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
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
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
(with or without non-measurable) vs. non-measurable disease, and prior chemotherapy for
metastatic disease vs. no prior chemotherapy.
Patients will be evaluated for disease response every 12 weeks and treated until disease
progression or unacceptable toxicity for a total of 12 cycles.
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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.
Every 3 months until progression or up to 3 years
Noah S Kornblum, MD
Saint Barnabas Cancer Center, Montefiore Medical Center
United States: Institutional Review Board
|Stanford University||Stanford, California 94305|
|St. Vincent Hospital||Green Bay, Wisconsin 54307-3508|
|McFarland Clinic, PC||Ames, Iowa 50010|
|Marin Cancer Care||Greenbrae, California 94904|
|SwedishAmerican Regional Cancer Center||Rockford, Illinois 61104|
|Hematology & Oncology Associates of Northeastern PA, PC||Dunmore, Pennsylvania 18512|
|Reading Hospital- McGlinn Family Regional Cancer Center||West Reading, Pennsylvania 19611|
|Charleston Area Medical Center (CAMC)||Charleston, West Virginia 25304|
|Gundersen Health System||Lacrosse, Wisconsin 54601|
|ProHealth Care Inc. (Waukesha)||Waukesha, Wisconsin 53188|