Inclusion Criteria:
* Known histologically confirmed diagnosis of nasopharyngeal carcinoma
* Measurable disease according to RECIST ver 1.1.
* Age 18 or above and younger than 80 years old; ECOG performance 0 or 1.
* Adequate bone marrow, renal and hepatic reserve, and clotting profile:
1. Absolute neutrophil count ≥ 1.5 × 10\^9 /L; Platelets ≥ 90×10\^9 /L; Hemoglobin \> 9 g/dL.
2. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula).
3. Total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 2.5 × ULN for patients without liver metastases.
4. Total bilirubin ≤ 3.0 × ULN, AST and ALT ≤ 5.0 × ULN for patients with liver metastases.
5. INR and APTT ≤ 1.5 × ULN
6. Electrocardiography (ECG): Friderica-corrected QT interval (QTcF): ≤470 (females) or ≤450 (males) milliseconds without a history of congenital long QT syndrome
* Urine strip test (multistix or dipstick) showing protein ≤2+; if urine protein characterization \>2+, 24 h urine protein quantification is required; if 24 h urine protein quantification \<1 g, it is acceptable;
* Female or male subjects of childbearing potential must agree to have no plans for childbearing and to voluntarily use highly effective contraception with their partner for the duration of the study for up to 6 months after the end of the last dose, and female subjects of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the first dose of study medication.
* Prior treatment with PD1/PDL1 inhibitor as part of neoadjuvant treatment or concurrently with radical radiotherapy with curative intent is allowed as long as there is an interval of 6 or more months since administration of the last dose of PD1 inhibitor and more than 12 months since radical radiotherapy +/- concomitant chemotherapy.
* Prior treatment with PD1/PDL1 inhibitor for the first-line treatment of R/N NPC is allowed, as long as there is an interval of 6 or more months since administration of the last dose of PD1/PDL1 inhibitor.
Exclusion Criteria:
* Prior radical RT to the primary NPC within 12 months
* Known history of nasopharyngeal necrosis
* Presence of locoregional tumor recurrence or distant metastatic disease associated with invasion of major vascular structure(s) on imaging which may increase the risk of serious bleeding. This may include (but not limited to) regional neck recurrence invading major vascular structures or ;
* Presence of central lung lesions involving major blood vessels;
* History of clinically significant bleeding defined as Grade 2 epistaxis or Grade 3 bleeding at other sites occurring within 4 weeks prior to the first dose of study drug.
* Prior therapy with anti-vascular agents in any clinical setting, including anti-VEGF antibodies or tyrosine kinase-inhibitors targeting VEGFR.
* Uncontrolled hypertension defined as consistently more than 150/100 mmHg despite adequate medical therapy or history of hypertensive crisis or hypertensive encephalopathy;
* Known history of hypersensitivity to any components of the study drug formulation, or other monoclonal antibodies
* Prior therapy with anti-vascular agents in any clinical setting, including anti-VEGF antibodies, tyrosine kinase-inhibitor agent targeting at VEGFR.
* Patients who are on anticoagulants.
* Presence of significant bleeding tendencies or history of severe coagulation disorders;
* Known history of nasopharyngeal necrosis
* Patients with arteriovenous thrombosis events, such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep venous thrombosis (except venous thrombosis caused by intravenous catheterization due to early chemotherapy) and pulmonary embolism, occurred within 6 months.
* Patients with urine strip test (multi-stix or dipstick) indicating urine protein \> 2+ will need a 24-hour urine protein collection. They are excluded if the 24-hour urine protein is \>1.0g.
* Presence of symptomatic central nervous system metastases that require use of steroids of dose \> prednisolone 10mg daily or equivalent.
* Presence of active autoimmune disease not related to prior use of PD1/PDL1 inhibitor, that require systemic therapy (e.g., use of corticosteroids or immunosuppressive medications) within 2 years prior to the first dose, including, but not limited to: systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease or vasculitis. However, enrollment is allowed for patients with hypothyroidism, adrenal gland, hypophysis, or pituitary gland dysfunction, or type 1 diabetes mellitus that can be controlled with hormone replacement therapy only or vitiligo or psoriasis not requiring systemic therapy;
* History of interstitial lung disease or prior history of pneumonitis that required immunosuppressive therapy including steroids; patients with a history of Grade 1 radiation pneumonitis are eligible;
* Gastrointestinal (GI) perforation of or fistula involving internal organs or intra-abdominal or thoracic abscesses within 6 months prior to the first dose of study drug;
* Presence of severe, unhealed or open wounds, active ulcers or untreated fractures;
* Presence of significant bleeding tendencies or history of severe coagulation disorders;
* Presence of poorly controlled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure \>100 mmHg) on more than 3 separate readings obtained on different days at the clinic, or history of hypertensive crisis or hypertensive encephalopathy;
* History of immunodeficiency, including a positive test for human immunodeficiency virus (HIV), or a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
* Have serious cardiovascular disease including, but not limited to, myocardial infarction, severe/unstable angina pectoris, myocarditis, pericarditis, congestive heart failure (NYHA cardiac function class ≥ grade 2), clinically significant supraventricular or ventricular arrhythmia requiring pharmacologic intervention, aortic aneurysm requiring surgical repair, any arterial thrombotic/embolic event, grade 3 and above (Generic for adverse events, Terminology Criteria \[CTCAE 65.0) venous thrombotic/embolic event, transient ischemic attack, cerebrovascular accident;
* Active infections that require intravenous anti-infective agents within 28 days prior to the first study dose. Known active tuberculosis, uncontrolled hepatitis B (hepatitis B surface antigen \[HBsAg\] positive and HBV DNA above the lower limit of detection of the study center), hepatitis C (HCV Ab positive and HCV RNA above the lower limit of detection of the study center);
* History of another primary malignancy, except for malignancies that were radically treated with curative intent prior to the first dose of study intervention and there is no known active disease (more than 5 years, no time limit for dose-escalation phase patients) and a low risk of potential recurrence (e.g., basal cell carcinoma of the skin and squamous cell carcinoma of the skin, which have been treated with potentially curative therapy);
* Major surgery (excluding placement of central vascular access), radiotherapy within 28 days prior to the first dose (palliative radiotherapy for localized non-target lesions is allowed as long as there is a 14-day washout prior to the day 1 of starting study treatment).
* Any live or live attenuated vaccine within 28 days prior to the first dose, or the need for a live or live attenuated vaccine is anticipated during the study;
* Use of antiplatelet therapy including aspirin, adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), adenosine reuptake inhibitors (e.g., dipyridamole), glycoprotein platelet inhibitors (abciximab), phosphodiesterase inhibitors (cilostazol), and protease-activated receptor (PAR-1) antagonist (vorapaxar), administered for therapeutic purposes within 10 days prior to the first dose;
* Breastfeeding women;
* Presence of other serious physical or mental illnesses, abnormal laboratory tests, or other conditions that may increase the risk of participation in the study, affect treatment compliance, or interfere with the results of the study, and which the investigator considers not suitable for participation in this study;
Specific exclusion criteria for phase II component:
* Patients with any prior grade 2 or higher autoimmune toxicities that are directly related to PD1/PDL1 inhibitor that required the use of immunosuppressive agents including steroids (at dose of \> prednisolone 10mg daily dose or equivalent dose of other steroids). This may include but not limited to grade 2 or higher autoimmune pneumonitis, hepatitis, pancreatitis, nephritis, myocarditis, neurological, myositis, skin toxicity and hypophysitis.
* Patients with immune-checkpoint inhibitor related autoimmune thyroid and adrenal insufficiency who are clinically stable on hormonal replacement are not excluded.
