Exemestane-RAD001-Metformin
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Everolimus; Exemestane; Metformin
Intervention description: 10 mg by mouth once daily.; 25 mg by mouth once daily.; 500 mg by mouth per day for three days. If there are no dose limiting toxicities, the dose of metformin will be increased by 500 mg orally every three days to reach the target dose of 1,000 mg orally twice daily.
Intervention MeSH terms: Metformin; Everolimus; Exemestane
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; Hormone Receptor Positive Metastatic Breast Cancer; Hormone-sensitive; Postmenopausal; Body Mass Index; BMI; Everolimus; Afinitor; RAD001; Exemestane; Aromasin; Metformin

Summary:

      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.
    

Eligibility criteria:

        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.