Breast Cancer
Conditions
Keywords
stage IV breast cancer, male breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Fulvestrant and bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving fulvestrant together with bevacizumab may be an effective treatment for metastatic breast cancer. PURPOSE: This phase II trial is studying how well giving fulvestrant together with bevacizumab works in treating patients with metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * Assess the efficacy of fulvestrant and bevacizumab, in terms of 6-month progression-free survival (PFS), in patients with metastatic breast cancer previously treated with an aromatase inhibitor. Secondary * Assess the quality of life of patients treated with this regimen. * Determine the adverse-event profile in these patients. * Determine the PFS and overall survival of these patients. * Determine the confirmed response rate, duration of response, time to treatment failure, and time to first cytotoxic agent in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive fulvestrant intramuscularly on day 1 and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, prior to every other course, and at the completion of study treatment. After completion of study treatment, patients are followed every 3-6 months for 5 years. PROJECTED ACCRUAL: A total of 51 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
DRUGfulvestrant
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed breast cancer * Metastatic disease * Must have received an aromatase inhibitor (e.g., letrozole, anastrozole, or exemestane) in an adjuvant or metastatic setting * If tumor is HER2 positive (3+ by immunohistochemistry or amplified by fluorescent in situ hybridization) the patient must have received ≥ 1 prior trastuzumab (Herceptin®)-containing regimen unless there is a contraindication to trastuzumab * Measurable or nonmeasurable disease, including any of the following : * Bone metastasis * Pleural/pericardial effusion * Ascites * Inflammatory skin changes * No microscopic residual disease only * Enrolled on or refused enrollment on clinical trial NCCTG-N0392 * No evidence of active brain metastasis including leptomeningeal involvement * CNS metastasis controlled (i.e., at least 2 months of no symptoms or evidence of progression) by prior surgery and/or raditherapy are allowed * Hormone receptor status: * Estrogen and/or progesterone receptor-positive tumor PATIENT CHARACTERISTICS: * Male or female * Female patients must be post-menopausal based on any 1 of the following criteria: * Age ≥ 60 years * Age ≥ 45 years with last menstrual period ≥ 12 months prior to study entry * Estradiol and follicle-stimulating hormone levels in postmenopausal range * History of bilateral oophorectomy * ECOG performance status 0-2 * Life expectancy \> 3 months * Fertile patients must use effective contraception during and for 30 days after completion of study treatment * WBC ≥ 3,000 mg/dL * Hemoglobin \> 8 g/dL * Absolute neutrophil count \> 1,000/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * Alkaline phosphatase ≤ 2.5 times ULN * AST and ALT ≤ 2.5 times ULN * Creatinine ≤ 1.5 times ULN * Urine protein \< 1+ OR \< 1 g of protein by 24-hour urine collection * No nephrotic syndrome * No uncontrolled hypertension (i.e., blood pressure \[BP\] \> 160/90 mm Hg on ≥ 2 occasions at least 5 minutes apart) * Patients who have recently started or adjusted antihypertensive medications are eligible provided BP is \< 140/90 mm Hg on any new regimen for ≥ 3 different observations in ≥ 14 days * No clinically significant cardiac disease, including any of the following: * Congestive heart failure * Symptomatic coronary artery disease * Unstable angina * Cardiac arrhythmias not well controlled with medication * Myocardial infarction within the past 12 months * No arterial or venous thrombosis within the past 12 months * No hemoptysis or gastrointestinal hemorrhage within the past 6 months * No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 4 weeks * No significant traumatic injury within the past 4 weeks * No active, unresolved infection * No history of hypertensive crisis or hypertensive encephalopathy * No history of bleeding diathesis or uncontrolled coagulopathy * No history of cerebrovascular accident, hemorrhage, or stroke * No allergy or hypersensitivity to drug product excipients, murine antibodies, or agents chemically similar to study drugs * No other malignancy within the past 3 years except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * No other serious medical condition that would preclude study therapy or compliance PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior radiotherapy to a target lesion allowed provided there has been clear progression since radiotherapy was completed * At least 4 weeks since prior radiotherapy * Single-dose radiation for palliation or to a nontarget lesion only allowed within the past 4 weeks * No more than 1 prior chemotherapy regimen for metastatic disease * No more than 2 prior endocrine (hormonal) therapy regimens in the neoadjuvant, adjuvant, or metastatic setting * At least 4 weeks since prior major surgery or open biopsy * At least 4 weeks since prior chemotherapy or immunologic therapy * At least 2 weeks since prior and no concurrent use of any of the following agents: * Aspirin (daily low-dose \[81 mg\] aspirin allowed\]) * Thrombolytic agents * Anticoagulants (low-dose anticoagulation therapy to maintain patency of a vascular access device is allowed) * No concurrent treatment in another clinical study with investigational procedures or investigational therapies * No other concurrent anticancer therapy, including chemotherapy, biologic agents, or radiotherapy * No routine use of granulocyte colony-stimulating factors during course 1 * No concurrent oprelvekin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Six-month Progression-free Survival (PFS) Rate at 6 Months | at 6 months | The primary endpoint of this trial is the 6-month progression-free survival rate. A patient is considered to be a 6-month progression-free survivor if the patient is on study treatment 6 months from registration without a documentation of disease progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Additionally, if some patients are lost to follow-up not having been observed for at least 6 months, an estimate and 95% confidence interval for the 6-month progression-free survival rate incorporating censoring will be computed using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 5 years | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier (1958). |
| Quality of Life, as Measured by the Largest Mean Change in LASA Overall QOL and Physical Well-being Items | Up to 5 years | Quality of life (QOL) assessment will be a secondary exploratory component of this trial. QOL of patients was measure using the 6-item Linear Analogue Self-Assessment (LASA).The LASA consists of six single-item numeric analog scales measuring overall QOL; mental, physical, emotional, and spiritual well-being; and level of activity each on a scale of 0 ('As bad as it can be') to 10 ('As good as it can be') during the past week. Items were transformed to a 0 (worst QOL or well-being) to 100 (best QOL or well-being) scale for statistical analysis. Mean change from baseline of the largest mean change in overall QOL and physical well-being are reported below. |
| Progression Free Survival | Up to 5 years | Time to disease progression is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Time to First Cytotoxic Agent | Up to 5 years | Time to first dose of a cytotoxic agent is defined to be the time from the date of registration to the date at which a patient recieves the first dose of a cytotoxic agent. The distribution of time to first dose of a cytotoxic agent will be estimated using the method of Kaplan-Meier (1958). |
| Duration of Response/Time to Disease Progression in Patients With Measurable Disease | Up to 5 years | Duration of response is defined for all evaluable patients with measurable disease who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. In the case of a patient failing to return for evaluations before a documentation of disease progression, the patient will be censored for progression on the date of last evaluation. The distribution of duration of response will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Objective Response Rate as Measured by RECIST Criteria in Patients With Measurable Disease | Up to 5 years | A confirmed response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. The confirmed response rate will be estimated by the number of confirmed responses in evaluable patients with measurable disease divided by the total number of evaluable patients with measurable disease. The appropriate confidence interval will be calculated. 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant + Bevacizumab Patients receive Fulvestrant 250 mg intramuscularly every 28 days and Bevacizumab 10mg/kg intravenously with a rate-regulating device on days 1 and 15. Loading dose of fulvestrant for the first cycle will consist of an extra 250 mg on day 1 (for total of 500 mg Cycle 1, Day 1). The initial bevacizumab dose will be delivered over 90 minutes. If the first infusion is tolerated without infusion-associated adverse events (fever and/or chills), the second infusion may be delivered over 60 minutes. If the 60-minute infusion is well-tolerated, all subsequent infusions may be delivered over 30 minutes.Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Cancel | 2 |
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Fulvestrant + Bevacizumab |
|---|---|
| Age, Continuous | 65 years |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 29 / 33 |
| serious Total, serious adverse events | 4 / 33 |
Outcome results
Primary
Six-month Progression-free Survival (PFS) Rate at 6 Months
The primary endpoint of this trial is the 6-month progression-free survival rate. A patient is considered to be a 6-month progression-free survivor if the patient is on study treatment 6 months from registration without a documentation of disease progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Additionally, if some patients are lost to follow-up not having been observed for at least 6 months, an estimate and 95% confidence interval for the 6-month progression-free survival rate incorporating censoring will be computed using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: at 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant + Bevacizumab | Six-month Progression-free Survival (PFS) Rate at 6 Months | 39 percentage of patients |
Secondary
Duration of Response/Time to Disease Progression in Patients With Measurable Disease
Duration of response is defined for all evaluable patients with measurable disease who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. In the case of a patient failing to return for evaluations before a documentation of disease progression, the patient will be censored for progression on the date of last evaluation. The distribution of duration of response will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 5 years
Population: Evaluable patients with measurable disease who experienced a confirmed response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Bevacizumab | Duration of Response/Time to Disease Progression in Patients With Measurable Disease | 11.9 months |
Secondary
Objective Response Rate as Measured by RECIST Criteria in Patients With Measurable Disease
A confirmed response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. The confirmed response rate will be estimated by the number of confirmed responses in evaluable patients with measurable disease divided by the total number of evaluable patients with measurable disease. The appropriate confidence interval will be calculated. 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: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant + Bevacizumab | Objective Response Rate as Measured by RECIST Criteria in Patients With Measurable Disease | 22 percentage of patients |
Secondary
Overall Survival
Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier (1958).
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Bevacizumab | Overall Survival | 26.9 months |
Secondary
Progression Free Survival
Time to disease progression is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Bevacizumab | Progression Free Survival | 6.2 months |
Secondary
Quality of Life, as Measured by the Largest Mean Change in LASA Overall QOL and Physical Well-being Items
Quality of life (QOL) assessment will be a secondary exploratory component of this trial. QOL of patients was measure using the 6-item Linear Analogue Self-Assessment (LASA).The LASA consists of six single-item numeric analog scales measuring overall QOL; mental, physical, emotional, and spiritual well-being; and level of activity each on a scale of 0 ('As bad as it can be') to 10 ('As good as it can be') during the past week. Items were transformed to a 0 (worst QOL or well-being) to 100 (best QOL or well-being) scale for statistical analysis. Mean change from baseline of the largest mean change in overall QOL and physical well-being are reported below.
Time frame: Up to 5 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant + Bevacizumab | Quality of Life, as Measured by the Largest Mean Change in LASA Overall QOL and Physical Well-being Items | Overall Quality of Life | -5.0 mean change in LASA QOL scaled score | Standard Deviation 15 |
| Fulvestrant + Bevacizumab | Quality of Life, as Measured by the Largest Mean Change in LASA Overall QOL and Physical Well-being Items | Physical Well-Being | -6.8 mean change in LASA QOL scaled score | Standard Deviation 14.9 |
Secondary
Time to First Cytotoxic Agent
Time to first dose of a cytotoxic agent is defined to be the time from the date of registration to the date at which a patient recieves the first dose of a cytotoxic agent. The distribution of time to first dose of a cytotoxic agent will be estimated using the method of Kaplan-Meier (1958).
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Bevacizumab | Time to First Cytotoxic Agent | 9.9 months |