until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 25% of
patients experience dose-limiting toxicity. Once the MTD is determined, an additional 6
patients per stratum are enrolled and treated at the MTD.
After completion of study, patients are followed at 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose, defined as the dose at which the model estimates that 25% of patients will experience dose-limiting toxicity as measured by NCI CTCAE v4.0
Estimated using the modified Continual Reassessment Method (CRM).
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
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