Breast Cancer
Conditions
Keywords
Breast cancer, Fulvestrant, Everolimus
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.
Interventions
DRUGEverolimus
Everolimus tablets, two-5 mg tablets a day
DRUGFulvestrant
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
Sponsors
Novartis
Mara Chambers
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to Progression | Duration of time start of treatment to time of documented progression or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at a single location, University of Kentucky Markey Cancer Center, between March 2008 and October 2012.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Fulvestrant & Everolimus |
|---|---|
| 3 or more prior endocrine therapies No | 23 participants |
| 3 or more prior endocrine therapies Yes | 8 participants |
| Age, Continuous | 54 years |
| AI Sensitivity Resistant | 10 participants |
| AI Sensitivity Sensitive | 21 participants |
| Bone Disease No | 11 participants |
| Bone Disease Yes | 20 participants |
| Gender Female | 31 Participants |
| Gender Male | 0 Participants |
| Histology Ductal | 26 participants |
| Histology Intracystic papillary | 1 participants |
| Histology Lobular | 3 participants |
| Histology Mixed ductal and lobular | 1 participants |
| Hormone Receptor Status ER-positive/progesterone receptor (PgR)-negative | 5 participants |
| Hormone Receptor Status ER-positive/progesterone receptor (PgR)-positive | 26 participants |
| Human epidermal growth factor receptor 2 (HER2) Status Negative | 29 participants |
| Human epidermal growth factor receptor 2 (HER2) Status Positive | 2 participants |
| Intact Primary Tumor No | 25 participants |
| Intact Primary Tumor Yes | 6 participants |
| Liver Disease No | 12 participants |
| Liver Disease Yes | 19 participants |
| Lung Disease No | 14 participants |
| Lung Disease Yes | 17 participants |
| Number of metastatic sites 1 | 4 participants |
| Number of metastatic sites 2 | 10 participants |
| Number of metastatic sites 3 or more | 17 participants |
| Prior aromatase inhibitor (AI) therapy within 6 months of enrollment | 31 participants |
| Prior Chemotherapy No | 9 participants |
| Prior Chemotherapy Yes | 22 participants |
| Prior tamoxifen therapy No | 6 participants |
| Prior tamoxifen therapy Yes | 25 participants |
| Race/Ethnicity, Customized Black | 3 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants |
| Race/Ethnicity, Customized White | 27 participants |
| Relapsed versus de novo metastasis De novo | 7 participants |
| Relapsed versus de novo metastasis Relapse | 24 participants |
| Skin Disease No | 27 participants |
| Skin Disease Yes | 4 participants |
| Two prior aromatase inhibitor therapy No | 24 participants |
| Two prior aromatase inhibitor therapy Yes | 7 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 33 |
| serious Total, serious adverse events | 5 / 33 |
Outcome results
Primary
Time to Progression
Time frame: Duration of time start of treatment to time of documented progression or death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Everolimus | Time to Progression | 7.4 months |
Comparison: We hypothesized that median time to progression (TTP) in our trial will increase from 3.7 months for the historical fulvestrant-only control to 7.0 months on the combination of fulvestrant and everolimus in the current trial. A sample of 40 evaluable patients was calculated to show the increase in TTP with 80% power and 5% significance level based on a two sided test of differences in survival times between historical controls and treated group.95% CI: [1.9, 12.1]
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.
Time frame: Duration of response or stable disease for 24 weeks or more
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant + Everolimus | Clinical Benefit Rate | 15 participants |
95% CI: [30.15, 66.94]
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.
Time frame: Evaluated 60 days after therapy start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant + Everolimus | Objective Response Rates | 4 participants |
95% CI: [3.63, 29.83]