A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib

* ECOG PS of 0 or 1
* Child-Pugh score of 9 (Child-Pugh A or B [B7 or B8])
* BCLC stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy
* diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation
* There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis
* The patient has a liver mass measuring at least 2 cm with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium.
* The patient has a serum alpha-fetoprotein (AFP) concentration greater than the institutional upper limit of normal (ULN).
* At least 1 measurable or evaluable lesion that is viable (ie, is vascularized), and has not been previously treated with
locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable
progression following locoregional therapy.
* Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Patients may have experienced
* Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
* Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC
* The patient has received sorafenib as the only systemic therapeutic intervention for advanced HCC. Any hepatic locoregional therapy that has been;administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone) following sorafenib therapy is permitted.;* Except where otherwise noted in the eligibility criteria, the patient has a resolution to grade * 1 by the NCI-CTCAE v. 4.0 of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization or sorafenib. ;Adequate organ function defined as:;* Total bilirubin < 3.0 mg/dL (51.3 *mol/L), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) * 5 × ULN;;* Serum creatinine * 1.2 × ULN or calculated creatinine clearance > 50 mL/minute;;* Absolute neutrophil count (ANC) * 1.0 × 10exp3/*L (1.0 × 10exp9/L), hemoglobin * 9 g/dL (5.58 mmol/L), and platelets * 75 × 10exp3/*L (75 × 10exp9/L);;* International Normalized Ratio (INR) * 1.5. Patients receiving prophylactic low dose anticoagulant therapy are eligible provided that INR * 1.5.;* The patient's urinary protein is * 1+ on dipstick or routine urinalysis.;If urine dipstick or routine analysis indicates * 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.;* The study population is limited to patients with Child- Pugh Class A score without a history of hepatic encephalopathy or clinically meaningful ascites. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis

* Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization. ;* Hepatic locoregional therapy within 28 days prior to randomization. ;* Radiation to any nonhepatic (eg, 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 to randomization or is concurrently enrolled in any other type of medical research judged not to;be scientifically or medically compatible with this study. ;* 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, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization. ;* Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR * 1.5) are met. ;* Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal).Aspirin (ASA) at doses up to 100 mg/day is permitted. ;* Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia. ;* Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization. ;* Uncontrolled arterial hypertension * 150 / * 90 mm Hg despite standard medical management. ;* Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (patients with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status). ;* Esophageal or gastric varices that require immediate intervention (eg, banding, sclerotherapy) or represent a high bleeding risk. Patients with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Patients with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, these eligible patients must receive supportive therapy (eg, beta blocker therapy) according to institutional standards and clinical guidelines during study participation. ;* Central nervous system (CNS) metastases or carcinomatous meningitis. ;* Exclude patients with Child-Pugh Class B score.;*The study (Ramucirumab or placebo) should be discontinued in patiens with new occurrence of hepatic encephalopathy and/or hepatorenal syndrome. Following discontinuation of study drug for either of these 2 reasons, retreatment with study drug will not be permitted.