Chemotherapy & Bevacizumab for Human Epidermal Growth Factor Receptor 2 (HER2)/Neu-Negative Stage II/III Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving combination chemotherapy together with bevacizumab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying the side effects and how well giving combination chemotherapy together with bevacizumab works in treating women with HER2/neu-negative stage II or stage III breast cancer

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the feasibility of administering two sequential chemotherapy doublets with Avastin in the adjuvant setting. II. To assess the safety of Avastin in the adjuvant setting particularly regarding cardiac function, wound healing and toxicity of radiation. SECONDARY OBJECTIVES: I. To determine the effect of Avastin on immunity, especially Vascular endothelial growth factor A (VEGF-A) upregulation of myeloid-derived suppressor cells (MDSC) and suppression of T-Cells. II. To determine the effect of therapy on numbers of myeloid derived suppressor cells and compare the humoral and cellular response to p53 in breast cancer patients treated with the same chemotherapy. III. Patients will be followed for freedom from tumor progression and survival. OUTLINE: COURSES 1-4: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of unacceptable toxicity or disease progression. COURSES 5-7: Patients receive paclitaxel IV and gemcitabine hydrochloride IV on day 1 and pegfilgrastim SC on day 1. Patients also receive bevacizumab IV on day 1 in courses 5-7. Treatment repeats every 2 weeks for 4 courses in the absence of unacceptable toxicity or disease progression. COURSES 8-16: Patients receive bevacizumab IV alone on day 1. Treatment repeats every 3 weeks for 8 courses in the absence of unacceptable toxicity or disease progression. After course 8, patients may undergo radiotherapy and hormone therapy, if clinically indicated. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 5 years.

Official Title
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Adjuvant Doxorubicin, Cyclophosphamide Followed by Avastin Given With Paclitaxel and Gemcitabine for Stage II and III Breast Cancer That Does Not Over-express Human Epidermal Growth Factor Receptor 2 (HER-2)/Neu

Conditions
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HER2-negative Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: cyclophosphamide
* Biological: bevacizumab
* Drug: paclitaxel
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis
* Biological: pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of invasive breast cancer: By pathologic evaluation, primary tumor must be T1-4N1-3M0 or T3-4N 0M0 that is ER/PR positive or negative and HER-2/neu negative (1+) immunocytochemistry or not amplified by Fluorescence in situ hybridization (FISH) OR By pathologic evaluation, primary tumor must be T2N0 that is estrogen receptor (ER), progesterone receptor (PR) and HER-2neu negative Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ an effective barrier method of birth control throughout the study and for up to 6 months following treatment Women of child-bearing potential, must have a negative pregnancy test within 7 days of initiating study (no childbearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Definitive surgery, lumpectomy and axillary sampling or modified radical mastectomy Three weeks since last surgery other than port or right atrial catheter placement No significant cardiac disease and a normal left ventricular ejection fraction No significant open wounds, uncontrolled hypertension, history of venous or arterial clotting Adequate laboratory parameters within 30 days prior to enrollment defined as: Absolute neutrophil count greater than or equal to 1,500/mcl Platelet count equal to or greater than 150,000/mcl Hemoglobin >11gm/dl Alkaline phosphatase equal or less than 1.5 times the upper limit normal (ULN) Total bilirubin equal to or less than 1.5 times the ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 1.5 times the ULN Creatinine less than 1.5 times the ULN Urine protein < 2+ on urinalysis, UPC 1.0 or 24 hour urine < 1 g protein No active serious infections or other condition precluding chemotherapy Able to give informed consent Able to return for treatment and follow-up on the specified days Exclusion Criteria: Prior malignancy; except for adequately treated basal cell or squamous cell skin cancer or noninvasive carcinomas, or other cancer from which the patient has been disease free for 5 years Prior chemotherapy or radiation therapy Breast cancer that over expresses Her-2/neu Stage IV or metastatic breast cancer Inability to cooperate with treatment protocol Any comorbidity or condition which, in the opinion of the investigator, may interfere with the assessments and procedures of this protocol Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications Any prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction or unstable angina within 12 months of study enrollment Any history of stroke or transient ischemic attack at any time Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment Serious, non-healing wound, ulcer, or bone fracture Proteinuria at screening as demonstrated by either urine protein/creatinine (UPC) ratio >= 1.0 at screening OR urinalysis for proteinuria >= 2+ (patients discovered to have >= 2+ proteinuria on urinalysis at baseline and undergo a 24 hour urine collection and demonstrate > 1g of protein in 24 hours are ineligible) Known hypersensitivity to any component of Avastin or gemcitabine or other required drugs in the study History of venous or arterial thrombosis Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) for any reason (ASA okay)

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy with Bevacizumab<br>Doxorubicin 60 mg /M2 followed by cyclophosphamide 600 mg/M2 (AC) will be given every 2 weeks for cycles 1-4. Paclitaxel 175 mg/M2 followed by gemcitabine 1500 mg/M2 (TG) will be given every 2 weeks for cycles 5-8. Beginning cycle 5, B1= Avastin 10 mg/kg will be given as a single IV dose following each TG treatment every 2 weeks for cycles 5-7. | Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>Biological: pegfilgrastim<br>* Given subcutaneously<br>* Other names: SD-01 sustained duration G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Study Drug-associated Adverse Events Leading to Dose Holds or Reductions | This outcome is to measure the feasibility of the of administering two sequential chemotherapy doublets with Avastin in the adjuvant setting in women with stage II and III breast cancer that does not over-express human epidermal growth factor receptor 2 (HER 2)/neu | through study completion, an average of 10 months | 
| Count of Participants With Related Serious Adverse Events (SAEs) by NCI Common Toxicity Criteria v3.0 | Assess the safety of Avastin in the adjuvant setting particularly regarding cardiac function, wound healing and toxicity of radiation. | through study completion, an average of 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival as Assessed by the Kaplan and Meier Method | Overall survival as assessed by the Kaplan and Meier method at 5 years | Original time frame: Up to 5 years from date of first treatment; study terminated at 2.5 years | 
| Disease-free Survival | Disease-free survival as assessed by the Kaplan and Meier method | From the date of first treatment to the date of disease progression/recurrence, second cancer, or death, whichever came first: Original time frame up to 5 years from date of first treatment; study terminated at 2.5 years |