Study of Combined Fulvestrant and Everolimus in Advanced/Metastatic Breast Cancer After Aromatase Inhibitor Failure (BRE-43)

January 8, 2017 updated by: Mara Chambers

A Phase II Study of Combined Fulvestrant (Faslodex) and Everolimus in Advanced/Metastatic Breast Cancer After Aromatase Inhibitor Failure

The primary objective of this study is to determine if estrogen receptor-targeted therapy with fulvestrant used in combination with Everolimus is an effective and safe therapy for women with hormone receptor positive metastatic breast cancer after failure of aromatase inhibitor therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Fulvestrant, which degrades ER, is used after aromatase inhibitor (AI) failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mammalian target of rapamycin (mTOR), a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Postmenopausal status, defined as any one of the following criteria: Documented history of bilateral oophorectomy, Age 60 years or more, OR Age 45 to 59 and satisfying one or more of the following criteria: Amenorrhea for at least 12 months and intact uterus OR Amenorrhea for less than 12 months and a follicle stimulating hormone (FSH) concentration - within postmenopausal range including: Patients who have had a hysterectomy or Patients who have received hormone replacement
  • Patients must have histologically confirmed invasive breast cancer
  • Metastatic or locally advanced disease
  • Patients must have estrogen receptor and/or progesterone receptor positive disease
  • Measurable or evaluable disease
  • Failure of aromatase inhibitor therapy within the previous 6 months. Patients who received prior tamoxifen are eligible to enroll
  • Prior aromatase inhibitor therapy or other endocrine therapy must be discontinued at least 1 week prior to enrollment and any toxicity from such therapy must have reverted to grade I or less at the time of enrollment
  • Patients must not have received chemotherapy, radiation therapy, or had surgery within 4 weeks prior to enrollment and any toxicity from such therapy must have recovered to grade 1 or less prior to enrollment
  • Patients must not have received either of the study medications previously
  • WHO performance status of 0, 1, or 2
  • Adequate organ function defined as follows: Adequate renal function, defined by a serum creatinine within the upper limits of normal, Adequate liver function, defined by a bilirubin of < 1.5 the upper limit of normal (ULN) and aspartate aminotransferase (AST), alanine aminotransferase (ALT) of ≤ 2.5 times the ULN, Adequate bone marrow function, defined as an absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count (PLT) >100,000/ul, Hb >9 gm/dl, international normalized ratio (INR) <1.3, and because fulvestrant is administered intramuscularly, it should not be used in patients with bleeding diatheses, thrombocytopenia or in patients on anticoagulants
  • Patients will be asked to provide a tumor paraffin block if available
  • Ability to understand and sign a written informed consent for participation in the trial

Exclusion Criteria:

  • Known severe hypersensitivity to everolimus (or similar drugs) or any of the excipients of this product
  • Premenopausal status
  • Other coexisting malignancies with the exception of basal cell carcinoma or cervical cancer in situ
  • Patients with brain metastasis or leptomeningeal involvement
  • Patients with malignant pleural effusion or ascites only disease
  • Rapidly progressive visceral disease
  • WHO performance status of 3 or 4
  • As judged by the investigator, uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, Symptomatic congestive heart failure, Unstable angina pectoris or significant cardiac arrhythmia, Psychiatric illness/social situations that would limit compliance with study requirements, Severely impaired lung function such as severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease, a known forced expiratory volume at one second (FEV1) of < 1.5 liters, or dyspnea of grade III or greater, Uncontrolled diabetes as defined by a fasting blood sugar (FBS) of > 1.5 ULM, Known liver disease such as cirrhosis or chronic hepatitis, Known HIV positivity, OR known condition causing malabsorption
  • Chronic treatment with systemic steroids or other immunosuppressive agents
  • Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
  • Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the clinical trial
  • Prior treatment with an mTOR inhibitor
  • Treatment with a non-approved or investigational drug within 30 days or 5 half-lives of the drug, whichever is greater, before Day 1 of study treatment
  • In the opinion of the investigator, bleeding diathesis or anticoagulation therapy that would preclude intramuscular injections
  • History of hypersensitivity to castor oil

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fulvestrant + Everolimus

Fulvestrant + Everolimus

Fulvestrant was administered intramuscularly (in the gluteus maximus) in a loading dose schedule as follows: 500 mg in two divided doses-one on each side on day 1, then 250 mg on day 14, and then 250 mg on day 28 and every 4 weeks ± 3 days thereafter. Everolimus was administered initially at a dose of 5 mg daily in the first 5-patient cohort for the first month of treatment and then increased to 10 mg PO daily after that.
Drug: Everolimus
Everolimus tablets, two-5 mg tablets a day
Other Names:
  • RAD001
Drug: Fulvestrant
intramuscular, 500 mg in two divided doses- one on each side- on day 1, then 250mg on day 14, then 250 mg on day 28 and every 4 weeks +/- 3 days thereafter
Other Names:
  • Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time to Progression
Time Frame: Duration of time start of treatment to time of documented progression or death
Duration of time start of treatment to time of documented progression or death

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rates
Time Frame: Evaluated 60 days after therapy start
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Evaluated 60 days after therapy start
Clinical Benefit Rate
Time Frame: Duration of response or stable disease for 24 weeks or more
Clinical benefit rate is defined as a complete response, partial response, or stable disease (CR, PR, SD) by Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for a minimum of at least 24 weeks or more.
Duration of response or stable disease for 24 weeks or more

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mara Chambers

Collaborators

Novartis

Investigators

  • Principal Investigator: Mara Chambers, M.D., University of Kentucky

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2008

Primary Completion (Actual)

February 1, 2013

Study Completion (Actual)

January 1, 2015

Study Registration Dates

First Submitted

December 7, 2007

First Submitted That Met QC Criteria

December 7, 2007

First Posted (Estimate)

December 11, 2007

Study Record Updates

Last Update Posted (Actual)

February 23, 2017

Last Update Submitted That Met QC Criteria

January 8, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 07-BRE-43-NP

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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