A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer

Inclusion Criteria:

- Patient is able to provide signed informed consent

- Patient is female and ≥ 18 years of age or older if required by local laws or
regulations

- Patient has histologically or cytologically confirmed adenocarcinoma of the breast
that is now metastatic or locally-recurrent and inoperable with curative intent.
Every effort should be made to make paraffin-embedded tissue or slides from the
diagnostic biopsy or surgical specimen available for confirmation of diagnosis

- Patient has measurable and/or non-measurable disease

- Patients' primary and/or metastatic tumor is HER2-negative by fluorescence in-situ
hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+
overexpression by immunohistochemistry (IHC)

- Patient has not received prior chemotherapy for metastatic or locally-recurrent and
inoperable breast cancer

- Patient completed (neo) adjuvant taxane therapy at least 6 months prior to
randomization

- Patient completed (neo) adjuvant biologic therapy at least 6 weeks prior to
randomization

- Patient completed all prior radiotherapy with curative intent ≥ 3 weeks prior to
randomization

- Patient may have received prior hormonal therapy for breast cancer in the (neo)
adjuvant and/or the metastatic setting ≥ 2 weeks prior to randomization

- Patient's left ventricular ejection fraction is within normal institutional ranges

- Patient has resolution to grade ≤ 1 by the National Cancer Institute Common
Terminology Criteria for Adverse Events, Version 3 (NCI-CTCAE v 3.0) of all
clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or
hormonal therapy with the exception of peripheral neuropathy which must have resolved
to grade ≤ 2

- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Patient is amenable to compliance with protocol schedules and testing

- Patient has adequate hematological functions (absolute neutrophil count [ANC] ≥ 1500
cells/uL, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000 cells/uL and ≤ 850,000
cells/uL)

- Patient has adequate hepatic function (bilirubin within normal limits [WNL],
aspartate transaminase [AST] and alanine transaminase [ALT] ≤ 2.5 times the upper
limit of normal [ULN], or ≤ 5.0 times the ULN if the transaminase elevation is due to
liver metastases, and alkaline phosphatase ≤ 5.0 times the ULN)

- Patient has serum creatinine ≤ 1.5 x ULN. If serum creatinine > 1.5 x ULN the
calculated creatinine clearance should be > 40 mL/min)

- Patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if urine
protein ≥ 2+, a 24-hour urine collection must demonstrate < 1000 mg of protein in 24
hours to allow participation in the study

- Patient must have adequate coagulation function as defined by international
normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN if
not receiving anticoagulation therapy. Patients on full-dose anticoagulation must be
on a stable dose of oral anticoagulant or low molecular weight heparin and if on
warfarin must have a INR between 2 and 3 and have no active bleeding (defined as
within 14 days of randomization) or pathological condition that carries a high risk
of bleeding (eg, tumor involving major vessels or known varices)

- Women of childbearing potential must implement adequate contraception in the opinion
of the investigator

- Patient has not received prior biologic therapy for metastatic or locally recurrent
and inoperable breast cancer

Exclusion Criteria:

- Patient has a concurrent active malignancy other than breast adenocarcinoma,
adequately treated non melanomatous skin cancer, or other non-invasive carcinoma or
in situ neoplasm. A patient with previous history of malignancy is eligible,
provided that she has been disease free for > 3 years

- Patient has a known sensitivity to docetaxel or other drugs formulated with
polysorbate 80

- Patient has a known sensitivity to agents of similar biologic composition as
ramucirumab or other agents that specifically target VEGF

- Patient has a history of chronic diarrheal disease within 6 months prior to
randomization

- Patient has received irradiation to a major bone marrow area as defined as > 25% of
bone marrow (eg, pelvic or abdominal radiation) within 30 days prior to randomization

- Patient has participated in clinical trials of experimental agents within 4 weeks
prior to randomization

- Patient has a history of uncontrolled hereditary or acquired bleeding or thrombotic
disorders

- Patient has active, high risk bleeding (eg, via gastric ulcers or gastric varices)
within 14 days prior to randomization

- Patient has an ongoing or active infection requiring parenteral antibiotic,
antifungal, or antiviral therapy

- Patient has uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric
illness/social situations, or any other serious uncontrolled medical disorders in the
opinion of the investigator

- Patient has brain metastases, uncontrolled spinal cord compression, or carcinomatous
meningitis, or new evidence of brain or leptomeningeal disease

- Patient has known human immunodeficiency virus infection or acquired immunodeficiency
syndrome-related illness

- Patient has pulmonary lymphangitic involvement that results in pulmonary dysfunction
requiring active treatment, including the use of oxygen.

- Patient is pregnant or lactating