Phase I/ II Trial Combining PD-1 Inhibition and Neoadjuvant Proton or Photon Radiation Therapy in Recurrent Head and Neck Squamous Cell Carcinoma

The purpose of the Phase I study is to see if it is safe to use X-ray photon radiation (XRT) and proton radiation (PT) before surgery in patients with recurrent head and neck squamous cell carcinoma (rHNSCC). The purpose of the Phase II study is to see if using XRT or PT before immunotherapy (pembrolizumab) prior to surgery benefits patients with recurrent head and neck squamous cell carcinoma (rHNSCC).

Inclusion Criteria (Both Phase I and Phase II) 1. Patients must have histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma including oral cavity, laryngeal, hypopharyngeal, or oropharyngeal (HPV-) SCC. 2. Patients must be a candidate for salvage surgical resection. 3. Patients must have failed prior RT \>6 months prior to recurrence with at least 30 Gy delivered to the current target volume. 4. Disease must be limited to a single site or adjacent sites that can be treated in a single contiguous target volume for which the maximum total tumor dimension (GTV) must be \10 mg prednisone, except for non-systemically absorbed treatments (such as inhaled or topical steroid therapy for asthma, COPD, allergic rhinitis). 7. Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous, in the opinion of the Investigator. 8. Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with breastfeeding should be discontinued if the mother is treated with pembrolizumab.