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

Phase 2

Completed

Conditions: Breast Cancer

Interventions: Drug: Everolimus
Drug: Fulvestrant

Registration Number: NCT00570921

Lead Sponsor: Mara Chambers

Brief 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 33

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

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Fulvestrant + Everolimus	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.
Fulvestrant + Everolimus	Fulvestrant	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.

Primary Outcome Measures

Name	Time	Method
Time to Progression	Duration of time start of treatment to time of documented progression or death

Secondary Outcome Measures

Name	Time	Method
Objective Response Rates	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.
Clinical Benefit Rate	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.