Breast Cancer, Metastatic Breast Cancer, Progressive Breast Cancer
Conditions
Keywords
carboplatin, bevacizumab
Brief summary
The purpose of this research study is to determine how well the combination of bevacizumab and carboplatin works in treating breast cancer that has spread to the brain. Bevacizumab is an antibody (a protein that attacks a foreign substance in the body) that is made in the laboratory. Bevacizumab works differently from the way chemotherapy drugs work. Usually chemotherapy drugs attack fast growing cancer cells in the body. Bevacizumab works to slow or stop the growth of cells in cancer tumors by decreasing the blood supply to the tumors. When the blood supply is decreased, the tumors don't get the oxygen and nutrients they need to grow. Carboplatin is in a class of drugs known as platinum-containing compounds and has been approved for use in the treatment of ovarian cancer. Information from other research studies suggests that the combination of bevacizumab with carboplatin may be effective in treating breast cancer.
Detailed description
This study used a two-stage design to evaluate efficacy bevacizumab and carboplatin based on Central Nervous System (CNS) response. The null and alternative therapy response rates are 5% versus 20%. If 1 or more participants assessable in the stage one cohort (n=12 assessable participants) achieve CNS response then accrual proceeds to stage two (n=25 additional assessable participants). If at least 4 participants in the final set of 37 assessable participants achieve CNS response then this regimen would be deemed worthy of further study. The probability of stopping early is 0.54 if the true CNS response rate is 5% and 0.07 if the true CNS response rate is 20%. The probability of deeming the treatment worthy of further study is 0.10 and 0.90 if the true CNS response rate is 5% and 20%, respectively.
Interventions
DRUGcarboplatin
DRUGbevacizumab
DRUGherceptin
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Genentech, Inc.
Dana-Farber Cancer Institute
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
* Histologically or cytologically confirmed invasive breast cancer, with metastatic disease. patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study * Measurable disease. Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension \>/= 10mm by local radiology review * New or progressive CNS lesions, as assessed by the patient's treating physician * No increase in corticosteroid dose in the week prior to the baseline brain MRI * 18 years of age or older * Life expectancy of greater than 12 weeks * Eastern Cooperative Oncology Group Performance Score (ECOG PS) performance status 0-2 * Normal organ and marrow function as outlined in the protocol * Left ventricular ejection fraction \>/= 50%, as determined by radionuclide ventriculography (RVG) or echocardiogram within 60 days prior to initiation of protocol therapy * Prior carboplatin is allowed if it was not given in conjunction with bevacizumab * Prior trastuzumab is allowed * No prior bevacizumab since diagnosis of CNS metastases or within 6 months prior to diagnosis of CNS metastases * Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation
Exclusion criteria
* Patients who have had chemotherapy within 14 days prior to entering the study, or those who have not recovered adequately from adverse events due to agents administered earlier * Patients may not receive any concurrent investigational agents while on study * Patients may not receive any cancer-directed concurrent therapy , such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates is allowed * History of Grade 3 or 4 allergic reactions attributed to compounds of similar or identical biologic composition to bevacizumab, carboplatin, or trastuzumab * Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker, shrapnel, or ocular foreign body * Leptomeningeal carcinomatosis as the only site of CNS involvement * More than 2 seizures over last 4 weeks prior to study entry * Grade 1 or higher CNS hemorrhage on baseline brain MRI * History of grade 2 or higher CNS hemorrhage within 12 months of study entry * Inadequately controlled hypertension * Prior history of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Grade II or greater congestive heart failure * History of myocardial infraction or unstable angina within 6 months prior to day 1 * Significant vascular disease within 6 months prior to day 1 * History of hemoptysis within 1 month prior to day 1 * Evidence of bleeding diathesis or significant coagulopathy * Current, ongoing treatment with full-dose warfarin or its equivalent * Use of aspirin (\>325 mg/day) within 10 days prior to day 1 * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 or anticipation of need for major surgical procedure during the course of the study. * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1 * History of abdominal fistula or gastrointestinal perforation within 6 months prior to day 1 * Serious, non-healing wound, active ulcer, or untreated bone fracture * Proteinuria as demonstrated by a urine protein-creatinine ratio \>/= 1.0 at screening * Known hypersensitivity to any component of bevacizumab * Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Central Nervous System (CNS) Objective Response Rate | Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length. | CNS objective response rate is the percentage of participants that achieve CNS complete or partial response as follows: CNS complete response (CR) is achieved if all of the following are satisfied: * Complete resolution of all measurable (\>= 1 cm in longest dimension \[LD\]) and non-measurable brain metastases * No new CNS lesions (defined as any new lesion \>= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST CNS partial response (PR) is achieved if all of the following are satisfied: -\>/= 50% reduction in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * No progression on non-measurable lesions * No new CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Disease was evaluated radiologically at baseline, cycle 2, cycle 4 and thereafter on treatment every 2 cycles (CNS disease) and every 4 cycles (non-disease). Maximum PFS follow-up for this study cohort was 18.6 months. | Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of disease progression (PD), second cancer, or death, whichever occurs first. PD if any of the following occur: CNS Disease * \>/=40% increase in the volumetric sum of all measurable lesions as compared to the smallest volume on treatment * Progression of non-measurable lesions * New lesions (\>/=6 mm) Non-CNS Disease • RECIST 1.0 criteria: at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded on treatment or the appearance of \>/=1 new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Symptomatic * Increasing steroid requirement * Global deterioration of health status requiring discontinuation of treatment * New/progression tumor-related neurologic signs and symptoms except for transient worsening lasting \</=14 days |
| CNS Best Response | Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length. | CNS best response was defined based on standard criteria. Adding to CR and PR (defined in the primary outcome measure): CNS stable disease (SD) is achieving all the following: * \< 50% reduction in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * No progression on non-measurable lesions * No new CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST CNS Progressive Disease (PD) was experiencing any of the following: -\>/- 40% increase in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * Progression on non-measurable lesions * New CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Increasing steroid dose * New/progressive tumor-related neurologic signs or symptoms * Progression of extra-CNS disease as assessed by RECIST |
| Site of First Progression | Disease was evaluated radiologically at baseline, cycle 2, cycle 4 and thereafter on treatment every 2 cycles (CNS disease) and every 4 cycles (non-disease). Maximum progression follow-up for this study cohort was 18.6 months. | Site of first progression is classified as follows: CNS Disease * \>/=40% increase in the volumetric sum of all measurable lesions as compared to the smallest volume on treatment * Progression of non-measurable lesions * New lesions (\>/=6 mm) Non-CNS Disease * Per RECIST 1.0 criteria: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Symptomatic * Increasing steroid requirement * Global deterioration of health status requiring discontinuation of treatment * New/progression tumor-related neurologic signs and symptoms (NSS) except for transient worsening lasting \</=14 days |
| Overall Survival | Maximum survival follow-up for the study cohort was 66 months. | Participants were assessed every 6 months post-treatment. Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between November 2009 and August 2012.
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) Participants received treatment until disease progression in either CNS or non-CNS site. Cycle duration is 28 days.
carboplatin: AUC=5 dose given intravenously on day 8 of cycle one and Day 1 of each subsequent cycle
bevacizumab: 15 mg/kg dose given intravenously on day 1 of each cycle
trastuzumab\*: 6 mg/kg dose given intravenously on day 8 of each cycle for patients with HER2-positive breast cancer only
\*8mg/kg loading dose in cycle 1 for some participants
HER-2: human epidermal growth factor receptor 2 | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease in CNS and Non-CNS | 2 |
| Overall Study | Progressive Disease in CNS Only | 16 |
| Overall Study | Progressive Disease in Non-CNS Only | 16 |
| Overall Study | Symptomatic Deterioration | 2 |
Baseline characteristics
| Characteristic | Carboplatin, Bevacizumab, Trastuzumab (if HER2+) |
|---|---|
| Age, Customized | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 participants |
| Race/Ethnicity, Customized Black or African-American | 1 participants |
| Race/Ethnicity, Customized White | 34 participants |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 38 / 38 |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 16 / 38 |
Outcome results
Primary
Central Nervous System (CNS) Objective Response Rate
CNS objective response rate is the percentage of participants that achieve CNS complete or partial response as follows: CNS complete response (CR) is achieved if all of the following are satisfied: * Complete resolution of all measurable (\>= 1 cm in longest dimension \[LD\]) and non-measurable brain metastases * No new CNS lesions (defined as any new lesion \>= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST CNS partial response (PR) is achieved if all of the following are satisfied: -\>/= 50% reduction in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * No progression on non-measurable lesions * No new CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST
Time frame: Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length.
Population: The analysis dataset is comprised of assessable participants. Per protocol, assessable is defined as those who have at least one lesion on baseline MRI with longest with longest diameter \>10 mm on T1-weighted, gadolinium-enhanced. All enrolled participants were assessable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Central Nervous System (CNS) Objective Response Rate | 63 percentage of participants |
Secondary
CNS Best Response
CNS best response was defined based on standard criteria. Adding to CR and PR (defined in the primary outcome measure): CNS stable disease (SD) is achieving all the following: * \< 50% reduction in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * No progression on non-measurable lesions * No new CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms * No progression of extra-CNS disease as assessed by RECIST CNS Progressive Disease (PD) was experiencing any of the following: -\>/- 40% increase in the volumetric sum of all measurable (\>/= 1 cm in LD) brain metastases compared to baseline * Progression on non-measurable lesions * New CNS lesions (defined as any new lesion \>/= 6 mm in LD) * Increasing steroid dose * New/progressive tumor-related neurologic signs or symptoms * Progression of extra-CNS disease as assessed by RECIST
Time frame: Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length.
Population: The analysis dataset is comprised of assessable participants. Per protocol, assessable is defined as those who have at least one lesion on baseline MRI with longest with longest diameter \>10 mm on T1-weighted, gadolinium-enhanced. All enrolled participants were assessable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | CNS Best Response | Complete Response | 0 Participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | CNS Best Response | Partial Response | 24 Participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | CNS Best Response | Stable Disease >/=24 weeks | 2 Participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | CNS Best Response | Stable Disease < 24 weeks | 5 Participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | CNS Best Response | Progressive Disease | 7 Participants |
Secondary
Overall Survival
Participants were assessed every 6 months post-treatment. Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods.
Time frame: Maximum survival follow-up for the study cohort was 66 months.
Population: The analysis dataset is comprised of enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Overall Survival | 14 months |
Secondary
Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of disease progression (PD), second cancer, or death, whichever occurs first. PD if any of the following occur: CNS Disease * \>/=40% increase in the volumetric sum of all measurable lesions as compared to the smallest volume on treatment * Progression of non-measurable lesions * New lesions (\>/=6 mm) Non-CNS Disease • RECIST 1.0 criteria: at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded on treatment or the appearance of \>/=1 new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Symptomatic * Increasing steroid requirement * Global deterioration of health status requiring discontinuation of treatment * New/progression tumor-related neurologic signs and symptoms except for transient worsening lasting \</=14 days
Time frame: Disease was evaluated radiologically at baseline, cycle 2, cycle 4 and thereafter on treatment every 2 cycles (CNS disease) and every 4 cycles (non-disease). Maximum PFS follow-up for this study cohort was 18.6 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Progression-Free Survival | 5.6 months |
Secondary
Site of First Progression
Site of first progression is classified as follows: CNS Disease * \>/=40% increase in the volumetric sum of all measurable lesions as compared to the smallest volume on treatment * Progression of non-measurable lesions * New lesions (\>/=6 mm) Non-CNS Disease * Per RECIST 1.0 criteria: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Symptomatic * Increasing steroid requirement * Global deterioration of health status requiring discontinuation of treatment * New/progression tumor-related neurologic signs and symptoms (NSS) except for transient worsening lasting \</=14 days
Time frame: Disease was evaluated radiologically at baseline, cycle 2, cycle 4 and thereafter on treatment every 2 cycles (CNS disease) and every 4 cycles (non-disease). Maximum progression follow-up for this study cohort was 18.6 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Site of First Progression | CNS | 15 participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Site of First Progression | Non-CNS | 12 participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Site of First Progression | Both CNS and Non-CNS | 6 participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Site of First Progression | Symptomatic | 2 participants |
| Carboplatin, Bevacizumab, Trastuzumab (if HER2+) | Site of First Progression | No Site | 3 participants |