A Safety and Efficacy Study for Combinational Treatment of DaRT and Check Point Inhibitor for Recurrent Unresectable or mHNSCC

Inclusion Criteria:

1. Pathologically confirmed, metastatic, or recurrent unresectable squamous cellcarcinoma of the head and neck.

2. Ability to provide tissue sample, either from an archive or undergo another biopsyto provide a fresh sample

3. Targetable lesion must be technically amenable for the DaRT seeds implantation

4. Brachytherapy indication validated by a multidisciplinary team

5. Targetable lesion according to RECIST v1.1

6. Age ≥ 18 years old

7. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ≤ 2

8. Subjects' life expectancy is more than 6 months

9. White Blood Count (WBC) ≥ 3500/µl, granulocyte ≥ 1500/µl

10. Platelet count ≥ 100,000/µl

11. Hemoglobin ≥ 9 g/dl

12. Calculated or measured creatinine clearance ≥ 60 cc/min

13. Aspartate Aminotransferase (AST) and Alanine Transaminase (ALT) ≤ 2.5 X Upper Limitof Normal (ULN) or ≤ 5 X ULN for subjects with liver metastases

14. International normalized ratio (INR) <1.4 for patients not on Warfarin

15. Subjects are willing and able to sign an informed consent form

16. Women of childbearing potential (WOCBP) will have evidence of negative pregnancytest before the Ra-224 implantation and are required to use an acceptablecontraceptive method to prevent pregnancy for 3 months after brachytherapy.

Exclusion Criteria:

1. Previous treatment for metastatic disease (for recurrent unresectable disease,previous treatment is allowed given that 6 months had elapsed from completion oftreatment for primary disease)

2. Patients with brain metastases

3. Combined Positive Scores (CPS) <1

4. Patients with known contraindications to radiotherapy

5. Any prior therapy with anti-PD-L1 (Programmed death-ligand), anti-PD-L2, anti-CTLA-4 (Cytotoxic T lymphocyte antigen) antibody, etc.

6. Any history of a sever hypersensitivity reaction to any monoclonal antibody.

7. Known hypersensitivity to any of the components of the DaRT.

8. Has a known history of active TB (Tuberculosis Bacillus )

9. Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy or in situ cervical cancer.

10. Any diagnosis of immunodeficiency or current immunosuppressive therapy including >10mg/day of prednisone within 14 days of enrollment is not permitted

11. Clinically significant cardiovascular disease, e.g. cardiac failure of New YorkHeart Association classes III-IV, uncontrolled coronary artery disease,cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history ofmyocardial infarction in the last 12 months.

12. Patients with uncontrolled intercurrent illnesses including, but not limited to anactive infection requiring systemic therapy or a known psychiatric or substanceabuse disorder(s) that would interfere with cooperation with the requirements of thetrial or interfere with the study endpoints.

13. Patient requires treatment which may conflict with the endpoints of this studyincluding evaluation of response or toxicity of DaRT.

14. Has a known history of Human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

15. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected)

16. Pregnancy or lactation.

17. Patients must agree to use adequate contraception (abstinence, barrier method ofbirth control, or any other medically acceptable form of contraception) prior tostudy entry, for the duration of study participation and for 6 months after lastdose of Pembrolizumab.