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).

In phase I, cohorts of 3 to 6 patients will be treated with 3 fractions of RT prior to surgery. A de-escalation cohort is planned if toxicity is exceeded in Cohort 1. The types of RT (XRT and PT) will be tested sequentially. The first cohort will include XRT followed by salvage surgery and adjuvant immunotherapy. The RP2D or dose found to be safe will be decided for XRT first. The RP2D for XRT will then be the starting dose cohort for PT to ensure the dose remains safe. The highest dose found to be safe for both types of RT will be used for Phase II. The dose escalation criteria must be met at each dose level including up to 28 days post-surgical resection in order to enroll and treat pts for phase II or de-escalate to the indicated dose level.

Phase II is a two arm window of opportunity multi-center study investigating XRT or PT with PD-1 inhibition in recurrent HNSCC. The study will be conducted in two stages with 2 independent experimental arms based on a Simons 2 Stage Design. PT followed by PD-1 inhibition (Arm 1) or XRT followed by PD-1 inhibition (Arm 2) will be independently compared to a historical control group with the primary endpoint of major pathological response (MPR) and a goal of 35% of patients achieving MPR compared to a baseline of 10% with PD-1 alone. Forty total patients with recurrent HNSCC will be screened and randomized to avoid selection bias to either PT or XRT. Based on a Simon Stage 2 Design, nine patients are required for stage I. Stage II will proceed after determination of Stage I MPR.

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 <7 cm.

5. Patients must have a CPS PD-L1 of ≥1%. This may be tested on a new biopsy or archival tissue.

6. Age ≥18 years.

7. ECOG performance status ≤1 (or Karnofsky ≥70%, see Appendix A).

8. Patients must have adequate organ and marrow function as defined below:

   Platelets ≥100,000/mcL Total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN Creatinine ≤ 1.5x institutional upper limit of normal (ULN) OR glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (see Appendix B).

9. Archival tissue must be available for baseline analysis. Either a tumor block or at least 20 slides must be available.

10. Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

11. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

12. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

13. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

14. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

15. Women of child-bearing potential and men must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of pembrolizumab administration.

16. Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria (Phase I & II)

1. Patients who have metastatic disease.
2. Patients who have ongoing adverse events from prior anti-cancer therapy that would preclude completion of the proposed study treatment at the opinion of the treating investigators.
3. Patients who are receiving any other investigational agents. Patients who have received other investigational agents previously who are no longer receiving these investigational agents may be eligible at the discretion of the PI.
4. Prior treatment with PD-1 inhibitors in the last 6 months or progression on a PD-1 inhibitor at any time.
5. Autoimmune disease or other pro-inflammatory conditions other than treated stable asthma, minor allergies (such as seasonal allergies), vitiligo or hypothyroidism.
6. Active and ongoing steroid use >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.