Breast Cancer
Conditions
Keywords
ER-Positive Breast Cancer, HER2-Negative Breast Cancer, everolimus, anti-estrogen therapy, PR-Positive Breast Cancer, Afinitor
Brief summary
Many patients with ER-positive or PR-positive breast cancer are treated with endocrine therapy. Although most ER/PR-positive tumors initially respond to hormonal therapy, patients often experience disease progression. Everolimus, in combination with exemestane, has shown activity in endocrine-resistant disease. This study will evaluate the efficacy of Everolimus+ anti-estrogen therapy in patients with ER-positive metastatic breast cancer who have progressed after receiving anti-estrogen therapy.
Detailed description
This is a multi-centered, open-labeled, Phase II study on metastastic breast cancer (MBC). The patient population includes locally recurrent or MBC patients with cytologically or histologically confirmed hormone receptor-positive breast cancer who have demonstrated disease progression on prior anti-estrogen therapy or therapies. Investigators propose to evaluate the efficacy of Everolimus in patients with ER-positive (estrogen receptor-positive) metastatic breast cancer who have progressed on anti-estrogen therapy. Forty-six (46) patients are planned for enrollment in the trial.
Interventions
DRUGEverolimus
DRUGExemestane
Anti-estrogen therapy
DRUGTamoxifen
Anti-estrogen therapy
DRUGFulvestrant
Anti-estrogen therapy
DRUGAnastrozole
Anti-estrogen therapy
DRUGLetrozole
Anti-estrogen therapy
DRUGToremifine
Anti-estrogen therapy
Sponsors
Novartis
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologic diagnosis of unresectable, locally recurrent or MBC. 2. ER and/or PR-positive tumors with staining by immunohistochemistry (IHC) based on the most recent biopsy. 3. Only 1 previous chemotherapy regimen for MBC. Patients progressing while receiving adjuvant endocrine therapy or progressing \<12 months from completion of adjuvant endocrine therapy are eligible. 4. Progressed on anti-estrogen therapy (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy) defined as: * Recurrence while on, or within 12 months of end of anti-estrogen therapy for early stage breast cancer, or * Progression while on, or within one month of anti-estrogen therapy for locally advanced or metastatic breast cancer. Note: No washout for anti-estrogen therapy required. Anti-estrogen therapy does not have to be the last treatment prior to study entry. 5. Post-menopausal or pre/peri-menopausal women on tamoxifen. LHRH agonists may be used to render ovarian suppression with postmenopausal ranges of estradiol or FSH per institutional guidelines. 6. HER2-negative breast cancer, defined as follows: * Fluorescent In Situ Hybridization (FISH)-negative (FISH ratio \<2.0), or * IHC 0-1+, or * IHC 2-3+ AND FISH-negative (FISH ratio \<2.0). 7. Measureable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 or evaluable bone lesions, lytic or mixed, in absence of measureable disease by RECIST criteria. 8. Adequate hematologic, hepatic and renal function. 9. International normalized ratio (INR) ≤1.5 or prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy). 10. Age ≥ 18 years. 11. ECOG Performance Status score of 0-2. 12. Life expectancy of ≥ 12 weeks.
Exclusion criteria
1. Previous therapy or known intolerance/hypersensitivity with any approved or investigational mTOR inhibitor (e.g., temsirolimus, everolimus, sirolimus). 2. Patients who are ≤21 days after their most recent chemotherapy and have not recovered from side effects. 3. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of everolimus. For investigational drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the investigational drug and administration of everolimus is required. 4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days for metastatic disease prior to first dose of everolimus or has not recovered from side effects of such therapy. 5. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Patients are not permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs) during the study and should not be receiving chronic corticosteroid therapy for CNS metastases. 6. Patients with known active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients with risk factors for hepatitis must have HBV DNA and HCV RNA testing by PCR, and are ineligible if these tests are positive. 7. Patients receiving immunization with attenuated live vaccines within 1 week of study entry or during study period. NOTE: There are additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | up to 3 years | PFS is defined as the time from Day 1 of study drug administration to disease progression as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, or death on study. Participants who are alive and free from disease progression will be censored at the date of last radiologic tumor assessment. Participants who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. Participants who do not have a post-baseline tumor assessment will be censored at the date of first treatment (Day 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability | Up to 20 months | Assessments were made through analysis of the reported incidence of treatment-emergent AEs. All participants who received at least one dose of protocol treatment were followed for safety. Adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR). | every 8 weeks until discontinuation, up to 20 months | Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST version 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. |
| Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR) | Up to 20 months | The proportion of patients with Complete Response (CR) or Partial Response (PR) or 6 months or more of Stable Disease (SD). A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. SD is not meeting the criteria for PR or a 20% increase in target lesions called Progressive Disease (PD). |
| Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR) | every 8 weeks until discontinuation, up to 20 months | Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. DOR is defined as time from first date of response of CR or PR to disease progression or death as defined by RECIST v1.1 criteria. Participants who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. |
| Median Overall Survival (OS) | up to 3 years from first treatment | Defined as the time from date of first study treatment to date of death due to any cause. Patients who are alive will be censored at the date of last known date alive. |
Countries
United States
Participant flow
Recruitment details
Between December 2014 to December 2015, 48 patients who had locally recurrent or metastatic breast cancer with cytologically or histologically confirmed hormone receptor-positive breast cancer who have demonstrated disease progression on prior anti-estrogen therapy. Study was closed after enrollment goal was reached.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Everolimus will be administered at a dose of 10 mg by mouth daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. A treatment cycle was defined as 4 weeks, with radiological evaluations every 8 weeks.
Everolimus
Exemestane: Anti-estrogen therapy
Tamoxifen: Anti-estrogen therapy
Fulvestrant: Anti-estrogen therapy
Anastrozole: Anti-estrogen therapy
Letrozole: Anti-estrogen therapy
Toremifine: Anti-estrogen therapy | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Death | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 32 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 19 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 62 years |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 48 Participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 32 / 48 |
| other Total, other adverse events | 48 / 48 |
| serious Total, serious adverse events | 15 / 48 |
Outcome results
Primary
Median Progression Free Survival (PFS)
PFS is defined as the time from Day 1 of study drug administration to disease progression as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, or death on study. Participants who are alive and free from disease progression will be censored at the date of last radiologic tumor assessment. Participants who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. Participants who do not have a post-baseline tumor assessment will be censored at the date of first treatment (Day 1).
Time frame: up to 3 years
Population: Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment were evaluable for PFS analysis per protocol. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Median Progression Free Survival (PFS) | 7.2 months |
Secondary
Median Overall Survival (OS)
Defined as the time from date of first study treatment to date of death due to any cause. Patients who are alive will be censored at the date of last known date alive.
Time frame: up to 3 years from first treatment
Population: Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment were evaluable for OS analysis per protocol. 36 of the total 48 patients were analyzed for OS. The remaining 12 treated patients did not meet this criteria to be analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Median Overall Survival (OS) | 26.7 months |
Secondary
Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR)
Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. DOR is defined as time from first date of response of CR or PR to disease progression or death as defined by RECIST v1.1 criteria. Participants who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
Time frame: every 8 weeks until discontinuation, up to 20 months
Population: Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR) | 8.8 months |
Secondary
Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR)
The proportion of patients with Complete Response (CR) or Partial Response (PR) or 6 months or more of Stable Disease (SD). A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. SD is not meeting the criteria for PR or a 20% increase in target lesions called Progressive Disease (PD).
Time frame: Up to 20 months
Population: Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus | Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR) | 12 Participants |
Secondary
Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability
Assessments were made through analysis of the reported incidence of treatment-emergent AEs. All participants who received at least one dose of protocol treatment were followed for safety. Adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: Up to 20 months
Population: Number of participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus | Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability | 48 Participants |
Secondary
Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR).
Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST version 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
Time frame: every 8 weeks until discontinuation, up to 20 months
Population: Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus | Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR). | 2 Participants |