Background: Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor (PD-1) thereby preventing reduction in the number and efficacy of activated T-cells. Tremelimumab is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) thereby resulting in enhanced T-cell activation and anti-tumour activity. Monotherapy with the anti-PD-1 agent pembrolizumab has demonstrated significant activity in CRC pts with tumours demonstrating microsatellite instability (MSI-H). Inhibiting PD-1/PD-L1 alone is likely of limited benefit in advanced CRC as only 5% of pts are MSI-H. Targeting both PD-L1 and CTLA-4 may have additive or synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition will lead to improved patient survival vs BSC alone in advanced CRC, regardless of MSI status. Methods: This randomized phase II study (ClinicalTrials.gov NCT02870920) will assess the efficacy and safety of D+T vs BSC in pts with metastatic or advanced, unresectable, refractory CRC (n = 180). Pts have failed standard chemotherapy based regimens containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor, if Ras wild type) and no other therapeutic options. Pts are randomized in a 2:1 ratio to receive D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival; secondary endpoints include progression free survival, safety, overall response rate and quality of life. Analysis will be according to randomized group stratified by ECOG PS (0 vs 1) and site of tumour (right vs transverse vs left vs rectum). In addition, blood, plasma, and archival tissue will be collected and assessed for potential prognostic and predictive biomarkers, including tumour MSI status. As of February 1 2017, 20 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02870920