NEO-SPACE Trial: Pembrolizumab and Chemoradiation in Nasopharyngeal Cancer

Inclusion Criteria: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of nasopharyngeal carcinoma (from primary lesion and/or lymph nodes) of WHO type II-III histology type will be enrolled in this study. 2. Tumor confirmed EBV positive by EBER ISH assay 3. AJCC 8th edition Stage IVA (i.e any T4 or any N3) based on the following diagnostic workup: 1. Evaluation of tumor extent with MRI of the nasopharynx and neck. If MRI is medically contraindicated, CT scan with ≤ 3 mm and intravenous contrast is acceptable. 2. Distant metastasis staging: i. CT scan with contrast of the chest, abdomen, and pelvis or a total body PET/CT scan; ii. Bone scan, if a PET/CT scan is not performed. 4. A male participant must agree to use contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days plus an additional 120 days (a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose after the last dose of study treatment and refrain from donating sperm during this period. 5. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR 2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity after the last dose of study treatment. 6. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut. 8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization. 9. Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study treatment. Exclusion Criteria: 1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to first dosing (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 3. Has received any prior systemic anti-cancer therapy including investigational agents. 4. Has received any prior radiotherapy. 5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 7. Has a known additional malignancy. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 8. Has known active CNS metastases and/or carcinomatous meningitis. 9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 12. Has an active infection requiring systemic therapy. 13. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority. 14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Subjects who have been treated and now have a viral load that is undetectable are eligible. 15. Has a known history of active TB (Bacillus Tuberculosis). 16. Has prior solid organ transplant or bone marrow transplant. 17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.