Metformin Hydrochloride and Doxycycline in Treating Patients With Localized Breast or Uterine Cancer

PRIMARY OBJECTIVES:

I. To determine if treatment with a combination of metformin and doxycycline can increase the
percentage of cells that express Caveolin-1 in the cancer associated fibroblasts of patients
with breast, or uterine, and cervical cancers.

SECONDARY OBJECTIVES:

I. To determine the effect of metformin and doxycycline treatment on the percentage of cells
that express monocarboxylate transporter (MCT)4 in cancer associated fibroblasts and MCT1 and
transporter of outer mitochondrial membrane (TOMM)20 in the cancer cells of breast and
uterine cancer patients.

II. To assess safety and tolerability of metformin and doxycycline treatment in subjects with
breast and uterine cancer.

III. To determine the relationship of the percentage of stromal cells expressing caveolin
(CAV)1 or MCT4 and tumor cells that express MCT1 and TOMM20 at baseline and after treatment
with metformin and doxycycline with the percentage of cells expressing estrogen receptor (ER)
and progesterone receptor (PR) for breast and uterine samples and human epidermal growth
factor (HER)2 in breast cancer samples.

TERTIARY OBJECTIVES:

I. To assess the effect of combined metformin and doxycycline therapy on the metabolic
profile of cancer cells and stroma using mass spectroscopy imaging (MSI) on paired samples,
comparing metabolite profiles in the pre-metformin and post-metformin tumor sample.

II. To assess, when possible, the impact of a patient's nutritional status, estimated using 3
day dietary recall versus caloric needs as calculated by the Harris-Benedict equation on the
baseline and net change in CAV1 III. To assess the effect of combined metformin and
doxycycline therapy on oncomiR micro ribonucleic acid (RNA) (miR-21) after intervention.

IV. To assess the effect of combined metformin and doxycycline therapy on adipokines and the
insulin-like growth factor (IGF)-1/insulin signaling pathways through assessment of serum
triglycerides, IGF-1, IGF-binding protein (BP)3, erythrocyte sedimentation rate (ESR),
adiponectin, leptin, IGF-1 receptor (R), exosome evaluation, metabolomics profile, and
microRNA expression profile.

Inclusion Criteria:

In order to be eligible for participation in this trial, the subject must:

1. Diagnosis of localized breast or uterine cancer that is either biopsy proven or
suspected based on history, physical, and or radiographic findings, and who are
planned for definitive resection of the tumor without the use of neoadjuvant
chemotherapy or radiation therapy at TJUH are eligible to participate.

2. Subjects must be ≥ 18 years of age at time of consent.

3. Subjects must be newly diagnosed or suspected to have breast, uterine (endometrial
cancer with histologies including endometrioid, serous, clear cell, and
carcinosarcoma) or cervical cancer.

4. Patient must be able to swallow pills.

5. Patients with serum creatinine levels less than 1.5 mg/dL.

6. Women of child bearing potential must have a negative urine or blood pregnancy test
within 14 days of study enrollment.

7. Informed Consent: All subjects must be able to comprehend and sign a written informed
consent document.

8. ECOG Performance status <1

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

1. Received any prior cancer therapy for the breast or uterine cancer that is being
resected, including progesterone therapy for endometrial cancer patients.

a. Patients may have had prior therapy for other contra-lateral breast cancer.

2. Subjects who are pregnant or breastfeeding or may become pregnant during metformin and
doxycycline administration.

3. Subjects on metformin or doxycycline for any reason during the preceding 4 weeks.

4. Diabetic subjects that are managed by taking metformin or insulin.

5. Subjects who have received iodinated contrast dye must wait 12 hours prior to starting
Metformin. If a CT scan with contrast is scheduled after screening and consent, the
metformin cannot be taken until after the CT with contrast has been completed and they
have waited 12 hours.

6. Patients with serum creatinine level greater than 1.5 mg/dL.

7. Patients with history of lactic or any other metabolic acidosis.

8. Patients with history of congestive heart failure stage III or greater.

9. Patients scheduled for definitive cancer surgical resection less than 7 days from
beginning of study drug administration or greater than 6 weeks from beginning study
drug administration.

10. Patients with history of hepatic dysfunction or hepatic disease and abnormal liver
function tests defined as AST, ALT, Alk Phos, and or total bilirubin greater than 2.5
times the upper limit of normal.

a. Patients who have a history of hepatic dysfunction or hepatic disease and normal
liver function tests will be eligible to participate.

11. Patients with a current history (in the past 30 days) of heavy drinking which is
defined in accordance with CDC definition as more than 8 drinks per week for women and
more than 15 drinks per week for men. A standard drink contains .6 ounces of pure
alcohol. Generally, this amount of pure alcohol is found in 12-ounces of beer,
8-ounces of malt liquor, 5-ounces of wine, 1.5-ounces or a "shot" of 80-proof
distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey). While on study,
patients should limit their alcohol consumption to no more than 8 drinks per week for
women and no more than 15 drinks per week for men. Patients who feel they cannot
comply with this recommendation are not eligible.

12. Prior allergic reaction to metformin, doxycycline, or any other tetracycline
antibiotic in the past.

13. Patient is on medications that are contraindicated with metformin or doxycycline under
current FDA recommendations. The following is a list of medications identified as
class D (consider therapy modification) when treatment with metformin or doxycycline
is considered:

- Class D:

- Bismuth Subsalicylate

- Cimetidine

- Iodinated contrast agents

- Somatropin