Phase III Trial of EBV-DNA-Guided Adaptive Immunotherapy for Advanced Nasopharyngeal Carcinoma

Multicenter, Prospective Phase III Clinical Trial of EBV-DNA-Guided Adaptive Immunotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma

This trial evaluated the efficacy of two adjuvant regimens following identical induction and concurrent chemoradiotherapy (IC+CCRT) in locoregionally advanced nasopharyngeal carcinoma (LANPC) patients with persistent EBV DNA positivity or stable disease after three IC cycles. The control arm received adjuvant adebrelimab, while the experimental arm received adebrelimab plus capecitabine.

This study will enroll patients with stage II-III LANPC (AJCC 9th edition, excluding T3N0-1). After three cycles of induction chemotherapy (gemcitabine, cisplatin, and adebrelimab), eligible patients with persistent EBV DNA or stable disease will be randomized 1:1. All patients will undergo CCRT followed by adjuvant therapy. The control arm will receive five cycles of adebrelimab. The experimental arm will receive five cycles of adebrelimab in combination with capecitabine, which will be administered for one year.

Inclusion Criteria:

1. Age ≥18 and ≤65 years

2. Patients with histologically confirmed non-keratinizing nasopharyngeal carcinoma according to WHO criteria.

3. Eastern Cooperative Oncology Group performance score of 0-1.

4. Tumor staged as II-III disease (AJCC 9th edition), excluding T3N0-1.

5. Adequate marrow function: white blood cell count > 4 × 10⁹/L hemoglobin >90g/L and platelet count >100×10⁹/L

6. Adequate hepatic and renal function：

   • Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
   • Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×ULN
   • Alkaline phosphatase ≤ 2.5 × ULN
   • clearance rate ≥ 60 ml/min

7. Other laboratory and clinical criteria

   • Normal thyroid function, serum amylase and lipase, pituitary hormone levels, inflammatory markers, cardiac enzyme tests and electrocardiogram (ECG)
   • For patients aged >50 years with a history of smoking, normal pulmonary function test (PFT) results are required
   • For patients with abnormal ECG findings or a prior history of cardiovascular disease (not meeting any exclusion criteria listed in Item 8), additional assessments including myocardial function evaluation and cardiac ultrasound (echocardiography) must be performed, with results within normal limits

8. Patients with persistent EBV DNA positivity or stable disease following 3 cycles of induction chemotherapy (gemcitabine, cisplatin, and adebrelimab).

9. Patients must be informed of the investigational nature of this study and give written informed consent, and be willing and able to comply with the study schedule, including follow-up visits, treatment procedures, laboratory testing, and other protocol-related requirements.

10. Women of childbearing potential (WOCBP) must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of study drug (e.g., condoms, physician-guided regular use of oral contraceptives).

Exclusion Criteria:

1. Disease progression after induction chemotherapy

2. Positive for hepatitis B surface antigen (HBsAg) with hepatitis B virus DNA >1×103 copies/mL, positive for anti-hepatitis C virus (HCV) antibody , positive for anti-hepatitis C virus (HCV) antibody

3. Positive for anti-HIV antibody or diagnosed with acquired immunodeficiency syndrome (AIDS).

4. Active pulmonary tuberculosis: Patients with a history of active tuberculosis within the past year should be excluded regardless of treatment status. Patients with a history of active pulmonary tuberculosis more than one year prior should also be excluded, unless they received confirmed and regular anti-tuberculosis treatment.

5. Active, known, or suspected autoimmune diseases, including but not limited to uveitis, colitis, hepatitis, hypophysitis, nephritis, vasculitis, systemic lupus erythematosus, hyperthyroidism, hypothyroidism, and asthma requiring bronchodilators. Type I diabetes, hypothyroidism treated with replacement therapy, and skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia) are allowed.

6. History of interstitial lung disease or pneumonia requiring oral or intravenous corticosteroids within the past year; use of vancomycin within the past month.

7. Ongoing chronic systemic corticosteroid therapy (equivalent to or greater than prednisone >10mg per day) or any other immunosuppressive therapy. Patients received inhale or topical corticosteroid are allowed.

8. Uncontrolled cardiac conditions, such as:

   • Heart failure with New York Heart Association (NYHA) classification ≥ Class II;
   • Unstable angina;
   • History of myocardial infarction within the past year;
   • Supraventricular or ventricular arrhythmias requiring treatment or intervention

9. Pregnant or breastfeeding women (pregnancy testing should be considered for women of childbearing potential with active sexual life)

10. History or presence of other malignancies, except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, and papillary thyroid carcinoma.

11. Known hypersensitivity to macromolecule protein products or any component of adebrelimab.

12. Active infections requiring systemic treatment within 1 week prior to enrollment.

13. Administration of live vaccines within 30 days prior to the first dose of adebrelimab.

14. Factors significantly affecting the absorption of oral drugs, such as inability to swallow, chronic diarrhea, or intestinal obstruction.

15. History of organ transplantation or hematopoietic stem cell transplantation.

16. Any other condition assessed by the investigator as potentially compromising patient safety or compliance, such as severe illnesses requiring urgent treatment (including psychiatric disorders), significantly abnormal laboratory values, or other psychological, familial, or social risk factors.