Combining Immunotherapy Salvage Surgery & IORT Tx Persistent/Recurrent Head & Neck Cancer

This phase I trial is to find out the possible side effects of pembrolizumab and radiation therapy before and during surgery in treating patients with head and neck squamous cell cancer that remains despite treatment (persistent) or has come back (recurrent). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays or protons to kill tumor cells and shrink tumors. Giving pembrolizumab and radiation therapy before and during surgery may kill more tumor cells.

PRIMARY OBJECTIVE:

I. To evaluate the potential toxicity of immunotherapy and preoperative radiation combined with intra-operative radiation in patients with recurrent or persistent head and neck squamous cell carcinoma (HNSCC).

SECONDARY OBJECTIVES:

I. To evaluate the clinical efficacy, measured as a locoregional control rate (LCR) and progression-free survival (PFS), of immunotherapy and preoperative radiation combined with intra-operative radiation in patients with recurrent or persistent HNSCC.

II. To evaluate the pre-operative radiation dose effect (0 Gy, 2 Gy X 2, 8 Gy X 2) on anti-tumor immune response in the setting of immunotherapy in patients with recurrent or persistent HNSCC.

III. To evaluate the radiation dose effect (0 Gy, 2 Gy X 2, 8 Gy X 2) on the expression of the deoxyribonucleic acid (DNA) exonuclease Trex1.

IV. To compare the overall survival (OS) of pembrolizumab and pre and post-operative external beam radiation therapy (EBRT) plus intraoperative radiation therapy (IORT) in subjects with recurrent or persistent HNSCC.

V. To assess the overall safety and tolerability of pre-operative pembrolizumab and pre-operative EBRT and IORT plus post-operative pembrolizumab versus pre-operative pembrolizumab plus IORT and post-operative pembrolizumab in subjects with with recurrent or persistent HNSCC.

VI. To evaluate whether PD-L1 expression is a predictive biomarker for LCR and PFS.

VII. To evaluate whether TNF-alpha expression is a predictive biomarker for LCR and PFS.

VIII. To evaluate whether NFkappaB expression is a predictive biomarker for LCR and PFS.

IX. To evaluate whether tumor mutational burden is predictive of immunotherapy response.

X. To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-HN35.

EXPLORATORY OBJECTIVES:

I. To evaluate associations between gene expression status of tumor samples and clinical efficacy (LRC, PFS and overall survival \[OS\]).

II. To evaluate whether mutational burden is a predictive biomarker for LCR and PFS.

III. To explore potential biomarkers associated with clinical efficacy (LRC, PFS, and OS) by analyzing circulating tumor DNA quantitative load with polymerase chain reaction (PCR), chemokines/cytokines and immune cells (e.g. CD8+ T cells, regulatory T cells \[Tregs\], myeloid derived suppressor cells \[MDSCs\]) with FACS in blood, tumor tissue and correlating those with clinical outcomes.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) on day 1 of week 1, and undergo salvage surgery during week 4. Beginning week 8, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo intraoperative radiation therapy (IORT) for 1 fraction during week 9. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

ARM B: Patients receive pembrolizumab IV on day 1 of week 1, and undergo low dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

ARM C: Patients receive pembrolizumab IV on day 1 of week 1, and undergo high dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

After completion of study treatment, patients are followed up at 90 and 180 days, then every 90 weeks for 24 months, and then every 6 months up to year 5.

Eligibility Criteria:
Inclusion Criteria:

* Pathologically confirmed either persistent and/ or locoregionally recurrent HNSCC of oral cavity, pharynx, larynx, unknown primary head and neck (H\&N) squamous cell carcinoma
* Resectable disease as determined by the surgeon and team
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) \< 2
* At least 18 years of age
* Adequate hematologic, renal, and hepatic function
* Must have at least 2 week washout period from prior therapy
* Willingness and ability to provide informed consent
* Negative pregnancy test for females of reproductive potential
* Patients who have undergone therapy for their cancer, such as surgery and/or chemotherapy and/or radiotherapy and recurred
* Disease measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria.
* Prior definitive and palliative chemotherapy will be allowed
* Prior radiation therapy will be allowed
* Tumor tissue from resected site of disease must be provided for biomarker analyses, in addition to urine and blood sample as scheduled per protocol
* White blood cell (WBC) \>= 2000/uL (obtained within 14 days of randomization)
* Neutrophils \>= 1500/uL (obtained within 14 days of randomization)
* Platelets \>= 100 x10\^3/uL (obtained within 14 days of randomization)
* Hemoglobin \> 9.0 g/dL (obtained within 14 days of randomization)
* Serum creatinine =\< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) \>= 40 mL/min (Cockcroft and Gault or Wright formula may be used according to local practice) (obtained within 14 days of randomization)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x institutional ULN
* Total Bilirubin =\< 1.5 x institutional ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
* Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for four months after the last dose of pembrolizumab.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\])
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of four months after the last dose of investigational product

Exclusion Criteria:

* Requirement of immunosuppressive therapy within 14 days of randomization
* Salivary gland carcinomas, lip carcinoma, adenocarcinoma of the skin
* Prior use of immune checkpoint blockade agent
* History of human immunodeficiency virus (HIV), hepatitis B, C: Participants who test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection, those who test positive for human immunodeficiency virus (HIV) or have known acquired immunodeficiency syndrome (AIDS)
* Unresectable disease, as determined by the surgeon and team
* Subjects with history of grade 3 toxicity with prior immunotherapy
* Patients with distant metastases
* Subjects with active autoimmune disease
* Breastfeeding women
* Additional prior malignancy within the previous 3 years (treated or untreated, except for skin carcinomas treated with excision alone and carcinoma in situ of the cervix)
* Palliative radiotherapy less than 14 days prior to first dose of study drug
* Any history of hypersensitivity to any of the trial medications
* Poorly controlled or serious medical or psychiatric illness likely to interfere with participation and/or compliance in this clinical trial
* Prisoners or subjects who are involuntarily incarcerated
* Patients not available for follow-up/future contact as defined in the ICF
* Note: Patients on this protocol are not excluded from participation in other clinical trials