A Study of Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) Versus Placebo and BSC as 2nd-Line Treatment in Participants With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib

Inclusion criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1

• Child-Pugh score of <7 (Child-Pugh Class A only)

• Barcelona Clinic Liver Cancer (BCLC) Stage C or BCLC stage B not amenable tolocoregional therapy or refractory to locoregional therapy

• Diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic orcytologic confirmation

• There are either clinical, laboratory, or radiographic findings consistent with adiagnosis of liver cirrhosis

• Has a liver mass measuring at least 2 centimeters (cm) with characteristicvascularization seen on either triphasic computed tomography (CT) scan or magneticresonance imaging (MRI) with gadolinium

• At least 1 measurable or evaluable lesion that is viable [that is (i.e.), isvascularized], and has not been previously treated with locoregional therapy. A lesionthat has been previously treated will qualify as a measurable or evaluable lesion ifthere was demonstrable progression following locoregional therapy

• Previously treated with sorafenib and has discontinued sorafenib treatment at least 14days prior to randomization. Participants may have experienced:

• Radiographically documented disease progression during sorafenib therapy or afterdiscontinuation of sorafenib therapy, or

• Discontinuation of sorafenib due to an adverse drug reaction, despite dosereduction by 1 level and BSC

• The participant has received sorafenib as the only systemic therapeutic intervention.Any hepatic locoregional therapy that has been administered prior to sorafenib isallowed, but not following sorafenib. Radiation to metastatic sites [for example (e.g.), bone] following sorafenib therapy is permitted.

• Resolution of clinically significant toxicity of any anti-cancer therapy to Grade ≤1by the National Cancer Institute Common Terminology Criteria for Adverse Events volume 4.0 (NCI-CTCAE v. 4.0). Adequate Organ Function defined as:

• Total bilirubin <3.0 milligrams/deciliter (mg/dL) [51.3 micromole/liter (µmol/L)],aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × upper limitof normal (ULN)

• Serum creatinine ≤1.2 × ULN or calculated creatinine clearance >50 milliliters/minute (mL/min)

• Absolute neutrophil count (ANC) ≥1.0 × 10^3/microliter (μL) (1.0 × 10^9/liter (L)]),hemoglobin ≥9 grams/deciliter (g/dL) [5.58 millimoles/liter (mmol/L)], and platelets ≥75 × 10^3/µL (75 × 10^9/L)

• International Normalized Ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤5seconds above ULN. Participants receiving prophylactic low-dose anticoagulant therapyare eligible provided that INR ≤1.5 and PTT ≤5 seconds above the ULN

• The participant's urinary protein is ≤1+ on dipstick or routine urinalysis. If urinedipstick or routine analysis indicates ≥2+ proteinuria, then a 24-hour urine must becollected and must demonstrate <1000 milligrams (mg) of protein in 24 hours to allowparticipation in the study

Exclusion criteria:

• Major surgery within 28 days prior to randomization, or central venous access deviceplacement within 7 days prior to randomization

• Hepatic locoregional therapy within 28 days prior to randomization

• Radiation to any nonhepatic (e.g., bone) site within 14 days prior to randomization

• Sorafenib within 14 days prior to randomization

• Received any investigational therapy or non-approved drug within 28 days prior torandomization

• Received any previous systemic therapy with vascular endothelial growth factor (VEGF)inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC

• Fibrolamellar carcinoma

• Received any transfusion, blood component preparation, erythropoietin, albuminpreparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior torandomization

• Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similaragents. Participants receiving prophylactic, low-dose anticoagulation therapy areeligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT ≤5 seconds above the ULN) are met

• Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g.,indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similaragents) or other antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel,dipyridamole, picotamide, indobufen, anagrelide, triflusal). Aspirin (ASA) at doses upto 100 milligrams/day (mg/day) is permitted

• Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic orpoorly controlled cardiac arrhythmia

• Any arterial thrombotic event, including myocardial infarction, unstable angina,cerebrovascular accident, or transient ischemic attack, within 6 months prior torandomization

• Uncontrolled arterial hypertension systolic ≥150 / diastolic ≥90 millimeters ofmercury (mm Hg) despite standard medical management

• Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 monthsprior to randomization requiring transfusion, endoscopic or operative intervention (participants with any bleeding episode considered life-threatening during the 3months prior to randomization are excluded, regardless of transfusion or interventionstatus)

• Esophageal or gastric varices that require immediate intervention (e.g., banding,sclerotherapy) or represent a high bleeding risk. Participants with evidence of portalhypertension (including splenomegaly) or any prior history of variceal bleeding musthave had endoscopic evaluation within the 3 months immediately prior to randomization.Participants with evidence of portal hypertension are eligible for study participationif endoscopic evaluation does not indicate esophageal or gastric varices that requireimmediate intervention or represent a high bleeding risk; however, these eligibleparticipants must receive supportive therapy (e.g., beta blocker therapy) according toinstitutional standards and clinical guidelines during study participation

• Central nervous system (CNS) metastases or carcinomatous meningitis

• History of or current hepatic encephalopathy or current clinically meaningful ascites