S1222 Trial (Everolimus, Anastrozole and Fulvestrant) in Post-Menopausal Stage IV Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Fulvestrant; Anastrozole; Everolimus; Placebo - Anastrozole; Placebo - Everolimus
Intervention MeSH terms: Everolimus; Fulvestrant; Anastrozole
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 37.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic breast cancer; Invasive breast carcinoma; estrogen receptor-positive breast cancer; HER2-negative breast cancer; Stage IV breast cancer; progesterone receptor-positive breast cancer

Summary:

      This randomized Phase III trial studies how well the combination of fulvestrant and
      everolimus together or the combination of anastrozole, fulvestrant and everolimus together,
      improve progression-free survival (PFS) versus fulvestrant alone.
    

Eligibility criteria:

        -  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.