tReatment Individualisation By EBV stratificatiON in Nasopharyngeal Carcinoma: an Umbrella Platform Study (RIBBON-Umbrella)

Inclusion Criteria:

Each patient eligible to participate in this study must meet all the following criteria:

1. Able to provide written informed consent and can understand and agree to comply withthe requirements of the study and the schedule of assessments.

2. Age ≥21 years on the day of signing the ICF

3. Fulfil one of the following three scenarios:

4. Suspected NPC cases, diagnosed clinically based on symptoms (neck swelling,unilateral epistaxis, nasal obstruction etc.)

5. Newly-diagnosed, histologically confirmed NPC patients with Stages 2-4A diseasebased on the AJCC/UICC 8th Edition TNM stage classification

6. Newly-diagnosed patients with RM-NPC All confirmed NPC patients must meet these additional criteria before they cancontinue participation in the study:

7. NPC associated with EBV infection, determined as:

8. The presence of EBV has been confirmed in the tumour by immunohistochemistryfor EBV antigens or in situ hybridization for EBV early RNA (EBER), or

9. NPC occurred in association with a raised serum titre of IgA to EBV viralcapsid antigen (VCA) or early antigen (EA) in a patient living in endemic areaof high incidence of EBV+ undifferentiated NPC, or

10. NPC in the context of an elevated circulating EBV genome level

11. AJCC 8th edition stage 2-4A or RM NPC based on the following diagnostic workup:

12. Evaluation of tumour extent with magnetic resonance imaging (MRI) of thenasopharynx and neck. If MRI is medically contraindicated, computed tomography (CT) scan with ≤3 mm and intravenous contrast is acceptable.

13. Distant metastasis staging:

• CT scan with contrast of the chest, abdomen, and pelvis or a total body 18F-Fluorodeoxygenase positron emission tomography CT (18F-FDG-PET-CT)scan;
• Bone scan, if a 18F-FDG-PET-CT scan is not performed.

6. ECOG Performance Status ≤1

7. Adequate organ function

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible to enrol:

1. Age <21 years or >99 years old

2. Has received any prior RT or systemic anti-cancer therapy including investigationalagents that are not part of the intended treatment plan for NPC

3. Any known central nervous system metastases and/or carcinomatous meningitis

4. Any active malignancy ≤2 years before start of study except for the specific cancerunder investigation in this study and any locally recurring cancer that has beentreated curatively (e.g., resected basal or squamous cell skin cancer, superficialbladder cancer, carcinoma in situ of the cervix or breast)

5. Patients with severe chronic or active infections requiring systemic antibacterial,antifungal or antiviral therapy, including tuberculosis infection, etc. a. Severe infections within 4 weeks before start of study, including but not limitedto hospitalization for complications of infection, bacteremia, or severe pneumonia.

6. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV)carriers whose HBV DNA is >500 IU/mL or patients with active hepatitis C virus (HCV)should be excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stablehepatitis B (HBV DNA <500 IU/mL), and cured hepatitis C patients can be enrolled

7. Prior allogeneic stem cell transplantation or organ transplantation

8. Any of the following cardiovascular risk factors:

9. Cardiac chest pain, defined as moderate pain or any cardiac condition e.g.,arrhythmias, malignant hypertension, etc. that limits instrumental activitiesof daily living, ≤28 days before start of study

10. Pulmonary embolism ≤28 days before start of study

11. Any history of cerebrovascular accident or seizure ≤ 28 days before start ofstudy

12. A history of severe hypersensitivity reactions to gemcitabine, cisplatin,capecitabine and/or any of its excipients

13. Has received any herbal medicine used to control cancer within 14 days of the startof study

14. Patients with toxicities (as a result of prior anticancer therapy) which have notrecovered to baseline or stabilized, except for adverse events (AEs) not considereda likely safety risk (eg, alopecia, neuropathy and specific laboratoryabnormalities)

15. Underlying medical conditions (including laboratory abnormalities) or alcohol ordrug abuse or dependence that, will be unfavorable for the administration oftreatment or affect the explanation of drug toxicity or AEs or result ininsufficient or might impair compliance with study conduct

16. Concurrent participation in another therapeutic clinical study