A Phase 2 Study of ZD6474 (Vandetanib) in Patients With Von Hippel Lindau Disease and Renal Tumors
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 VEGF, GLUT-1, TGF-alpha, 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). KDR/VEGFR2 is an endothelial
cell receptor for vascular endothelial growth factor (VEGF) and plays a crucial role in
mediating tumor angiogenesis, while EGFR (a receptor for TGF-alpha and EGF) is believed to
mediate tumor growth and proliferation.
To assess the overall response rate in VHL patients with renal tumors treated with single
To study the safety and tolerability of ZD6474
To evaluate time to progression and progression-free survival in VHL patients receiving
To study the effect of ZD6474 treatment on non-renal tumors associated with von Hippel
Lindau disease ( pancreatic tumors, pheochromocytoma, 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
To investigate the effect of ZD6474 on biomarkers of angiogenesis such as plasma VEGF and
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 (ECOG 0-2) and life expectancy (greater than 3
Single agent ZD6474 administered daily at a starting dose of 300mg per day
Patients will be evaluated for response every 12 weeks using RECIST criteria
The study is based on an open label two-stage optimal phase II design
Accrual of a maximum of 37 patients.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall response rate.
W. Marston Linehan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|