Inclusion Criteria:
* Participant is eligible to be included in the study only if all the following criteria are met:
1. The participant (or legally acceptable representative if applicable) provides written consent for the trial.
2. Participant is at least 21 years of age on the day of signing informed consent
3. Has a locally or centrally determined histologically or cytologically confirmed diagnosis of Epstein Barr Virus (EBV)-positive nasopharyngeal carcinoma Note: The EBV status is to be determined by the 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. If EBV status by EBER ISH assay has not been previously determined, tumour tissue from archival tissue may be submitted for EBV determination.
4. Has recurrent or metastatic (R/M) disease not amenable to curative local therapy (surgery or radiation)
5. Must have seen at least 1 prior line of systemic treatment and has progressed on prior platinum-based chemotherapy and anti-PD1 therapy in the R/M setting OR Progressed within 6 months of previous multimodal therapy containing platinum-based chemotherapy and anti-PD1 therapy in the locally advanced setting.
6. Has measurable disease based on iRECIST.
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Has an 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
9. Willing to provide blood and tumour tissue samples (newly obtained biopsy if clinically feasible or archival specimen) to support exploratory biomarker analysis.
Exclusion Criteria:
* Participant is excluded from the study if ANY of the following criteria apply:
1. 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.
2. Has prior anti-angiogenic therapy in the R/M setting or within 6 months as part of multimodality therapy in the locally advanced setting. \[Applies to cohort A only\]
3. Has tumour that encases major arteries which in the opinion of the investigator carries high risk of vessel wall dehiscence.
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.
Note: 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 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).
Note: 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 ivonescimab 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. Recent cardiovascular thromboembolic event, such as the following:
1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 4 weeks before enrolment
2. Symptomatic pulmonary embolism ≤ 4 weeks before enrolment
3. Any history of acute myocardial infarction ≤ 6 months before enrolment
4. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV (Appendix 4) ≤ 6 months before enrolment
5. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before enrolment
6. Any history of cerebrovascular accident ≤ 6 months before enrolment
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, 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 woman of childbearing potential (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: If 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 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. Known active Hepatitis B (defined as hepatitis B viral load detected) or Hepatitis C virus (defined as HCV RNA \[qualitative\] detected) infection. Patients on anti-virals but with undetectable Hepatitis B or C viral loads are not excluded.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
20. History of having received a live virus vaccination (e.g., yellow fever, MMR, nasal flu, chicken pox or Zostavax) within 4 weeks prior to the first dose of trial treatment. 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.
