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

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

Detailed Description
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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.

Official Title
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Digoxin as a Novel Inhibitor of Global Hypoxia Inducible Factor-1α (HIF-1α) Expression & Downstream Targets in Breast Cancer: DIG-HIF-1 Pharmacodynamic Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Digoxin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Digoxin<br>Digoxin administration for 2 weeks prior to surgery. | Drug: Digoxin<br>* Digoxin once daily for 2 weeks prior to definitive breast surgery.<br>|
| No Intervention: No drug administration prior to surgery<br>Group of participants who will not receive digoxin; however, tissue will be collected at time of definitive breast surgery. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HIF-1α Protein Expression | 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. | Baseline (biopsy prior to surgery) and at the end of 2 weeks digoxin treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events With Digoxin Treatment | 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. | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Digoxin