Everolimus Combined With Anti-estrogen Therapy in Hormone-Receptor-Positive HER-2 Negative Advanced Breast Cancer

Based on the activity of Everolimus in previous studies investigating endocrine-resistant
disease, the 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. It is hypothesized that in this group of endocrine-resistant
patients, resistance to anti-estrogen therapy is driven by the activation of the
PI3K/Akt/mTOR pathways and hence the addition of Everolimus, a mTOR inhibitor, to the
failing anti-estrogen therapy may result in reversing the resistance established by these
cellular mechanisms in these patients.

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.