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Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles.

Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles.

Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles).

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.

Everolimus 10 mg (2 tablets) daily x 12 cycles.

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.

Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.

Placebo

Noah S Kornblum, MD

Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients).

Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy.

Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth.

The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

Breast cancer is the most commonly diagnosed malignancy in women worldwide. In the United States, an estimated 230,480 new cases of invasive breast cancer were diagnosed in 2011, with 39,520 breast cancer deaths. In 40-80% of women with node-positive disease at diagnosis, their breast cancer will recur. When distant metastases occur, median survival is 18 to 36 months from time of recurrence. Among the 60-70% of women with HR+ breast cancer, 40-60% of them will benefit from endocrine therapy. Endocrine therapy has shown to yield similar survival rates in hormone-sensitive disease as compared to chemotherapy; although response rates are lower and responses develop more slowly. Endocrine therapy is considerably less toxic than chemotherapy, and is therefore the preferred treatment option for patients with HR+ disease.

Endocrine therapy represents the foundation of treatment for HR+ metastatic and locally advanced breast cancer. Multiple compounds in varying classes exist, and those most widely used include the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and the selective estrogen receptor down-regulators (SERDs). Although the utility of these drugs is well established, as many as 50% of women with HR+ breast cancer will fail to respond to endocrine treatment. Moreover, those who do respond will inevitably develop acquired resistance.

Fulvestrant is the first drug which acts as a pure estrogen receptor (ER) antagonist without known agonist effects. It competitively binds to the ERs with an approximately 100 times greater affinity than that of tamoxifen. Fulvestrant promotes the degradation of ERs and subsequently prevents ER-mediated gene transcription.

Everolimus (RAD001) is an oral derivative of rapamycin that is an m-TOR inhibitor. At cellular and molecular levels, everolimus acts as a signal transduction inhibitor. Everolimus selectively inhibits mTOR (mammalian target of rapamycin); a key and highly conserved serine-threonine kinase which is present in all cells and is a central regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR is the only currently known target of everolimus.

In oncology, everolimus has been in clinical development since 2002 for patients with various hematologic and non-hematologic malignancies as a single agent or in combination with antitumor agents, including cytotoxic chemotherapeutic agents, targeted therapies, antibodies and hormonal agents.

Patients will be randomized (1:1) to receive everolimus or placebo with fulvestrant after consideration of stratification factors of performance status (0 vs. 1), measurable disease (yes vs. no), and prior chemotherapy for metastatic disease (yes vs. no).

Patients will be evaluated for disease response every 12 weeks, and treated until disease progression or unacceptable toxicity or withdrawal of consent for a maximum of 12 cycles (48 weeks).

Patients with no evidence of progressive disease who remain on study after completing 12 cycles are unblinded and continue to receive fulvestrant alone (if originally randomized to placebo) or in combination with everolimus (if originally randomized to everolimus) at the same dose and schedule. Patients will continue to be evaluated for disease response every 12 weeks and continue until disease progression or unacceptable toxicity.

Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI

Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) Plus Everolimus in Post-Menopausal Patients With Hormone-Receptor Positive Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Progression-free survival documented by Physical Exam, CT Scan or MRI in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is resistant to aromatase inhibitor therapy treated with fulvestrant and everolimus compared to fulvestrant alone from randomization to documented disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Clinical benefit rate is defined as number of patients with objective response (complete response or partial response) or stable disease for at least 24 weeks divided by number of patients randomized in each arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease; Complete Response (CR) is defined as disappearance of all target lesions.

Objective response rate is defined as number of patients with complete or partial response (by Physical Exam, CT or MRI) divided by number of patients randomized in each arm

Overall survival will be characterized using Kaplan-Meier plots and other descriptive metrics.

Novartis

PrECOG, LLC.

All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.

Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles.

Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles).

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.

Everolimus: Everolimus 10 mg (2 tablets) daily x 12 cycles.

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.

Fulvestrant & Everolimus

Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles.

Fulvestrant: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles).

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.

Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.

Spots Global Cancer Trial Database for resistant to aromatase inhibitor therapy