Background: Ramucirumab, an anti-VEGFR2 fully human monoclonal IgG1 antibody showed survival benefits in two randomized trials of 2nd line chemotherapy for advanced gastric cancer (AGC), and ramucirumab plus paclitaxel is recognized as 2nd line standard treatment. It has been suggested that sustained VEGF blockade might contribute to long-term disease control in various cancers. Methods: This randomized phase III study comparing irinotecan ± ramucirumab recruits patients with AGC from 110 institutions participating in 9 clinical trial groups in Japan. Primary endpoint is overall survival (OS), with the assumed hazard ratio of 0.77 (power of 80% and significance level of one-sided 0.05). Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, and safety. Major eligibility criteria are: 1) histologically proven gastric or esophagogastric adenocarcinoma, 2) unresectable or recurrent disease, 3) two or more lines of chemotherapy with platinum, fluoropyrimidines, taxanes, and ramucirumab (no prior use of irinotecan), 4) disease progression during prior chemotherapy containing ramucirumab, 5) age ≥ 20years, 6) performance status (PS) 0-1, 7) evaluable disease as defined in the RECIST v1.1, 8) adequate hematologic, renal, hepatic and metabolic function (including urinary protein = 0 or 1+), 9) expected survival ≥ 90 days, 10) written informed consent. Patients are randomly allocated (1:1) to ramucirumab plus irinotecan or irinotecan alone. Irinotecan is administered at a dose of 150 mg/m2, every two weeks, in both arms, and ramucirumab at a dose of 8 mg/kg is added biweekly. Status: Opened to accrual February 2017, at 31 Jan 2018, 87/400 patients have been enrolled. Clinical trial information: UMIN000023065.