Paclitaxel With or Without Carboplatin and/or Bevacizumab Followed by Doxorubicin and Cyclophosphamide in Treating Patients With Breast Cancer That Can Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether adding bevacizumab to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent dose-dense doxorubicin and cyclophosphamide (ddAC) significantly raises the rate of pathologic complete response (pCR) in the breast in patients with hormone receptor (HR)-poor/human epidermal growth factor receptor 2 (HER2) (-), resectable breast cancer. II. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with HR-poor/HER2(-), resectable breast cancer. III. To determine whether adding bevacizumab every 2 weeks to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent ddAC significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array. IV. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array. SECONDARY OBJECTIVES: I. To determine the pCR rates in the breast and axilla, using American Joint Committee On Cancer (AJCC) TNM criteria (version 6), to neoadjuvant weekly paclitaxel, with or without carboplatin, followed by ddAC, with or without bevacizumab, given concurrently with the weekly paclitaxel and ddAC, in (a) patients with HR-poor/HER2(-), resectable breast cancer and (b) the subset of patients with basal-like breast cancers, as defined by gene expression array. II. To assess whether there is an interaction between the addition of carboplatin and bevacizumab to neoadjuvant chemotherapy (NAC) with weekly paclitaxel followed by ddAC as regards the path pCR rates in (a) patients with HR-poor/HER2(-), resectable breast cancer and (b) the subset of patients with basal-like breast cancers, as defined by gene expression array. III. To assess the toxicity of the control regimen (weekly paclitaxel followed by ddAC) and any incremental toxicities associated with the addition of carboplatin and/or bevacizumab in this patient population, including the incidence of febrile neutropenia, grade >= 3 thrombocytopenia, grade >= 2 neurotoxicity, grade >= 3 hypertension, and clinically significant bleeding or thrombotic (including cardiovascular and cerebrovascular) events. IV. To determine the recurrence-free survival (RFS) measured from definitive surgery to first event, and time to first failure (TFF) measured from study entry to first event. V. To determine overall survival (OS), defined as time from registration to death from any cause. VI. To assess the impact of NAC with weekly paclitaxel followed by ddAC, with or without carboplatin and/or bevacizumab, on axillary lymph node involvement at surgery, particularly in patients with clinically or histologically positive axillary lymph nodes prior to initiation of NAC. VII. To assess the impact of the addition of bevacizumab to NAC on the incidence and severity of post-op complications, especially excessive bleeding, delayed wound healing, and thrombotic complications. VIII. To evaluate residual cancer burden (RCB) as a predictor of RFS, TFF and OS. IX. To determine the correlation between clinical, radiographic, and pathologic response. TERTIARY OBJECTIVES: I. To assess whether the impact of the addition of carboplatin and/or bevacizumab to NAC with weekly paclitaxel followed by ddAC on achievement of pathologic CRs in patients with HR-poor/HER2(-), resectable breast cancer is influenced by molecular subtype, as defined by gene expression array. II. To obtain blood, fresh frozen and fixed tumor tissue to test specific hypotheses for which biomarker data exist and to evaluate biomarkers in tissue, blood, and serum that may influence response to and toxicity of weekly paclitaxel, ddAC, carboplatin, and/or bevacizumab. III. To obtain blood samples to test specific hypotheses for which biomarker data exist and to evaluate biomarkers in blood that may influence response to and toxicity of weekly paclitaxel, ddAC, carboplatin and/or bevacizumab. IV. To determine the surgical practice patterns for breast conservation and sentinel lymphadenectomy in patients undergoing neoadjuvant chemotherapy. V. To examine the practice patterns and use of sentinel lymphadenectomy (pre-chemotherapy or post-chemotherapy) in patients with T2 or T3 breast cancer. VI. To examine the proportion of patients who presented with T2 or T3 cancers who undergo mastectomy despite cytoreduction adequate for breast conservation. VII. To determine the radiotherapy practice patterns for post-mastectomy and regional nodal irradiation in patients undergoing neoadjuvant chemotherapy. OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 3-10 minutes and cyclophosphamide IV over 5-60 minutes (ddAC) once in weeks 13, 15, 17, and 19. ARM II: Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes once in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. ARM III: Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. ARM IV: Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III. Patients in all arms undergo definitive surgery (i.e., modified radical mastectomy or breast-conserving surgery with appropriate management of the axilla) between 4-8 weeks after completion of neoadjuvant therapy. After completion of study treatment, patients are followed up periodically for up to 10 years.

Official Title
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Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer

Conditions
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Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage IIIA Breast Cancer AJCC v7, Triple-Negative Breast Carcinoma, Male Breast Carcinoma

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Carboplatin
* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Invasive breast cancer, diagnosed by core needle or incisional biopsy (excisional biopsy not permitted) The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor (ER) and progesterone receptor (PgR) negative or staining present in =< 10% of invasive cancer cells by immunohistochemistry (IHC) The invasive tumor must be HER2-negative, defined as IHC 0-1+ or with a fluorescent in situ hybridization (FISH) ratio (HER2 gene copy/chromosome 17) of < 2.0 if IHC 2+ Clinical stage II-III invasive breast cancer with intent to perform surgical resection after neoadjuvant therapy; patients with inflammatory breast cancer are not eligible; staging to rule out metastatic disease is recommended for clinical stage III patients Patients with multicentric or bilateral disease are eligible if the target lesion meets eligibility criteria Patient agrees to undergo pretreatment research biopsies No prior chemotherapy, hormone therapy, or radiation therapy with therapeutic intent for this cancer The target lesion in the breast must be >= 1 cm, clinically or radiographically; palpable or radiographically measurable axillary adenopathy will be recorded but will not serve as measurable disease for the primary endpoint; patients with axillary disease only (no identifiable tumor in the breast that is >= 1 cm on physical exam or radiographic study) are not eligible to participate Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower gastrointestinal [GI] bleeding) within 6 months of registration are not eligible No serious or non-healing wound, skin ulcers or bone fracture; no abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the past 6 months; no major surgical procedure within 28 days prior to randomization or anticipation of need for major surgery during the course of study The following are not considered to be major surgical procedures that would be prohibited in the 28 days prior to, or following study randomization: obtaining the required research needle biopsies; placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical resection; placement of a port for central venous access; fine needle aspiration of a prominent or suspicious axillary lymph node; needle biopsy of a clinically or radiographically detected lesion to rule out metastatic disease; or pretreatment sentinel lymph node sampling No baseline neuropathy grade >= 2 Zubrod performance status 0-1 Pregnant or nursing women are not eligible; all women of reproductive potential must have a negative pregnancy test at baseline and agree to use an effective, non-hormonal method of contraception during the entire period of treatment on the study Patients with congestive heart failure are not eligible, nor are patients with myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack (TIA) within the past 12 months, uncontrolled hypertension (systolic blood pressure [SBP] > 160 or diastolic blood pressure [DBP] > 90), uncontrolled or symptomatic arrhythmia, or grade II or greater peripheral vascular disease Patients must have a pretreatment multi gated acquisition (MUGA) scan or echocardiogram with a left ventricular ejection fraction (LVEF) above the institutional lower limit of normal Granulocytes > 1,000/mcl Platelets > 100,000/mcl Total bilirubin =< 1.5 x upper limits of normal Calculated or measured > 30 ml/min Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1 Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study Serum alanine aminotransferase (ALT) =< 2.5 x upper limits of normal Serum beta human chorionic gonadotropin (HCG) negative (for women of child bearing potential) Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) Unless patient is on therapeutic doses of warfarin; if so, the patient must have an INR =< 3 on a stable dose of warfarin, must have not active bleeding or pathologic condition that is associated with a high risk of bleeding

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (paclitaxel, doxorubicin, cyclophosphamide)<br>Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm II (paclitaxel, ddAC, bevacizumab)<br>Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm III (paclitaxel, ddAC, carboplatin)<br>Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)<br>Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is). | Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain carboplatin (arms 3&4) versus not (arms 1&2) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods. | At the time of definitive surgical removal, up to 28 weeks | 
| Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is). | Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods. | At the time of definitive surgical removal, up to 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0). | Comparing regimens that contain carboplatin (arms 3&4) versus not (arms 1&2). | At the time of definitive surgical removal, up to 28 weeks | 
| Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0). | Comparing regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3). | At the time of definitive surgical removal, up to 28 weeks | 
| Pathologic Stage in the Breast and in the Breast Plus Axilla as Measured by American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Staging Criteria (Version 6) | Stage II is (T2,T3, N0, M0) tumor size more than 2 cm but no deep extradermal structure invasion, no regional lymph node metastasis, and no distant metastasis. Stage III is (T4, N0, M0) tumor invasion of deep extradermal structures, no regional lymph node metasis, and no distant metasasis or (Any T, N1, M0) Any tumor size, regional lymph node metastasis, and no distant metastasis. | at definitive surgery, up to 28 weeks | 
| Radiographic Response Assessed by Tumor Measurement | Assessed by RECIST, each patient will have a pre-therapy baseline radiographic tumor measurement, preferably by MRI, however if logistic or practical or financial issues preclude MRI use, mammogram or ultrasound may be substituted. The longest diameter (LD) of the target lesion at the time of study initiation will be reported as the baseline LD. The baseline LD of the target lesion will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease. Radiographic complete response: Disappearance of the target lesion. Radiographic partial response (PR): At least a 30% decrease in the longest diameter (LD) of the target lesion taking as reference the baseline LD. | Baseline; at completion of neoadjuvant therapy | 
| Clinical Response Assessed by Tumor Measurement | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Both target and, in the event of multifocal or multicentric invasive breast cancer, nontarget lesions should be followed clinically and their clinical size recorded at aseline. Measurements thereafter are required at the completion of 12 weeks of paclitaxel or paclitaxel/carboplatin and at the completion of all neoadjuvant chemotherapy. At any time point, these lesions should be categorized regarding whether there is evidence of progression. If yes, the study chair should be notified in order to determine whether the patient should come off protocol treatment. In-situcarcinoma does not represent a non-target lesion and should not be recorded or followed. | Baseline; at completion of neoadjuvant therapy | 
| Overall Survival | Number of Participants who Died Due to Any Cause | up to 10 years | 
| Recurrence-free Survival | From definitive surgery to first instance of ipsilateral invasive breast tumor recurrence, local/regional invasive breast cancer recurrence, distant recurrence, or death from any cause. Number of Participants who Died Due to Any Cause or had a recurrence. | up to 10 years | 
| Count of Participants With a First Failure, Defined as First Instance of Ipsilateral Invasive Breast Tumor Recurrence, Local/Regional Invasive Breast Cancer Recurrence, Distant Recurrence, or Death From Any Cause | From study entry to first event. | up to 10 years | 
| Incidence and Severity of Post-op Complications, Namely Excessive Bleeding, Delayed Wound Healing, and Wound Dehiscence. | Assessed by physician observation. | at definitive surgery, up to 28 weeks |