Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Vandetanib in Treating Patients With Unresectable or Metastatic Kidney Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	NCI-08-C-0039 08-C-0039, NCI-P07217, NCT00608114

Special Category: NIH Clinical Center trial, NCI Web site featured trial

Objectives

Primary

1. To assess the efficacy (i.e., overall response rate, complete response, and partial response) of vandetanib in patients with metastatic or unresectable clear cell renal cell cancer.

Secondary

1. To evaluate progression-free survival in patients treated with this drug.
2. To study the safety and tolerability of this drug in these patients.
3. To evaluate the correlation between von Hippel-Lindau mutational status and response in patients treated with this drug.
4. To investigate the effect of this drug on circulating endothelial cells and endothelial progenitor cells and to explore the utility of these markers as surrogates of angiogenesis inhibition.
5. To investigate the effect of this drug on potential biomarkers of angiogenesis in plasma such as VEGF and soluble VEGFR2.
6. To study the effect of this drug therapy on tumor vascular flow and permeability using dynamic contrast-enhanced MRI.
7. To investigate the effect of this drug on EGFR and VEGFR mediated signaling using tumor biopsy tissue from these patients (when available).

Entry Criteria

Disease Characteristics:

• Histologically confirmed clear cell renal cell carcinoma
  • Metastatic or unresectable disease



• Measurable disease, defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan



• Must have received prior sunitinib or sorafenib (discontinued for disease progression or unacceptable toxicity) OR be ineligible to receive sunitinib or sorafenib
  • Patients who discontinued sunitinib or sorafenib for life-threatening toxicities that are also known to occur with vandetanib (i.e., skin, gastrointestinal toxicities, or bowel perforation) are eligible provided, in the opinion of the investigator, the life-threatening event is not likely to recur with vandetanib



• Must have failed, be ineligible to receive, or decline treatment with high-dose aldesleukin



• No von Hippel-Lindau disease



• No known brain metastases except when adequately treated ≥ 6 months prior to study entry and no evidence of recurrence

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from acute toxicity of prior therapy (to ≤ grade 1 CTCAE v3.0)
• At least 4 weeks since prior major surgery and surgical incision has healed
• At least 30 days since prior and no other concurrent investigational agents
• No concurrent 5HT-3 antagonists
• No concurrent drugs that could induce Torsades de pointes
• No concurrent antiretroviral therapy for HIV-positive patients
• No concurrent potent inducers of CYP3A4 function (e.g., rifampin, rifabutin, phenytoin, carbamazepine, or barbiturates such as phenobarbital or Hypericum perforatum [St. John wort])
• No blood donation during and for 3 months after the last dose of study drug

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy > 3 months
• WBC ≥ 3,000/mm³
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or creatinine clearance ≥ 50 mL/min
• AST and ALT < 2.5 times ULN
• Total bilirubin < 1.5 times ULN (3 times ULN for patients with Gilbert disease)
• Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
• Potassium concentration ≥ 4.0 mEq/L
• Calcium (ionized calcium or adjusted for albumin) and magnesium concentrations normal
  • Optimal supplementation/correction allowed
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after completion of study treatment
• No prior malignancy of other histology except carcinoma in situ of the cervix or adequately treated basal cell or squamous cell carcinoma of the skin, or any other malignancy for which the patient has not required active treatment for > 3 years
• No clinically significant cardiac event within the past 3 months, including any of the following:
  • Symptomatic congestive heart failure
  • Myocardial infarction
  • Angina
• No cardiac disease that, in the opinion of the principal investigator, increases the risk of ventricular arrhythmia
• No history of clinically significant cardiac arrhythmia that is symptomatic or requires treatment (CTCAE grade 3), including any of the following:
  • Multifocal premature ventricular contraction (PVC)
  • Bigeminy
  • Trigeminy
  • Ventricular tachycardia
  • Asymptomatic sustained ventricular tachycardia
• No uncontrolled atrial fibrillation (atrial fibrillation controlled on medication is allowed)
• No left bundle-branch block
• No history of QTc prolongation while taking other medications that required discontinuation of that medication
• No congenital long QT syndrome or first-degree relative with unexplained sudden death under the age of 40
• No QTc with Bazett's correction unmeasurable or ≥ 480 msec on screening ECG OR > 480 msec on average of 3 ECGs taken 24 hours apart
  • Patients who are receiving a drug that has a risk of QTc prolongation are not eligible if QTc is ≥ 460 msec
• LVEF ≥ 45% by MUGA or ECHO
• No hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg) despite medical therapy
• No uncontrolled intercurrent illness including, but not limited to, any of the following:
  • Ongoing or active infection
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirement
• No active diarrhea that may affect the ability of the patient to absorb study drug or tolerate further diarrhea
• No hypersensitivity to vandetanib or its excipients

Expected Enrollment

Outcomes

Clinical response (i.e., complete or partial response)

Effect of vandetanib on EGFR and VEGFR mediated signaling; tumor microvessel density, plasma biomarkers of angiogenesis such as VEGF; tumor vascular flow and permeability as measured by DCE-MRI
Effect of vandetanib on circulating endothelial progenitor cells and circulating endothelial cells
Progression-free survival as defined by RECIST criteria
Safety and tolerability

Outline

Patients receive oral vandetanib once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo dynamic contrast-enhanced MRI at baseline, 24 hours after the first dose of study drug, and at the end of courses 1 and 2 to measure tumor vascular flow and permeability. Blood is collected at weeks 1 and 3 of course 1, at the beginning of course 2 and each subsequent course, and then at the completion of study treatment. Samples are analyzed by immunohistochemistry to evaluate the effect of vandetanib on tumor microvessel density, proliferation and apoptosis; RT-PCR for transcriptional targets affected by EGFR and VEGF signaling pathways, including p27, KIP1, E-cadherin, and b-catenin; cDNA arrays to compare gene expression profiles in tumor cells before and during treatment with vandetanib; and flow cytometry for evaluation of basal plasma levels of angiogenesis biomarkers such as VEGF. HIF, EGFR, and VEGFR2 expression may be performed on available resected primary tumors to explore the correlation between these biomarkers and clinical response.

After completion of study treatment, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

William Linehan, MD, Principal investigator		Ph: 301-496-6353

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Related Information

Featured trial article

Registry Information
Official Title		A Phase II Study of ZD6474 (vandetanib) in Subjects with Advanced Clear Cell Renal Carcinoma
Trial Start Date		2007-09-15
Trial Completion Date		2009-09-15 (estimated)
Registered in ClinicalTrials.gov		NCT00608114
Date Submitted to PDQ		2008-01-18
Information Last Verified		2008-03-30

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