Study of Combined Fulvestrant and Everolimus in Advanced/Metastatic Breast Cancer After Aromatase Inhibitor Failure

Breast Cancer Clinical Trial

— BRE-43  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00570921
• Other study ID #: 07-BRE-43-NP
• Status: Completed
• Phase: Phase 2
• First received: December 7, 2007
• Last updated: January 8, 2015
• Start date: April 2008
• Est. completion date: January 2015

Study information

• Verified date: January 2015
• Source: University of Kentucky
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: January 2015
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Everolimus
Everolimus tablets, two-5 mg tablets a day
• 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

Locations

Country	Name	City	State
United States	University of Kentucky	Lexington	Kentucky

Sponsors (2)

Lead Sponsor	Collaborator
Suleiman Massarweh	Novartis

Country where clinical trial is conducted

United States, 

References & Publications (1)

Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, Stevens M, Elledge R. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibito — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Progression		Duration of time start of treatment to time of documented progression or death	No
Secondary	Objective Response Rates	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	No
Secondary	Clinical Benefit Rate	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	No