Background: Immune therapies benefit only the small subset of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients who have microsatellite instability-high (MSI-H) tumors (approximately 1%). Most PDAC tumors are microsatellite stable (MSS) and have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make most mPDAC tumors resistant to conventional immunotherapy including checkpoint inhibitors. Pelareorep is a naturally occurring, non-genetically modified reovirus that selectively infects cancer cells following intravenous administration. Upon infection, pelareorep’s double-stranded RNA genome stimulates a pro-inflammatory response that primes tumors for immunologic killing. This includes increased T cell infiltration into tumors, expansion of tumor-infiltrating lymphocyte clones, increased PD-L1 expression, and stimulation of tumor-directed innate and adaptive immune responses. Pelareorep combined with chemotherapy, checkpoint inhibitors, or both has shown promising efficacy in several malignancies, including mPDAC. This study is designed to evaluate pelareorep plus modified FOLFIRINOX with or without the PD-L1 inhibitor atezolizumab as first-line therapy in patients with mPDAC. Methods: This trial represents a new cohort within the ongoing GOBLET signal finding platform study in gastrointestinal cancers. This is a phase 1/2 randomized, open-label study that uses a screened selection design within a Simon two-stage approach. Eligible patients must be 18 years or older and have newly diagnosed, radiologically evaluable mPDAC with no prior chemotherapy and an ECOG performance status of 0 or 1. Patients are randomized 1:1 to receive either pelareorep + mFOLFIRINOX orpelareorep + mFOLFIRINOX + atezolizumab. The first stage enrolls 15 evaluable patients into each arm. If pre-specified efficacy criteria are met in Stage 1, one or both arms may be expanded to Stage 2 and enroll 17 additional evaluable patients per arm. The first 3-6 patients enrolled into both arms comprise a safety run-in that must be successfully concluded prior to enrolling additional patients. The treatment period consists of 4-week treatment cycles. The primary objectives are 1) safety and tolerability of pelareorep + mFOLFIRINOX with or without atezolizumab and 2) efficacy based on objective response rate per RECIST v1.1. Secondary objectives include duration of response, progression-free survival, and overall survival. In addition, tumor and blood samples are being collected to evaluate the immunological effects of treatment and to explore potential biomarkers of response. Clinical trial information: Eudra-CT: 2020-003996-16.