Everolimus Combined With Anti-estrogen Therapy in Hormone-Receptor-Positive HER-2 Negative Advanced Breast Cancer
Everolimus Combined With Anti-estrogen Therapy in Hormone-Receptor-Positive HER-2 Negative Advanced Breast Cancer
Many patients with ER-positive or PR-positive breast cancer are treated with endocrine
 therapy. Although most ER/PR-positive tumors initially respond to hormonal therapy, patients
 often experience disease progression. Everolimus, in combination with exemestane, has shown
 activity in endocrine-resistant disease. This study will evaluate the efficacy of Everolimus+
 anti-estrogen therapy in patients with ER-positive metastatic breast cancer who have
 progressed after receiving anti-estrogen therapy.
This is a multi-centered, open-labeled, Phase II study on metastastic breast cancer (MBC).
 The patient population includes locally recurrent or MBC patients with cytologically or
 histologically confirmed hormone receptor-positive breast cancer who have demonstrated
 disease progression on prior anti-estrogen therapy or therapies. Investigators propose to
 evaluate the efficacy of Everolimus in patients with ER-positive (estrogen receptor-positive)
 metastatic breast cancer who have progressed on anti-estrogen therapy. Forty-six (46)
 patients are planned for enrollment in the trial.
Inclusion Criteria:

 1. Histologic diagnosis of unresectable, locally recurrent or MBC.

 2. ER and/or PR-positive tumors with staining by immunohistochemistry (IHC) based on the
 most recent biopsy.

 3. Only 1 previous chemotherapy regimen for MBC. Patients progressing while receiving
 adjuvant endocrine therapy or progressing <12 months from completion of adjuvant
 endocrine therapy are eligible.

 4. Progressed on anti-estrogen therapy (tamoxifen, fulvestrant, anastrozole, letrozole,
 exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy)
 defined as:

 -  Recurrence while on, or within 12 months of end of anti-estrogen therapy for
 early stage breast cancer, or

 -  Progression while on, or within one month of anti-estrogen therapy for locally
 advanced or metastatic breast cancer.

 Note: No washout for anti-estrogen therapy required. Anti-estrogen therapy does not
 have to be the last treatment prior to study entry.

 5. Post-menopausal or pre/peri-menopausal women on tamoxifen. LHRH agonists may be used
 to render ovarian suppression with postmenopausal ranges of estradiol or FSH per
 institutional guidelines.

 6. HER2-negative breast cancer, defined as follows:

 -  Fluorescent In Situ Hybridization (FISH)-negative (FISH ratio <2.0), or

 -  IHC 0-1+, or

 -  IHC 2-3+ AND FISH-negative (FISH ratio <2.0).

 7. Measureable disease as measured by Response Evaluation Criteria in Solid Tumors
 (RECIST) criteria version 1.1 or evaluable bone lesions, lytic or mixed, in absence of
 measureable disease by RECIST criteria.

 8. Adequate hematologic, hepatic and renal function.

 9. International normalized ratio (INR) ≤1.5 or prothrombin time (PT)/partial
 thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is
 not on anti-coagulation therapy).

 10. Age ≥ 18 years.

 11. ECOG Performance Status score of 0-2.

 12. Life expectancy of ≥ 12 weeks.

 Exclusion Criteria:

 1. Previous therapy or known intolerance/hypersensitivity with any approved or
 investigational mTOR inhibitor (e.g., temsirolimus, everolimus, sirolimus).

 2. Patients who are ≤21 days after their most recent chemotherapy and have not recovered
 from side effects.

 3. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior
 to the first dose of everolimus. For investigational drugs for which 5 half-lives is
 ≤21 days, a minimum of 10 days between termination of the investigational drug and
 administration of everolimus is required.

 4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
 administered ≤28 days or limited field radiation for palliation ≤7 days for metastatic
 disease prior to first dose of everolimus or has not recovered from side effects of
 such therapy.

 5. Previously untreated brain metastases. Patients who have received radiation or surgery
 for brain metastases are eligible if there is no evidence of central nervous system
 (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Patients
 are not permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs) during the
 study and should not be receiving chronic corticosteroid therapy for CNS metastases.

 6. Patients with known active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients
 with risk factors for hepatitis must have HBV DNA and HCV RNA testing by PCR, and are
 ineligible if these tests are positive.

 7. Patients receiving immunization with attenuated live vaccines within 1 week of study
 entry or during study period.

 NOTE: There are additional inclusion/exclusion criteria. The study center will determine
 patient eligibility and respond to any questions.