Phase II Bevacizumab + Tax In Advanced Breast Cancer

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.

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