A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination with Bevacizumab and Paclitaxel or AMG386 plus Paclitaxel as First-Line Therapy in Subjects with Her2-Negative, Metastatic or Locally Recurrent Breast Cancer.

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 (see
Appendix G).
• Complete radiology and tumor measurement within 28 days prior to randomization:
o Chest: CT / MRI scan with intravenous contrast if the contrast is not medically
contraindicated
o Abdomen: CT / MRI scan with intravenous contrast if the contrast is not
medically contraindicated
o Pelvis: CT / MRI scan with intravenous contrast if the contrast is not medically
contraindicated
o Head/ Brain: CT / MRI scan
o Bone: Whole body Bone Scintigraphy
Demographic
• Female 18 years of age or older at the time the written informed consent is obtained
• Subjects of child-bearing potential and sexually active must use an accepted and
effective non-hormonal method of contraception (ie, double barrier method [eg, condom
plus diaphragm]) from signing the informed consent through 6 months following last
administration of study drug
General
• Able to tolerate intravenous infusions
• ECOG of 0 or 1 (within 14 days prior to randomization)
Laboratory
Adequate organ and hematological function as evidenced by the following laboratory studies
within 28 days prior to randomization:
• Hematological function, as follows:
* Absolute neutrophil count (ANC) >= 1.5 x 109/L
* Platelet count >= 100 x 109/L and <= 850 x 109/L
* Hemoglobin >= 9 g/dL
* PTT or aPTT and INR <= 1.0 x ULN, per institutional laboratory range
• Renal function, as follows:
* Calculated creatinine clearance > 40 cc/min according to the Cockcroft-Gault
formula
GFR (mL/min) = (140-age) x actual body weight (kg) (x 0.85 for females)
72 x serum creatinine (mg/dL)
* Urinary protein quantitative value of <= 30 mg in urinalysis or <= 1+ on dipstick,
unless quantitative protein is <= 1000 mg in a 24 hour urine sample
• Hepatic function, as follows:
* Total bilirubin <= 2.0 x ULN, per institutional laboratory range
* SGOT (AST) and SGPT (ALT) <= 2.5 x ULN, per institutional laboratory range (<= 5 x ULN if liver metastases are
present)
* 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 14 days prior to
randomization

Disease Related
• 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).
* Eligibility of subjects with 2+ immunohistochemistry must be confirmed by a
negative FISH assay
• 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
• Exclude subjects with a history of prior malignancy, except:
- Malignancy treated with curative intent and with no known active disease present for >= 3 years before enrollment and felt to be at low risk for recurrence by treating physician
- Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
- Adequately treated cervical carcinoma in situ without evidence of disease
• 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
• Ongoing or active infection
• 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
Medications
• 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
• Concurrent or prior (within 1 week before randomization) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (i.e. <= 1mg daily) for prophylaxis against thrombosis is acceptable while on study
• 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 14 days prior to randomization
General
• Any condition which in the investigator*s opinion makes the subject unsuitable for study participation
• Participation in other investigational device or drug trials or administration of other
investigational treatments within 30 days prior to randomization
• Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding
• Previously enrolled into this study
• Inability to comply with protocol and/or not available for follow-up assessments