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

OBJECTIVES:

Primary

- Determine the clinical response in patients with HER2/neu-positive stage I-III breast
cancer and bone marrow micrometastases treated with docetaxel, carboplatin, trastuzumab,
and bevacizumab.

Secondary

- Investigate the specific contribution of VEGF and CXCL-12 (SDF-1) signaling to bone
marrow support of HER2/neu-positive breast cancer cells.

- Evaluate growth factor and chemokine expression profiles to investigate the potential
correlation of expression with patient outcome and frequency of tumor cell clusters
(mammospheres with tumor stem cell phenotype) in microenvironment supported cultures.

OUTLINE: Patients receive docetaxel IV, carboplatin IV, and bevacizumab IV over 30-90 minutes
on day 1 and trastuzumab IV over 30-90 minutes on days 1, 8, and 15. Treatment repeats every
21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6
courses, treatment modifications may apply according to response.

Tumor tissue and bone marrow samples may be collected for further laboratory analysis.

After completion of study therapy, patients are followed up for 30 days.

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