Background: PT886 is a novel bispecific antibody that targets Claudin 18.2 (CLDN18.2) and CD47. CLDN18.2 is overexpressed in a significant proportion of gastric and pancreatic adenocarcinomas and its restricted expression makes it a promising therapeutic target for the treatment of these carcinomas. Moreover, studies have found that immunoglobulin superfamily CD47 is overexpressed widely across tumor types, and CD47 plays an important role in suppressing phagocytes activity through binding to the transmembrane protein SIRPα in phagocytic cells. Hence, by targeting both pathways, one can direct macrophage-mediated phagocytotic activity to tumor cells by blocking the “don’t eat me” signal mediated by CD47/ SIRPα interaction, potentially offering a better safety profile than anti-CD47 monoclonal antibodies. Additionally, PT886 utilizes IgG1 to enhance antibody-dependent cellular cytotoxicity (ADCC) by NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages and thus increases the antitumor activity. The combined cancer killing effects by the above mechanisms therefore represent a novel approach in treating CLDN18.2-positive malignancies. Methods: This is an open label, Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PT886 in subjects with unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC) for which there is no available standard therapy. Approximately 34-58 patients will be enrolled. The study consists of 2 parts: Dose Escalation, and Dose Expansion. The dose escalation study of PT886 will be guided by a standard 3+3 dose escalation study design to determine the maximum tolerated dose (MTD) and/or the optimal biological doses for expansion. The MTD or the optimal biological dose and a lower dose level will be further evaluated in a dose expansion cohort to determine a recommended phase II dose (RP2D). Each enrolled patient will receive PT886 as a monotherapy (0.1, 0.3, 1, 3 or 6 mg/kg QW) as an intravenous infusion continuously (over 60 minutes) in 28-day cycles. The primary endpoints are Dose Limiting Toxicity (DLT) and MTD, if reached, and RP2D of PT886 as a single agent. PD markers of PT886 biological activity will be measured, including T-cell receptor sequencing on circulating T cells, T-cell activation studies, serum cytokines and assessing CLDN18.2 expression in tumor tissues. PT886, which was recently granted orphan drug designation by the FDA for the treatment of pancreatic cancer, has the potential to be a new treatment option for pancreatic and gastric cancer patients whose current standard of care is limited. Preliminary safety and efficacy data are anticipated in the second quarter of 2023. Clinical trial information: NCT02178241.