Vandetanib to Treat Advanced Kidney Cancer
Condition: Advanced Clear Cell Renal Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms
Intervention: vandetanib
Intervention description: Daily dose 300mg/day by mouth, 28 day cycle
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Clear Cell Renal Cell Carcinoma; Cancer; Renal; Renal Cell Carcinoma; Kidney Cancer

Summary:

      Background:

        -  One way tumors are able to grow is by forming new blood vessels that supply it with
           nutrients and oxygen.

        -  Vandetanib (ZD6474) is an experimental drug that blocks certain proteins on the surface
           of tumor and blood vessel cells that are involved with the formation of new blood
           vessels.

        -  Blocking these proteins may prevent the tumor cells or blood vessels from continuing to
           grow.

      Objectives:

        -  To determine whether vandetanib can cause tumors to shrink or stabilize in patients with
           advanced kidney cancer.

        -  To determine how vandetanib may work in people with kidney cancer and to develop tests
           that may be helpful in studying kidney cancer.

      Eligibility:

      -Patients 18 years of age or older with advanced clear cell kidney cancer whose disease has
      worsened after treatment with one or more of the following drugs: sunitinib, sorafenib,
      interleukin-2 and temsirolimus; or patients who have had to stop treatment with these drugs
      due to unacceptable side effects; or patients who are unable to receive standard treatment.

      Design:

        -  Patients take a vandetanib pill once a day in 28-day cycles.

        -  Patients are followed in the clinic every 2 weeks during the first month of treatment
           and then every 4 weeks for a physical examination, blood and urine tests,
           electrocardiogram and a review of any drug side effects.

        -  Patients have imaging scans (computed tomography (CT) or magnetic resonance imaging
           (MRI)) about every 8 weeks to monitor tumor growth. MRI scans are also done to look at
           tumor blood flow when treatment begins, 24 hours after the first dose of treatment, and
           again about 4 and 8 weeks after starting treatment

        -  Optional tumor biopsies (surgical removal of a sample of tumor tissue) may be done
           before starting vandetanib treatment and after 4 weeks of treatment to look for drug
           effects on the tumor.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients must meet all the following criteria to be eligible for study enrolment:

        Histologically confirmed clear cell renal cell carcinoma (to be confirmed at the Dept. of
        Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI)).

        Patients must have advanced disease (metastatic or unresectable) disease.

        Measurable disease, defined as at least one lesion that can be accurately measured in at
        least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm
        with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.

        See section 6.2 for the evaluation of measurable disease.

        Prior therapy:

          1. All patients must have either received prior sunitinib or sorafenib (discontinued for
             disease progression or unacceptable toxicity) or be unable to receive these agents.
             Patients who have discontinued sunitinib or sorafenib for life threatening toxicities
             that are also known to occur with vandetanib (such as skin, GI toxicities, bowel
             perforation etc.) will not be eligible.

          2. All patients must have failed high dose IL-2, be ineligible to receive this agent or
             decline this therapy.

             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 3,000/microL, absolute neutrophil count greater
             than or equal to 1,500/microL, platelet count greater than or equal to 100,000/microL,
             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 Gilbert's
             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))

             Recovery from acute toxicity of prior treatment for RCC (to less than or equal to
             grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v3.0).

             At least 4 weeks from completion of major surgery and a healed surgical incision.

             Negative pregnancy test in female patients of childbearing potential within 7 days of
             enrollment.

             Ability to understand and the willingness to sign a written informed consent document.

             EXCLUSION CRITERIA:

             Prior malignancy of other histology, with the exception of cervical carcinoma in situ
             or adequately treated basal or squamous cell carcinoma of the skin, or any other
             malignancy for which the patient has not required active treatment for more than three
             years.

             Patients with VHL disease will be excluded from this study.

             Patients may not be receiving any other investigational agents or have received
             treatment with a non-approved or investigational drug within 30 days before Day 1 of
             study treatment.

             Patients with known brain metastases (except when adequately treated greater than or
             equal to 6 months before enrollment with no evidence of recurrence).

             Use of 5HT-3 antagonists because of the potential effect on corrected Q wave, T wave
             (QTc) interval.

             Any concurrent medication that may cause QTc prolongation or induce Torsades de
             Pointes (Appendix C).

             Drugs listed in Appendix C, Table 2, that in the investigator's opinion cannot be
             discontinued, are allowed, but must be monitored closely.

             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.

             Patients with a history a major cardiac event more than 3 months prior to enrolment
             will be evaluated by a cardiologist to assess cardiac status and potential for
             increased risk with ZD6474 therapy.

             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 symptomatic/ 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 Bazett's correction that is unmeasurable, or greater than or equal to 480
             msec on screening 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 electrocardiograms (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 (see Appendix C,
             Group/Table 2) 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.

             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 ZD 6474 or other excipients of ZD6474.

             Concomitant medications that are potent inducers of cytochrome P450 3A4 (CYP3A4)
             function, such as rifampin, rifabutin, phenytoin, carbamazepine, barbiturates such as
             phenobarbital, or St. John's Wort.

             Inclusion of Women and Minorities:

             Both men and women and members of all races and ethnic groups are eligible for this
             trial.