Stereotactic Body Radiation Therapy and Durvalumab With or Without Tremelimumab Before Surgery in Treating Participants With Human Papillomavirus Positive Oropharyngeal Squamous Cell Caner

This phase Ib/II trial studies the side effects and how well stereotactic body radiation therapy and durvalumab with or without tremelimumab before surgery work in treating participants with human papillomavirus positive oropharyngeal squamous cell cancer. Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy and durvalumab with or without tremelimumab before surgery may work better in treating participants with oropharyngeal squamous cell cancer.

PRIMARY OBJECTIVES: I. To determine the safety and tolerability associated with the following treatment regimens: Cohort 1: stereotactic body radiation therapy (SBRT) and durvalumab, followed by transoral robotic surgery (TORS) and adjuvant durvalumab and cohort 2: SBRT and durvalumab + tremelimumab, followed by TORS and adjuvant durvalumab. (Phase I safety lead-in) II. To assess the efficacy of the treatment combination deemed safe from Phase I in terms of progression free survival, in order to determine the non-inferiority of tumor control (progression-free survival \[PFS\] of 85% at 2 years) compared to conventional large field adjuvant radiotherapy +/- concurrent chemotherapy. (Phase II) III. To determine Common Terminology Criteria for Adverse Events (CTCAE) grade 3+ acute and chronic toxicities at the end of radiation, after surgery, at the end of adjuvant immunotherapy infusion, at 3 month, at 6 month, at 1 year, and at 2 years. (Phase II) SECONDARY OBJECTIVES: I. To determine the objective response rate to durvalumab +/- tremelimumab + SBRT prior to TORS. II. To determine the rate of subclinical lymph node involvement at time of TORS and neck dissection. III. To determine the rate of contra-lateral neck failure with medial oropharyngeal and base of tongue primary lesions. IV. To determine the potential salvage rate. V. To determine the locoregional control, distant control, and overall survival. VI. To determine the incidence of all toxicity associated with treatment protocol. VII. To determine the short- and long-term quality of life of patients on protocol. TRANSLATIONAL OBJECTIVES: I. To evaluate the impact of KRAS gene-variant mutation on immune response and treatment outcome. II. To evaluate the impact of PI3K gene mutation on immune response and treatment outcome. III. Saliva samples to evaluate biomarkers for immune response to human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) to be collected prior to treatment, at time of TORS, and at each yearly follow-up visit. IV. Blood samples to evaluate biomarkers of immune response to HPV associated OPSCC to be collected prior to treatment, at time of TORS, and at each yearly follow-up visit. V. Tumor tissue taken at the time of initial biopsy and at time of resection will be profiled for tumor infiltrating lymphocytes; activation markers and antigen specific T-cell receptor (TCR) utilization/diversity will be evaluated for additional checkpoint targets. VI. On long-term follow-up, tumor antigen specific T lymphocyte memory populations will be monitored for representation and robustness in in-vitro stimulation assays as potential biomarker of continued anti-tumor activity. VII. Immortalization of tumor infiltrating B-cells for identification of antigen presenting complex, antibody specificity, and potential serologic markers of continuing long-term immune response in patients. OUTLINE: Participants are assigned to 1 or 2 cohorts. COHORT I: Beginning day 0 of course 1, participants undergo stereotactic body radiation therapy 5 days a week for 1 week and receive durvalumab intravenously (IV) over 1 hour on days 0 and 27 in the absence of disease progression or unacceptable toxicity. Participants then undergo transoral robotic surgery and modified radical neck dissection between weeks 6-8. Beginning week 12, participants then receive durvalumab IV over 1 hour every 4 weeks. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. COHORT II: Beginning day 0 of course 1, participants undergo stereotactic body radiation therapy 5 days a week for 1 week and receive tremelimumab IV and durvalumab IV over 1 hour on days 0 and 27 in the absence of disease progression or unacceptable toxicity. Participants then undergo transoral robotic surgery and modified radical neck dissection between weeks 6-8. Beginning week 12, participants then receive durvalumab IV over 1 hour every 4 weeks. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up every 12 weeks for 2 years and then periodically thereafter.