Effect of Vandetanib on Cellular Markers in Invasive Breast Cancer

The purpose of this research study is to test whether vandetanib has an effect on tumor
growth markers. Vandetanib is not approved by the FDA for use in treating breast cancer. This
study will compare vandetanib to a placebo.

The proposed study is designed to determine the change in Ki-67 expression on paired breast
cancer samples obtained before and after treatment with vandetanib. Other tumor markers
including RET, TUNEL and phosphorylation specific levels of ERK1/2, AKT and mTOR will also be
assessed on the paired samples.

Those who have a core biopsy of the breast which demonstrates invasive breast cancer and
requires surgical excision of the lesion will be eligible for inclusion in the study. The
tyrosine kinase inhibitor, vandetanib 300 mg, will be given once a day for 7-14 days prior to
surgery. Following surgery, tissue markers would be analyzed on each of the paired samples,
allowing for rapid assessment of in vivo response to TKI treatment.

Inclusion Criteria:

- Patients with core breast biopsy that, on pathology review, demonstrates invasive
breast cancer and are determined to need surgical excision of the lesion. All subtypes
of invasive breast cancer will be enrolled. Core biopsy specimens of enrolled patients
will be stained for RET by immunohistochemistry and scored, however, patients will not
be excluded according to RET expression.

- Female gender

- Age >/= 18 years of age

- ECOG performance status
- Life expectancy of greater than 6 months

- Ability and willingness to provide informed consent to participate in study

Exclusion Criteria:

- Prolonged QT interval (QTc > 480 milliseconds) on screening EKG or congenital long QT
syndrome

- Any concomitant medications that are known to be associated with Torsades de Pointes
or QT elongation (see appendix 2).

- Hypertension not controlled by medical therapy (systolic BP greater than 160
millimeters of mercury [mmHg] or diastolic blood pressure great than 100 mmHg).

- Patients taking metformin or digoxin.

- History of arrhythmia (multifocal premature ventricular contractions, bigeminy,
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE
Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or
asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation
controlled by medication are permitted.

- Significant cardiac event (e.g., myocardial infarction), superior vena cava syndrome,
New York Heart Association (NYHA) classification of heart disease ≥2 within 12 weeks,
or presence of cardiac disease that in the opinion of the Investigator increases the
risk of ventricular arrhythmia.

- Serum calcium or magnesium outside the institutional range of normal.

- Serum Potassium < 4.0 mmol/L or above 5.0 mmol/L

- Creatinine clearance < 50 ml/min

- PT > 12 seconds or PTT > 31 seconds

- Platelet count of < 100,000

- Serum bilirubin greater than 1.5 mg/dl

- Alanine aminotransferase (ALT) > 50 U/L, aspartate aminotransferase (AST) > 65 U/L, or
alkaline phosphatase (ALP) > 250 U/L

- Any cytotoxic treatments, such as neoadjuvant chemotherapy, planned before subsequent
surgical procedure.

- Previous exposure to Vandetanib

- Previous enrollment or randomization in this study

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and staff at UIHC).

- Previous or current malignancies of other histologies within the last 5 years, with
the exception of in situ carcinoma of the cervix, and adequately treated basal cell or
squamous cell carcinoma of the skin.

- Patients who have received prior surgical site radiation.

- Patients on CYP3A4 inhibitors or inducers (see appendix 1).

- Inability to test core biopsy for study markers

- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be
performed within 2 weeks prior to randomization according to institutional standards
for women of childbearing potential.)