Bevacizumab, Doxorubicin, and Cyclophosphamide Followed By Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Bevacizumab in Treating Patients Who Have Undergone Surgery for Early-Stage Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: 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. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with chemotherapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This clinical trial is studying the side effects and how well giving bevacizumab together with doxorubicin and cyclophosphamide followed by paclitaxel albumin-stabilized nanoparticle formulation and bevacizumab works in treating patients who have undergone surgery for early-stage breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine the cardiac safety of adjuvant concurrent bevacizumab and dose-dense doxorubicin hydrochloride and cyclophosphamide followed by dose-dense paclitaxel albumin-stabilized nanoparticle formulation and maintenance therapy comprising bevacizumab alone in patients with early-stage breast cancer. Secondary Determine the noncardiac toxicity of this regimen in these patients. Determine the efficacy of this regimen, in terms of time to tumor recurrence and overall survival, in these patients. Explore changes in circulating endothelial cells and circulating tumor cells from pre-treatment levels in patients with no evidence of disease. Prospectively explore the use of serial troponin I as a predictor of cardiac toxicity in patients treated with this regimen. Prospectively explore the relationship between plasma renin activity and hypertension in patients treated with bevacizumab and chemotherapy. OUTLINE: This is a nonrandomized, pilot, multicenter study. Patients receive doxorubicin hydrochloride IV, cyclophophamide IV, and bevacizumab IV over 30-90 minutes on day 1 and pegfilgrastim subcutaneously (SC) on day 2. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1 and pegfilgrastim SC on day 2. Treatment with paclitaxel albumin-stabilized nanoparticle formulation and pegfilgrastim repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising bevacizumab IV over 30-90 minutes on day 1. Treatment with maintenance therapy repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and periodically during study treatment. Samples are analyzed for circulating endothelial cells (by flow cytomery [FC]), circulating epithelial cells (by immunocytochemistry and FC), troponin I concentrations (by enzyme immunoassay or chemiluminescent microparticle immunoassay), and plasma renin activity (by radioimmunoassay). After completion of study treatment, patients are followed every 4-6 months for 3 years, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.

Official Title
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A Pilot Study of Bevacizumab With Dose Dense Doxorubicin and Cyclophosphamide (AC) Followed by Dose Dense Nanoparticle Albumin Bound Paclitaxel for the Treatment of Early Stage Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Biological: pegfilgrastim
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Other: flow cytometry
* Other: immunoenzyme technique
* Other: immunologic technique
* Other: laboratory biomarker analysis
* Procedure: adjuvant therapy
* Procedure: immunoscintigraphy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed invasive breast cancer meeting the following criteria: Early-stage disease No stage IV disease More than one synchronous primary breast tumor Lymph node positive OR high-risk lymph node negative Candidate for treatment with anthracycline- and taxane-based chemotherapy in the adjuvant setting Must begin therapy within 84 days after the final required surgical procedure HER2/neu-negative breast cancer, defined as an immunohistochemistry (IHC) score of 0, 1+ or 2+ and fluorescent in situ hybridization (FISH) not amplified No CNS disease (e.g., primary brain tumor or brain metastasis) Hormone receptor status known PATIENT CHARACTERISTICS: Male or female Pre- or post-menopausal ECOG performance status 0-1 Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin normal AST or ALT ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min Urine protein:creatinine ratio ≤ 1.0 PT and PTT normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of study therapy LVEF normal by MUGA scan at baseline No significant bleeding within the past 6 months No uncontrolled underlying bleeding diathesis No nonmalignant systemic disease (e.g., cardiovascular, renal, or hepatic) that would preclude study therapy, including any of the following conditions: Blood pressure > 150/100 mm Hg Unstable angina New York Heart Association class II -IV congestive heart failure Myocardial infarction or stroke within the past 12 months Clinically significant peripheral vascular disease No seizures not controlled with standard medical therapy No history of stroke No known allergy or hypersensitivity to study drugs (prior hypersensitivity to paclitaxel allowed) No significant traumatic injury within the past 28 days No serious nonhealing wound, ulcer, or bone fracture No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No active gastroduodenal ulcer No uncontrolled intercurrent illness, including psychiatric illness or social situation that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior therapy for an ipsilateral or contralateral breast cancer primary allowed provided the following criteria are met: No prior anthracycline therapy Prior hormonal therapy for this previous breast cancer is allowed, but must be stopped during study therapy At least 1 year since prior taxane therapy More than 28 days since prior and no concurrent major surgery or open biopsy Anticipated reconstructive surgery (e.g., tissue expander exchange) is allowed during the course of the study (bevacizumab will be held during that time as per protocol guidelines) More than 7 days since prior minor surgery, including fine-needle aspiration or core biopsy At least 24 hours since prior indwelling catheter placement No prior bevacizumab or other KDR inhibitors (e.g., VEGF Trap, semaxanib, SU6668, vandetanib, vatalanib, AEE788, or IMC-1CII) No concurrent full-dose anticoagulation therapy No concurrent hormonal therapy as chemoprevention Concurrent participation in adjuvant hormone therapy or correlative or companion (e.g., bisphosphonate clinic) studies allowed No other concurrent anticancer therapy

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: Non-Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: bevacizumab|nan|
|Biological: pegfilgrastim|nan|
|Drug: cyclophosphamide|nan|
|Drug: doxorubicin hydrochloride|nan|
|Drug: paclitaxel albumin-stabilized nanoparticle formulation|nan|
|Other: flow cytometry|nan|
|Other: immunoenzyme technique|nan|
|Other: immunologic technique|nan|
|Other: laboratory biomarker analysis|nan|
|Procedure: adjuvant therapy|nan|
|Procedure: immunoscintigraphy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Noncardiac toxicity |  |  | 
| Time to tumor recurrence |  |  | 
| Overall survival |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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male breast cancer, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer