Chemotherapy With or Without Bevacizumab in Treating Women With Stage I, Stage II, or Stage IIIA Breast Cancer That Can Be Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. 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 chemotherapy and bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known which chemotherapy regimen is more effective with or without bevacizumab in treating breast cancer. PURPOSE: This randomized phase III trial is studying six different chemotherapy regimens to compare how well they work with or without bevacizumab in treating women with stage I, stage II, or stage IIIA breast cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Compare the efficacy of docetaxel followed by doxorubicin hydrocloride and cyclophosphamide (AC) vs docetaxel and capecitabine followed by AC vs docetaxel and gemcitabine hydrochloride followed by AC, with or without bevacizumab, in terms of an increase in the rate of pathologic complete response (pCR) in the breast, in women with palpable or operable breast cancer. Secondary Compare docetaxel/capecitabine with AC vs docetaxel/gemcitabine hydrochloride with AC vs docetaxel with AC, with or without bevacizumab, in terms of the rate of pCR in the breast and all post-therapy lymph nodes evaluated histologically (pCR breast and nodes). Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel and capecitabine with AC, and docetaxel and gemcitabine hydrochloride with AC) will increase the rate of pCR of the breast and nodes compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical overall response (cOR) compared to docetaxel alone with or without bevacizumab in these patients. Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens will increase the rate of cOR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical complete response (cCR) compared to docetaxel alone with or without bevacizumab in these patients. Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel/capecitabine with AC, and docetaxel/gemcitabine hydrochloride with AC) will increase the rate of cCR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. Identify gene expression profiles that can predict pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens with or without bevacizumab. Identify gene expression profiles that can predict cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride with or without bevacizumab. Determine the accuracy of an in vitro chemoresponse assay (ChemoFx®) as a predictor of pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens without bevacizumab. Determine the accuracy of ChemoFx® as a predictor of cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride without bevacizumab in these patients. Determine the impact of preoperative bevacizumab and sequential chemotherapy regimens and postoperative bevacizumab therapy on cardiac function in these patients. Determine the impact of bevacizumab on surgical complications in these patients. Determine the toxicity of the preoperative regimens and the toxicity of postoperative bevacizumab in these patients. Compare the docetaxel/anthracycline-based regimens with vs without bevacizumab, in terms of an increase in disease-free survival, of these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor size (2-4 cm vs > 4 cm), nodal status (negative vs positive), hormone receptor status (estrogen receptor [ER]-positive and/or progesterone-receptor [PgR]-positive vs ER- and PgR-negative), and age (< 50 years vs ≥ 50 years). Patients are randomized to 1 of 6 treatment arms. Core needle biopsies are performed at baseline. Tumor tissue samples are also collected during definitive surgery. Samples are examined for gene expression and polymorphism by reverse transcriptase-polymerase chain reaction analysis and chemoresponse assay (ChemoFx®). After completion of study therapy, patients are followed periodically for 10 years. PROJECTED ACCRUAL: A total of 1,200 patients will be accrued for this study.

Official Title
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A Randomized Phase III Trial of Neoadjuvant Therapy in Patients With Palpable and Operable Breast Cancer Evaluating the Effect on Pathologic Complete Response (pCR) of Adding Capecitabine or Gemcitabine to Docetaxel When Administered Before AC With or Without Bevacizumab and Correlative Science Studies Attempting to Identify Predictors of High Likelihood for pCR With Each of the Regimens

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: capecitabine
* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: doxorubicin hydrochloride (Adriamycin)
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must have consented to participate and must have signed and dated an appropriate Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines for the study treatment and submission of pre-entry core biopsy material for correlative studies. Patients must be female. Patients must be 18 years of age or older. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy. The primary breast tumor must be palpable and measure greater than or equal to 2.0 cm on physical exam. All patients must have their left ventricular ejection fraction (LVEF) assessed by multigated acquisition (MUGA) scan or echocardiogram within 3 months prior to study entry. The LVEF must be greater than or equal to the lower limit of normal (LLN) for the cardiac imaging facility performing the study. Note: If the cardiac imaging facility cannot provide a LLN, use 50% as the LLN value. - Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if bevacizumab therapy can be continued, it is critical that this baseline study be an accurate assessment of the patient's LVEF. If the baseline LVEF is greater than 75%, the investigator should have the study reviewed for accuracy prior to study entry. Following study entry, the LVEF determination may be reviewed up until the time of the post-chemotherapy (preoperative) evaluation. Please note that if a more accurate value is obtained from the review of the baseline MUGA or echocardiogram, the correct value must be submitted to the NSABP before the post-chemotherapy (preoperative) MUGA or echocardiogram is performed or it cannot be used for managing postoperative bevacizumab. All patients must have an EKG within 3 months prior to study entry. At the time of randomization: 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. Hemoglobin must be greater than or equal to 10 g/dL. There must be evidence of adequate hepatic function by these criteria: Total bilirubin must be less than or equal to the ULN for the lab unless the patient has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN) resulting from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and Alkaline phosphatase must be less than or equal 2.5 x ULN for the lab; and Aspartate Aminotransferase (AST) must be less than or equal to 1.5 x ULN for the lab. Alkaline phosphatase and 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 2.5 x ULN, then the AST must be less than or equal the ULN. If the AST is greater than the ULN but less than or equal 1.5 x ULN, then the alkaline phosphatase must be less than or equal ULN. Patients with either skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal 2.5 x ULN are eligible for inclusion in the study if bone scans do not demonstrate metastatic disease. Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy. Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion in the study if liver imaging does not demonstrate metastatic disease and adequate bone marrow and liver function results as described above are met. The following criteria for evidence of adequate renal function must be met: Serum creatinine less than or equal ULN for the lab. Calculated creatinine clearance must be greater than 50 mL/min. Urine protein/urine creatinine (UPC) ratio must be less than 1.0. Patient must be able to swallow oral medications. Exclusion criteria: Tumor determined to be strongly human epidermal growth factor receptor 2 (HER2)-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization (positive for gene amplification). Excisional or incisional biopsy for this primary breast tumor. Surgical axillary staging procedure prior to study entry. Exceptions: 1) Fine Needle Aspiration (FNA) or core biopsy of an axillary node is permitted for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel lymph node biopsy for patients with clinically negative axillary nodes is permitted. Tumors clinically staged as T4. Ipsilateral cN2b or cN3 disease. (Patients with cN1 or cN2a disease are eligible.) Definitive clinical or radiologic evidence of metastatic disease. Synchronous bilateral breast cancer (invasive or DCIS). Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry. Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible if this therapy is discontinued prior to randomization.) Therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention. (Patients are eligible only if these medications are discontinued prior to randomization.) Prior history of breast cancer, including DCIS. (Patients with a history of lobular carcinoma in situ [LCIS] are eligible.) Prior therapy with anthracyclines, taxanes, capecitabine, 5-FU (fluorouracil), gemcitabine, or bevacizumab for any malignancy. Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to randomization and is deemed by her physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin. Cardiac disease that would preclude the use of anthracyclines. This includes: angina pectoris that requires the use of anti-anginal medication; history of documented congestive heart failure; serious cardiac arrhythmia requiring medication; severe conduction abnormality; valvular disease with documented cardiac function compromise; and uncontrolled hypertension defined as BP greater than 150/90 on antihypertensive therapy. (Patients with hypertension that is well controlled on medication are eligible.) History of myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function. History of transient ischemic attack (TIA) or cerebrovascular accident (CVA). History of other arterial thrombotic event within 12 months before study entry. Symptomatic peripheral vascular disease. Any significant non-traumatic bleeding within 6 months before study entry. Serious or non-healing wound, skin ulcers, or incompletely healed bone fracture. Gastroduodenal ulcer(s) determined by endoscopy to be active. Invasive procedures defined as follows: Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy. (Note: Placement of a vascular access device is not considered a major surgical procedure.) Anticipation of need for major surgical procedures (other than the required breast surgery) during the course of the study. Known bleeding diathesis or coagulopathy. (Patients on warfarin with an in-range international normalized ratio [INR] [usually between 2 and 3] are eligible.) Sensory/motor neuropathy greater than or equal grade 2, as defined by the NCI's Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0). Other non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude treatment with any of the treatment regimens or would prevent required follow-up. Conditions that would prohibit administration of corticosteroids. History of severe hypersensitivity reaction to drugs formulated with polysorbate 80. Administration of any investigational agents within 30 days before study entry. Pregnancy or lactation at the time of proposed randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Arm 1A: Docetaxel then AC<br>Patients receive docetaxel IV on day 1 every 3 weeks for up to 4 cycles. Patients then receive AC IV every 3 weeks for up to 4 cycles. Patients then undergo surgery (lumpectomy or mastectomy). | Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>|
| Experimental: Arm 1B Docetaxel + Bev then AC + Bev<br>Patients receive bevacizumab (bev) IV on day 1 and docetaxel every 3 weeks for up to 4 cycles. Patients then receive AC every 3 weeks for up to 4 cycles and 2 additional cycles of bevacizumab concurrent with the first 2 cycles of AC. Patients then undergo surgery as in Arm 1A. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab IV every 3 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. | Biological: bevacizumab<br>* 15 mg/kg IV<br>Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>|
| Experimental: Arm 2A: Docetaxel + Capecitabine then AC<br>Patients receive docetaxel as in Arm 1A and oral capecitabine (cape) twice daily on days 1-14 every 3 weeks for up to 4 cycles. Patients then receive AC as in Arm 1A. Patients then undergo surgery as in Arm 1A. | Drug: capecitabine<br>* 825 mg/m2 orally<br>Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>|
| Experimental: Arm 2B: Docetaxel + Cape + Bev then AC + Bev<br>Patients receive bevacizumab as in Arm 1B and docetaxel and capecitabine as in Arm III. Treatment repeats every 3 weeks for up to 4 cycles. Patients then receive AC every 3 weeks for up to 4 cycles and 2 additional cycles of bevacizumab concurrent with the first 2 cycles of AC. Patients then undergo surgery as in Arm 1B. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab as in Arm 1B. | Biological: bevacizumab<br>* 15 mg/kg IV<br>Drug: capecitabine<br>* 825 mg/m2 orally<br>Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>|
| Experimental: Arm 3A: Docetaxel + Gem then AC<br>Patients receive docetaxel as in Arm 1A and gemcitabine hydrochloride IV on days 1 and 8 of each cycle every 3 weeks for up to 4 cycles. Patients then receive AC as in Arm 1A. Patients then undergo surgery as in Arm 1A. | Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>Drug: gemcitabine hydrochloride<br>* 1000 mg/m2 IV<br>|
| Experimental: Arm 3B: Docetaxel + Gem + Bev then AC + Bev<br>Patients receive docetaxel as in Arm 1A, gemcitabine hydrochloride as in Arm 3A, and bevacizumab as in Arm 1B. Patients then receive AC every 3 weeks for up to 4 cycles and 2 additional cycles of bevacizumab concurrent with the first 2 cycles of AC. Patients then undergo surgery as in Arm 1A. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab as in Arm 1B. | Biological: bevacizumab<br>* 15 mg/kg IV<br>Drug: cyclophosphamide<br>* 600 mg/m2 IV<br>Drug: docetaxel<br>* 100 mg/m2 IV<br>Drug: doxorubicin hydrochloride (Adriamycin)<br>* 60 mg/m2 IV<br>Drug: gemcitabine hydrochloride<br>* 1000 mg/m2 IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) of the Primary Tumor in the Breast | Percentage of patients absent of histologic evidence of invasive tumor cells in the surgical breast specimen. | Time of surgery, on average 6 or 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR in the Breast and Nodes | Percentage of patients absent of histologic evidence of invasive tumor cells in the surgical breast specimen and axillary lymph nodes. | Time of surgery, on average 6 or 13 months | 
| Clinical Overall Response (cOR) Following Docetaxel Alone, Docetaxel/Capecitabine, and Docetaxel/Gemcitabine Hydrochloride, With or Without Bevacizumab, as Assessed by Physical Exam at the Completion of the Docetaxel-based Portion of Chemotherapy | Percentages of patients assessed as Clinical Complete Response or Clinical Partial Response according to RECIST. | Assessed at cycle 5 of chemotherapy, on average at 15 weeks | 
| Clinical Overall Response: cOR as Assessed by Physical Exam at the Completion of the Sequential Chemotherapy Regimens | The percentage of patients assessed by physical exam as Clinical Complete Response or Clinical Partial Response according to RECIST. | Three to four weeks after the last chemotherapy dose on average 6 or 13 months | 
| Clinical Complete Response (cCR) Following Docetaxel Alone, Docetaxel/Capecitabine, and Docetaxel/Gemcitabine Hydrochloride, With or Without Bevacizumab, as Assessed by Physical Exam at Completion of Therapy | Percentages of patients assessed as Clinical Complete Response or Clinical Partial Response according to RECIST. | Assessed at cycle 5 of chemotherapy, on average at 15 weeks | 
| Clinical Complete Resonse: cCR as Assessed by Physical Exam at the Completion of the Sequential Chemotherapy Regimens | The percentage of patients assessed by physical exam as Clinical Complete Response according to RECIST. | Three to four weeks after the last chemotherapy dose, on average at 6 or 13 months | 
| Percentage of Cardiac Events |  | After each cycle, 3-5 weeks postoperative, 9 and 12 months from study entry, every 6 month years 2-5, and annually years 6-10, for postoperative bevacizumab patients, every 6 weeks during postoperative therapy and at 18 months following study entry. | 
| Surgical Complication | Number of patients with Grade 4 or above surgery-related toxicities | 24 months after study entry | 
| Toxicities Including Events Other Than Congestive Heart Failure, of Chemotherapy Alone, Bevacizumab With Chemotherapy, and Bevacizumab Alone | The number of patients who experienced Grade 1 or above Adverse Events. Referring to the Adverse Events tables for specifics. | 24 months after study entry | 
| Disease-free Survival (DFS) | Percentage of patients free from local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral breast cancer, second primary cancer after 5 years. | Measured through 5 years after study enrollment | 

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