Background: Checkpoint blockade therapy only benefits a small subset of GI cancer patients (approximately 4%) with microsatellite instability-high (MSI-H) tumors, which are characterized as immunologically ‘hot’ (Bonneville et al., 2017). Most GI cancers, however, have microsatellite stable (MSS) tumors, which have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make MSS tumors resistant to conventional immunotherapy including checkpoint blockade therapy (Ooki et al., 2021). Pelareorep is a naturally occurring, non-genetically modified reovirus. Upon intravenous administration, pelareorep selectively kills tumor cells and promotes several immunologic effects that prime tumors to respond to checkpoint blockade. These include the stimulation of tumor-directed innate and adaptive immune responses, increased T cell infiltration, expansion of new T cell clones, and increased PD-L1 expression in tumors (Samson et al., 2018, Manso et al. 2021 AACR). Given its expected synergy with checkpoint blockade, as well as its encouraging efficacy in prior GI cancer studies (Mahalingam et al. 2020), the GOBLET study is designed to evaluate pelareorep plus atezolizumab in multiple GI cancer indications. Methods: GOBLET is an open-label, non-randomized, multiple-cohort, phase 1/2 study in patients with advanced or metastatic GI cancers. This study employs a Simon two-stage design. Stage 1 comprises four treatment groups: Cohort 1 – First-line pancreatic cancer treated with pelareorep plus atezolizumab and chemotherapy (gemcitabine and nab-paclitaxel) (N = 12); Cohort 2 – First-line MSI-H colorectal cancer (CRC) treated with pelareorep plus atezolizumab (N = 19); Cohort 3 – Third-line CRC treated with pelareorep plus atezolizumab and chemotherapy (trifluridine/tipiracil) (N = 14); and Cohort 4 – Second-line or later squamous cell carcinoma of the anal canal treated with pelareorep plus atezolizumab (N = 10). The first 3-6 patients enrolled into the chemotherapy-containing cohorts (Cohorts 1 and 3) comprise a safety run-in that must be successfully concluded prior to enrolling additional patients into these cohorts. The primary objectives are safety and efficacy based on objective response rate (ORR) at week 16. Any cohort showing a promising ORR in Stage 1, based on pre-specified criteria, may be advanced to Stage 2 and enroll additional patients. Clinical trial information: 2020-003996-16.