A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination With Bevacizumab and Paclitaxel or AMG 386 Plus Paclitaxel as First-Line Therapy in Subjects With Her2-Negative, Metastatic or Locally Recurrent Breast Cancer

Inclusion Criteria:

- Subjects must have histologically or cytologically confirmed adenocarcinoma of the
breast with locally recurrent or metastatic disease. Locally recurrent disease must
not be amenable to resection with curative intent.

- Measurable or non-measurable disease per modified RECIST guidelines

- ECOG of 0 or 1 (within 14 days prior to randomization)

- Adequate organ and hematological function as evidenced by the following laboratory
studies within 14 days prior to randomization:

• Cardiac function, as follows:

- Normal sinus rhythm (no significant ECG changes)

- Left ventricular ejection fraction ≥ LLN, as determined by echocardiogram or MUGA
scan, according to institutional standards within 28 days prior to randomization

Exclusion Criteria:

- Inflammatory Breast Cancer

- Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral
neuropathy > grade 1 at randomization

- History of arterial or venous thrombosis, including transient ischemic attack (TIA),
within 1 year prior to randomization

- Adjuvant or neoadjuvant taxane treatment within 12 months of randomization. Any other
adjuvant chemotherapy regimen must be discontinued at least 21 days prior to
randomization

- Prior chemotherapy, vaccine, or biological therapy for locally recurrent or
metastatic breast cancer (prior endocrine therapy is permitted)

- Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or hepatic
chemoembolization on all sites of disease unless disease progression was subsequently
documented 14 days prior to randomization.

- Overexpression of HER-2 (gene amplification by FISH or 3+ over expression by
immunohistochemistry).

- Current or prior history of central nervous system metastasis

- History of bleeding diathesis or clinically significant bleeding within 6 months
prior to randomization

- Major surgical procedure within 28 days prior to randomization

- Open breast biopsy within 14 days prior to randomization

- Minor surgical procedure, placement of access device, or fine needle aspiration
within 7 days of first dose

- Prior malignancy (other than thyroid cancer, in situ cervical cancer, or basal cell
cancer of the skin, treated with curative intent and without evidence of disease for
≥ 3 years prior to randomization)

- Clinically significant cardiac disease within 12 months prior to randomization,
including myocardial infarction, unstable angina, grade 2 or greater peripheral
vascular disease, cerebrovascular accident, transient ischemic attack, congestive
heart failure, or arrhythmias not controlled by outpatient medication

- Non-healing wound, ulcer or fracture

- Known hypersensitivity to paclitaxel or drugs using the vehicle cremophor

- Known hypersensitivity to bacterial proteins, or any of the drugs required in this
study

- Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis
B surface antigen

- Known active or chronic hepatitis

- Uncontrolled hypertension as defined as systolic blood pressure ≥ 150 mm Hg and
diastolic blood pressure ≥ 90 mm Hg. Anti-hypertensive medications are allowed if
the subject is stable on their current dose at the time of randomization

- Currently or previously treated with any VEGF or VEGFr inhibitor, including but not
limited to, bevacizumab, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788,
BAY 43-9006 (sorafenib) and AMG 706.

- Treatment with coumarin-type anticoagulants, (other than low dose prophylaxis for
central venous catheters ≤ 1mg/day) within 7 days prior to randomization

- Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1
or TIE-2 including, but not limited to, AMG 386, XL880, XL820

- Treatment with immune modulators such as cyclosporine and tacrolimus within 30 days
prior to randomization

- Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulators (SERMS), given for breast cancer prevention or
for osteoporosis. Subjects must have discontinued these agents 28 days prior to
randomization

- Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding