Komen Foundation Funding Terminated

The goal of this clinical research study is to learn if exemestane and everolimus combined with metformin can help to control breast cancer in patients who are obese or overweight and post-menopausal with hormone-receptor-positive breast cancer that has spread to other parts of the body.

Exemestane is designed to decrease the ability of estrogen to help cancer cells grow. This could cause the cancer cells to die.

Metformin is commonly used to control blood sugar levels in patients with diabetes. It is designed to lower insulin levels, which may slow or stop the growth of breast cancer cells.

Everolimus is designed to block cells from dividing. This may cause cancer cells to die. Everolimus may also stop the growth of new blood vessels that help tumors grow.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take an exemestane and everolimus tablet by mouth every day. You will also take tablets of metformin by mouth 2 times a day. The drugs should be taken at about the same time each day.

The study drugs will be given in 28-day cycles.

Study Visits:

On Day 1:

• You will have a physical exam, including a measurement of your weight and vital signs.
• You will be asked about any side effects you may be having.
• You will be asked about any drugs you may have taken or may be taking.
• Your performance status will be recorded.
• Blood (about 1-2 teaspoons) will be drawn for routine tests.
• Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.

At Weeks 4 and 12:

• You will have a physical exam, including a measurement of your vital signs.
• You will be asked about any side effects you may be having.
• You will be asked about any drugs you may have taken or may be taking.
• Blood (about 1-2 teaspoons) will be drawn for routine tests.
• Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.

At Weeks 8, 16 and then every 2 months after that, and after your last dose of study drugs:

• You will have a physical exam, including a measurement of your vital signs.
• You will be asked about any side effects you may be having.
• You will be asked about any drugs you may have taken or may be taking.
• Blood (about 1-2 teaspoons) will be drawn for routine tests.
• Blood (about 4 teaspoons) will be drawn for biomarker testing (at weeks 8, 16 and 24 only).
• Blood (about 1 teaspoon) will be drawn for blood sugar tests. If you have a history of diabetes, you will need to fast for 8 hours before these blood sugar tests.
• You will have imaging scans to check the status of the disease.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Exemestane is FDA approved and commercially available for the treatment of metastatic breast cancer. Metformin is FDA approved and commercially available for the treatment of diabetes. Everolimus is FDA approved and commercially available to treat metastatic breast cancer, advanced kidney cancer in some patients and a certain type of brain tumor. The use of this drug combination is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Postmenopausal overweight or obese women with a history of biopsy-proven hormone receptor-positive breast cancer and clinical evidence of metastatic disease. Overweight is defined as body mass index (BMI) of 25 - 29.9 kg/m2 while obese is defined as BMI >/= 30 kg/m2. Postmenopausal status is defined by one of the following: a) no spontaneous menses for over 1 year, in women >/=55 years; b) no spontaneous menses within the past 1 year in women < 55 years with postmenopausal gonadotrophin levels (LH and FSH levels > 40 IU/L) or postmenopausal estradiol levels (by local laboratory range); or c) bilateral oophorectomy.
2. Prior hormonal therapy for metastatic breast cancer is allowed. Patients who develop progressive metastatic disease on a non-steroidal aromatase inhibitor are eligible. Patients who develop metastatic disease while receiving a non-steroidal aromatase inhibitor in the adjuvant setting are eligible.
3. One prior chemotherapy line for metastatic breast cancer is allowed if there is evidence of progressive disease. Patients treated with chemotherapy to best response and no evidence of progression are not eligible.
4. Prior tamoxifen, LH/RH agonist, anastrozole or letrozole therapy in the adjuvant and/or neoadjuvant settings is allowed. Prior adjuvant and/or neoadjuvant chemotherapy is allowed.
5. Patients must have: [1] at least one lesion that can be accurately measured in at least one dimension >/= 20 mm with conventional imaging techniques or >/= 10 mm with spiral CT or MRI; or [2] bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease; the following will be considered disease progression among these patients: a) the appearance of one or more new lytic lesions in bone; b) the appearance of one or more new lesions outside of bone; c) unequivocal progression of existing bone lesions.
6. Localized radiotherapy, which does not influence the signal of evaluable lesion, is allowed prior to the initiation of study medications.
7. ECOG performance status </= 2.
8. Absolute neutrophil count (ANC) >/= 1000/microliter, platelets >/= 75,000/microliter, hemoglobin >/= 8.5 gm/dL; creatinine clearance >60 mg/dL; bilirubin < 1.5 mg/dL (</= 3 × ULN for patients known to have Gilbert Syndrome); ALT <3 x upper limit of normal (or </= 5 if hepatic metastases are present); alkaline phosphatase < 3 x upper limit of normal; calcium </= 11.0 mg/dL.
9. Fasting serum cholesterol </= 300 mg/dl or 7.75 mmol/L and fasting triglycerides </= 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved.
10. Bisphosphonate treatment is permitted for the management of bone loss and/or bone metastases.
11. Patients must be competent to give informed consent and to state that they understand the investigational nature of the proposed treatment.

Exclusion Criteria:

1. HER2-overexpressing breast cancer (IHC 3+ staining or in situ hybridization positive).
2. Diabetes mellitus on active treatment or hemoglobin A1C >/= 6.5% or random plasma glucose > 200 mg/dL in patients without known diabetes.
3. Treatment with metformin in the 30 days prior to enrollment.
4. Known hypersensitivity or intolerance to metformin.
5. Previous treatment with exemestane or mTOR inhibitors.
6. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
7. History of acromegaly, Cushing's syndrome, Cushing's disease, Addison's disease (treated or untreated).
8. Patients with unstable angina, uncontrolled ischemic cardiac disease or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association's Functional Classification).
9. Other investigational drugs within the past 3 weeks or concurrently.
10. Patients with known chronic liver diseases (e.g., chronic active hepatitis, and cirrhosis).
11. Another malignancy within 5 years prior to registration, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer.
12. Radiotherapy within four weeks prior to registration except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to registration. Patients must have recovered from radiotherapy toxicities.
13. History of brain or other central nervous system metastases.
14. Bilateral diffuse lymphangitic carcinomatosis.
15. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitic spread. Subjects with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not compromised as a result of disease.
16. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before enrollment are allowed.
17. Any severe and / or uncontrolled medical conditions such as: Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction </= 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia; Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN; Acute and chronic, active infectious disorders (except for Hep B and Hep C positive patients) and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy; Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome); Active skin, mucosa, ocular or GI disorders of Grade > 1
18. Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air will be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
19. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) within the last 5 days prior to registration.

Adverse events collected from the initiation of study drugs until disease progression, death, unacceptable toxicity, or withdraw of study consent, whichever occurred first assessed up to 67 months

There were no deaths. All participants survived.