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Background: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer., Methods: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing., Findings: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1])., Interpretation: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests JWV reports personal fees from Agios, AstraZeneca, Debiopharm, Delcath Systems, Genoscience Pharma, Imaging Equipment, Incyte, Ipsen, Keocyt, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pieris Pharmaceuticals, QED, and Wren Laboratories; personal fees and non-financial support from Pfizer; grants and personal fees from Servier; and grants, personal fees, and non-financial support from NuCana, outside of the submitted work. AV reports personal fees from Eli Lilly and Company, during the conduct of the study; and personal fees from Roche, AstraZeneca, EISAI, Bayer, Merck, Bristol Myers Squibb, Merck Sharp & Dohme, Incyte, PierreFabre, Ipsen, and Sanofi, outside of the submitted work. CSD reports honoraria from Bristol Myers Squibb, Merck Zymeworks, BeiGene, Taiho Onoclogy, Exelixis, Eli Lilly and Company, Astellas, and Bayer; grants and personal fees from Bristol Myers Squibb, Zymeworks, Beigene, and Exelixis; personal fees from Merck, Taiho Oncology, Eli Lilly and Company, Astellas, and Bayer; grants and non-financial support from AstraZeneca; and grants from Amgen, Agios Pharmaceuticals, Array BioPharma, Genmab, Macrogenics, and Merrimack Pharmaceuticals, outside of the submitted work. J-SC reports grants from Eli Lilly and Company, Ono Pharmaceutical, Janssen, AstraZeneca, Merck KGaA, Astellas Pharma, Senhwa Biosciences, and Syncore, outside of the submitted work. EVC reports consulting fees from Array, Astellas, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; and grants from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier paid to the institution, outside of the submitted work. L-TC reports grants from Ministry of Science and Technology, Taiwan, Ministry of Health and Welfare, Taiwan, Pfizer, GlaxoSmithKline, Merck Serono, OBI, and Polaris; personal fees from Eli Lilly and Company, PharamEngine, Shire, Merck Sharp & Dohme, Bristol Myers Squibb, ONO, and Five Prime; grants and non-financial support from Celgene; and grants, personal fees, and non-financial support from Novartis, TTY, and Syncore, outside of the submitted work. HW reports personal fees and non-financial support from CELGENE; non-financial support from AstraZeneca; personal fees and honoraria from Incyte; grants, personal fees, and consulting from SIRTEX medical; personal fees from and advisory board for Zymeworks; and personal fees from BTG, outside of the submitted work. L-YB reports funding related to the JSBF clinical trial from Eli Lilly and Company, during the conduct of the study. RC was employed by Eli Lilly and Company, during the conduct of the study; and is a shareholder of Eli Lilly and Company, outside of the submitted work. RAW reports employment with and stock ownership in Eli Lilly and Company, during the conduct of the study; and has patents pending related to clinical use of merestinib and ramucirumab. ACG, WZ, JL, CT, PJE, AA, SCM, and BAM were employees and shareholders of Eli Lilly and Company, during the conduct of the study. JMO was an employee of Eli Lilly and Company, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)