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

Fulvestrant Alone Versus Fulvestrant and Everolimus Versus Fulvestrant, Everolimus and Anastrozole: A Phase III Randomized Placebo-Controlled Trial in Postmenopausal Patients

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Fulvestrant; Drug: Everolimus; Drug: Anastrozole; Drug: Placebo - Anastrozole; Drug: Placebo - Everolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Alaska Breast Care and Surgery LLC
    • Anchorage, Alaska, United States, 99508
      • Alaska Women's Cancer Care
    • Anchorage, Alaska, United States, 99508
      • Anchorage Oncology Centre
    • Anchorage, Alaska, United States, 99508
      • Katmai Oncology Group
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Virginia G. Piper Cancer Center
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center - North Campus
    • Tucson, Arizona, United States, 85704
      • University of Arizona Cancer Center - Orange Grove
    • Tucson, Arizona, United States, 85724
      • University of Arizona Medical Center - Univ Campus
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Burbank, California, United States, 91505
      • Providence St. Joseph Medical Ctr/Disney Family CC
    • Corona, California, United States, 92879
      • City of Hope-Corona
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Lancaster, California, United States, 93534
      • City of Hope Antelope Valley
    • Oakland, California, United States, 94609
      • Bay Area Tumor Institute
    • Oakland, California, United States, 94609
      • Summit Medical Center
    • Oakland, California, United States, 94612
      • Epic Care - Oakland
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Connecticut
    • Bridgeport, Connecticut, United States, 06610
      • Bridgeport Hospital
    • Hartford, Connecticut, United States, 06105
      • St. Francis Hospital and Medical Center
    • New Haven, Connecticut, United States, 06520
      • Yale University
    • North Haven, Connecticut, United States, 06473
      • Yale-New Haven Hospital North Haven Medical Center
  • Florida
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Hospital
    • Weston, Florida, United States, 33331
      • Cleveland Clinic - Weston
  • Georgia
    • Valdosta, Georgia, United States, 31602
      • South Georgia Medical Center - Pearlman Cancer Ctr
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Pali Momi Medical Center
    • 'Aiea, Hawaii, United States, 96701
      • Oncare Hawaii, Inc - Pali Momi
    • Honolulu, Hawaii, United States, 96813
      • Straub Clinic and Hospital
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
    • Honolulu, Hawaii, United States, 96813
      • Oncare Hawaii Inc-POB I
    • Honolulu, Hawaii, United States, 96813
      • Oncare Hawaii, Inc - POB II
    • Honolulu, Hawaii, United States, 96817
      • Oncare Hawaii, Inc - Kuakini
    • Honolulu, Hawaii, United States, 96817
      • Oncare Hawaii, Inc - Liliha
    • Lihue, Hawaii, United States, 96766
      • Wilcox Memorial Hospital and Kauai Medical Clinic
  • Idaho
    • Boise, Idaho, United States, 83706
      • St. Alphonsus Regional Medical Center
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Medical Center
    • Post Falls, Idaho, United States, 83854
      • Kootenai Cancer Center
    • Sandpoint, Idaho, United States, 83864
      • Kootenai Cancer Clinic
  • Illinois
    • Centralia, Illinois, United States, 62801
      • Centralia Oncology Clinic
    • DeKalb, Illinois, United States, 60115
      • Kishwaukee Community Hospital
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Decatur, Illinois, United States, 62526
      • Heartland Cancer Research NCORP
    • Decatur, Illinois, United States, 62526
      • Cancer Care Specialists of Central Illinois
    • Effingham, Illinois, United States, 62401
      • Crossroads Cancer Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Stritch School of Medicine
    • Melrose Park, Illinois, United States, 60160
      • Marjorie Weinberg Cancer Center
    • Mount Vernon, Illinois, United States, 62864
      • Good Samaritan Regional Health Center
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
    • Springfield, Illinois, United States, 62702
      • Central Illinois Hematology Oncology Center
    • Springfield, Illinois, United States, 62703
      • Springfield Clinic
    • Swansea, Illinois, United States, 62226
      • Cancer Care Specialists of Illinois-Swansea
  • Indiana
    • Richmond, Indiana, United States, 47374
      • Reid Hospital and Health Care Services
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas - El Dorado
    • Fort Scott, Kansas, United States, 66701
      • Cancer Center of Kansas - Fort Scott
    • Independence, Kansas, United States, 67301
      • Cancer Center of Kansas - Independence
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas - Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Liberal, Kansas, United States, 67901
      • Cancer Center of Kansas - Liberal
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas - Newton
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas - Pratt
    • Salina, Kansas, United States, 67401
      • Cancer Center of Kansas - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas - Wellington
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Wichita
    • Wichita, Kansas, United States, 67214
      • Wichita NCI Community Oncology Research Program
    • Wichita, Kansas, United States, 67214
      • Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67208
      • Associates in Women's Health
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas - Medical Arts Tower
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas - Winfield
  • Louisiana
    • Mansfield, Louisiana, United States, 71052
      • De Soto Regional Medical Center
    • Monroe, Louisiana, United States, 71210
      • University Health Conway
    • Shreveport, Louisiana, United States, 71105
      • Highland Clinic
    • Shreveport, Louisiana, United States, 71130
      • Louisiana State University Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
  • Massachusetts
    • Beverly, Massachusetts, United States, 01915
      • Beverly Hospital
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
    • Gloucester, Massachusetts, United States, 01930
      • Addison Gilbert Hospital
    • Winchester, Massachusetts, United States, 01890
      • Winchester Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Michigan Cancer Research Consortium NCORP
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Hospital
    • Dearborn, Michigan, United States, 48123
      • Oakwood Healthcare, Inc.
    • Detroit, Michigan, United States, 48236
      • St. John Hospital and Medical Center
    • Detroit, Michigan, United States, 48202
      • Wayne State University Medical Center
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grosse Pointe, Michigan, United States, 48230
      • William Beaumont Hospital-Grosse Pointe
    • Jackson, Michigan, United States, 49201
      • Allegiance Health
    • Lansing, Michigan, United States, 48909
      • Sparrow Health System
    • Livonia, Michigan, United States, 48154
      • St. Mary Mercy Hospital
    • Midland, Michigan, United States, 48670
      • MidMichigan Medical Center - Midland
    • Pontiac, Michigan, United States, 48341
      • St Joseph Mercy Hospital - Oakland
    • Port Huron, Michigan, United States, 48060
      • St. Joseph Mercy Port Huron
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Children's Hospital-Royal Oak
    • Royal Oak, Michigan, United States, 48073
      • Beaumont NCI Community Oncology Research Program
    • Saginaw, Michigan, United States, 48601
      • St. Mary's Health System
    • Troy, Michigan, United States, 48085
      • Beaumont Hospital, Troy Campus
    • Warren, Michigan, United States, 48093
      • St. John Macomb Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Bolivar, Missouri, United States, 65613
      • Central Care Cancer Ctr-Carrie J. Babb Cancer Ctr
    • Branson, Missouri, United States, 65616
      • Cox Cancer Center Branson
    • Cape Girardeau, Missouri, United States, 63701
      • St. Francis Medical Center
    • Joplin, Missouri, United States, 64804
      • Mercy Hospital - Joplin
    • Rolla, Missouri, United States, 65401
      • Phelps County Regional Medical Center
    • Rolla, Missouri, United States, 65401
      • Mercy Clinic Care and Hematology - Rolla
    • Rolla, Missouri, United States, 65401
      • PCRMC Bond Clinic
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital St. Louis
    • Saint Louis, Missouri, United States, 63136
      • Christian Hospital
    • Saint Louis, Missouri, United States, 63109
      • St. Louis Cancer and Breast Institute-South City
    • Springfield, Missouri, United States, 65804
      • Cancer Research for the Ozarks NCORP
    • Springfield, Missouri, United States, 65807
      • CoxHealth South Hospital
    • Springfield, Missouri, United States, 65804
      • Mercy Hospital Springfield
    • Washington, Missouri, United States, 63090
      • Mercy Hospital Washington
  • Montana
    • Billings, Montana, United States, 59107
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59101
      • Montana Cancer Consortium NCORP
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Butte, Montana, United States, 59702
      • St. James Community Hosp and Cancer Treatment Center
    • Great Falls, Montana, United States, 59405
      • Benefis Healthcare West Campus
    • Helena, Montana, United States, 59601
      • St. Peter's Community Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Missoula, Montana, United States, 59801
      • Community Medical Center
    • Missoula, Montana, United States, 59806
      • St. Patrick Hospital
  • Nebraska
    • Kearney, Nebraska, United States, 68847
      • CHI Health Good Samaritan Hospital
  • North Carolina
    • Clinton, North Carolina, United States, 28328
      • Southeastern Medical Oncology Center-Clinton
    • Goldsboro, North Carolina, United States, 27534
      • Southeastern Medical Oncology Center-Goldsboro
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Hendersonville, North Carolina, United States, 28739
      • Hendersonville Hematology and Oncology at Pardee
    • Hendersonville, North Carolina, United States, 28792
      • Park Ridge Health
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R. Pardee Memorial Hospital
    • Jacksonville, North Carolina, United States, 28546
      • Southeastern Medical Oncology Center-Jacksonville
    • Wilson, North Carolina, United States, 27893
      • Southeastern Medical Oncology Center-Wilson
    • Wilson, North Carolina, United States, 27893
      • Wilson Medical Center
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Cleveland Clinic Cancer Center - Beachwood
    • Belpre, Ohio, United States, 45714
      • Strecker Cancer Center-Belpre
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45220
      • VA Medical Center - Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center - Fairview Hospital
    • Columbus, Ohio, United States, 43213
      • Mount Carmel East Hospital
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health Center West
    • Columbus, Ohio, United States, 43215
      • Columbus NCI Community Oncology Research Program
    • Columbus, Ohio, United States, 43219
      • The Mark H. Zangmeister Center
    • Dayton, Ohio, United States, 45415
      • Samaritan North Health Center
    • Dayton, Ohio, United States, 45420
      • Dayton NCI Community Oncology Research Program
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital and Health Center
    • Dayton, Ohio, United States, 45428
      • VA Medical Center - Dayton
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Independence, Ohio, United States, 44131
      • Cleveland Clinic Cancer Center - Independence
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Mansfield, Ohio, United States, 44906
      • Cleveland Clinic Cancer Center - Mansfield
    • Marietta, Ohio, United States, 45750
      • Marietta Memorial Hospital
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
    • Mount Vernon, Ohio, United States, 43050
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Hospital
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center
    • Sandusky, Ohio, United States, 44870
      • North Coast Cancer Care, Inc.
    • Springfield, Ohio, United States, 45504
      • Springfield Regional Cancer Center
    • Springfield, Ohio, United States, 45501
      • Springfield Regional Medical Center
    • Strongsville, Ohio, United States, 44136
      • Cleveland Clinic Strongsville Family Health Center
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Centers
    • Warrensville Heights, Ohio, United States, 44122
      • South Pointe Hospital
    • Westerville, Ohio, United States, 43081
      • St. Ann's Hospital
    • Wooster, Ohio, United States, 44691
      • Cleveland Clinic Cancer Center - Wooster
    • Zanesville, Ohio, United States, 43701
      • Genesis Healthcare System Cancer Care Center
  • Oregon
    • Bend, Oregon, United States, 97701
      • St. Charles Health System
    • Clackamas, Oregon, United States, 97015
      • Clackamas Radiation Oncology Center
    • Clackamas, Oregon, United States, 97015
      • Providence Oncology and Hematology Care Southeast
    • Newberg, Oregon, United States, 97132
      • Providence Newberg Medical Center
    • Oregon City, Oregon, United States, 97045
      • Providence Willamette Falls Medical Center
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
  • South Carolina
    • Florence, South Carolina, United States, 29501
      • McLeod Regional Medical Center
    • Gaffney, South Carolina, United States, 29341
      • Gibbs Cancer Center-Gaffney
    • Greer, South Carolina, United States, 29651
      • Gibbs Cancer Center-Pelham
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Cancer
    • Union, South Carolina, United States, 29379
      • MGC Hematology Oncology-Union
  • Tennessee
    • Bristol, Tennessee, United States, 37620
      • Wellmont Bristol Regional Medical Center
    • Bristol, Tennessee, United States, 37620
      • Wellmont Medical Associates Oncology and Hematology
    • Johnson City, Tennessee, United States, 37604
      • Wellmont Medical Assoc Onc and Hem-Johnson City
    • Kingsport, Tennessee, United States, 37660
      • Holston Valley Hospital and Medical Center
    • Kingsport, Tennessee, United States, 37660
      • Wellmont Medical Assoc Onc and Hem-Kingsport
    • Knoxville, Tennessee, United States, 37916
      • Thompson Cancer Survival Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Don and Sybil Harrington Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center
  • Virginia
    • Norton, Virginia, United States, 24273
      • Southwest Virginia Cancer Center
  • Washington
    • Anacortes, Washington, United States, 98221
      • Island Hospital
    • Auburn, Washington, United States, 98001
      • Auburn Regional Medical Center
    • Bainbridge Island, Washington, United States, 98110
      • Virginia Mason Bainbridge Island Medical Center
    • Bellevue, Washington, United States, 98004
      • Overlake Hospital Medical Center
    • Bellevue, Washington, United States, 98005
      • Swedish Cancer Inst-Eastside Oncology Hematoly
    • Bellingham, Washington, United States, 98225
      • PeaceHealth St. Joseph Medical Center
    • Edmonds, Washington, United States, 98026
      • Swedish Medical Center - Edmonds
    • Federal Way, Washington, United States, 98002
      • Virginia Mason Federal Way Medical Center
    • Gig Harbor, Washington, United States, 98335
      • MultiCare Gig Harbor Medical Park
    • Gig Harbor, Washington, United States, 98332
      • Tacoma/Valley Radiation Oncology Ctrs-Gig Harbor
    • Issaquah, Washington, United States, 98029
      • Swedish Cancer Institute-Issaquah
    • Longview, Washington, United States, 98632
      • PeaceHealth St. John Medical Center
    • Lynnwood, Washington, United States, 98036
      • Virginia Mason Lynnwood Medical Center
    • Puyallup, Washington, United States, 98372
      • MultiCare Good Samaritan Hospital
    • Puyallup, Washington, United States, 98372
      • Tacoma/Valley Radiation Oncology Ctrs-Puyallup
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98112
      • Group Health Cooperative-Seattle
    • Seattle, Washington, United States, 98104
      • Minor and James Medical, PLLC
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
    • Seattle, Washington, United States, 98104
      • Pacific Cancer Research Consortium Ncorp
    • Seattle, Washington, United States, 98104
      • Pacific Medical Center - First Hill
    • Seattle, Washington, United States, 98107
      • Swedish Medical Center - Ballard Campus
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center
    • Tacoma, Washington, United States, 98405
      • MultiCare Tacoma General Hospital
    • Tacoma, Washington, United States, 98405
      • Northwest NCI Community Oncology Research Program
    • Tacoma, Washington, United States, 98415
      • MultiCare Health System
    • Tacoma, Washington, United States, 97405
      • Tacoma/Valley Radiation Oncology Ctrs-Jackson Hill
    • Tacoma, Washington, United States, 98405
      • Tacoma/Valley Radiation Oncology Ctrs-Saint Joe's
    • Vancouver, Washington, United States, 98668
      • PeaceHealth Southwest Medical Center
  • Wyoming
    • Cody, Wyoming, United States, 82414
      • Billings Clinic-Cody
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center - Sheridan Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm 1: fulvestrant + everolimus placebo + anastrozole placebo; 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.	Drug: Fulvestrant; Other Names: Faslodex; NSC-719276; Drug: Placebo - Anastrozole; Drug: Placebo - Everolimus
Experimental: Arm 2: fulvestrant + everolimus + anastrozole placebo; 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.	Drug: Fulvestrant; Other Names: Faslodex; NSC-719276; Drug: Everolimus; Other Names: Afinitor; Zortress; NSC-733504; Drug: Placebo - Anastrozole
Experimental: 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 everolimus and anastrozole by mouth daily. This treatment regimen will continue until disease progression or toxicity.	Drug: Fulvestrant; Other Names: Faslodex; NSC-719276; Drug: Everolimus; Other Names: Afinitor; Zortress; NSC-733504; Drug: Anastrozole; Other Names: Arimidex; NSC-719344

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (Fulvestrant vs Fulvestrant + Everolimus )	From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive are censored at date of last contact.	up to 5 years
Progression-free Survival (Fulvestrant Versus Fulvestrant + Everolimus + Anastrozole)	From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.	up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (Fulvestrant + Everolimus vs Fulvestrant + Everolimus + Anastrozole)	From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.	up to 5 years
Overall Survival	From date of registration to date of death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.	up to 5 years
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs	Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.	Duration of treatment and follow up until death or 5 years post registration
Response Rate	Proportion of participants who have confirmed or unconfirmed partial or complete response to therapy	assessed every 12 weeks, up to 5 years
Clinical Benefit Rate	Proportion of participants who have confirmed and unconfirmed partial response, complete response or stable disease.	assessed every 12 weeks, up to 5 years
Molecular Determinants of Response in Circulating Tumor Cells: CTC-ETI	CTC-Endocrine Therapy Index (CTC-ETI) on the CellSearch® platform. Based on enumeration of CTC/7.5 mL of whole blood, with >= 5 being elevated. (Due to limited samples collected, full analysis was not able to be performed as planned, so outcome measure reported here is number with elevated Day 1 CTC.)	Day 1, Day 29, time of progression (Day 29 to be collected only if Day 1 CTC was elevated.)

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: Novartis; AstraZeneca
• Investigators: Study Chair: Halle Moore, M.D., The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (Estimate): May 14, 2014

Study Record Updates

• Last Update Posted (Actual): January 28, 2021
• Last Update Submitted That Met QC Criteria: January 5, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Invasive breast carcinoma; estrogen receptor-positive breast cancer; Metastatic breast cancer; progesterone receptor-positive breast cancer; Stage IV breast cancer; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant; Everolimus; Anastrozole
• Other Study ID Numbers: S1222