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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

Phase 2
18 Years
Open (Enrolling)
Metastatic Breast Cancer

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Trial Information

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

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.

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

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

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

Type of Study:


Study Design:

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

Outcome Measure:

Progression-free survival

Outcome Description:

Progression-free survival documented by Physical Exam, CT Scan or MRI in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is resistant to aromatase inhibitor therapy treated with fulvestrant and everolimus compared to fulvestrant alone from randomization to documented disease progression or death.

Outcome Time Frame:

Every 3 months until progression or up to 3 years

Safety Issue:


Principal Investigator

Noah S Kornblum, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Saint Barnabas Cancer Center, Montefiore Medical Center


United States: Institutional Review Board

Study ID:




Start Date:

May 2013

Completion Date:

November 2015

Related Keywords:

  • Metastatic Breast Cancer
  • Post-Menopausal Patients
  • Hormone-Receptor Positive
  • Resistant to Aromatase Inhibitor Therapy
  • Fulvestrant
  • Faslodex
  • mTOR Inhibitor
  • Everolimus
  • RAD001
  • Afinitor
  • Breast Neoplasms



Stanford UniversityStanford, California  94305
St. Vincent HospitalGreen Bay, Wisconsin  54307-3508
McFarland Clinic, PCAmes, Iowa  50010
Marin Cancer CareGreenbrae, California  94904
SwedishAmerican Regional Cancer CenterRockford, Illinois  61104
Hematology & Oncology Associates of Northeastern PA, PCDunmore, Pennsylvania  18512
Reading Hospital- McGlinn Family Regional Cancer CenterWest Reading, Pennsylvania  19611
Charleston Area Medical Center (CAMC)Charleston, West Virginia  25304
Gundersen Health SystemLacrosse, Wisconsin  54601
ProHealth Care Inc. (Waukesha)Waukesha, Wisconsin  53188