This is an open-label, phase 1/2, multiple-indication platform study to explore safety, potential predictive immune-related biomarkers, and early efficacy (as measured by objective response rate [ORR; Cohorts 1,2, 4,and 5] and disease control rate [DCR; Cohort 3]) in patients with advanced or metastatic gastrointestinal (GI) tumors. Cohorts 1-4 are not randomized; however, Cohort 5 is comprised of two treatment arms to which patients are randomized in a 1:1 ratio.

The overall aim is to assess safety, predictive biomarkers, and preliminary efficacy as assessed by tumor response criteria at week 16 for cohorts1, 2, 3, and 4, and best overall response rate and OS in Cohort 5. If a cohort shows a promising ORR in Stage 1 of the Simon two-stage design, that cohort may be expanded to enroll additional patients (up to 50 patients in Cohorts 1 and 3 , up to 28 patients in Cohort 4, and up to 64 patients in Cohort 5) in an extension phase per predetermined statistical conditions. In addition, either or both arms of Cohort 5 may expand if the data collected in Stage 1 suggest that expansion may help in assessing the potential survival benefit of the investigational therapy(ies). In this study, we hypothesize that treatment with pelareorep will prime the tumor microenvironment (TME) for checkpoint blockade therapy, thereby increasing PD-L1 expression and the number of new T cell clones within the tumor, both of which are associated with increased response to checkpoint blockade.

Cohorts 1-5 Inclusion Criteria:

• ECOG performance status of 0 or 1
• Have measurable lesions per RECIST v1.1
• Patients must have adequate hematological, renal, and hepatic function
• Have recovered to ≤grade 1 or baseline for all adverse events (AEs) due to previous therapies or surgeries.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly-effective form(s) of contraception and to continue its use for 6 months after the last dose of study drug.

Exclusion Criteria:

• Undergone systemic chemotherapy, radiotherapy, or surgery, <4 weeks before study treatment.
• Received previous treatment with immune checkpoint inhibitors
• Uncontrolled or severe cardiac disease
• Active, uncontrolled infections
• Symptomatic brain metastasis
• Interstitial lung disease with symptoms or signs of activity.
• Autoimmune disease that has required systemic treatment in the past 2 years with disease modifying agents, corticosteroids, or immunosuppressive drugs.
• A seizure disorder that requires pharmacotherapy.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
• A non-healing wound, non-healing ulcer, or non-healing bone fracture within 4 weeks prior to the start of study drug.
• Women who are pregnant or breastfeeding.
• A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy
• Any vaccine within 28 days prior to first treatment or during the first cycle of study treatment.

Exclusion Criteria:

• In Cohort 1, 2, 3, 4: Life expectancy less than 3 months
• In Cohort 1, 2, 3: known active Hepatitis B (HBV) or Hepatitis C (HCV) infection that requires anti-viral treatment.
• In Cohort 4: Prior HIV infection if the CD4+ T cell is <300 cells/µl
• In Cohort 5: Known low or absent dihydropyrimidine dehydrogenase (DPD) activity.
• In Cohort 5: Known leptomeningeal disease.
• In Cohort 5: History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ