Fulvestrant Alone Versus Fulvestrant and Everolimus Versus Fulvestrant, Everolimus and Anastrozole: A Phase III Randomized Placebo-Controlled Trial In Postmenopausal Patients With Hormone-Receptor Positive Stage IV Breast Cancer.

Patients must have a histologically confirmed diagnosis of invasive breast
carcinoma with positive estrogen and/or progesterone receptor status, and
negative HER-2, for whom endocrine therapy is planned.
Patients must be post-menopausal women with a confirmed diagnosis of
metastatic breast cancer.
Patients must have measurable or non-measurable disease.
Patients must have H&P within 28 days piror to registration.
Patients must have a chest and abdominal CT and bone scan within 28 days prior
to registration.
Patients with a history of prior chemotherapy or hormone therapy or
immunotherapy for recurrent or metastatic disease are NOT eligible. Prior
adjuvant or neoadjuvant chemotherapy if completed more than 12 months prior to
registration is acceptable. Any number of prior hormonal therapy regimens for the
adjuvant setting but not for metastatic or recurrent disease is allowed; prior
adjuvant or neoadjuvant treatment with an aromatase inhibitor (e.g. anastrozole,
letrozole, exemestane) is allowed, if completed more than 12 months prior to
randomization.
Patients who have taken luteinizing hormone-releasing hormone (LHRH)
analogue as adjuvant therapy are eligible provided they have a) discontinued
such therapy at least 12 months prior to registration AND b) have not resumed
their menstrual periods.
Patients must not have had prior exposure to fulvestrant or mTOR inhibitors (e.g.,
rapamycin, everolimus, temsirolimus, deforolimus). Concurrent bisphosphonate
therapy is allowed. Patients must not have prior treatment with any
investigational drug within 28 days prior to registration and must not be planning
to receive any other investigational drug for the duration of the study.
Patients must have an International Normalized Ratio (INR) </= 1.6.
Patients must have adequate bone marrow function, as defined by ANC of >/= 1,500/mL, hemoglobin >/= 9 g/dL and a platelet count >/=100,000/ mL.
Patients must have adequate hepatic function obtained and documented by all of the following:
� Bilirubin </= 1.5 mg/dL (or </= 3.0 mg/dL if due to Gilbert's Syndrome)
� ALT (SGPT) and AST (SGOT) </= 2.5 x Institutional Upper Limit of Normal
(IULN), or </= 5 x IULN if hepatic metastases are present.
Patients must have adequate renal function with serum creatinine level </= IULN.
Patients must have a fasting cholesterol </= 300 mg/dL and triglycerides </= 2.5 x
IULN. Patients may be on lipid
lowering agents to reach these values.
Patients with bleeding diathesis (i.e., disseminated intravascular coagulation
[DIC], clotting factor deficiency) or long-term anti-coagulant therapy (other than
antiplatelet therapy) are NOT eligible.
Patients with 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 are
not eligible. Patients with discrete pulmonary parenchymal metastases are
eligible, provided their respiratory function is not significantly compromised as a result of disease in the opinion of the investigator.
Patients must have a performance status of 0 - 2 by Zubrod criteria.
Patients must not have any Grade III/IV cardiac disease as defined by the New
York Heart Association Criteria (i.e., patients with cardiac disease resulting in
marked limitation of physical activity or resulting in inability to carry on any
physical activity without discomfort), unstable angina pectoris, myocardial
infarction within 6 months, or serious uncontrolled cardiac arrhythmia.
Patients must not have uncontrolled diabetes (defined as an Hg A1C >7%).
Patients must not have an organ allograft or other history of immune
compromise. Patients must not be receiving chronic, systemic treatment with
corticosteroids or other immunosuppressive agent. Topical or inhaled
corticosteroids are allowed.
Patients known to be HIV positive may be enrolled if baseline CD4 count is > 500
cells/mm3 AND not taking anti-retroviral therapy. Patients with known chronic or
active hepatitis are not eligible. Patients must not have any known uncontrolled
underlying pulmonary disease.
Patients must be able to take oral medications. Patient may not have any
impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection).
Patients must not have received immunization with an attenuated live vaccine
(e.g. intranasal influenza, MMR, oral polio, varicella, zoster, yellow fever and BCG
vaccines) within seven days prior to registration nor have plans to receive such
vaccination while on protocol treatment.
Patients must not have taken within 14 days prior to registration, be taking, nor
plan to take while on protocol treatment, strong CYP3A4 inhibitors, and/or
CYP3A4 inducers. No other prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other cancer for which the patient has been disease-free for 5 years.