DIG-HIF-1 Pharmacodynamic Trial in Newly Diagnosed Operable Breast Cancer

Phase 2

Completed

Conditions: Breast Cancer

Interventions: Drug: Digoxin

Registration Number: NCT01763931

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary: The purpose of this study is to learn what effects digoxin (DIG) may have on human breast cancer tissue.

Detailed Description: 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 Hypoxia-inducible factor (HIF)-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 the 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 6

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 estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (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.
Eastern Cooperative Oncology Group (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 forced expiratory volume (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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Digoxin	Digoxin	Digoxin administration for 2 weeks prior to surgery.

Primary Outcome Measures

Name	Time	Method
Change in HIF-1α Protein Expression	Baseline (biopsy prior to surgery) and at the end of 2 weeks digoxin treatment	To assess whether two weeks of daily oral digoxin therapy, as compared to no study drug, reduces the expression of Hypoxia-inducible factor (HIF)-1α protein, measured by immunohistochemistry (IHC), in surgically resected breast cancer tissue obtained from women undergoing lumpectomy or mastectomy for invasive breast cancer.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events With Digoxin Treatment	2 weeks	To assess safety and tolerability of two weeks of digoxin therapy in the pre-surgical setting graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.