Vandetanib to Treat Advanced Kidney Cancer
Vandetanib to Treat Advanced Kidney Cancer
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.
Background:

 -  von Hippel-Lindau (VHL) inactivation by mutation or promoter hypermethylation is seen in
 a high proportion of sporadic clear cell renal cancers.

 -  Inactivation of VHL 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-a), platelet derived growth factor (PDGF), and erythropoietin, which are
 believed to play a role in tumorigenesis, tumor progression and metastasis.

 -  Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2
 (kinase insert domain receptor (KDR)/vascular endothelial growth factor 2 (VEGFR2)) is
 an endothelial cell receptor for vascular endothelial growth factor (VEGF) and plays a
 crucial role in mediating tumor angiogenesis, while EGFR (a receptor for TGF-a and
 epidermal growth factor (EGF) is believed to mediate tumor growth and proliferation.

 -  ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity
 against the KDR/VEGFR2 and the epidermal growth factor receptor (EGFR).

 Objective:

 Primary Objective

 -To evaluate the efficacy (overall response rate) of single agent ZD6474 in advanced clear
 cell renal cell carcinoma (RCC).

 Secondary Objectives

 -  To evaluate progression free survival in patients treated with ZD6474.

 -  To study the safety and tolerability of ZD6474.

 -  To evaluate the correlation between VHL mutational status and response to ZD6474.

 -  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 potential biomarkers of angiogenesis in plasma
 such as VEGF and soluble VEGFR2.

 -  To study the effect of ZD6474 treatment on tumor vascular flow and permeability using
 dynamic contrast enhanced magnetic resonance imaging.

 -  To investigate the effect of ZD6474 on EGFR and VEGFR mediated signaling using tumor
 biopsy tissue (when available).

 Eligibility:

 -  Adults with measurable advanced clear cell renal carcinoma

 -  Patients must have received no more than three prior systemic therapies (no more than
 two agents known to inhibit VEGF or VEGFR) and must have either progressed on or be
 unable to receive 1) Sunitinib or sorafenib, and 2) High dose interleukin-2 (IL-2).

 Design:

 -  Single agent ZD6474 administered daily at a dose of 300mg/day.

 -  Patients will be evaluated for response every 8 weeks using Response Evaluation Criteria
 in Solid Tumors (RECIST) criteria.

 -  The study is based on an open label Simon two-stage optimal phase II design and will
 accrue a maximum of 37 patients.
-  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.