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Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI

Information source: PrECOG, LLC.
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Breast Cancer

Intervention: Fulvestrant (Drug); Everolimus (Drug); Placebo (for Everolimus) (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: PrECOG, LLC.

Official(s) and/or principal investigator(s):
Noah S Kornblum, MD, Study Chair, Affiliation: Saint Barnabas Cancer Center, Montefiore Medical Center

Overall contact:
Carolyn Andrews, RN, Phone: 267-207-4070, Email: candrews@precogllc.org


Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients). Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy. Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth. The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

Clinical Details

Official title: Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) Plus Everolimus in Post-Menopausal Patients With Hormone-Receptor Positive Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Progression-free survival

Secondary outcome:

Participant Adverse Events as a Measure of Safety and Tolerability

Objective Response Rate

Time to Progression

Overall Survival

Detailed description: Breast cancer is the most commonly diagnosed malignancy in women worldwide. In the United States, an estimated 230,480 new cases of invasive breast cancer were diagnosed in 2011, with 39,520 breast cancer deaths. In 40-80% of women with node-positive disease at diagnosis, their breast cancer will recur. When distant metastases occur, median survival is 18 to 36 months from time of recurrence. Among the 60-70% of women with HR+ breast cancer, 40-60% of them will benefit from endocrine therapy. Endocrine therapy has shown to yield similar survival rates in hormone-sensitive disease as compared to chemotherapy; although response rates are lower and responses develop more slowly. Endocrine therapy is considerably less toxic than chemotherapy, and is therefore the preferred treatment option for patients with HR+ disease. Endocrine therapy represents the foundation of treatment for HR+ metastatic and locally advanced breast cancer. Multiple compounds in varying classes exist, and those most widely used include the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and the selective estrogen receptor down-regulators (SERDs). Although the utility of these drugs is well established, as many as 50% of women with HR+ breast cancer will fail to respond to endocrine treatment. Moreover, those who do respond will inevitably develop acquired resistance. Fulvestrant is the first drug which acts as a pure estrogen receptor (ER) antagonist without known agonist effects. It competitively binds to the ERs with an approximately 100 times greater affinity than that of tamoxifen. Fulvestrant promotes the degradation of ERs and subsequently prevents ER-mediated gene transcription. Everolimus (RAD001) is an oral derivative of rapamycin that is an m-TOR inhibitor. At cellular and molecular levels, everolimus acts as a signal transduction inhibitor. Everolimus selectively inhibits mTOR (mammalian target of rapamycin); a key and highly conserved serine-threonine kinase which is present in all cells and is a central regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR is the only currently known target of everolimus. In oncology, everolimus has been in clinical development since 2002 for patients with various hematologic and non-hematologic malignancies as a single agent or in combination with antitumor agents, including cytotoxic chemotherapeutic agents, targeted therapies, antibodies and hormonal agents. Patients will be randomized (1: 1) to receive everolimus or placebo with fulvestrant after consideration of stratification factors of performance status (0 vs. 1), measurable disease (with or without non-measurable) vs. non-measurable disease, and prior chemotherapy for metastatic disease vs. no prior chemotherapy. Patients will be evaluated for disease response every 12 weeks and treated until disease progression or unacceptable toxicity for a total of 12 cycles. Patients with no evidence of progressive disease who remain on study after completing 12 cycles are unblinded and continue to receive fulvestrant alone (if originally randomized to placebo) or in combination with everolimus (if originally randomized to everolimus) at the same dose and schedule. Patients will continue to be evaluated for disease response every 12 weeks and continue until disease progression or unacceptable toxicity.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria: 1. Signed informed consent. 2. ≥18 years. 3. ECOG Performance Status 0 or 1. 4. Histologically or cytologically confirmed adenocarcinoma of the breast. 5. Stage IV disease or inoperable locally advanced disease. 6. ER and/or PR-positive disease. Tumors must be HER-2/neu negative or equivocal. 7. Aromatase Inhibitor (AI) resistant, defined as:

- relapsed while receiving adjuvant therapy with an AI or,

- progressive disease while receiving an AI for metastatic disease

8. Received one prior cycle of fulvestrant within 28 days of randomization are eligible.

- ≥2 prior doses of fulvestrant are not eligible

9. Must be female and postmenopausal. 10. May have received ≤1 prior systemic chemotherapy regimen for metastatic disease. 11. Adequate organ function:

- WBC ≥3. 0 x 10⁹/L, ANC ≥1. 5 x 10⁹/L and platelet count ≥100 x 10⁹/L

- hemoglobin ≥9 g/dL

- serum bilirubin ≤1. 5 X ULN (Upper Limit of Normal)

- AST or ALT ≤2. 5 X ULN (≤5 x ULN in patients with liver metastases)

- serum creatinine ≤1. 5 X ULN

- serum albumin ≥3 g/dL

- fasting serum cholesterol ≤300 mg/dL OR ≤7. 75 mmol/L AND fasting triglycerides

≤2. 5 x ULN.

- PT with INR ≤1. 5

12. May have measurable disease, non-measurable disease, or both. 13. Basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix within the past five years treated with curative intent. History of prior malignancy are eligible if disease-free for >3 years. Exclusion Criteria: 1. Major surgery or significant traumatic injury within 4 weeks of randomization or patients that may require major surgery during the course of the study. 2. Investigational agents within 4 weeks of randomization. 3. Anticancer treatment within 4 weeks of randomization, with the following exceptions:

- Bisphosphonates or Zometa for bone metastases

- a GnRH analog is permitted if the patient had progressive disease on a GnRH

(Gonadotropin-Releasing Hormone) analog plus a SERM (Selective Estrogen Receptor Modulators) or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 4. Prior treatment with an mTOR inhibitor. 5. Receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent ≥ 5 mg prednisone or equivalent daily. 6. Receive immunization with attenuated live vaccines within one week of randomization or during the study period. 7. Current or a prior history of brain metastases or leptomeningeal disease. Must not have rapidly progressive, life-threatening metastases. 8. Known hypersensitivity/history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or fulvestrant. 9. Congenital or acquired immune deficiency at increased risk of infection. 10. Impairment of gastrointestinal function/disease that may significantly alter the absorption of everolimus. 11. Active, bleeding diathesis. 12. History of any condition or uncontrolled intercurrent illness that in the opinion of the local investigator might interfere with or limit the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient. 13. Severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York Heart Association Class III or


- Unstable angina pectoris, myocardial infarction within 6 months of

randomization, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease

- History of symptomatic pulmonary disease or non-malignant pulmonary disease

requiring treatment.

- Uncontrolled diabetes as defined by fasting serum glucose >1. 5 x ULN

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class

C). Note: Detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening.

Locations and Contacts

Carolyn Andrews, RN, Phone: 267-207-4070, Email: candrews@precogllc.org

Marin Cancer Care, Greenbrae, California 94904, United States; Recruiting
Jaime Chang, Phone: 415-925-5040, Email: jchang@marinspecialtycare.com
Bobbie Head, MD, Principal Investigator

Stanford University, Stanford, California 94305, United States; Recruiting
Pei-Jen Chang, Phone: 650-725-0866, Email: peijenc@stanford.edu
Melinda Telli, MD, Principal Investigator

SwedishAmerican Regional Cancer Center, Rockford, Illinois 61104, United States; Recruiting
Lori Kline, RN, BS, CCRP, Phone: 815-489-4413, Email: lkline@swedishamerican.org
Harvey E Einhorn, MD, Principal Investigator

McFarland Clinic, PC, Ames, Iowa 50010-3014, United States; Recruiting
Janet Mannetter, Phone: 515-239-2621, Email: mannetter@mgmc.com
Joseph Merchant, MD, Principal Investigator

Johns Hopkins University, Baltimore, Maryland 21287, United States; Recruiting
Patricia Rennie, Phone: 410-955-9869, Email: prennio1@jhmi.edu
Bridget Walsh, Phone: 410-502-3613, Email: bwalsh9@jhmi.edu
Antonio Wolff, MD, Principal Investigator

St. Joseph Mercy Hospital (MI Cancer Consortium), Arbor, Michigan 48158, United States; Recruiting
Melissa Case, Phone: 734-712-3621, Email: casemr@trinity-health.org
Shannon Porter, RN, Phone: 734-712-2704, Email: porters@trinity-health.org
Phillip Stella, MD, Principal Investigator

Metro MN, St. Louis Park, Minnesota 55416, United States; Recruiting
Betsy Wagner, Phone: 952-993-1555, Email: elizabeth.wagner@parknicollet.com
Andrea de Jesus, Phone: 952-993-3252, Email: andrea.dejesus@parknicollet.com
Jonathan Leach, MD, Principal Investigator

Missouri Valley Cancer Consortium, Omaha, Nebraska 68106, United States; Recruiting
Erin Smith, Phone: 402-991-8070, Ext: 201, Email: esmith@mvcc.cc
Mary Beth Wilwerding, RN, Phone: 402-991-8070, Ext: 202, Email: mwilwerding@mvcc.cc
Gamini Soori, MD, Principal Investigator

Montefiore Medical Center, Bronx, New York 10466, United States; Recruiting
Kathy Lora, Phone: 718-405-8523, Email: klora@montefiore.org
Karen Fehn, RN, Phone: 718-405-8446, Email: kfehn@montefiore.org
Della Makower, MD, Principal Investigator

Beth Israel, New York, New York 10011, United States; Recruiting
Damien Francois, Phone: 212-367-1740, Email: dfrancoi@chpnet.org
Sherly Jacob-Perez, Phone: 212-844-8292, Email: sjacob@chpnet.org
Paula Klein, MD, Principal Investigator

Ohio State University Medical Center, Columbus, Ohio 43210, United States; Recruiting
Jennifer Sensenig, Phone: 614-366-5844, Email: Jennifer.Sensenig@osumc.edu
Susan Ottman, Phone: 614-293-0069, Email: Susan.Ottman@osumc.edu
Bhuvaneswari Ramaswamy, MD, Principal Investigator

Toledo COP, Toledo, Ohio 43617, United States; Recruiting
Jessica Ciesler, Phone: 419-843-6147, Ext: 221, Email: jciesler@tcop.info
Joanne Lenkay, Phone: 419-843-6147, Ext: 228, Email: jlenkay@tcop.info
Rex Mowat, MD, Principal Investigator

Hematology & Oncology Associates of Northeastern PA, PC, Dunmore, Pennsylvania 18512, United States; Recruiting
Lee Ann Haefele, Phone: 570-342-3675, Ext: 218, Email: Leeann.Haefele@hemonc1.com
Richard Emanuelson, MD, Principal Investigator

Penn State University, Hershey, Pennsylvania 17033, United States; Recruiting
Jo Ann Fahringer, RN, BSN, Phone: 717-531-0003, Ext: 285237, Email: jfahringer@hmc.psu.edu
Brittany Lamke, Phone: 717-531-0003, Ext: 289437, Email: blamke@hmc.psu.edu
Cristina Truica, MD, Principal Investigator

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States; Recruiting
Cecilia McAleer, Phone: 215-728-2981, Email: cecilia.mcaleer@fccc.edu
Joanne Ley, RN, CCRP, Phone: 215-214-1724, Email: joanne.ley@fccc.edu
Lori Goldstein, MD, Principal Investigator

Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States; Active, not recruiting

University of Pittsburgh- Magee Women's Hospital, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Brenda Lee Steele, Phone: 412-641-2261, Email: steelebl@upmc.edu
Veronica Wahula, Phone: 412-641-2283, Email: wahuvf@upmc.edu
Adam Brufsky, MD, Principal Investigator

Reading Hospital- McGlinn Family Regional Cancer Center, West Reading, Pennsylvania 19611, United States; Recruiting
Christine Wolfe, RN, CCRP, Phone: 484-628-8194, Email: Christine.Wolfe@readinghealth.org
Patricia A. Weiser, RN, CCRP, Phone: 484-628-8193, Email: Patricia.Weiser@readinghealth.org
Terrence Cescon, MD, Principal Investigator

Main Line Heath System, Wynnewood, Pennsylvania 19096, United States; Recruiting
Diana Blade, Phone: 484-476-2649, Email: bladed@mlhs.org
Sandra Lyon, RN, Phone: 484-476-3494, Email: LyonS@mlhs.org
Paul Gilman, MD, Principal Investigator

University of Texas Southwestern, Dallas, Texas 75390, United States; Recruiting
Morella Menicucci, Phone: 214-590-2173, Email: morella.menicucci@utsouthwestern.edu
Todd Morgan, Phone: 214-648-7020, Email: todd.morgan@utsouthwestern.edu
Barbara Haley, MD, Principal Investigator

Charleston Area Medical Center (CAMC), Charleston, West Virginia 25304, United States; Recruiting
Augusta Kosowicz, PA-C, Phone: 304-388-9940, Email: augusta.kosowicz@camc.org
Karen Shirey, RN, Phone: 304-388-9936, Email: karen.shirey@camc.org
Arun Nagarajan, MD, Principal Investigator

St. Vincent Hospital, Green Bay, Wisconsin 54301, United States; Recruiting
Jolene Cheslock, Phone: 920-433-8272, Email: jolene.cheslock@stvgb.org
Gerald K. Bayer, MD, Principal Investigator

Gundersen Health System, Lacrosse, Wisconsin 54601, United States; Recruiting
Deb Kettner-Sieber, Phone: 608-775-1195, Email: dlkettner@gundersenhealth.org
Nancy Ruther, Phone: 608-775-2733, Email: nrruther@gundersenhealth.org
Kurt Oettel, MD, Principal Investigator

ProHealth Care Inc. (Waukesha), Waukesha, Wisconsin 53188, United States; Recruiting
Chanda Miller, Phone: 262-928-5539, Email: Chanda.Miller@phci.org
Timothy Wassenaar, MD, Principal Investigator

Aurora Cancer Care, Wauwatosa, Wisconsin 53226, United States; Recruiting
Liz Sieber, Phone: 414-778-4347, Email: Elizabeth.sieber@aurora.org
Patti Allard, Phone: 414-778-4346, Email: Patti.allard@aurora.org
Michael Thompson, MD, Principal Investigator

Additional Information

Related publications:

Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth inhibition. Recent Results Cancer Res. 2007;172:99-124. Review.

Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, Littlewood-Evans A, Maira SM, Martiny-Baron G, Schnell CR, Sini P, O'Reilly T. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res. 2009 Mar 1;15(5):1612-22. doi: 10.1158/1078-0432.CCR-08-2057. Epub 2009 Feb 17.

Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. doi: 10.1056/NEJMoa1109653. Epub 2011 Dec 7.

Starting date: May 2013
Last updated: June 10, 2015

Page last updated: August 23, 2015

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