Phase II Study of Vandetanib in Individuals With Kidney Cancer

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Brief Title

Phase II Study of Vandetanib in Individuals With Kidney Cancer

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Response Rate.

Secondary Outcome

 Number of Participants With Adverse Events

Condition

Renal Cancer

Intervention

ZACTIMA (Vandetanib) (ZD6474)

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

37

Start Date

February 7, 2008

Completion Date

March 2015

Primary Completion Date

June 20, 2014

Eligibility Criteria

        -  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.
      

Gender

All

Ages

18 Years - 100 Years

Accepts Healthy Volunteers

No

Contacts

W. Marston Linehan, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00566995

Organization ID

080020

Secondary IDs

08-C-0020

Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

W. Marston Linehan, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

October 2018