Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
HER2 negative, HER2 positive
Brief summary
The purpose of this research study is to see what effects trastuzumab in combination with vinorelbine has on breast cancer when the participant has circulating tumor cells that are positive for the protein called HER2. Trastuzumab is an FDA approved drug that targets HER2. The drug combination of trastuzumab and vinorelbine is an effective treatment for patients with breast cancers that are positive for HER2. This trial seeks to determine if the combination can also benefit participants whose original breast cancer was HER2 negative but whose circulating tumor cells are HER2 positive.
Detailed description
OBJECTIVES: Primary * To assess the objective response rate (ORR) of trastuzumab and vinorelbine in patients with metastatic breast cancer with HER2 negative primary tumors and HER2 positive circulating tumor cells. Secondary * To describe the number of CTCs and the CTCs characteristics before and after therapy, and to explore the correlation of these findings with response. * To further characterize the safety and tolerability. * To evaluate progression-free survival. * To evaluate clinical benefit rate \[complete response (CR)+partial response (PR)+stable disease (SD)\>24 weeks\]. Exploratory * To determine the clinical feasibility of high-throughput mutation profiling on circulating tumor cells (CTCs).
Interventions
DRUGtrastuzumab
DRUGvinorelbine
Sponsors
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
Genentech, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The analysis was performed for 2 separate cohorts due to a change in study conduct during the trial (see arm description).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed metastatic invasive mammary carcinoma. The primary cancer must be HER2 negative by fluorescence in situ hybridization and/or immunohistochemistry. * Patients must have CTCs with HER2 amplification by FISH. * Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as 20mm or greater with conventional techniques of as 10mm or greater with spiral CT scan. * Study participants must have either archival primary tumor or metastatic tumor tissue available to allow analysis to confirm their HER2 status. * Patients must have received at least 1 prior chemotherapy regimen for metastatic breast cancer or evidence of disease progression within 6 months of completing adjuvant chemotherapy. Patients can receive any number of biological or hormonal regimens and remain eligible. * 18 years of age or older * Life expectancy of greater than 3 months * ECOG Performance Status of 0, 1 or 2 * Normal organ and marrow function as outlined in the protocol * 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
* Participants must have recovered from all reversible toxicities related to prior therapy before beginning protocol treatment, and may not have any pre-existing treatment-related toxicities in excess of grade 2 * Participants may not be receiving any other investigational agents while participating in this study * Participants may not have received trastuzumab or vinorelbine in the past * Participants receiving any medications or substances that are inhibitors of cytochrome P450 isoenzymes in the CYP3A subfamily are ineligible. * EKG abnormalities of known clinical significance, such as prolonged QT. * Left ventricular ejection fraction \< 50% * Patients with peripheral neuropathy of any etiology that exceeds grade 1 are ineligible * Uncontrolled intercurrent illness * Individuals with symptomatic or progressive brain metastases are ineligible. Subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for 1 month or longer after completion of local therapy. Any corticosteroid use for brain metastases must have been discontinued without subsequent appearance of symptoms for more than 4 weeks prior to study treatment. * Individuals with active second malignancy are ineligible. Patients that are disease-free from a previously treated non-breast malignancy and have a 20% or less chance of recurrence are eligible. * Pregnant or breast feeding women * HIV-positive individuals on combination antiretroviral therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks; Median (range) trt duration was 12 weeks (3-67). | ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks; Median (range) trt duration was 12 weeks (3-67). | CBR was defined as achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. SD needed to be a minimum 24 weeks in duration |
| Progression-Free Survival (PFS) | Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks and within 2 wks off-study; Median follow-up was 2.7 months. | PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
| Baseline Level of Circulating Tumor Cells (CTCs) | Assessed at baseline | CTCs levels were determined based on established methods. |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from November 2010 through July 2014.
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab and Vinorelbine - Cohort A Cycle 1: Patients received trastuzumab 8 mg/kg intravenously (IV) on day 1 and vinorelbine 25 mg/kg IV on days 1, 8 and 15 of each 21 day cycle Cycles 2+: Patients received trastuzumab 6 mg/kg IV on day 1 and vinorelbine 25 mg/kg IV on days 1, 8 and 15 of each 21 day cycle Patients were treated until disease progression or unacceptable toxicity. Eligibility required patients to have HER2 amplification by FISH (mean ratio \> 2.0). The CTC tests of the first 11 patients were done at DFCI. The study team then decided to proceed with a different CTC test performed outside of DFCI. Because the method of CTC isolation was different from that performed by DFCI, the first 11 patients were placed into a separate cohort (Cohort A) and the remaining 20 patients represented the main cohort. | 11 |
| Trastuzumab and Vinorelbine - Main Cohort Cycle 1: Patients received trastuzumab 8 mg/kg intravenously (IV) on day 1 and vinorelbine 25 mg/kg IV on days 1, 8 and 15 of each 21 day cycle Cycles 2+: Patients received trastuzumab 6 mg/kg IV on day 1 and vinorelbine 25 mg/kg IV on days 1, 8 and 15 of each 21 day cycle Patients were treated until disease progression or unacceptable toxicity. Eligibility required patients to have HER2 amplification by FISH (mean ratio \> 2.0). The CTC tests of the first 11 patients were done at DFCI. The study team then decided to proceed with a different CTC test performed outside of DFCI. Because the method of CTC isolation was different from that performed by DFCI, the first 11 patients were placed into a separate cohort (Cohort A) and the remaining 20 patients represented the main cohort. | 20 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Intercurrent Illness | 0 | 1 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Progression/Relapse | 9 | 15 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Trastuzumab and Vinorelbine - Cohort A | Trastuzumab and Vinorelbine - Main Cohort | Total |
|---|---|---|---|
| Age, Continuous | 50 years | 54 years | 54 years |
| Estrogen Receptor Status at Metastatic Diagnosis Negative | 2 Participants | 5 Participants | 7 Participants |
| Estrogen Receptor Status at Metastatic Diagnosis Positive | 9 Participants | 8 Participants | 17 Participants |
| Estrogen Receptor Status at Metastatic Diagnosis Unknown | 0 Participants | 7 Participants | 7 Participants |
| Progesterone Receptor Status at Metastatic Diagnosis Negative | 7 participants | 9 participants | 16 participants |
| Progesterone Receptor Status at Metastatic Diagnosis Positive | 4 participants | 4 participants | 8 participants |
| Progesterone Receptor Status at Metastatic Diagnosis Unknown | 0 participants | 7 participants | 7 participants |
| Region of Enrollment United States | 11 participants | 20 participants | 31 participants |
| Sex: Female, Male Female | 11 Participants | 20 Participants | 31 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 20 / 20 |
| serious Total, serious adverse events | 9 / 11 | 11 / 20 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks; Median (range) trt duration was 12 weeks (3-67).
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab and Vinorelbine - Cohort A | Objective Response Rate (ORR) | 18.2 percentage of patients |
| Trastuzumab and Vinorelbine - Main Cohort | Objective Response Rate (ORR) | 5.0 percentage of patients |
Secondary
Baseline Level of Circulating Tumor Cells (CTCs)
CTCs levels were determined based on established methods.
Time frame: Assessed at baseline
Population: The CTCs in cohort A were analyzed using a non-CLIA approved assay and thus it was felt that the outcome data for this cohort were not evaluable. A new CLIA approved assay was used for the main cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab and Vinorelbine - Cohort A | Baseline Level of Circulating Tumor Cells (CTCs) | 5.5 cells per 7.5 ml blood |
Secondary
Clinical Benefit Rate (CBR)
CBR was defined as achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. SD needed to be a minimum 24 weeks in duration
Time frame: Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks; Median (range) trt duration was 12 weeks (3-67).
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab and Vinorelbine - Cohort A | Clinical Benefit Rate (CBR) | 63.6 percentage of patients |
| Trastuzumab and Vinorelbine - Main Cohort | Clinical Benefit Rate (CBR) | 20.0 percentage of patients |
Secondary
Progression-Free Survival (PFS)
PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: Disease was evaluated radiologically at baseline, on trt every 6 weeks (wks) for the first 18 wks and then every 12 wks and within 2 wks off-study; Median follow-up was 2.7 months.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab and Vinorelbine - Cohort A | Progression-Free Survival (PFS) | 6.9 months |
| Trastuzumab and Vinorelbine - Main Cohort | Progression-Free Survival (PFS) | 2.7 months |