Background: Colon cancer with deficient mismatch repair (dMMR) and POLE mutations are characterised by a high tumor mutational burden (TMB) and an immunogenic lymphocyte infiltrate. Approximately 12% of stage III colon cancer have dMMR. POLE mutations occur in 1% of colon cancers, but is enriched in patients <50 years of age. Colon cancer with high TMB have demonstrated to be sensitive to immune checkpoint inhibition in the metastatic setting. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody, avelumab following adjuvant chemotherapy can improve disease free survival (DFS) in patients with stage III colon cancer with dMMR or POLE mutations. Methods: We are recruiting patients with curatively resected, stage III colon cancer which are dMMR or have a centrally confirmed POLE exonuclease domain mutation. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (CAPOX [capecitabine, oxaliplatin] for 12 weeks or capecitabine for 24 weeks) or chemotherapy followed by avelumab (10mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life, and health resource use. Exploratory objectives will investigate circulating, tumor and stool based biomarkers of avelumab benefit. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (i.e. 87%). Target accrual is 402 patients which provides 80% power to detect a hazard ratio of 0.48 for DFS at a two–sided alpha of 0.05. This trial is a national, multi-centre phase III trial and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. Clinical trial information: NCT03827044