Randomised Trial of Induction Gemcitabine and Cisplatin Versus Gemcitabine, Cisplatin, Pembrolizumab and Bevacizumab (GPPB) in Nasopharyngeal Cancer

Inclusion Criteria:

1. The participant (or legally acceptable representative if applicable) provides written consent for the trial.
2. Participants who are at least 21 years of age on the day of signing informed consent with histologically or cytologically confirmed diagnosis of non-keratinizing nasopharyngeal carcinoma (NPC).
3. Have measurable disease based on RECIST 1.1.
4. Tumour stage III (except for T3N0 and T3N1) or IVA according to the American Joint Committee on Cancer (AJCC) 8th edition criteria.
5. Have locally or centrally determined EBV-positive NPC by EBV-encoded small RNA in situ hybridization (EBER in situ hybridization \[ISH\]) assay. If EBV-positive status has been previously determined by EBER ISH assay, then no re-testing is required.

   Note: If EBV status by EBER ISH assay has not been previously determined, tumor tissue from archival tissue may be submitted for EBV determination.
6. Did not receive any prior treatment
7. Willingness to donate blood for mandatory translational research studies.
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Have an adequate organ function
10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 of study protocol OR
    2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 of study protocol during the treatment period and for at least 120 days after the last dose of study medication.
11. A male participant must agree to use a contraception as detailed in Appendix 3 of study protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

Exclusion Criteria:

1. Stage III NPC with T3N0 or T3N1 staged by AJCC 8th edition
2. Has received prior systemic anti-cancer therapy including chemotherapy, radiotherapy, immunotherapy or investigational agents
3. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study treatment.
4. Has a condition requiring systemic steroid therapy (\> 10 mg daily prednisone equivalents) or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \< or = 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
5. 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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
6. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
7. Has hypersensitivity to bevacizumab or any of its components.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

   Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast or cervical carcinoma in situ) that have undergone potentially curative therapy are not excluded.
9. Has an active infection requiring systemic therapy, or serious non-healing wound, ulcer or bone fracture.
10. Uncontrolled hypertension (failure of diastolic blood pressure to fall below 90 mmHg, despite the use of = 3 anti-hypertensive drugs or systolic blood pressure greater than 150 mmHg).
11. History of cardiac disease: congestive heart failure \> New York Heart Association (NYHA) Class II; active coronary artery disease (unstable angina \[anginal symptoms at rest\] or new-onset angina \[began within the last 3 months\] or myocardial infarction within the past 6 months). Cardiac arrhythmias requiring anti-arrhythmic therapy (ß-blockers or digoxin are permitted).
12. Persistent proteinuria of NCI-CTCAE Grade 3 or higher (\> 3.5 g/24 hours, measured by urine protein/creatinine ratio on a random urine sample).
13. Clinically significant bleeding (NCI-CTCAE Grade 3 or higher) within 30 days prior to start of study medication.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
17. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization/allocation (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.
18. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
19. 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.

    Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
20. Has received a live vaccine within 30 days of 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-Guerin (BCG), and typhoid vaccine.

Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.