Pilot Study of GW786034 (Pazopanib), a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Operable Breast Cancer
I. Determine the biologic effect of pazopanib hydrochloride, in terms of decreased
phosphorylation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and/or
decreased microvessel density, in patients with newly diagnosed or locally and/or regionally
recurrent operable breast cancer.
II. Determine the mechanism of antitumor effect of this drug, in terms of reduced tumor cell
proliferation (Ki67) or increased apoptosis, in these patients.
I. Determine the change in levels of tissue VEGF in patients treated with this drug.
II. Determine the change in phosphorylation of epidermal growth factor receptor (EGFR),
MAPK, and AKT in patients treated with this drug.
III. Evaluate gene expression patterns in patients treated with this drug. IV. Evaluate the
change in VEGF and VEGFR-2 as circulating biomarkers in patients treated with this drug.
V. Evaluate the changes in circulating tumor cells in patients treated with this drug.
VI. Determine if steady-state plasma concentration of this drug correlates with inhibition
VII. Evaluate the change in vascular permeability by bilateral dynamic contrast-enhanced MRI
(DCE-MRI) of the breast in patients treated with this drug.
VIII. Compare DCE-MRI imaging of the tumor vasculature in the breast before, during, and
after treatment with this drug.
OUTLINE: This is an open-label, pilot study.
Patients receive pazopanib hydrochloride orally (PO) once daily for 12-20 days. Patients
then undergo surgical resection of tumor between days 13 and 21 (24 hours after completion
of pazopanib hydrochloride).
Blood samples are collected periodically for analysis of circulating tumor cells and
pharmacokinetic studies. Patients also undergo tumor biopsy at the time of surgery. Samples
are analyzed by immunohistochemistry, microarray (gene expression profiling), and TUNEL
assays to assess vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2),
epidermal growth factor receptor (EGFR), MAPK, AKT, phosphorylated (p) VEGFR-2, pEGFR,
pMAPK, and pAKT activity, tumor cell proliferation (Ki67) and apoptosis, and microvessel
density (using endothelial markers CD31 [PECAM-1], CD34, and CD 133).
Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Response to GW786034 defined as change in molecular parameters such as phosphorylated VEGFR-2, microvessel density, tumor proliferation (Ki67), and apoptosis
The pre-post comparison of the biologic effects in the tumor can be done by a paired t-test as they are all continuous variables. If the differences are not normally distributed, transformations or non-parametric methods will be applied. We will adjust for multiple comparisons using Bonferroni method as the biologic effects are measured by four variables. The relationship among these four variables will be analyzed using factor analysis to see if they can be reduced to one or two representative indices.
Baseline to 4 years
Cancer Institute of New Jersey
United States: Food and Drug Administration
|Cancer Institute of New Jersey||New Brunswick, New Jersey 08901|