DIG-HIF1 Pharmacodynamic Trial in Newly Diagnosed Operable Breast Cancer

Breast cancer cells grow in a low oxygen environment called hypoxia. The body normally
controls the amount of oxygen in cells with what is known as HIF-1, hypoxia inducible factor
1. HIF-1 helps cancer cells grow in low oxygen environments; therefore, if this function can
be blocked, it may make it harder for breast cancer cells to grow. Digoxin is a drug that has
been shown to block HIF-1 in lab studies. The investigators want to learn if it blocks HIF-1
in human breast cancer tissue. This will be done by comparing the tumor tissue from your
original diagnostic biopsy to tissue that is taken at the time of surgery. The investigators
will also be comparing tumor tissue of patients who are not randomized to take digoxin.

Inclusion Criteria:

- Female sex

- 18-70 years of age at time of consent.

- Histologically confirmed infiltrating carcinoma of the breast (Stage I-III)

- Unresected disease that meets scheduled to undergo definitive surgery; tumor size ≥
1cm; grade 2 or 3 tumor or Ki-67 proliferation index of ≥ 10%; and, any ER, PR or HER2
status

- Patients must not have received any prior treatment of any kind to treat the current
breast cancer.

- Prior use of hormone contraceptives and replacement therapy is allowed, but must have
been discontinued at least 30 days prior to the diagnostic biopsy.

- ECOG performance status of 0 or 1 (Karnofsky 80%-100%)

- Patients must have normal organ and marrow function: absolute neutrophil count (ANC) ≥
1,500/mm3; platelet count ≥ 100,000/mm3; bilirubin (total) less than or equal to the
upper limit of normal; creatinine ≤ 1.5 times the upper limit of normal with
creatinine clearance ≥ 50 mL/min using the Modified Cockcroft-Gault method; and, all
of the following within normal limits: thyroid stimulating hormone (TSH), magnesium,
potassium, sodium, calcium.

- Heart rate > 60 beats/minute and < 100 beats/minute (clinical exam).

- Not pregnant or nursing

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Current use of any investigational agents

- Radiological evidence of metastatic disease

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to digoxin

- Concomitant use of these drugs at baseline and for the duration of digoxin
administration (if randomized to receive it): the calcium channel blockers diltiazem
or verapamil; cardiac arrhythmic agents (such as quinidine, amiodarone); indomethacin
(Indocin); alprazolam (Xanax); diuretics (such as furosemide, spironolactone,
itraconazole); beta-blockers (such as atenolol, metoprolol); calcium carbonate
antacids (e.g., Maalox, Tums, Rolaids); proton pump inhibitors; antidiarrheal
adsorbents (kaolin and pectin); antibiotics; other P450 inducer/inhibitors. NOTE:
Patients already receiving digoxin are also excluded.

- Presence of any of the following on electrocardiogram (ECG): atrial arrhythmias,
including atrial fibrillation and flutter; AV block; heart rate < 60 beats/minute and
> 100 beats/minute; ventricular Fibrillation; ventricular tachycardia; premature
ventricular contractions; Wolff-Parkinson-White syndrome. NOTE: Any questions on
cardiac eligibility should be reviewed by the Study Cardiologist for approval in
advance of enrollment.

- History of any of the following, unless approval is given by the Protocol Chair: heart
disease, including acute myocardial infarction; cardiac arrhythmias, including sick
sinus syndrome; pulmonary disease with a known FEV of <1.5 or on oxygen;
gastrointestinal disease, surgery or malabsorption that could potentially impact the
absorption of the study drug; patients requiring the use of a feeding tube; inability
to swallow tablets

- 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 will limit compliance with
study requirements

- Any medical condition which in the opinion of the investigator puts the patient at
risk of potentially serious complications while on this therapy