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

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IITreatmentActive18 and overPharmaceutical / IndustryPrE0102

Trial Description


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.

Further Study Information

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.

Eligibility Criteria

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 dose 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 IV
  • 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.

Trial Contact Information

Trial Lead Organizations/Sponsors


  • Novartis Pharmaceuticals Corporation
Noah S Kornblum, MD, Study Chair
Carolyn Andrews, RN
Ph: 267-207-4070

Trial Sites



Marin Cancer Care

Jaime Chang
Ph: 415-925-5040

Bobbie Head, MD
Principal Investigator


Stanford Cancer Center

Pei-Jen Chang
Ph: 650-725-0866

Melinda Telli, MD
Principal Investigator


SwedishAmerican Regional Cancer Center

Lori Kline, RN, BS, CCRP
Ph: 815-489-4413

Harvey E Einhorn, MD
Principal Investigator


Indiana University Melvin and Bren Simon Cancer Center

Lauren Baker
Ph: 317-278-5160

Ashley Grist
Ph: 317-278-6680

Kathy Miller
Principal Investigator


McFarland Clinic, PC

Janet Mannetter
Ph: 515-239-2621

Joseph Merchant, MD
Principal Investigator


Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Patricia Rennie
Ph: 410-955-9869

Bridget Walsh
Ph: 410-502-3613

Antonio Wolff, MD
Principal Investigator


St. Joseph Mercy Hospital (MI Cancer Consortium)

Melissa Case
Ph: 734-712-3621

Shannon Porter, RN
Ph: 734-712-2704

Phillip Stella, MD
Principal Investigator

St. Louis Park

Metro MN

Betsy Wagner
Ph: 952-993-1555

Andrea de Jesus
Ph: 952-993-3252

Jonathan Leach, MD
Principal Investigator


Missouri Valley Cancer Consortium

Erin Smith
Ph: 402-991-8070Ext. 201

Mary Beth Wilwerding, RN
Ph: 402-991-8070Ext. 202

Gamini Soori, MD
Principal Investigator

New York

Albert Einstein Cancer Center at Albert Einstein College of Medicine

Kathy Lora
Ph: 718-405-8523

Karen Fehn, RN
Ph: 718-405-8446

Della Makower, MD
Principal Investigator

New York

Beth Israel Medical Center - Petrie Division

Damien Francois
Ph: 212-367-1740

Sherly Jacob-Perez
Ph: 212-844-8292

Paula Klein
Principal Investigator


Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Jennifer Sensenig
Ph: 614-366-5844

Susan Ottman
Ph: 614-293-0069

Bhuvaneswari Ramaswamy
Principal Investigator


Toledo COP

Jessica Ciesler
Ph: 419-843-6147Ext. 221

Joanne Lenkay
Ph: 419-843-6147Ext. 228

Rex Mowat, MD
Principal Investigator


Hematology and Oncology Associates of Northeastern Pennsylvania

Lee Ann Haefele
Ph: 570-342-3675Ext. 218

Richard Emanuelson, MD
Principal Investigator


Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center

Jo Ann Fahringer, RN, BSN
Ph: 717-531-0003Ext. 285237

Brittany Lamke
Ph: 717-531-0003Ext. 289437

Cristina Truica, MD
Principal Investigator


Fox Chase Cancer Center - Philadelphia

Cecilia McAleer
Ph: 215-728-2981

Joanne Ley, RN, CCRP
Ph: 215-214-1724

Lori J. Goldstein
Principal Investigator

Kimmel Cancer Center at Thomas Jefferson University - Philadelphia

Melisa Mordenti, MPH
Ph: 215-955-8979

Nicole Napowanetz
Ph: 215-503-3037

Allison Zibelli
Principal Investigator


UPMC Cancer Centers

Brenda Lee Steele
Ph: 412-641-2261

Veronica Wahula
Ph: 412-641-2283

Adam Brufsky
Principal Investigator

West Reading

McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center

Christine Wolfe, RN, CCRP
Ph: 484-628-8194

Patricia A. Weiser, RN, CCRP
Ph: 484-628-8193

Terrence P. Cescon
Principal Investigator


Main Line Heath System

Diana Blade
Ph: 484-476-2649

Sandra Lyon, RN
Ph: 484-476-3494

Paul Gilman, MD
Principal Investigator


Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas

Morella Menicucci
Ph: 214-590-2173

Todd Morgan
Ph: 214-648-7020

Barbara B. Haley
Principal Investigator

West Virginia

Charleston Area Medical Center (CAMC)

Augusta Kosowicz, PA-C
Ph: 304-388-9940

Karen Shirey, RN
Ph: 304-388-9936

Arun Nagarajan, MD
Principal Investigator

Green Bay

St. Vincent Hospital Regional Cancer Center

Jolene Cheslock
Ph: 920-433-8272

Gerald K. Bayer, MD
Principal Investigator


Gundersen Health System

Deb Kettner-Sieber
Ph: 608-775-1195

Nancy Ruther
Ph: 608-775-2733

Kurt Oettel, MD
Principal Investigator


ProHealth Care Inc. (Waukesha)

Chanda Miller
Ph: 262-928-5539

Timothy Wassenaar, MD
Principal Investigator


Aurora Cancer Care

Liz Sieber
Ph: 414-778-4347

Patti Allard
Ph: 414-778-4346

Michael Thompson, MD
Principal Investigator

Link to the current record.
NLM Identifier NCT01797120 processed this data on March 03, 2015

Note: Information about this trial is from the database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the record to standardize the names of study sponsors, sites, and contacts. only lists sites that are recruiting patients for active trials, whereas lists all sites for all trials. Questions and comments regarding the presented information should be directed to