This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Several recent studies have validated anti-angiogenesis by vascular endothelial growth factor (VEGF) blockade as effective cancer therapy. Pazopanib (GW786034) is a potent and selective multi-target receptor tyrosine kinase inhibitor (TKI) of VEGF receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor (PDGF) receptors- and - . Preclinical experiments demonstrate that pazopanib causes significant and dose-dependent inhibitory effects on cell proliferation and inhibition of vascular endothelial growth factor (VEGF)-induced VEGFR-2 phosphorylation, growth inhibition of a variety of human tumor xenografts in mice, and inhibition of basic fibroblast growth factor- (bFGF) and VEGF induced angiogenesis in murine models. Pazopanib has been evaluated in adult subjects with solid tumors in Phase I and II studies and objective anti-tumor activity has been observed in a variety of tumor types. Pazopanib as a single agent will be administered orally on a once daily basis. Treatment cycles will be defined as 28 days in duration. Patients may receive a total of 24 cycles of therapy with pazopanib in the absence of progressive disease or unacceptable toxicity. Patients will be accrued to a dose level in cohorts of 2 to 6 using the rolling six Phase I trial design. Toxicity will be graded using CTCAE version 3.0 and response will be assessed using RECIST. Part 1 (Phase I Dose Escalation): The starting dose of pazopanib will be 275mg/m2/dose, which is approximately 60% of the adult recommended dose. Escalations in subsequent cohorts will occur in increments of approximately 30%. There will be no intrapatient dose escalation. In consenting patients, blood samples will be obtained for the pharmacokinetic analysis and correlative biology studies including VEGF haplotype, plasma levels of VEGF, placental growth factor (PlGF), soluble VEGFR1, and soluble VEGFR2 and measurement of circulating endothelial cells and peripheral blood monocytes. Changes in tumor vascular permeability in response to pazopanib will also be explored using DCE-MRI. Part 2a (Suspension Formulation Component): Once the MTD or highest dose level has been reached, the cohort will be expanded in order to obtain additional safety information and pharmacokinetic data for the suspension formulation. Pharmacokinetic studies will be required in all patients who participate in this component of the trial. Part 2b (Expanded Imaging Cohort): In addition, at the MTD or recommended Phase II dose, a cohort of up to 10 patients with recurrent/refractory soft tissue sarcoma and a measurable (at least 2 cm) lesion in the head, neck, extremity or fixed within the abdomen or pelvis such that is not sensitive to motion artifact will be accrued to further explore changes in tumor vascular permeability using dynamic contrast enhanced MRI (DCE-MRI). Imaging studies and limited pharmacokinetic sampling will be required in all patients who participate in this component of the trial.
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