Renal CancerPhase 2NCT00566995
Phase II Study of Vandetanib in Individuals With Kidney Cancer
A Phase 2 study testing ZACTIMA (Vandetanib) (ZD6474) in people with Renal Cancer and Von Hippel Lindau, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Renal Cancer, Von Hippel Lindau
- What is being tested?
- ZACTIMA (Vandetanib) (ZD6474)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 1 siteUnited States
- Study dates
- 7 Feb 2008to Mar 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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....
Read the 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.
- Conditions
- Renal Cancer, Von Hippel Lindau
- Being tested
- ZACTIMA (Vandetanib) (ZD6474)
- Keywords
- Kidney Tumors, Clear Cell Renal Cancer, VEGFR Inhibitor, EGFR Inhibitor, VHL, Von Hippel Lindau, Kidney Tumor
- Medical subject headings
- Kidney Neoplasms, Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZACTIMA (Vandetanib) (ZD6474)Drug
Also called Vandetanib
| Study group | Role | What they receive |
|---|---|---|
| Vandetanib in Participants with Kidney Cancer | Experimental | 300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days Receives: Drug: ZACTIMA (Vandetanib) (ZD6474) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and every 3 cycles, up to 2 years
Secondary outcomes (8)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and every 3 cycles while on study, up to 2 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2007 (estimated)
- Study start7 Feb 2008
- Primary completion20 Jun 2014
- Study completionMar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Renal CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, W. Marston Linehan, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- W. Marston Linehan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00566995
- Sponsor's protocol ID
- 080020
- Other IDs
- 08-C-0020
- Status last verified
- Oct 2018
- First submitted
- 1 Dec 2007
- Last updated
- 30 Oct 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 7837390Clifford 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.
PubMed 11447766Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. doi: 10.1038/nrc885.
PubMed 12209156Brooks 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.
PubMed 21422355Vitael, 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.
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Study of ZD6474 (Vandetanib) in Patients With Von Hippel Lindau Disease and Renal Tumors
- ClinicalTrials.gov ID
- NCT00566995
- Acronym / sponsor ID
- 080020
- Conditions
- Renal Cancer, Von Hippel Lindau
- Keywords
- Kidney Tumors, Clear Cell Renal Cancer, VEGFR Inhibitor, EGFR Inhibitor, VHL, Von Hippel Lindau, Kidney Tumor
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 7 Feb 2008 (actual)
- Primary completion
- 20 Jun 2014 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 4 Dec 2007 (estimated)
- Results
- Posted 11 Mar 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Vandetanib in Participants with Kidney Cancer | Experimental | Drug: ZACTIMA (Vandetanib) (ZD6474)300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZACTIMA (Vandetanib) (ZD6474)Also: Vandetanib | Drug | Vandetanib in Participants with Kidney Cancer |
Primary outcome
Overall Response Rate.
Time frame: 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.
8 secondary outcomes
Number of Participants With Adverse Events
Time frame: 72 months and 14 days
Time To Progression (TTP)
Time frame: Baseline and every 3 cycles while on study, up to 2 years.
Progression Free Survival (PFS)
Time frame: Baseline and every 3 cycles while on study, up to 2 years.
Effect of Vandetanib (ZD6474) on Endothelial Progenitor Cells
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Baseline and every 3 cycles while on study, up to 2 years.
Response in Pheochromocytomas Associated With Von Hippel Lindau (VHL)
Time frame: Baseline and every 3 cycles while on study, up to 2 years.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 7837390Linehan 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.
- Background: PubMed 11447766Clifford 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.
- Background: PubMed 12209156Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. doi: 10.1038/nrc885.
- Background: PubMed 21422355Brooks 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.
- BackgroundVitael, 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
- BackgroundVitael, 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
W. Marston Linehan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ZACTIMA (Vandetanib) (ZD6474) in people with Renal Cancer and Von Hippel Lindau, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Mar 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Response Rate. (time frame: Baseline and every 3 cycles, up to 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00566995, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2018.