Phase II Study of Vandetanib in Individuals With Kidney Cancer

Phase 2

Completed

Conditions: Renal Cancer
Von Hippel Lindau

Interventions: Drug: ZACTIMA (Vandetanib) (ZD6474)

Registration Number: NCT00566995

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Vandetanib in Participants with Kidney Cancer	ZACTIMA (Vandetanib) (ZD6474)	300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days

Primary Outcome Measures

Name	Time	Method
Overall Response Rate.	Baseline and every 3 cycles, up to 2 years	Overall response rate is defined as the percentage of participants with either a partial or complete response occurring at any time after initiation of therapy. Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Complete response (CR) is a disappearance of all target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease), taking as reference the smallest sum LD since the treatment started.

Secondary Outcome Measures

Name	Time	Method
Response in Pancreatic Tumors/Cysts Associated With Von Hippel Lindau (VHL)	Baseline and every 3 cycles while on study, up to 2 years.	Tumor measurements for non-renal tumors were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Tumor measurements for non-renal tumors were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest um LD recorded since treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Time To Progression (TTP)	Baseline and every 3 cycles while on study, up to 2 years.	Time to progression is defined as the time from the start of treatment to progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, with death being treated as a censored event. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Complete response (CR) is a disappearance of all target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, the appearance of one or more new lesions, developing a surgical size tumor that should be resected. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease), taking as reference the smallest sum LD since the treatment started.
Progression Free Survival (PFS)	Baseline and every 3 cycles while on study, up to 2 years.	Progression free survival is defined as time from initiation of treatment to either progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Complete response (CR) is a disappearance of all target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease), taking as reference the smallest sum LD since the treatment started.
Effect of Vandetanib (ZD6474) on Endothelial Progenitor Cells	Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)	Peripheral blood was collected and analyzed by multiparametric flow cytometry for analysis of angiogenesis markers.
Effect of Vandetanib (ZD6474) on Circulating Endothelial Cells (CEC)	Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)	Peripheral blood was collected and analyzed by multiparametric flow cytometry.
Number of Participants With Adverse Events	72 months and 14 days	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Response in Central Nervous System (CNS) Hemangioblastomas Associated With Von Hippel Lindau (VHL)	Baseline and every 3 cycles while on study, up to 2 years.	Tumor measurements for non-renal tumors were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest um LD recorded since treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Response in Pheochromocytomas Associated With Von Hippel Lindau (VHL)	Baseline and every 3 cycles while on study, up to 2 years.	Tumor measurements for non-renal tumors were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Tumor measurements for non-renal tumors were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest um LD recorded since treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.