Efficacy and Tolerance Study of Bevacizumab in Her2- Inflammatory Breast Cancer Patients

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. 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 bevacizumab and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab and radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying giving bevacizumab together with chemotherapy before surgery and bevacizumab and radiation therapy after surgery to see how well it works in treating patients with inflammatory breast cancer.

Detailed Description
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OBJECTIVES: Primary Evaluate the complete histological response rate in patients with inflammatory HER2-negative breast cancer treated with bevacizumab and concurrent chemotherapy followed by bevacizumab and concurrent hormonal therapy after surgery and radiotherapy. Secondary Evaluate the progression-fee and overall survival of these patients at 3 and 5 years. Evaluate the tolerance of bevacizumab in these patients. Assess circulating metastatic disease before, during, and after treatment. Assess circulating endothelial cells before, during, and after treatment. Assess predictive factors of response by genomic and proteomic studies on frozen tumor samples and fluid samples (i.e., serum and plasma). OUTLINE: This is a multicenter study. Neoadjuvant induction therapy: Courses 1-4: Patients receive bevacizumab IV over 30-90 minutes, fluorouracil IV, epirubicin hydrochloride IV over 10 minutes, and cyclophosphamide IV over 5 minutes on day 1. Courses 5-8: Patients receive bevacizumab IV over 30-90 minutes and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Surgery: Patients undergo surgery 4-6 weeks after completion of bevacizumab. Adjuvant therapy: Beginning 2-4 weeks after surgery, patients undergo radiotherapy for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes beginning 2-4 weeks after surgery, during the radiotherapy period. Treatment with bevacizumab repeats every 3 weeks for 30 weeks in the absence of disease progression or unacceptable toxicity. Patients who are estrogen receptor- or progesterone receptor-positive (≥ 10% by IHC) receive the following concurrent hormonal therapy beginning in week 7: Premenopausal patients: Patients receive tamoxifen citrate for 5 years. Postmenopausal patients: Patients receive aromatase-inhibitor therapy (or tamoxifen citrate if unable to tolerate anti-aromatase therapy) for 5 years. Perimenopausal patients: Patients receive tamoxifen citrate for 2-3 years and aromatase-inhibitor therapy for 2-3 years OR tamoxifen citrate for 5 years followed by aromatase-inhibitor therapy for 2-3 years (if follicle-stimulating hormone > 30 IU/L and/or estradiol < 30 ng/L). After completion of study treatment, patients are followed for at least 3 years.

Official Title
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Phase II Study Evaluating the Efficacy and Tolerance of Bevacizumab (Avastin) in HER2- Inflammatory Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: epirubicin hydrochloride
* Drug: fluorouracil


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed inflammatory breast cancer, meeting 1 of the following staging criteria: T4d, any N (AJCC stage IIIB or IIIC) Gustave-Roussy Institute (IGR) classification Poussee evolutirie (PEV; measures tumor growth over time) 2 PEV 2: tumor with underlying breast tissue, especially skin, that is affected by subacute inflammation and edema involving < ½ of breast surface IGR classification PEV 3 PEV 3: acute or subacute inflammation and edema involving > ½ of breast surface Biopsy-confirmed presence of tumor embolism in surface lymph nodes HER2-negative (HER2 0 or 1+, or HER2 2+ by IHC if FISH-negative allowed) No metastatic disease No non-inflammatory breast cancer with edema, ulceration, or satellite skin nodules No bilateral breast cancer Hormone receptor status known PATIENT CHARACTERISTICS: Any menopausal status allowed WHO performance status 0-2 Life expectancy ≥3 months LVEF normal by ECHO ANC >1.5 x 10^9/L Platelet count >100 x 10^9/L INR ≤1.5 (except for patients on prophylactic anticoagulants) aPTT ≤1.5 times upper limit of normal (ULN) Total bilirubin normal SGOT and SGPT ≤1.25 times ULN Alkaline phosphatase ≤2.5 times ULN Creatinine clearance ≥60 mL/min Proteinuria <2+ or 24-hour urine protein ≤1 g No unhealed wound, stomach ulcer, or bone fracture No history of thrombotic or hemorrhagic disorders No significant cardiovascular disease including the following: Cerebrovascular accident within the past 6 months Unstable angina Cardiac failure Myocardial infarction Arrhythmia requiring treatment No uncontrolled hypertension (i.e., systolic BP >150 mm Hg and/or diastolic BP >100 mm Hg) No other active infection or serious illness that would preclude patient from receiving study treatment No hypersensitivity to any active products or excipients of study drugs Not pregnant or nursing Fertile patients must use effective contraception during and for 6 months after completion of study treatment No social or psychologic reasons that would prevent study compliance or follow-up No patients who are incarcerated or on probation PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, or hormonal therapy for this disease More than 4 weeks since prior surgery (diagnostic biopsy or installation of implant allowed) More than 10 days since prior chronic non-inflammatory steroids (e.g., acetylsalicylic acid >325 mg/day) or platelet anticoagulation treatment (e.g., dipyridamole, ticlopidine, clodiprogel, cilostazol) More than 10 days since prior oral or parenteral anticoagulant or thrombolytic drugs (preventative thrombolytic drugs allowed) No concurrent participation in another experimental clinical trial

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (FEC / Docetaxel) + Bevacizumab<br>Neoadjuvant treatment: 4 cycles FEC + Bevacizumab followed by 4 cycles Docetaxel + Bevacizumab Adjuvant: Bevacizumab for 1 year | Biological: bevacizumab<br>* During neoadjuvant phase: 15 mg/kg, d1 q3w, 8 cycles During adjuvant phase:15 mg/kg, d1 q3w, 10 cycles<br>Drug: cyclophosphamide<br>* Neoadjuvant: 500 mg/m2 d1 q3w, 4 cycles<br>Drug: docetaxel<br>* Neoadjuvant: 100 mg/m2 q3w, 4 cycles<br>Drug: epirubicin hydrochloride<br>* Neoadjuvant: 100 mg/m2, d1 q3w, 4 cycles<br>Drug: fluorouracil<br>* Neoadjuvant: 500 mg/m2, d1 q3w, 4 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete histologic response rate |  | Post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 3 and 5 years | 
| Overall survival |  | 3 and 5 years | 
| Toxicity as assessed by CTCAE v3.0 |  | 3 and 5 years | 
| Predictive factors of response to bevacizumab |  | 3 and 5 years | 
| Circulating peripheral cells (circulating endothelial and tumor cells): correlation of initial rate and association with histological response after surgery |  | Post-surgery | 
| Genomic and proteomic analyses and correlation with histologic response |  | Post surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inflammatory breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, male breast cancer, HER2-negative breast cancer