Phase II Study of Vandetanib in Individuals With Kidney Cancer
Condition: Renal Cancer; Von Hippel Lindau
MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell; Von Hippel-Lindau Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will examine the effectiveness of an investigational drug called ZD6474 (also
      known as vandetanib or ZACTIMA). Vandetanib is an experimental drug that is designed to
      prevent the growth and development of new blood vessels on tumors and to prevent the direct
      growth of cancer cells. It has been tested in a number of clinical trials on adults with
      cancer, but the United States (U.S.) Food and Drug Administration has not specifically
      approved it as a cancer treatment. The purpose of this investigational study is to better
      understand how vandetanib affects humans who have kidney cancer related to von Hippel-Lindau
      (VHL) disease, and to develop tests that may improve researchers understanding of kidney
      cancer and its effects.

      Volunteers must be at least 18 years old and must have been diagnosed with kidney cancer
      related to VHL. Candidates must have a life expectancy greater than three months and must
      have at least one measurable renal tumor for study purposes. Candidates may not be receiving
      any other investigational agents or have been treated with an investigational drug within the
      past four weeks. Candidates who have had surgery, chemotherapy, or radiotherapy within the
      past four weeks will be excluded from the study. Candidates will be screened with a physical
      examination and medical history.

      During the study, participants will receive an oral dose of vandetanib once a day for 28 days
      (a treatment period known as a cycle). Participants will need to return to the National
      Institutes of Health every two weeks on the same day of the week as the first dose of
      vandetanib for a series of tests and procedures, including blood and urine tests and an
      electrocardiogram. Every 12 weeks, computerized tomography (CT) or magnetic resonance imaging
      (MRI) scans will be done to assess the size of participants tumors. Participants whose tumors
      do not grow and who do not have unacceptable side effects may continue to receive vandetanib
      to maintain the current condition, until researchers conclude the study....
    

Detailed description: 
      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.
    

Intervention name(s): ZACTIMA (Vandetanib) (ZD6474)
Intervention type(s): Drug
Other intervention name(s): Vandetanib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney Tumors; Clear Cell Renal Cancer; VEGFR Inhibitor; EGFR Inhibitor; VHL; Von Hippel Lindau; Kidney Tumor