This is an open-label, randomized, multicenter Phase 2 study to assess the efficacy and safety of FOLFIRI + bevacizumab + pelareorep vs. FOLFIRI + bevacizumab in patients with RAS-mutated, MSS mCRC who have progressed after one prior line of oxaliplatin-based therapy.

Approximately 60 patients will be randomized 1:1 to the following study arms:

• Arm A: FOLFIRI + bevacizumab + pelareorep
• Arm B: FOLFIRI + bevacizumab The primary endpoint is ORR as assessed by the investigator per RECIST 1.1. OS, PFS, and assessment of the safety and tolerability of the study treatment combinations are secondary endpoints. The primary endpoint analysis will be performed after all patients have had at least one tumor assessment following initiation of study treatment or have progressed. The secondary endpoint analyses will take place at EOS.

Inclusion Criteria:

• Histologically confirmed cancer of the colon or rectum with documented metastasis
• Measurable disease per RECIST v. 1.1
• Not candidates for curative surgery or curative radiation
• Progressed on, or been intolerant to, a first-line, oxaliplatin-based chemotherapy regimen in the metastatic setting or relapsed within 6 months of completing adjuvant oxaliplatin
• Considered medically eligible to receive standard of care (SOC) FOLFIRI with bevacizumab
• Non-microsatellite instability high or non-deficient mismatch repair (non-MSI-H/non dMMR) tumor status per a standard local testing method
• Tumor confirmed to harbor a known RAS mutation per a standard local testing method
• ECOG performance status of 0 or 1
• Patients must have adequate hematological, renal, and hepatic function
• Female patients of childbearing potential must have a negative pregnancy test
• Life expectancy of at least 6 months

Exclusion Criteria:

• Undergone systemic chemotherapy, radiotherapy, or surgery, <4 weeks before study treatment
• Ongoing AEs of Grade ≥2 that are related to anti-cancer treatment
• Prior treatment with irinotecan
• Symptomatic brain metastases
• Active autoimmune disease
• Receiving immunosuppressive or myelosuppressive medications
• Active, uncontrolled infections
• Known HIV infection or active hepatitis B or C that requires anti-viral treatment
• History of another primary cancer within the last 3 years except for non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ
• History of allergy or known hypersensitivity to any of the study drugs, study drug classes,
• Uncontrolled or severe cardiac disease
• Received any vaccine within 28 days prior to first study treatment