Background: Ramucirumab (Ram) is a human IgG1 monoclonal antibody that inhibits ligand activation of the vascular endothelial growth factor receptor 2 (VEGFR2). The Phase 3 REACH study assessed Ram in the treatment of patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib. Ram was well tolerated. A significant improvement in overall survival (OS) in the overall population (N = 565) was not demonstrated (Hazard Ratio [HR] = 0.866; p = 0.1391). However, a meaningful improvement in OS was observed in the pre-specified subgroup of patients with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (N = 250)(HR = 0.674; p = 0.0059) and warrants confirmation. Methods: REACH-2 is a randomized, double-blind, placebo-controlled phase III study of Ram and best supportive care (BSC) versus placebo and BSC in patients with HCC and elevated baseline AFP following prior therapy with sorafenib. Eligible patients will be randomized 2:1 to receive Ram (8mg/kg, IV) or placebo on Day 1 of each 14-day cycle until disease progression or other discontinuation criteria. Eligible patients must have a diagnosis of HCC (tissue or tumor with classical imaging characteristics); prior sorafenib; Child-Pugh score < 7; Barcelona Clinic Liver Cancer Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥ 400 ng/mL; ECOG performance status < 2. Patients with history of encephalopathy, ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. The primary objective is to assess the OS for patients treated with Ram versus placebo, and assumes an OS HR of 0.7 (85% power; 2 sided type I error 0.05). Target enrollment is 399 patients with the primary analysis at 318 events (20% censoring). Secondary objectives include progression free survival, objective response rate, safety, and patient focused outcomes. Additional objectives include assessment of biomarkers relevant to angiogenesis and HCC. Clinical trial information: NCT02435433