Phase II Study of Vandetanib in Individuals With Kidney Cancer

A Phase 2 Study of ZD6474 (Vandetanib) in Patients With Von Hippel Lindau Disease and Renal Tumors

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....

Study Overview

• Status: Completed
• Conditions: Renal Cancer; Von Hippel Lindau
• Intervention / Treatment: Drug: ZACTIMA (Vandetanib) (ZD6474)

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Patients must satisfy all the following criteria to be eligible for study enrolment.

Clinical diagnosis of von Hippel Lindau disease.

The presence of at least one measurable (as defined by RECIST) renal tumor (renal cell carcinoma (RCC)). Patients with tumors localized to the kidney as well as those with metastatic RCC are eligible.

Age greater than or equal to 18 years.

Life expectancy greater than 3 months

Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.

Patients must have normal organ and marrow function as defined below: white blood cell (WBC) count greater than or equal to 3,000micro/L, absolute neutrophil count greater than or equal to 1,500 micro/L platelet count greater than or equal to 100,000 micro/L, serum creatinine less than or equal to 1.5 times upper limit of reference range or measured 24 hr. creatinine clearance greater than or equal to 50 ml/min, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 times upper limit of reference range, total bilirubin less than 1.5 times upper limit of reference range (less than 3 times upper limit of reference range in patients with Gilberts disease), alkaline phosphatase less than or equal to 2.5 times upper limit of reference range (or less than or equal to 5 times upper limit of reference range if considered to be related to liver metastases by the principal investigator (PI)).

No history of serious intercurrent medical illness.

At least four weeks from completion of any other surgical or investigational therapy for von Hippel Lindau and at least 4 weeks from any major surgical procedure. In addition, patients who have undergone recent major surgery should have well healed surgical incisions.

All men and women of childbearing potential must use effective contraception.

Negative pregnancy test in female patients of childbearing potential within 7 days prior to enrolment on study

Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Prior or concomitant non-von Hippel Lindau associated malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ or any other malignancy from which the patient has remained disease free for more than five years.

Known brain metastases (unless adequately resected or irradiated with no evidence of recurrence for at least 6 months).

Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events (to less than or equal to grade 1 Common Terminology Criteria in Adverse Events (CTCAE) v3.0) due to agents administered more than 4 weeks earlier.

Patients may not be receiving any other investigational agents or have received treatment with a non-approved or investigational drug within 4 weeks prior to Day 1 of study treatment except those used for imaging studies.

Use of 5HT-3 antagonists because of the potential effect on corrected QT interval (QTc) interval.

Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes.

Concomitant medications that are potent inducers of cytochrome P450 3A4 (CYP3A4) function, such as rifampin, rifabutin, phenytoin, carbamazepine, barbiturates such as phenobarbital, or St. Johns Wort.

Clinically significant cardiac event (including symptomatic heart failure, myocardial infarction or angina) within 3 months of entry or presence of any cardiac disease that in the opinion of the Principal Investigator increases the risk of ventricular arrhythmia.

History of clinically significant arrhythmia [including multifocal premature ventricular contraction (PVC), bigeminy, trigeminy, ventricular tachycardia] that is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia

Uncontrolled atrial fibrillation. Atrial fibrillation controlled on medication is not excluded.

Presence of Left bundle branch block.

Previous history of QTc prolongation while taking other medications that required discontinuation of that medication.

Congenital long QT syndrome or first degree relative with unexplained sudden death under the age of 40 years QTc with Bazetts correction that is unmeasurable, or greater than or equal to 480 msec on screening electrocardiogram (ECG). If a patient has QTc greater than or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than 480 msec in order for the patient to be eligible for the study). Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec.

Potassium concentration less than 4.0 mEq/L, calcium (ionized calcium or adjusted for albumin), or magnesium concentrations outside normal limits despite optimal supplementation/correction

Left ventricular ejection fraction less than 45 percent measured by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO)

Hypertension not controlled by medical therapy (systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg).

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Patient known to be human immunodeficiency virus (HIV) positive and requiring antiretroviral therapy.

Currently active diarrhea that may affect the ability of the patient to absorb ZD6474 or tolerate further diarrhea.

Patients on therapeutic anticoagulation

Patients with known bleeding disorders

Pregnant women are excluded from this study because ZD6474 is an anti-angiogenic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZD6474, breastfeeding should be discontinued if the mother is treated with ZD6474.

Any known hypersensitivity to ZD6474 or other excipients of ZD6474.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vandetanib in Participants with Kidney Cancer; 300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days	Drug: ZACTIMA (Vandetanib) (ZD6474); Other Names: Vandetanib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate.	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.	Baseline and every 3 cycles, up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.	72 months and 14 days
Time To Progression (TTP)	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.	Baseline and every 3 cycles while on study, up to 2 years.
Progression Free Survival (PFS)	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.	Baseline and every 3 cycles while on study, up to 2 years.
Effect of Vandetanib (ZD6474) on Endothelial Progenitor Cells	Peripheral blood was collected and analyzed by multiparametric flow cytometry for analysis of angiogenesis markers.	Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)
Effect of Vandetanib (ZD6474) on Circulating Endothelial Cells (CEC)	Peripheral blood was collected and analyzed by multiparametric flow cytometry.	Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)
Response in Pancreatic Tumors/Cysts Associated With Von Hippel Lindau (VHL)	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.	Baseline and every 3 cycles while on study, up to 2 years.
Response in Central Nervous System (CNS) Hemangioblastomas Associated With Von Hippel Lindau (VHL)	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.	Baseline and every 3 cycles while on study, up to 2 years.
Response in Pheochromocytomas Associated With Von Hippel Lindau (VHL)	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.	Baseline and every 3 cycles while on study, up to 2 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Biomarkers Vascular Endothelial Growth Factor (VEGF) and Soluble Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Before and After Treatment With Vandetanib	5-10cc venous blood was collected for evaluation of basal plasma levels of angiogenesis biomarkers VEGF and VEGFR-2.	Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA. 1995 Feb 15;273(7):564-70. No abstract available.
• Clifford SC, Maher ER. Von Hippel-Lindau disease: clinical and molecular perspectives. Adv Cancer Res. 2001;82:85-105. doi: 10.1016/s0065-230x(01)82003-0.
• Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. doi: 10.1038/nrc885.
• Brooks S, Linehan WM, Srinivasan R, Kong HH. Successful laser treatment of vandetanib-associated cutaneous pigmentation. Arch Dermatol. 2011 Mar;147(3):364-5. doi: 10.1001/archdermatol.2011.30. No abstract available.
• Vitael, S, Cunningham, D. Meleth, A., Bishop R., Clayton, Datile, M, Linehan WM, Srinivasan R, Meyerle, C. Development of a New Grading System for Corneal Verticillata. ARVO meeting May 8, 2013
• Vitael, S, Cunningham, D. Meleth, A., Bishop R., Clayton, Datile, M, Linehan WM, Srinivasan R, Meyerle, C. Development of a New Grading System for Corneal Verticillata. ARVO meeting May 2012.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2008
• Primary Completion (Actual): June 20, 2014
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: December 1, 2007
• First Submitted That Met QC Criteria: December 1, 2007
• First Posted (Estimate): December 4, 2007

Study Record Updates

• Last Update Posted (Actual): October 30, 2018
• Last Update Submitted That Met QC Criteria: October 2, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: EGFR Inhibitor; VEGFR Inhibitor; VHL; Von Hippel Lindau; Kidney Tumor; Kidney Tumors; Clear Cell Renal Cancer
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Neurocutaneous Syndromes; Ciliopathies; Angiomatosis; Kidney Neoplasms; Carcinoma, Renal Cell; Von Hippel-Lindau Disease
• Other Study ID Numbers: 080020; 08-C-0020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No