"QUAD SHOT" Radiotherapy With Pembrolizumab in Patients With Recurrent Head & Neck Cancer

Inclusion Criteria:

1. Age 18 years and older

2. Written informed consent and any locally-required authorization obtained from thepatients prior to performing any protocol-related procedures, including screeningevaluations

3. Pathologically (histologically or cytologically) proven diagnosis of squamous cellcarcinoma of the head and neck (nasopharynx, oral cavity, oropharynx, hypopharynx,larynx, or unknown primary).

4. Locally recurrent or metastatic HNSCC not deemed amenable to curative-intent salvagetherapy, in whom at least six months have passed since their prior RT, if received.

5. Must have evaluable lesion per RECIST v1.1

6. Patients agree to provide their smoking history prior to registration

7. ECOG performance status of 0-2

8. Adequate bone marrow: absolute neutrophil count ≥ 1,500/μl, platelets ≥ 100,000/μl,hemoglobin ≥ 9 g/dL

9. Adequate hepatic function: total bilirubin ≤ 1.5 X upper normal limit (UNL) (exceptsubjects with Gilbert syndrome, who can have total bilirubin < 3 mg/dl), aspartateaminotransferase (AST) ≤ 2.5 X UNL, alanine aminotransferase (ALT) ≤ 2.5 X UNL

10. Adequate renal function: calculated serum creatinine clearance >40 mL/min by theCockcroft-Gault formula or by 24-hour urine collection or Serum creatinine less thanor equal to 1.5 x upper limit of normal (ULN)

11. Female patients of reproductive potential and their male partners must agree topractice total abstinence or use a highly effective method of contraception (failurerate < 1% per year) prior to study entry, during treatment and for 90 days followingthe last dose of study treatment.

12. Male patient agrees to use an adequate method of contraception

Exclusion Criteria:

1. Histologically confirmed other types (Non-SCC) of salivary gland cancer

2. History of another primary malignancy EXCEPT For:

3. malignancy treated with curative intent and with no known active disease ≥5years before the first dose of study drug and of low potential risk forrecurrence;

4. adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease; adequately treated carcinoma in situ without evidence of disease (eg, carcinoma in situ of the breast, oral cavity and cervix are allpermissible);

5. low to favorable intermediate risk prostate cancer based on NCCN criteria onactive surveillance, .

6. Prior radiotherapy to the region of the study cancer within less than 6 months

7. Patients who have received prior radiation therapy and who, in the opinion of thetreating radiation oncologist, cannot be reirradiated safely without excess risk ofsevere toxicity given prior radiation dose to critical structures.

8. Patients with known contraindications to radiotherapy, including inherited syndromesassociated with hypersensitivity to ionizing radiation (e.g., Ataxia-Telangiectasia,Nijmegen Breakage Syndrome)

9. Patients with inadequate renal function or other contraindications to IV contrast

10. Any previous treatment with PD-1 or PD-L1 inhibitors, including pembrolizumab

11. Current or prior use of immunosuppressive medication within 28 days before the firstdose of pembrolizumab, with the exceptions of intranasal and inhaled corticosteroidsor systemic corticosteroids at physiological doses, which are not to exceed 10mg/day of prednisone, or an equivalent corticosteroid

12. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy

13. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previousimmunotherapy agent, or any unresolved irAE >Grade 1

14. Active or prior documented autoimmune disease within the past 2 years (subjects withvitiligo, Grave's disease, or psoriasis not requiring systemic treatment within thepast 2 years are not excluded)

15. Patients with evidence of interstitial lung disease or active, non-infectiouspneumonitis

16. History of primary immunodeficiency

17. History of allogeneic organ transplant

18. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis,active bleeding diatheses including any subject known to have evidence of acute orchronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), orpsychiatric illness/social situations that would limit compliance with studyrequirements or compromise the ability of the subject to give written informedconsent

19. Severe, active co-morbidity, defined as follows:

20. Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

21. Transmural myocardial infarction within the last 6 months

22. Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

23. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy within 30 days ofregistration

24. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

25. Known history of active infection including tuberculosis

26. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of pembrolizumab.