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

About this trial
This is an interventional treatment trial for Breast Cancer focused on measuring Metastatic breast cancer, Invasive breast carcinoma, estrogen receptor-positive breast cancer, HER2-negative breast cancer, Stage IV breast cancer, progesterone receptor-positive breast cancer
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.
Sites / Locations
- Alaska Breast Care and Surgery LLC
- Alaska Women's Cancer Care
- Anchorage Oncology Centre
- Katmai Oncology Group
- Providence Alaska Medical Center
- Virginia G. Piper Cancer Center
- University of Arizona Cancer Center - Orange Grove
- University of Arizona Cancer Center - North Campus
- Southern Arizona VA Health Care System
- University of Arizona Medical Center - Univ Campus
- University of Arkansas for Medical Sciences
- Providence St. Joseph Medical Ctr/Disney Family CC
- City of Hope-Corona
- City of Hope National Medical Center
- City of Hope Antelope Valley
- Bay Area Tumor Institute
- Summit Medical Center
- Epic Care - Oakland
- City of Hope South Pasadena
- Bridgeport Hospital
- St. Francis Hospital and Medical Center
- Yale University
- Yale-New Haven Hospital North Haven Medical Center
- Sacred Heart Hospital
- Cleveland Clinic - Weston
- South Georgia Medical Center - Pearlman Cancer Ctr
- Oncare Hawaii, Inc - Pali Momi
- Pali Momi Medical Center
- Oncare Hawaii Inc-POB I
- Oncare Hawaii, Inc - POB II
- Straub Clinic and Hospital
- University of Hawaii Cancer Center
- Oncare Hawaii, Inc - Kuakini
- Oncare Hawaii, Inc - Liliha
- Kapiolani Medical Center for Women and Children
- Wilcox Memorial Hospital and Kauai Medical Clinic
- St. Alphonsus Regional Medical Center
- Kootenai Medical Center
- Kootenai Cancer Center
- Kootenai Cancer Clinic
- Centralia Oncology Clinic
- Cancer Care Specialists of Central Illinois
- Decatur Memorial Hospital
- Heartland Cancer Research NCORP
- Kishwaukee Community Hospital
- Crossroads Cancer Center
- Loyola University Stritch School of Medicine
- Marjorie Weinberg Cancer Center
- Good Samaritan Regional Health Center
- Central Illinois Hematology Oncology Center
- Springfield Clinic
- Memorial Medical Center
- Cancer Care Specialists of Illinois-Swansea
- Reid Hospital and Health Care Services
- Cancer Center of Kansas - Chanute
- Cancer Center of Kansas - Dodge City
- Cancer Center of Kansas - El Dorado
- Cancer Center of Kansas - Fort Scott
- Cancer Center of Kansas - Independence
- Cancer Center of Kansas - Kingman
- Lawrence Memorial Hospital
- Cancer Center of Kansas - Liberal
- Cancer Center of Kansas - Newton
- Cancer Center of Kansas - Parsons
- Cancer Center of Kansas - Pratt
- Cancer Center of Kansas - Salina
- Cancer Center of Kansas - Wellington
- Associates in Women's Health
- Cancer Center of Kansas - Medical Arts Tower
- Cancer Center of Kansas - Wichita
- Via Christi Regional Medical Center
- Wichita NCI Community Oncology Research Program
- Cancer Center of Kansas - Winfield
- De Soto Regional Medical Center
- University Health Conway
- Highland Clinic
- Louisiana State University Health Sciences Center
- Sinai Hospital of Baltimore
- Beverly Hospital
- Lahey Hospital and Medical Center
- Addison Gilbert Hospital
- Winchester Hospital
- Michigan Cancer Research Consortium NCORP
- St. Joseph Mercy Hospital
- University of Michigan Medical Center
- Oakwood Healthcare, Inc.
- Wayne State University Medical Center
- St. John Hospital and Medical Center
- Genesys Hurley Cancer Institute
- Hurley Medical Center
- William Beaumont Hospital-Grosse Pointe
- Allegiance Health
- Sparrow Health System
- St. Mary Mercy Hospital
- MidMichigan Medical Center - Midland
- St Joseph Mercy Hospital - Oakland
- St. Joseph Mercy Port Huron
- Beaumont Children's Hospital-Royal Oak
- Beaumont NCI Community Oncology Research Program
- St. Mary's Health System
- Beaumont Hospital, Troy Campus
- St. John Macomb Hospital
- University of Mississippi Medical Center
- Central Care Cancer Ctr-Carrie J. Babb Cancer Ctr
- Cox Cancer Center Branson
- St. Francis Medical Center
- Mercy Hospital - Joplin
- Mercy Clinic Care and Hematology - Rolla
- PCRMC Bond Clinic
- Phelps County Regional Medical Center
- St. Louis Cancer and Breast Institute-South City
- Christian Hospital
- Mercy Hospital St. Louis
- Cancer Research for the Ozarks NCORP
- Mercy Hospital Springfield
- CoxHealth South Hospital
- Mercy Hospital Washington
- Montana Cancer Consortium NCORP
- Billings Clinic Cancer Center
- Bozeman Deaconess Hospital
- St. James Community Hosp and Cancer Treatment Center
- Benefis Healthcare West Campus
- St. Peter's Community Hospital
- Kalispell Regional Medical Center
- Community Medical Center
- St. Patrick Hospital
- CHI Health Good Samaritan Hospital
- Southeastern Medical Oncology Center-Clinton
- Southeastern Medical Oncology Center-Goldsboro
- Wayne Memorial Hospital
- Hendersonville Hematology and Oncology at Pardee
- Margaret R. Pardee Memorial Hospital
- Park Ridge Health
- Southeastern Medical Oncology Center-Jacksonville
- Southeastern Medical Oncology Center-Wilson
- Wilson Medical Center
- Cleveland Clinic Cancer Center - Beachwood
- Strecker Cancer Center-Belpre
- Adena Regional Medical Center
- VA Medical Center - Cincinnati
- University of Cincinnati Medical Center
- Cleveland Clinic Cancer Center - Fairview Hospital
- Cleveland Clinic Foundation
- Mount Carmel East Hospital
- Columbus NCI Community Oncology Research Program
- The Mark H. Zangmeister Center
- Mount Carmel Health Center West
- Good Samaritan Hospital and Health Center
- Samaritan North Health Center
- Dayton NCI Community Oncology Research Program
- VA Medical Center - Dayton
- Wayne Hospital
- Cleveland Clinic Cancer Center - Independence
- Kettering Medical Center
- Fairfield Medical Center
- Cleveland Clinic Cancer Center - Mansfield
- Marietta Memorial Hospital
- Hillcrest Hospital Cancer Center
- Knox Community Hospital
- Licking Memorial Hospital
- Southern Ohio Medical Center
- North Coast Cancer Care, Inc.
- Springfield Regional Medical Center
- Springfield Regional Cancer Center
- Cleveland Clinic Strongsville Family Health Center
- Upper Valley Medical Centers
- South Pointe Hospital
- St. Ann's Hospital
- Cleveland Clinic Cancer Center - Wooster
- Genesis Healthcare System Cancer Care Center
- St. Charles Health System
- Clackamas Radiation Oncology Center
- Providence Oncology and Hematology Care Southeast
- Providence Newberg Medical Center
- Providence Willamette Falls Medical Center
- Providence Portland Medical Center
- Providence St. Vincent Medical Center
- McLeod Regional Medical Center
- Gibbs Cancer Center-Gaffney
- Gibbs Cancer Center-Pelham
- Spartanburg Medical Cancer
- MGC Hematology Oncology-Union
- Wellmont Bristol Regional Medical Center
- Wellmont Medical Associates Oncology and Hematology
- Wellmont Medical Assoc Onc and Hem-Johnson City
- Holston Valley Hospital and Medical Center
- Wellmont Medical Assoc Onc and Hem-Kingsport
- Thompson Cancer Survival Center
- Don and Sybil Harrington Cancer Center
- University of Utah Medical Center
- Southwest Virginia Cancer Center
- Island Hospital
- Auburn Regional Medical Center
- Virginia Mason Bainbridge Island Medical Center
- Overlake Hospital Medical Center
- Swedish Cancer Inst-Eastside Oncology Hematoly
- PeaceHealth St. Joseph Medical Center
- Swedish Medical Center - Edmonds
- Virginia Mason Federal Way Medical Center
- Tacoma/Valley Radiation Oncology Ctrs-Gig Harbor
- MultiCare Gig Harbor Medical Park
- Swedish Cancer Institute-Issaquah
- PeaceHealth St. John Medical Center
- Virginia Mason Lynnwood Medical Center
- MultiCare Good Samaritan Hospital
- Tacoma/Valley Radiation Oncology Ctrs-Puyallup
- Virginia Mason Medical Center
- Minor and James Medical, PLLC
- Pacific Cancer Research Consortium NCORP
- Pacific Medical Center - First Hill
- Swedish Medical Center
- Swedish Medical Center - Ballard Campus
- Fred Hutchinson Cancer Research Center
- Group Health Cooperative-Seattle
- Tacoma/Valley Radiation Oncology Ctrs-Jackson Hill
- Mary Bridge Children's Hospital and Health Center
- MultiCare Tacoma General Hospital
- Northwest NCI Community Oncology Research Program
- Tacoma/Valley Radiation Oncology Ctrs-Saint Joe's
- Multicare Health System
- PeaceHealth Southwest Medical Center
- Billings Clinic-Cody
- Welch Cancer Center - Sheridan Memorial Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Placebo Comparator
Experimental
Experimental
Arm 1: fulvestrant + everolimus placebo + anastrozole placebo
Arm 2: fulvestrant + everolimus + anastrozole placebo
Arm 3: fulvestrant + everolimus + anastrozole
Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive an oral placebo daily for both everolimus and anastrozole. This treatment regimen will continue until disease progression or toxicity.
Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive an oral everolimus and an oral placebo for anastrozole daily. This treatment regimen will continue until disease progression or toxicity.
Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive everolimus and anastrozole by mouth daily. This treatment regimen will continue until disease progression or toxicity.