First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER-2/NEU

PRIMARY OBJECTIVES:

I. Evaluate efficacy of the addition of bevacizumab in patients eligible for first-line
trastuzumab with chemotherapy for HER-2/NEU overexpressing metastatic breast cancer, by
assessing the progression-free survival (PFS) after initiation of combination therapy.

SECONDARY OBJECTIVES:

I. Evaluate response rates (RR) in patients with measurable disease (Response Evaluation
Criteria in Solid Tumors [RECIST]), when applicable.

II. Evaluate overall survival (OS). III. Evaluate time to progression (TTP). IV. Evaluate
the percent of patients who are progression-free (PPF) at 6 months.

V. Compare the toxicity of chemotherapy/trastuzumab to that of chemotherapy/trastuzumab in
combination with bevacizumab.

VI. Compare breast cancer symptoms and treatment related symptoms between patients receiving
chemotherapy and trastuzumab with or without bevacizumab.

VII. Evaluate whether PFS correlates with vascular endothelial growth factor (VEGF) levels
in breast tumor tissue.

VIII. Analysis of circulating tumor cells and circulating endothelial cells (CEC).

IX. Serially enumerate circulating tumor cells (CTC) and CEC in patients on study and
determine whether: the number of CTC and CEC decrease in responding patients; the extent of
CTC and CEC decrease is greater in the experimental arm, Arm B versus the control arm, Arm
A; enumeration of CTC and CEC in responding patients correlate with progression free
survival (PFS).

X. Perform an exploratory analysis of phosphorylation status of v-akt murine thymoma viral
oncogene homolog (akt)-2 in circulating tumor cells.

XI. Perform an exploratory analysis of reverse transcriptase (RT)-polymerase chain reaction
(PCR) of CTC messenger ribonucleic acid (mRNA) to determine whether change in expression of
selected downstream targets of bevacizumab therapy can serve as pharmacodynamic or surrogate
markers of bevacizumab targeting and modulation.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A:

INDUCTION THERAPY: Patients receive trastuzumab intravenously (IV) over 30-90 minutes on
days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over
60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day
1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients
receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1.
Treatment repeats every 3 weeks in the absence of disease progression or unacceptable
toxicity.

ARM B:

INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin
as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15.
Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients
receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1.
Treatment repeats every 3 weeks in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 10 years.

Inclusion Criteria:

- Histologically confirmed breast cancer that overexpresses HER-2/NEU with evidence of
metastatic disease and/or chest wall recurrence prior to randomization

- HER-2/NEU overexpression is defined as 3+ HER-2 positivity as measured by
immunohistochemistry OR HER-2 gene amplification as measured by fluorescent in situ
hybridization (FISH, e.g. Vysis), per American Society of Clinical Oncology
guidelines

- NOTE: representative diagnostic tissue must be submitted for central diagnostic
review for confirmation of HER-2/NEU overexpression within two weeks following
patient randomization

- Evaluable (measurable or non-measurable) disease is allowed if confirmed within 4
weeks prior to randomization

- Prior endocrine treatment in the adjuvant or metastatic setting is allowed, provided
last dose given >= 2 weeks prior to randomization

- Prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer is not
allowed

- Patients who have had a CUMULATIVE dose of doxorubicin of greater than 360 mg/m^2 or
epirubicin of greater than 640 mg/m^2 in the adjuvant or neo-adjuvant setting at any
time are not allowed

- Radiation therapy is allowed provided last dose is given >= 3 weeks prior to
randomization

- Adjuvant trastuzumab therapy for breast cancer is allowed provided last dose was
given >= 12 months prior to diagnosis of recurrence

- Adjuvant or neoadjuvant taxane therapy for breast cancer is allowed provided last
dose was given >= 12 months prior to diagnosis of recurrence

- Adjuvant or neoadjuvant therapy with lapatinib is allowed provided last dose is given
>= 4 weeks prior to diagnosis of recurrence

- Patients with grade 2-4 neuropathy are not allowed

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Absolute neutrophil count >= 1,000/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 mg/dL

- Aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (=< 5 times
normal in patients with known liver involvement)

- Serum creatinine =< 1.5 mg/dL

- Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1000 mg

- International normalized ratio (INR) =< 1.5 X ULN

- Partial thromboplastin time (PTT) =< 1.5 X ULN

- Multi gated acquisition scan (MUGA) scan or echocardiogram (ECHO) within 6 weeks
prior to randomization with an left ventricular ejection fraction (LVEF) above the
institutional lower limit of normal

- Patients must be able to understand and provide signed and dated written informed
consent

- Patients with a history or radiologic evidence of central nervous system (CNS)
disease are not allowed

- Major surgical procedure within 4 weeks prior to randomization is not allowed (except
for non-operative biopsy, which would not be considered major surgery); treatment can
not begin until seven (7) days after placement of a vascular access device

- Clinically significant cardiovascular disease is not allowed, including:

- History of cerebrovascular (CVA) within 6 months

- Uncontrolled hypertension

- Myocardial infarction or unstable angina within 6 months

- New York Heart Association class II or greater congestive heart failure, serious
cardiac arrhythmia requiring medication, unstable angina pectoris

- Clinically significant peripheral vascular disease

- Women must not be pregnant or breastfeeding; all females of childbearing potential
must have a blood or urine test within 2 weeks prior to randomization to rule out
pregnancy; women of childbearing potential and sexually active males must use an
accepted and effective method of contraception

- Patients on full-dose anticoagulants (e.g., warfarin) with PT/INR > 1.5 may be
eligible provided that both of the following criteria are met:

- The patient has an in-range INR (usually between 2 and 3) on a stable dose of
oral anticoagulant or on a stable dose of low molecular weight heparin

- The patient has not active bleeding or pathological condition that carries a
high risk of bleeding (e.g., tumor involving major vessels or known varices)

- Patients using any of the following drugs known to inhibit platelet function are not
eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and
cilostazol (Pletal)

- Patients must not have a current non-healing wound or fracture

- Patients must not have a hypersensitivity to paclitaxel or drugs using the vehicle
Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies

- Patients must not have a serious medical or psychiatric illness that would prevent
ability to safely participate or provide informed consent

- Patients with a concurrent active malignancy except carcinoma in situ of the cervix
or non-melanoma skin cancers (unless disease-free for at least 5 years at study
entry) are not allowed