A Phase II Study of ZD6474 (Vandetanib) in Subjects With Advanced Clear Cell Renal Carcinoma
- von Hippel-Lindau (VHL) inactivation by mutation or promoter hypermethylation is seen
in a high proportion of sporadic clear cell renal cancers.
- Inactivation of VHL 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-a), platelet derived growth factor (PDGF), and erythropoietin, which are
believed to play a role in tumorigenesis, tumor progression and metastasis.
- Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2
(kinase insert domain receptor (KDR)/vascular endothelial growth factor 2 (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-a and
epidermal growth factor (EGF) is believed to mediate tumor growth and proliferation.
- ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity
against the KDR/VEGFR2 and the epidermal growth factor receptor (EGFR).
-To evaluate the efficacy (overall response rate) of single agent ZD6474 in advanced clear
cell renal cell carcinoma (RCC).
- To evaluate progression free survival in patients treated with ZD6474.
- To study the safety and tolerability of ZD6474.
- To evaluate the correlation between VHL mutational status and response to ZD6474.
- 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
- To investigate the effect of ZD6474 on potential biomarkers of angiogenesis in plasma
such as VEGF and soluble VEGFR2.
- To study the effect of ZD6474 treatment on tumor vascular flow and permeability using
dynamic contrast enhanced magnetic resonance imaging.
- To investigate the effect of ZD6474 on EGFR and VEGFR mediated signaling using tumor
biopsy tissue (when available).
- Adults with measurable advanced clear cell renal carcinoma
- Patients must have received no more than three prior systemic therapies (no more than
two agents known to inhibit VEGF or VEGFR) and must have either progressed on or be
unable to receive 1) Sunitinib or sorafenib, and 2) High dose interleukin-2 (IL-2).
- Single agent ZD6474 administered daily at a dose of 300mg/day.
- Patients will be evaluated for response every 8 weeks using Response Evaluation
Criteria in Solid Tumors (RECIST) criteria.
- The study is based on an open label Simon two-stage optimal phase II design and will
accrue a maximum of 37 patients.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With a Clinical Response (Partial Response (PR) + Clinical Response (CR))
Clinical response is the best response recorded from the start of treatment until disease progression. Clinical response is assessed by the Response Evaluation in Solid Tumors (RECIST) criteria. A partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. A complete response (CR) is the disappearance of all target lesions.
Marston Linehan, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|