Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer

Female participants at least 18 years of age with histologically or cytologically confirmed,
human epidermal growth factor receptor 2 (HER2) negative breast adenocarcinoma that is
metastatic or locally-recurrent and inoperable with curative intent will be randomized.
Participants may not have received chemotherapy for metastatic or locally-recurrent,
inoperable breast cancer.

It is anticipated that 1113 participants will be randomized with 371 participants in the
docetaxel plus placebo arm and 742 participants in the docetaxel plus ramucirumab (IMC-1121B)
arm. There will be approximately 250 centers in North and South America, Europe, Asia, Middle
East, Africa, Australia, and New Zealand.

On Day 1 of each 21-day cycle, participants will receive docetaxel 75 mg/m² as a one-hour
I.V. infusion followed by either ramucirumab (IMC-1121B) 10 mg/kg or placebo 10 mg/kg as a
one-hour I.V. infusion. Each cycle is repeated every 21 days.

Treatment will continue until there is evidence of progressive disease, unacceptable
toxicity, or other withdrawal criteria are met. Participants who discontinue study treatment
with either ramucirumab (IMC-1121B) or placebo may continue to receive docetaxel.

Inclusion Criteria:

- Participant is able to provide signed informed consent

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

- Participant 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

- Participant has measurable and/or non-measurable disease

- Participants' primary and/or metastatic tumor is human epidermal growth factor
receptor 2 (HER2)-negative by fluorescence in-situ hybridization (FISH) or chromogenic
in-situ hybridization (CISH) or 0, 1+ overexpression by immunohistochemistry (IHC)

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

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

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

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

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

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

- Participant 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

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

- Participant is amenable to compliance with protocol schedules and testing

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

- Participant 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]

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

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

- Participant 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. Participants 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 (such as, tumor involving major vessels or known varices)

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

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

Exclusion Criteria:

- Participant 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 participant with previous history of malignancy is eligible, provided
that she has been disease free for > 3 years

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

- Participant has a known sensitivity to agents of similar biologic composition as
ramucirumab or other agents that specifically target vascular endothelial growth
factor (VEGF)

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

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

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

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

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

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

- Participant 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

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

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

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

- Participant is pregnant or lactating