Vandetanib to Treat Advanced Kidney Cancer

Phase 2

Terminated

Conditions: Advanced Clear Cell Renal Carcinoma

Interventions: Drug: vandetanib

Registration Number: NCT01372813

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Clear Cell Renal Carcinoma	vandetanib	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Clinical Response (Partial Response (PR) + Clinical Response (CR))	12 months	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.

Secondary Outcome Measures

Name	Time	Method
Effect of Vandetanib on Plasma Biomarkers-vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor 2 (VEGFR2)	12 months	Plasma VEGFR and VEGFR2 would have been measured using the (enzyme-linked immunosorbent assay)ELISA at baseline and specified timepoints following initiation of therapy.
Progression-free Survival as Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	12 months	Progression free survival is defined as the time from initiation of treatment to either progression or death. RECIST evaluates tumor response. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. For detailed information about RECIST, see the protocol Link module.
Number of Participants With Adverse Events	11.5 months	Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Number of Circulating Endothelial Cells (CEC) Per 10^6 Mononuclear Cells or Per Microliter of Peripheral Blood Analyzed in Samples Taken Before and After Treatment	12 months	CEC cell concentrations are calculated as a percentage of the total number of mononuclear cells or as the number of cells/microliter of whole blood after an evaluation of a minimum of 10\^5 cellular events, and preferably 10\^6 cellular events.
Number of Participants With Vandetanib (ZD6474) Effects on Tumor Vascular Flow and Permeability Using Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI)	12 months	Flow dynamics within specific tumor sites will be evaluated based on the results of the DCE-MRI obtained first without contrast enhancement and then after contrast enhancement. The parameter to be measured is the forward contrast transfer rate (Ktrans), the reverse contrast transfer rate (Kep), and/or the extravascular extracellular space volume fraction (Ve). Flow dynamics are a measure of blood flow changes in the tumor and are determined using the parameters previously defined (Ktrans, Kep, etc.).
Tumor Tissue Used to Evaluate Von Hippel-Lindau (VHL) Status and/or Components of the Vascular Endothelial Growth Factor (VEGF)/Epidermal Growth Factor Receptor (EGFR) Pathway	12 months	Components of the VEGF and EGFR pathways were to be evaluated using Western blot analysis at baseline and specified timepoints following initiation of therapy when tumor tissue was available.
The Effects of ZD6474 (Vandetanib) on Tumor Microvessel Density	12 months	Tumor tissue sections were to be stained with hematoxylin and eosin (H and E) and endothelial cell markers at baseline and specified timepoints following initiation of therapy (when tumor tissue was available)
Evaluate The Correlation Between Von Hippel-Lindau (VHL) Mutational Status and Response to ZD6474 (Vandetanib)	12 months	If an adequate number of responses were seen, the relation of these responses to the presence/absence of inactivating VHL mutations in tumor tissue would have been assessed.
Number of Circulating Endothelial Progenitor Cells (CEP) Per 10^6 Mononuclear Cells or Per Microliter of Peripheral Blood Analyzed in Samples Taken Before and After Treatment	12 months	CEP cell concentrations are calculated as a percentage of the total number of mononuclear cells or as the number of cells/microliter of whole blood after an evaluation of a minimum of 10\^5 cellular events, and preferably 10\^6 cellular events.