A Clinical Trial Comparing the Combination of TC Plus Bevacizumab to TC Alone and to TAC for Women With Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to learn if adding bevacizumab to standard treatment with chemotherapy (docetaxel, doxorubicin, and cyclophosphamide) for early stage HER2-negative breast cancer will prevent breast cancer from returning. A second purpose of this study is to learn if adding bevacizumab to treatment with chemotherapy will help women with HER2-negative breast cancer live longer. The researchers also want to learn about the side effects of the combination of drugs used in this study.

Detailed Description
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The B-46-I/07132 study, a multicenter, open-label, randomized Phase III, adjuvant therapy trial, will compare the value of adding bevacizumab to a non-anthracycline-based chemotherapy regimen relative to the same chemotherapy without bevacizumab and relative to an anthracycline-based chemotherapy regimen in women with resected node-positive or high-risk node-negative, HER2-negative breast cancer. This trial will determine whether the addition of bevacizumab to a regimen of docetaxel and cyclophosphamide (TCB) improves invasive disease-free survival relative to docetaxel and cyclophosphamide alone (TC). A secondary aim will be to determine whether the addition of bevacizumab to TC improves invasive disease-free survival compared to a regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC). Other secondary aims include whether TCB improves disease-free survival, overall survival, and recurrence-free interval relative to TC alone and to TAC. The toxicities of the three regimens will also be compared. Patients in the B-46-I/07132 study will be randomized to one of three treatment regimens: Group 1 patients will receive 6 cycles of TAC administered every 21 days (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); Group 2 patients will receive 6 cycles of TC administered every 21 days (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2); and Group 3 patients will receive 6 cycles of TCB every 21 days with bevacizumab therapy continuing every 21 days after completion of chemotherapy until 1 year following the first dose (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2, and bevacizumab 15 mg/kg). Primary prophylaxis with pegfilgrastim or filgrastim is required for Group 1 patients (optional for patients in Groups 2 and 3). Patients will also receive adjuvant radiation therapy as clinically indicated and endocrine therapy for hormone receptor-positive tumors. Tumor samples will be submitted for correlative science studies to evaluate predictors of study therapy benefit. Submission of a tumor sample is a study requirement for all patients.

Official Title
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A Phase III Clinical Trial Comparing the Combination of TC Plus Bevacizumab to TC Alone and to TAC for Women With Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: bevacizumab
* Drug: docetaxel
* Drug: doxorubicin
* Drug: cyclophosphamide
* Drug: pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be female. The patient must be greater than or equal to 18 years of age and less than or equal to 70 years of age. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination. The breast cancer must be HER2-negative based on current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. If the result of the in situ hybridization testing (FISH, chromagen in situ hybridization (CISH), or other) is equivocal, the patient is eligible if there is no plan to administer HER2-targeted therapy. All of the following staging criteria (according to the 6th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual) must be met: By pathologic evaluation, primary tumor must be pT1-3; By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b. If pN0, at least one of the following criteria must be met: ER negative and PgR negative; or Pathologic tumor size greater than 2.0 cm; or T1c (pathologic tumor size greater than 1.0 cm but less than or equal to 2.0 cm) and ER positive (PgR status may be positive or negative) and either Oncotype DX® Recurrence Score of greater than or equal to 25 or grade 3 histology. Patients must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy). For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures must be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection.) For patients who undergo mastectomy, margins must be histologically free of invasive tumor and DCIS. Patients must have completed one of the following procedures for evaluation of pathologic nodal status: Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is pN0, pN1mi, or pN1b; Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or Axillary lymphadenectomy without SN isolation procedure. The interval between the last surgery for breast cancer (treatment or staging) and randomization must be at least 28 days but no more than 84 days. Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed. (Either a core biopsy or surgical resection specimen can be used for ER/PgR testing.) The most recent postoperative blood counts must meet the following criteria: Absolute neutrophil count (ANC) must be greater than or equal to 1200/mm3; platelet count must be greater than or equal to 100,000/mm3; and hemoglobin must be greater than or equal to 10 g/dL. The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests: total bilirubin must be less than or equal to upper limits of normal (ULN)for the lab unless the patient has a bilirubin elevation less than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and AST must be less than or equal to 1.5 x ULN for the lab. Alkaline phosphatase and aspartate transaminase (AST) may not both be greater than the ULN. For example, if the alkaline phosphatase is greater than the ULN but less than or equal to 2.5 x ULN, then the AST must be less than or equal to the ULN. If the AST is greater than the ULN but less than or equal to 1.5 x ULN, then the alkaline phosphatase must be less than or equal to ULN. Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT, or PET scan) does not demonstrate metastatic disease and the requirements for adequate hepatic function are met. Patients with alkaline phosphatase that is greater than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT, or PET scan does not demonstrate metastatic disease. The most recent postoperative serum creatinine must be less than or equal to ULN for the lab. A urine sample must be tested for proteinuria by the dipstick method. Eligibility must be based on the most recent postoperative test result(s) performed within 6 weeks prior to randomization. Urine dipstick must indicate 0-1+ protein. If dipstick reading is greater than or equal to 2+, a 24-hour urine specimen must be collected and must demonstrate less than 1 gram of protein. Left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or multigated acquisition (MUGA) scan must be performed within 90 days prior to randomization. The LVEF must be greater than or equal to 50% regardless of the facility's lower limits of normal (LLN). Exclusion Criteria: T4 tumors including inflammatory breast cancer. Definitive clinical or radiologic evidence of metastatic disease. Synchronous or metachronous contralateral invasive breast cancer. (Patients with synchronous and/or metachronous contralateral DCIS are eligible.) Any history of ipsilateral invasive breast cancer or ipsilateral DCIS. History of non-breast malignancies within 5 years prior to randomization, except for the following: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinomas of the skin. Previous therapy with anthracyclines, taxanes, or bevacizumab for any malignancy. Chemotherapy administered for the currently diagnosed breast cancer prior to randomization. Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.) Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization. Active hepatitis B or hepatitis C with abnormal liver function tests. Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens. This includes but is not confined to 1) Active cardiac disease: angina pectoris that requires the use of anti-anginal medication; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis, 2) History of cardiac disease: myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function; history of documented congestive heart failure (CHF); and documented cardiomyopathy. Uncontrolled hypertension defined as systolic BP greater than 150 mmHg or diastolic BP greater than 90 mmHg, with or without anti-hypertensive medication. Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria. History of hypertensive crisis or hypertensive encephalopathy. History of transient ischemic attack (TIA) or cerebrovascular accident (CVA). History of any arterial thrombotic event within 12 months prior to randomization. Symptomatic peripheral vascular disease. Intrinsic lung disease resulting in dyspnea. Unstable diabetes mellitus. Active infection or chronic infection requiring suppressive antibiotics. History of a major organ allograft or condition requiring chronic immunosuppression, e.g., kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases. (Patients who have received corneal transplants, cadaver skin, or bone transplants are eligible.) Any significant bleeding within 180 days prior to randomization, exclusive of menorrhagia in premenopausal women. Non-healing wound, skin ulcers, or incompletely healed bone fracture. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the planned start of study therapy. Anticipation of need for major surgical procedures during study therapy and for at least 3 months following completion of bevacizumab. Gastroduodenal ulcer(s) documented by endoscopy to be active within 6 months before randomization. History of GI perforation, abdominal fistulae, or intra-abdominal abscess. Known bleeding diathesis or coagulopathy. Requirement for therapeutic doses of coumadin or equivalent. Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Conditions that would prohibit administration of corticosteroids. Chronic daily treatment with corticosteroids (dose of greater than or equal to 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids). History of hypersensitivity reaction to drugs formulated with polysorbate 80. Pregnancy or lactation at the time of study entry. Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements. Use of any investigational product within 4 weeks prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: TAC then pegfilgrastim<br>docetaxel, doxorubicin, cyclophosphamide, and pegfilgrastim/filgrastim | Drug: docetaxel<br>* docetaxel 75 mg/m2 IV every 21 days for 6 cycles<br>* Other names: T;Drug: doxorubicin<br>* doxorubicin 50 mg/m2 IV every 21 days for 6 cycles<br>* Other names: A;Drug: cyclophosphamide<br>* Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles Group 2 and 3: cyclophosphamide 600 mg/m2 IV every 21 days for 6 cycles<br>* Other names: C;Drug: pegfilgrastim<br>* pegfilgrastim 6 mg subcutaneous (SC) Day 2 every 21 days for 6 cycles [filgrastim (Neupogen®) 5 mcg/kg Days 2-10 may be given in lieu of pegfilgrastim (Neulasta®), but pegfilgrastim is preferred.]<br>|
| Active Comparator: Group 2: TC<br>docetaxel and cyclophosphamide | Drug: docetaxel<br>* docetaxel 75 mg/m2 IV every 21 days for 6 cycles<br>* Other names: T;Drug: cyclophosphamide<br>* Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles Group 2 and 3: cyclophosphamide 600 mg/m2 IV every 21 days for 6 cycles<br>* Other names: C;|
| Experimental: Group 3: TC + bevacizumab<br>docetaxel, cyclophosphamide, and bevacizumab | Drug: bevacizumab<br>* bevacizumab 15 mg/kg IV every 21 days for 6 cycles followed by bevacizumab 15 mg/kg IV every 21 days until 1 year following the first dose of bevacizumab<br>Drug: docetaxel<br>* docetaxel 75 mg/m2 IV every 21 days for 6 cycles<br>* Other names: T;Drug: cyclophosphamide<br>* Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles Group 2 and 3: cyclophosphamide 600 mg/m2 IV every 21 days for 6 cycles<br>* Other names: C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive disease-free survival(IDFS)relative to the TAC chemotherapy regimen alone |  | Every 12 months until recurrence | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive disease-free survival (IDFS) relative to the TAC chemotherapy regimen |  | Every 12 months until recurrence | 
| Disease-free survival (DFS-DCIS) relative to the TC alone regimen |  | Every 12 months until recurrence | 
| Overall survival (OS) relative to the TC alone regimen |  | Every 12 months from randomization until death from any cause | 
| OS relative to the TAC regimen |  | Every 12 months from randomization until death from any cause | 
| Recurrence-free interval (RFI) relative to the TC alone regimen |  | Every 12 months, from randomization to local, regional, or distant recurrence | 
| RFI relative to the TAC regimen |  | Every 12 months, from randomization to local, regional, or distant recurrence | 
| Develop molecular predictive markers for the degree of benefit from TCB over TC or TAC |  | 6 years | 
| Provide the efficacy data from Group 1 patients and Group 2 patients enrolled in B-46-I/07132 to US Oncology Research, Inc. (USOR) for a planned combined analysis with efficacy data from patients receiving the same regimens in the USOR 06-090 trial |  | 10 years | 
| Toxicity associated with each of the regimens |  | Every 6 months | 
| Determine the role of topoisomerase II alpha (TOP2A) in prognosis and prediction of degree of benefit from TAC over TC |  | 6 years | 
| Develop predictive markers for benefit from doxorubicin |  | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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National Surgical Adjuvant Breast and Bowel Project (NSABP), Taxotere, Docetaxel, Doxorubicin, Cyclophosphamide, Bevacizumab, Breast Neoplasms, Adenocarcinoma, Breast Diseases, Carcinoma, HER2 negative, Node negative, High risk node positive, Adjuvant Therapy