This randomized phase III trial studies first-line chemotherapy and trastuzumab to compare how well they work when given with or without bevacizumab in treating patients with breast cancer that overexpresses human epidermal growth factor receptor 2 (HER-2/NEU) and has spread to other areas of the body. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether giving first-line chemotherapy together with trastuzumab is more effective with or without bevacizumab in treating patients with metastatic breast cancer that overexpresses HER-2/NEU.
PRIMARY OBJECTIVES: I. Evaluate efficacy of the addition of bevacizumab in patients eligible for first-line trastuzumab with chemotherapy for HER-2/NEU overexpressing metastatic breast cancer, by assessing the progression-free survival (PFS) after initiation of combination therapy. SECONDARY OBJECTIVES: I. Evaluate response rates (RR) in patients with measurable disease (Response Evaluation Criteria in Solid Tumors \[RECIST\]), when applicable. II. Evaluate overall survival (OS). III. Evaluate the proportion of progression-free at 6 months. IV. Compare the toxicity of chemotherapy/trastuzumab to that of chemotherapy/ trastuzumab in combination with bevacizumab. V. Evaluate left ventricular ejection fraction (LVEF) decline and clinical congestive heart failure (CHF). EXPLORATORY OBJECTIVES: I. Compare breast cancer symptoms and treatment related symptoms between patients receiving chemotherapy and trastuzumab with or without bevacizumab. II. Evaluate whether PFS correlates with vascular endothelial growth factor (VEGF) levels in breast tumor tissue. III. Analysis of circulating tumor cells and circulating endothelial cells (CEC). 1. Serially enumerate circulating tumor cells (CTC) and CEC in patients on study and determine whether: the number of CTC and CEC decrease in responding patients; the extent of CTC and CEC decrease is greater in the experimental arm, Arm B versus the control arm, Arm A; enumeration of CTC and CEC in responding patients correlate with progression free survival (PFS). 2. Perform an exploratory analysis of phosphorylation status of v-akt murine thymoma viral oncogene homolog (akt)-2 in circulating tumor cells. 3. Perform an exploratory analysis of reverse transcriptase (RT)-polymerase chain reaction (PCR) of CTC messenger ribonucleic acid (mRNA) to determine whether change in expression of selected downstream targets of bevacizumab therapy can serve as pharmacodynamic or surrogate markers of bevacizumab targeting and modulation. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: INDUCTION THERAPY: Patients receive trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. ARM B: INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 10 years. PROJECTED ACCRUAL: 489 patients
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
96
Given IV
Given IV
Given IV
Given IV
Given IV
NEA Baptist Memorial Hospital
Jonesboro, Arkansas, United States
East Bay Radiation Oncology Center
Castro Valley, California, United States
Eden Hospital Medical Center
Castro Valley, California, United States
Valley Medical Oncology Consultants-Castro Valley
Castro Valley, California, United States
Bay Area Breast Surgeons Inc
Emeryville, California, United States
Progression-free Survival
Progression-free survival (PFS) was defined as time from date of randomization to first disease progression, new second breast primaries, or to death from any cause, whichever occurred first, otherwise cases were censored at date last documented to be free of progression. Disease progression was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0, 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. Kaplan-Meier method was used to estimate the median PFS.
Time frame: assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years
Overall Survival
Overall survival (OS) is defined as the time from randomization until death (event), or censored at last date known alive. Kaplan-Meier method was used to estimate the median OS.
Time frame: assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years
Proportion of Progression-free at 6 Months
Disease progression was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0, 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. Proportion of progression-free at 6 months was calculated using the Kaplan-Meier method.
Time frame: assessed at baseline, at 3 and 6 months after study entry
Overall Response Rate
Overall response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by all randomized patients. Responses are evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).
Time frame: assessed at baseline, every 12 weeks while on treatment, then very 3 months if patient is <2 years from study entry, every 6 months if 2-5 years from study entry, and annually if 6-10 years from study entry until disease progression
Number of Patients Experiencing Congestive Heart Failure
Clinical congestive heart failure (CHF) was assessed using Left Ventricular Ejection Fraction (LVEF) and symptom information via the Cardiac Toxicity Form as well as symptom information collected via the Adverse Event Form. Clinical CHF was defined as symptomatic decline in LVEF to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction.
Time frame: assessed every 3 months while on treatment and at 3 months post treatment
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