Bevacizumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER-2/NEU

Study Overview
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Brief Summary
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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.

Detailed Description
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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). 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). Perform an exploratory analysis of phosphorylation status of v-akt murine thymoma viral oncogene homolog (akt)-2 in circulating tumor cells. 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

Official Title
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A Randomized Phase III Double-Blind Placebo-Controlled Trial of First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab for Patients With HER-2/NEU Over-Expressing Metastatic Breast Cancer

Conditions
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Breast Carcinoma, Recurrent Breast Carcinoma, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Other: Placebo
* Biological: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed breast cancer that overexpresses HER-2/NEU with evidence of metastatic disease and/or chest wall recurrence prior to randomization HER-2/NEU overexpression is defined as 3+ HER-2 positivity as measured by immunohistochemistry OR HER-2 gene amplification as measured by fluorescent in situ hybridization (FISH, e.g. Vysis), per American Society of Clinical Oncology guidelines NOTE: representative diagnostic tissue must be submitted for central diagnostic review for confirmation of HER-2/NEU overexpression within two weeks following patient randomization Evaluable (measurable or non-measurable) disease is allowed if confirmed within 4 weeks prior to randomization Prior endocrine treatment in the adjuvant or metastatic setting is allowed, provided last dose given >= 2 weeks prior to randomization Radiation therapy is allowed provided last dose is given >= 3 weeks prior to randomization Adjuvant trastuzumab therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence Adjuvant or neoadjuvant taxane therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence Adjuvant or neoadjuvant therapy with lapatinib is allowed provided last dose is given >= 4 weeks prior to diagnosis of recurrence Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Absolute neutrophil count >= 1,000/mm^3 Platelet count >= 100,000/mm^3 Total bilirubin =< 1.5 mg/dL Aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (=< 5 times normal in patients with known liver involvement) Serum creatinine =< 1.5 mg/dL Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1000 mg International normalized ratio (INR) =< 1.5 X ULN Partial thromboplastin time (PTT) =< 1.5 X ULN Multi gated acquisition scan (MUGA) scan or echocardiogram (ECHO) within 6 weeks prior to randomization with an left ventricular ejection fraction (LVEF) above the institutional lower limit of normal Patients must be able to understand and provide signed and dated written informed consent Major surgical procedure within 4 weeks prior to randomization is not allowed (except for non-operative biopsy, which would not be considered major surgery); treatment can not begin until seven (7) days after placement of a vascular access device Women must not be pregnant or breastfeeding; all females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must use an accepted and effective method of contraception Patients on full-dose anticoagulants (e.g., warfarin) with PT/INR > 1.5 may be eligible provided that both of the following criteria are met: The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin The patient has not active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) Patients with a concurrent active malignancy except carcinoma in situ of the cervix or non-melanoma skin cancers (unless disease-free for at least 5 years at study entry) are not allowed Exclusion Criteria: Prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer Patients who have had a cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2 in the adjuvant or neo-adjuvant setting at any time Patients with grade 2-4 neuropathy Patients with a history or radiologic evidence of central nervous system (CNS) disease Patients have a current non-healing wound or fracture Patients have a hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies Patients have a serious medical or psychiatric illness that would prevent ability to safely participate or provide informed consent Patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal) Clinically significant cardiovascular disease, including: History of cerebrovascular (CVA) within 6 months Uncontrolled hypertension Myocardial infarction or unstable angina within 6 months New York Heart Association class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris Clinically significant peripheral vascular disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (chemotherapy and placebo)<br>INDUCTION THERAPY: Patients receive trastuzumab 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. | Drug: Carboplatin<br>* Given IV<br>* Other names: NSC-241240;Drug: Paclitaxel<br>* Given IV<br>* Other names: NSC 125973;Other: Placebo<br>* Given IV<br>* Other names: sham therapy;Biological: Trastuzumab<br>* Given IV<br>* Other names: Herceptin;|
| Experimental: Arm B (chemotherapy and bevacizumab)<br>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. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Avastin;Drug: Carboplatin<br>* Given IV<br>* Other names: NSC-241240;Drug: Paclitaxel<br>* Given IV<br>* Other names: NSC 125973;Biological: Trastuzumab<br>* Given IV<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | 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. | assessed every 3 months while on treatment and at 3 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab, Bevacizumab, Metastatic Breast Cancer, HER2/NEU