Risk-adapted Therapy in HPV-positive Oropharyngeal Cancer Using Circulating Tumor (ct) HPV DNA Profiling (ReACT 2.0)

This is a phase 2 randomized, open-label clinical trial to evaluate risk for HPV driven oropharyngeal cancers by using HPV blood tests and clinical features (such as tumor stage and smoking status) to determine appropriate treatment to improve survival outcomes for participants with stage I, II, or III, HPV-associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma,. Participants will be randomized 2:1 into one of two study arms: Arm 1 Pembroluzimab vs. Arm 2 Observation. Randomization is stratified by NavDx detectability at 6 weeks post curative intent therapy: yes/no. The U.S. Food and Drug Administration (FDA) has not approved NavDx® as a method for guiding treatment decision-making for human papillomavirus (HPV)-driven oropharyngeal cancers. The U.S. Food and Drug Administration (FDA) has approved pembrolizumab as a treatment option for human papillomavirus (HPV)-driven oropharyngeal cancers. The research study procedures include screening for eligibility, in-clinic visits, urine tests, questionnaires, tumor assessment by one or more of the following standard assessment tools: X-ray, CT (Computerized Tomography) scan, MRI (Magnetic Resonance Imaging) or PET (Positron Emission Tomography) scans, blood tests (including NavDx TTMV-HPV DNA Testing), biobanking, Electrocardiogram (ECG), and tumor tissue biopsy. It is expected that about 116 people will take part in this research study.