S1222 Trial (Everolimus, Anastrozole and Fulvestrant) in Post-Menopausal Stage IV Breast Cancer

OBJECTIVES:

Primary

- To test the benefit of interfering with the function of the estrogen receptor (ER) and
providing downstream target inhibition (PI3K/AKT/mTOR) with a combination of optimal
dose fulvestrant and everolimus (Arm 2) to improve progression-free survival compared to
the optimal dose fulvestrant alone (Arm 1).

- To test the benefit of adding the non-steroidal aromatase inhibitor anastrozole to
optimal dose fulvestrant and everolimus (Arm 3) in order to improve progression free
survival over optimal dose fulvestrant (Arm 1).

Secondary

- To compare progression-free survival among those receiving fulvestrant + everolimus +
anastrozole (Arm 3) versus fulvestrant + everolimus (Arm 2).

- To compare overall survival among the treatment arms in post-menopausal patients with
hormone-receptor positive (HR+) Stage IV breast cancer.

- To assess and compare toxicities, feasibility and compliance among the study regimens.

- To compare response rates and clinical benefit rates among the study regimens.

- To test molecular determinants of response to endocrine therapy and everolimus in
circulating tumor cells:

1. CTC-Endocrine Therapy Index (CTC ETI) on the CellSearch® platform.

2. CTC-Next Generation Sequencing Analysis (CTC-NGS) of single cells captured on the
HD-CTC® platform.

OUTLINE:

This is a multicenter study. Patients will be stratified according to the following factors:

- Measurable versus evaluable non-measurable disease

- Prior adjuvant hormonal therapy completed more than 5 years ago vs. prior adjuvant
hormonal therapy completed 1-5 years ago vs. de novo presentation of metastatic disease
or no prior adjuvant hormonal therapy.

ARMS:

- Arm 1: fulvestrant + placebo (everolimus) + placebo (anastrozole)

- Arm 2: fulvestrant + everolimus + placebo (anastrozole)

- Arm 3: fulvestrant + everolimus + anastrozole

Blood and tissue samples are collected for correlative science studies.

After completion of study treatment, patients are followed up every 6 months for 2 years and
then yearly thereafter for 5 years.

- Patients must have a histologically confirmed diagnosis of invasive breast carcinoma
with positive estrogen and/or progesterone receptor status, and negative human
epidermal growth factor receptor (HER-2), for whom endocrine therapy is planned.

- The HER-2 test result is negative (and should be reported as such), if a single test
(or all tests)performed in a tumor specimen show:

- Immunohistochemistries (IHC) 1+ negative or IHC 0 negative or

- in situ hybridization (ISH) negative using a single probe ISH or dual probe ISH.

- Estrogen receptor (ER) and progesterone receptor (PgR) positivity must be assessed
according to American Society of Clinial Oncology (ASCO)/College of American
Physicians (CAP) guidelines as either ER or PR ≥ 1% positive nuclear staining. If HER2
IHC is 2+, an evaluation for gene amplification must be performed and the gene must
not be amplified. Gene amplification evaluation is not required if evaluation by IHC
is 0 or 1+ by institutional standards.

- Patients must be post-menopausal women with a confirmed diagnosis of metastatic breast
cancer (M1). Pathologic confirmation of histology is preferable. In the case of bone
metastases only, biopsy-proven metastatic disease of solitary site, or multiple sites
of involvement are required. Post-menopausal is defined by one of the following
criteria as per National Comprehensive Cancer Network (NCCN) guidelines Version 3.
2013:

- Prior bilateral oophorectomy and/or hysterectomy

- Patients ≥ 60 years of age

- Patients < 60 years of age and amenorrheic for ≥ 12 months in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression and
follicle-stimulating hormone (FSH) and estradiol in the post-menopausal range

- Patients < 60 years of age taking tamoxifen or toremifene must have FSH and
plasma estradiol levels within post-menopausal ranges

- Patients must have measurable or evaluable disease. Patients must have a chest and
abdominal computerized tomography (CT) and bone scan within 28 days prior to
registration. All scans needed for assessment of measurable disease must be performed
within 28 days prior to registration. Evaluable disease must be assessed 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 within 28 days prior
to registration.

- Patients must have adequate bone marrow function, as defined by Absolute Neutrophil
Count (ANC) of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a peripheral platelet count ≥
100,000/ mL, all within 28 days prior to registration.

- Patients must have adequate hepatic function obtained within 28 days prior to
registration and documented by all of the following:

- Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome)

- alanine aminotransferase (ALT) (SGPT) and aspartate aminotransferase (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 within
28 days prior to registration.

- Patients must have a fasting cholesterol ≤ 300 mg/dL and triglycerides ≤ 2.5 x IULN
obtained within 28 days prior to registration. Patients may be on lipid lowering
agents to reach these values.

- Patients must have a complete history and physical examination within 28 days prior to
registration.

- 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% within 28 days
prior to registration).

- 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.