Phase II Study of Vandetanib in Individuals With Kidney Cancer

Background: Von Hippel Lindau disease is a hereditary cancer syndrome in which affected individuals are at risk for developing tumors in a number of organs, including the kidneys, brain, spine, adrenal glands, eyes and pancreas. The molecular hallmark of VHL is inactivation of the VHL gene which leads to accumulation of proteins targeted for degradation through the ubiquitin pathway, which includes a group of transcriptionally active proteins called the hypoxia inducible factors (HIF), whose alpha subunits undergo degradation in a VHL-dependent fashion. Accumulation of HIFs results in overexpression of several genes including vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), transforming growth factor (TGF)-alpha, platelet- derived growth factor (PDGF), and erythropoietin, which are believed to play a role in tumorigenesis, tumor progression and metastasis. ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity against the Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2) and the epidermal growth factor receptor (EGFR). Kinase insert domain receptor (KDR)/vascular growth factor receptor 2 (VEGFR2) is an endothelial cell receptor for vascular endothelial growth factor (VEGF) and plays a crucial role in mediating tumor angiogenesis, while epidermal growth factor receptor (EGFR) (a receptor for TGF-alpha and epidermal growth factor (EGF) is believed to mediate tumor growth and proliferation. Objective: Primary Objective To assess the overall response rate in VHL patients with renal tumors treated with single agent ZD6474 Secondary Objectives: To study the safety and tolerability of ZD6474 To evaluate time to progression and progression-free survival in VHL patients receiving ZD6474 To study the effect of ZD6474 treatment on non-renal tumors associated with von Hippel Lindau disease ( pancreatic tumors, pheochromocytoma, central nervous system (CNS) hemangioblastomas) To investigate the effect of ZD6474 on circulating endothelial cells and endothelial progenitor cells and to explore the utility of these markers as surrogates of angiogenesis inhibition To investigate the effect of ZD6474 on biomarkers of angiogenesis such as plasma VEGF and soluble VEGFR2 Eligibility: Adults with clinical diagnosis of von Hippel Lindau disease Presence of one or more measurable renal tumors Age greater than or equal to 18 years Adequate organ function, performance status (Eastern Cooperative Oncology Group (ECOG) 0-2) and life expectancy (greater than 3 months) Design: Single agent ZD6474 administered daily at a starting dose of 300mg per day Patients will be evaluated for response every 12 weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria The study is based on an open label two-stage optimal phase II design Accrual of a maximum of 37 patients.