Clinical Trials (PDQ®)
|Phase II||Treatment||Active||18 and over||Pharmaceutical / Industry||PrE0102|
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.
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.
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 Lead Organizations/Sponsors
PrECOG, LLCNovartis Pharmaceuticals Corporation
|Noah S Kornblum, MD||Study Chair|
|Carolyn Andrews, RN||Ph: 267-207-4070|
|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|
|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: 402-991-8070 Ext.201|
|Mary Beth Wilwerding, RN||Ph: 402-991-8070 Ext.202|
|Gamini Soori, MD||Principal Investigator|
|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|
|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|
|Jessica Ciesler||Ph: 419-843-6147 Ext.221|
|Joanne Lenkay||Ph: 419-843-6147 Ext.228|
|Rex Mowat, MD||Principal Investigator|
|Hematology and Oncology Associates of Northeastern Pennsylvania|
|Lee Ann Haefele||Ph: 570-342-3675 Ext.218|
|Richard Emanuelson, MD||Principal Investigator|
|Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center|
|Jo Ann Fahringer, RN, BSN||Ph: 717-531-0003 Ext.285237|
|Brittany Lamke||Ph: 717-531-0003 Ext.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|
|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|
|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|
|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 ClinicalTrials.gov record.
NLM Identifer NCT01797120
ClinicalTrials.gov processed this data on October 20, 2014
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