Background: The majority of gastric cancer (GC) patients fail to derive sufficient benefit from currently available therapies. Pembrolizumab received accelerated approval in 2017 as a third-line therapy in PD-L1 positive GC patients with an ORR of 13.3%. Further studies in second- and third-line GC patients showed comparable outcomes when pembrolizumab was combined with chemotherapy. Bavituximab, an investigational, chimeric monoclonal antibody designed to inhibit the immunosuppressive effects of phosphatidylserine (PS), is being evaluated in combination with pembrolizumab in patients with advanced gastric and gastroesophageal junction (GEJ) cancer. Bavituximab binds in a high-affinity complex with β2-glycoprotein and PS to reverse immunological non-responsiveness and activate multiple immune cell receptors, including TIMS and TAMS. Data from the Phase III Sunrise second-line lung cancer study indicated that patients who progressed on study treatment with bavituximab plus docetaxel and continued with a checkpoint inhibitor showed significantly improved overall survival. Cumulative data suggest that bavituximab may potentiate pembrolizumab-mediated checkpoint inhibition, potentially increasing overall clinical benefit. Methods: This phase 2, multicenter, open-label, single-arm global study is designed to assess the safety, tolerability and efficacy of the bavituximab-pembrolizumab combination in advanced gastric or GEJ adenocarcinoma patients, regardless of PD-L1 status, who have progressed on or after at least one prior standard therapy. Patients must be treatment naïve for checkpoint inhibitors. The study, started in August 2019, consists of an initial 3+3 de-escalation safety cohort to confirm the expansion cohort dose. A total of 80 patients will be enrolled. Primary endpoints will assess antitumor activity of the treatment combination on objective response rate using RECIST1.1, safety and tolerability. Secondary endpoints will evaluate antitumor characteristics, pharmacokinetics, and immunogenicity. Exploratory objectives include the evaluation of a novel biomarker signature panel and its relationship to efficacy outcomes.