Phase II Study of Vandetanib in Individuals With Kidney Cancer

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.

- 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.