Background: When surgery is used as the primary therapeutic modality for locally-advanced HNSCC, radiation therapy (XRT) is frequently recommended post-operatively due to high rates of recurrence. In high-risk patients; i.e., those with positive surgical margins or extra-nodal extension (ENE) on surgical pathology, the addition of chemotherapy to post-operative XRT (cCRT) provides a survival benefit. In contrast, there is no standard indication for adjuvant systemic therapy in intermediate risk HNSCC—defined in this study as having a T3/T4 primary tumor, perineural or lymphovascular space invasion, and/or lymph node metastasis without ENE. The anti-programmed cell death-ligand 1 (PD-L1) antibody durvalumab (D) has a manageable safety profile and encouraging clinical activity studies across multiple tumor types. Combining D with the anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody tremelimumab (T) may amplify antitumor T-cell responses and provide synergistic activity. D+T showed antitumor activity and manageable tolerability in advanced NSCLC. Furthermore in preclinical studies, D+T combined with XRT decreased regulatory T-cells and myeloid derived suppressor cells and increased CD8 T-cell recruitment to the tumor microenvironment. Methods: This two-part phase I study will include a safety run-in period using a 3+3 dose de-escalation design based on dose limiting toxicities (DLT). In Cohort 1, D (q3 weeks) +T (q3 weeks) will be given on cycle 1 followed by concurrent XRT for Cycles 2-4. Cycle 5 and 6 will include D only. If DLT’s are met, Cohort -1 will include D (q3 weeks) and T (q6 weeks). If DLT's are found in Cohort -1, Cohort -2 would include only D. A dose expansion cohort (N=24) will follow based on the safest combination in the safety run-in. Translational studies include correlation of pre-treatment immune characteristics including PD-L1 score, TMB, and IFN-gamma signature with disease free survival. DNA and RNA sequencing of pre-treatment tissue and at treatment failure/recurrence will attempt to identify genetic and molecular determinants of IO treatment resistance. (NCT02000947). Clinical trial information: NCT03529422