A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1)

This is a Phase III, multicenter, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared with chemotherapy alone in subjects with previously untreated metastatic breast cancer.

This study includes a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up phase. During the blinded treatment phase, patients receive chemotherapy and study drug (bevacizumab or placebo) every 3 weeks until disease progression, treatment-limiting toxicity, or death due to any cause. The optional open-label post-progression phase consists of chemotherapy treatment (per investigator discretion) and optional treatment with open-label bevacizumab. Patients who complete the study or who discontinue from treatment (regardless of participation in the optional open-label post-progression phase) will be followed for survival and subsequent anti-cancer therapies every 4 months until death, withdrawal of consent, loss to follow-up, or study termination. Patients who discontinue from treatment during the blinded treatment phase for reasons other than disease progression will have tumor assessments every 9 weeks until documented disease progression or death.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease.
* Signed Informed Consent Form.
* Age ≥ 18 years.
* For women of childbearing potential, use of accepted and effective method of non-hormonal contraception.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Ability and capacity to comply with study and follow-up procedures.
* For anthracycline cohort only: Adequate left ventricular function at study entry, defined as a left ventricular ejection fraction (LVEF) ≥ 50% by either multigated acquisition (MUGA) scan scan or echocardiography (ECHO).
* For subjects who have received recent radiation therapy, recovery prior to baseline (Day 0) from any significant (Grade ≥ 3) acute toxicity.

Exclusion Criteria:

* Unknown human epidermal growth factor receptor 2 (HER2) status or known HER2-positive status.
* Prior chemotherapy for locally recurrent or metastatic disease.
* Prior hormonal therapy less than 1 week prior to Day 0.
* Prior adjuvant or neoadjuvant chemotherapy within 12 months prior to Day 0.
* For anthracycline cohort only: Prior anthracycline as part of neoadjuvant or adjuvant therapy for localized breast cancer.
* Investigational therapy within 28 days of Day 0.
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study.
* Minor surgical procedures, such as fine needle aspirations or core biopsies, within 7 days prior to Day 0.
* Prior therapy with bevacizumab, sorafenib, sunitinib, or other vascular endothelial growth factor (VEGF) pathway-targeted therapy.
* Known brain or other central nervous system (CNS) metastases.
* Blood pressure of \> 150/100 mmHg.
* Unstable angina.
* New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF).
* History of myocardial infarction within 6 months prior to Day 0.
* History of stroke or transient ischemic attack within 6 months prior to Day 0.
* Clinically significant peripheral vascular disease.
* Evidence of bleeding diathesis or coagulopathy.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0.
* Serious non-healing wound, ulcer, or bone fracture.
* Pregnancy (positive serum pregnancy test) or lactation.
* Inadequate organ function, as evidenced by any of the following laboratory values: Absolute neutrophil count \< 1500/uL; platelet count \< 100,000/uL; total bilirubin \> 1.5 mg/dL; alkaline phosphatase, AST, and/or ALT \> 2x upper limit of normal (ULN) (\> 5x ULN in subjects with known liver or, for alkaline phosphatase elevations, bone involvement); alkaline phosphatase \> 2x ULN (\> 7x ULN in subjects with known bone involvement); serum creatinine \> 2.0 mg/dL; partial thromboplastin time (PTT) and/or either international normalized ratio (INR) or prothrombin time (PT) \> 1.5x upper limit of normal (except for subjects receiving anti-coagulation therapy); urine protein/creatinine ratio \> 1.0 at screening for U.S. subjects, or urine dipstick for proteinuria \>/= 1+ at screening followed by 24-hour urine collection demonstrating \> 1 g protein/24 hr for ex-U.S. subjects.
* Uncontrolled serious medical or psychiatric illness.
* Active infection requiring intravenous (iv) antibiotics at Day 0.
* History of other malignancies within 5 years of Day 0 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix (subjects with a history of bilateral breast cancer will be eligible).