Background: Angiogenesis and aberrant MET signaling are implicated in the pathogenesis and progression of invasive biliary tract cancers (BTC), including adenocarcinomas of the gallbladder, intra- and extra-hepatic bile ducts, and ampulla of Vater. JSBF (NCT02711553) is a phase II, multicenter, randomized, and double-blinded study, designed to evaluate the efficacy and safety of standard of care (SOC) gemcitabine and cisplatin in combination with either ramucirumab (human IgG1 VEGFR2 monoclonal antibody) or merestinib (oral type II MET kinase inhibitor) or respective placebo for the first-line treatment of advanced or metastatic BTC. Methods: Eligible patients with advanced or metastatic BTC will be randomized to oral merestinib 80 mg, oral placebo, intravenous (IV) ramucirumab 8mg/kg, or IV placebo, in a 2:1:2:1 fashion. Randomization will be stratified by primary tumor site, presence of metastases, and geographic region. In addition to the randomly assigned treatment, all patients will receive SOC first-line treatment with up to 8 cycles of IV gemcitabine 1000mg/m² + cisplatin 25mg/m² on days 1 and 8 of 21-day cycles. IV ramucirumab and placebo will be given on days 1 and 8 of each cycle; oral treatments will be taken daily. Investigational treatment or placebo may continue past 8 cycles until disease progression or a criterion for discontinuation is met. The primary endpoint is progression-free survival, by intention-to-treat analysis. Target enrollment is 300 patients with primary analysis at 210 events to detect potential superiority of each investigational treatment over pooled control. Secondary endpoints are overall survival, objective response, disease control rate, safety, pharmacokinetics, immunogenicity (ramucirumab), and patient reported outcomes. An exploratory endpoint is to correlate biomarkers with safety and clinical outcome; blood, plasma, serum, and tumor tissue collection is mandatory. The study began in May 2016. Clinical trial information: NCT02711553