Docetaxel,Carboplatin,Trastuzumab and Bevacizumab for Breast Cancer and Bone Marrow Micrometastases

Inclusion Criteria

• Patient with biopsy-proven primary stage I-III infiltrating adenocarcinoma of the breast.
• HER-2/neu (+) as determined by either IHC (3+) or FISH (≥ 2.2-fold amplification).
• Age ≥ 18 years.
• ECOG performance status 0-1.
• Negative CT C/A/P and TBBS.
• LVEF > 50% by MUGA or echocardiogram performed within 28 days prior to enrollment
• Positive BM aspirate for BC micrometastases by CLIA-certified laboratory.

• Adequate hematologic, hepatic, and renal function. All tests must be obtained ≤ 4 weeks prior to randomization.

  • Hematologic: Absolute neutrophil count > 1,500/mm3 Hemoglobin > 10.0 g/dl Platelet count > 100,000/mm3.
  • Hepatic: Total bilirubin must be within normal limits. Transaminases (AST and/or ALT) may be < 2.5 x institutional upper limit of normal (ULN) if alkaline phosphatase is < ULN, or alkaline phosphatase may be < 4 x ULN if transaminases are < ULN
  • Renal: Normal creatinine and BUN; if abnormal, calculated creatinine clearance must be> 60 mg/dL
• Patients must be disease-free of prior invasive malignancies for ≥ 5 years, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Surgery: all patients must have completed surgery with sentinel and/or axillary lymph node dissection according to participating institutional guidelines.
• Women of childbearing potential must have a negative pregnancy test and must be willing to consent to using an accepted and effective barrier form method of contraception while on treatment and for a reasonable period thereafter.
• Patients must provide written informed consent.
• Note: Hormonal therapy: patients with ER+ and/or PR+ tumors may receive concurrent hormonal therapy according to participating institutional guidelines. The choice of hormonal therapy is at the discretion of the treating physician.
• Note: Radiation therapy: patients receiving adjuvant radiation therapy to the involved breast (after partial mastectomy) or chest wall (after mastectomy) may receive concurrent trastuzumab and bevacizumab therapy.

Exclusion Criteria

• Known metastatic BC.
• Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Pregnant or lactating women.
• Prior chemotherapy, hormonal therapy, trastuzumab and bevacizumab therapy.
• History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias
• Ejection fraction <50% or below the lower limit of the institutional normal range, whichever is lower.
• Hypersensitivity to trial medications.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest.
• Active or uncontrolled infection.
• Psychiatric, addictive, or any disorder that compromises the ability to give informed consent to participate in or to comply with the requirements of the study.

Bevacizumab-Specific Exclusions

• Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of stroke or transient ischemic attack within 6 months prior to study enrollment
• Known CNS disease
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
• Symptomatic peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
• Serious, non-healing wound, ulcer, or bone fracture
• Proteinuria at screening as demonstrated by either
• Urine protein:creatinine (UPC) ratio >/= 1.0 at screening OR
• Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
• Known hypersensitivity to any component of bevacizumab
• Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential
• History of stroke or transient ischemic attack at any time
• History of myocardial infarction or unstable angina within 12 months of study enrollment