Clinical trial NCT01372813
Conditions: Advanced Clear Cell Renal Carcinoma
Keywords: Advanced Clear Cell Renal Cell Carcinoma Cancer Renal Renal Cell Carcinoma Kidney Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2007-12-01; Completion date: 2010-06-01
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* One way tumors are able to grow is by forming new blood vessels that supply it with nutrients and oxygen.
* Vandetanib (ZD6474) is an experimental drug that blocks certain proteins on the surface of tumor and blood vessel cells that are involved with the formation of new blood vessels.
* Blocking these proteins may prevent the tumor cells or blood vessels from continuing to grow.

Objectives:

* To determine whether vandetanib can cause tumors to shrink or stabilize in patients with advanced kidney cancer.
* To determine how vandetanib may work in people with kidney cancer and to develop tests that may be helpful in studying kidney cancer.

Eligibility:

-Patients 18 years of age or older with advanced clear cell kidney cancer whose disease has worsened after treatment with one or more of the following drugs: sunitinib, sorafenib, interleukin-2 and temsirolimus; or patients who have had to stop treatment with these drugs due to unacceptable side effects; or patients who are unable to receive standard treatment.

Design:

* Patients take a vandetanib pill once a day in 28-day cycles.
* Patients are followed in the clinic every 2 weeks during the first month of treatment and then every 4 weeks for a physical examination, blood and urine tests, electrocardiogram and a review of any drug side effects.
* Patients have imaging scans (computed tomography (CT) or magnetic resonance imaging (MRI)) about every 8 weeks to monitor tumor growth. MRI scans are also done to look at tumor blood flow when treatment begins, 24 hours after the first dose of treatment, and again about 4 and 8 weeks after starting treatment
* Optional tumor biopsies (surgical removal of a sample of tumor tissue) may be done before starting vandetanib treatment and after 4 weeks of treatment to look for drug effects on the tumor.

Detailed description:
Background:

* 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).

Objective:

Primary Objective

-To evaluate the efficacy (overall response rate) of single agent ZD6474 in advanced clear cell renal cell carcinoma (RCC).

Secondary Objectives

* 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 angiogenesis inhibition.
* 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).

Eligibility:

* 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).

Design:

* 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.

Arms: arm 1: Clear cell renal cancer is a highly vascular tumor characterized by mutations in the von Hippel-Lindau (VHL) gene in the majority of patients, an alteration that leads to overexpression vascular endothelial growth factor (VEGF) as well as other genes such as transforming growth factor-alpha, platelet derived growth factor and glucose transporter 1. Patients received ZD6474 300 mg/day by mouth daily on days 1-28.
Interventions: intervention 1: vandetanib
Intervention descriptions: intervention 1: Daily dose 300mg/day by mouth, 28 day cycle

Protocol documents: