Phase II Bevacizumab + Tax In Advanced Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Combining chemotherapy with monoclonal antibody therapy may kill more tumor cells. PURPOSE: This randomized phase II trial is to see if docetaxel with or without bevacizumab followed by surgery, radiation therapy, and combination chemotherapy works better in treating patients who have stage III or stage IV breast cancer.

Detailed Description
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OBJECTIVES: Determine the effect of bevacizumab and docetaxel on reduction of microvessel density and induction of apoptosis of endothelial and tumor cells in patients with locally advanced breast cancer. Determine the safety profile of this regimen in these patients. Compare the effect of docetaxel and bevacizumab, in terms of objective response, stabilization of disease, and progression-free survival, in these patients. OUTLINE: This is a randomized study. Patients are stratified according to disease stage. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6 and bevacizumab IV over 60 minutes once every 2 weeks on weeks 1-8. Arm II: Patients receive docetaxel as in arm I. Treatment in both arms repeats every 8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After the second course, patients with stable or responsive disease undergo modified radical mastectomy or breast-conserving surgery. Three to six weeks after surgery, patients undergo radiotherapy 5 days a week for 7 weeks. Approximately 4 weeks after the completion of radiotherapy, patients receive doxorubicin IV over 5 minutes and cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with estrogen and/or progesterone receptor-positive disease also receive oral tamoxifen daily for 5 years beginning after the completion of chemotherapy. Post-menopausal patients may receive oral anastrozole once daily for 5 years instead of tamoxifen. Patients are followed at 3, 6, and 12 months, every 6 months for 4 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 60 patients (30 per treatment arm) will be accrued for this study.

Official Title
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A Randomized Phase II Study of Bevacizumab in Combination With Docetaxel in Locally Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: doxorubicin hydrochloride
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast Stage IIIA or IIIB Stage IV if patient has clinical evidence of locally advanced breast cancer only Inoperable disease Prior carcinoma in situ of the breast or bilateral breast cancer is allowed No CNS metastases Hormone receptor status: Estrogen and progesterone receptor status known PATIENT CHARACTERISTICS: Age: 18 and over Sex: Female or male Menopausal status: Not specified Performance status: ECOG 0-2 OR Karnofsky 60-100% Life expectancy: More than 6 months Hematopoietic: WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin normal (no greater than 2 times upper limit of normal [ULN] in patients with an inherited disorder) AST/ALT no greater than 2.5 times ULN INR and PTT normal Renal: Creatinine normal OR Creatinine clearance at least 60 mL/min No proteinuria or clinically significant renal impairment Cardiovascular: LVEF at least 45% by echocardiogram or MUGA scan No New York Heart Association class III or IV heart disease No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No inadequately controlled hypertension No history of deep vein thrombosis or other thromboses No clinically significant peripheral artery disease No arterial thromboembolic event within the past 6 months including the following: Transient ischemic attack Cerebrovascular accident Myocardial infarction Other: No other prior or concurrent malignancy within the past 10 years except inactive nonmelanoma skin cancer or carcinoma in situ of the cervix No other uncontrolled concurrent illness No ongoing or active infection No non-healing wounds No psychiatric illness or social situation that would preclude study participation No prior allergic reaction to compounds of similar chemical or biological composition to bevacizumab, docetaxel, polysorbate 80 (Tween) formulations, or other agents used in this study Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent cytokines during docetaxel/bevacizumab administration Concurrent cytokines during doxorubicin/cyclophosphamide administration allowed at the discretion of the treating physician Chemotherapy: No prior chemotherapy Endocrine therapy: Prior hormonal therapy (e.g., tamoxifen) allowed Radiotherapy: Prior radiotherapy to affected breast allowed Surgery: More than 28 days since prior major surgery Other: At least 10 days since prior thrombolytic agents At least 10 days since prior full-dose oral or parenteral anticoagulants except to maintain patency of permanent indwelling IV catheters Concurrent warfarin allowed provided INR is less than 1.5 Concurrent bisphosphonates allowed for osseous metastases provided they are not initiated on day 1 of cycle 1 No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent full-dose oral or parenteral anticoagulants except to maintain patency of permanent indwelling IV catheters No concurrent thrombolytic agents No other concurrent anticancer agents or therapies No other concurrent investigational agents

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Docetaxel<br>Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6. | Drug: cyclophosphamide<br>* Approximately 4 weeks after the completion of radiotherapy, patients receive cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Drug: docetaxel<br>* Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6.<br>* Other names: Taxotere;Drug: doxorubicin hydrochloride<br>* Approximately 4 weeks after the completion of radiotherapy, patients receive doxorubicin IV over 5 minutes. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Procedure: adjuvant therapy<br>* After the second course, patients with stable or responsive disease undergo modified radical mastectomy or breast-conserving surgery. Three to six weeks after surgery, patients undergo radiotherapy 5 days a week for 7 weeks. Approximately 4 weeks after the completion of radiotherapy, patients receive doxorubicin IV over 5 minutes and cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Procedure: conventional surgery<br>* After the second course, patients with stable or responsive disease undergo modified radical mastectomy or breast-conserving surgery.<br>Procedure: neoadjuvant therapy<br>* Arm I: Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6 and bevacizumab IV over 60 minutes once every 2 weeks on weeks 1-8. Arm II: Patients receive docetaxel as in arm I. Treatment in both arms repeats every 8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.<br>Radiation: radiation therapy<br>* Three to six weeks after surgery, patients undergo radiotherapy 5 days a week for 7 weeks.<br>|
| Experimental: Combine bevacizumab and docetaxel.<br>Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6 and bevacizumab IV over 60 minutes once every 2 weeks on weeks 1-8. | Biological: bevacizumab<br>* Patients receive bevacizumab IV over 60 minutes once every 2 weeks on weeks 1-8.<br>Drug: cyclophosphamide<br>* Approximately 4 weeks after the completion of radiotherapy, patients receive cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Drug: doxorubicin hydrochloride<br>* Approximately 4 weeks after the completion of radiotherapy, patients receive doxorubicin IV over 5 minutes. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Procedure: adjuvant therapy<br>* After the second course, patients with stable or responsive disease undergo modified radical mastectomy or breast-conserving surgery. Three to six weeks after surgery, patients undergo radiotherapy 5 days a week for 7 weeks. Approximately 4 weeks after the completion of radiotherapy, patients receive doxorubicin IV over 5 minutes and cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>Procedure: conventional surgery<br>* After the second course, patients with stable or responsive disease undergo modified radical mastectomy or breast-conserving surgery.<br>Procedure: neoadjuvant therapy<br>* Arm I: Patients receive docetaxel IV over 1 hour once weekly on weeks 1-6 and bevacizumab IV over 60 minutes once every 2 weeks on weeks 1-8. Arm II: Patients receive docetaxel as in arm I. Treatment in both arms repeats every 8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.<br>Radiation: radiation therapy<br>* Three to six weeks after surgery, patients undergo radiotherapy 5 days a week for 7 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the ability of bevacizumab and docetaxel to reduce microvessel density and induce apoptosis of endothelial and tumor cells. | The primary outcome measure is the difference in change in biologic parameters between the two arms. Tumor biopsies are required to perform pre- and post-treatment tumor microvessel density determination, apoptosis by TUNEL assay, proliferation markers by immunohistochemistry(e.g. PCNA, Ki-67), and expression of nuclear clusterin/XIP8. | weeks 8 and 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with objective response | Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, male breast cancer