Camrelizumab for the Treatment of Locally Advanced Nasopharyngeal Carcinoma

Objectives:To investigate the clinical efficacy of camrelizumab in the treatment of locoregionally-advanced nasopharyngeal carcinoma (LANPC).

Outline:Patients with stage III-IVA (AJCC 8th, included T1-2N2-3 and/or T3-4N0-3 M0) locoregionally-advanced nasopharyngeal carcinoma will be randomized in a 1:1 ratio to experimental arm and active comparator arm. Patients in experimental arm will receive induction chemotherapy with gemcitabine (1g/m2, d1 \& 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Camrelizumab 200mg will be given every 3 weeks for 3 cycles started on day 1 of induction chemotherapy and every 2 weeks for 9 cycles thereafter. Patients in active comparator arm will receive induction chemotherapy with gemcitabine (1g/m2, d1 \& 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Concurrent cisplatin of 100mg/m2 will be administered every 3 weeks for 2 cycles during IMRT.

• Camrelizumab (Drug), also known as PD-1 antibody: Camrelizumab 200mg will be given every 3 weeks for 3 cycles started on day 1 of induction chemotherapy and every 2 weeks for 9 cycles thereafter.
• Gemcitabine (Drug), also known as Gem: Gemcitabine 1g/m2, d1 \& 8 of every cycle, every 3 weeks for 3 cycles before radiation
• Induction Cisplatin (Drug), also known as DDP: Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation
• intensity-modulated radiotherapy (Radiation), also known as IMRT: Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.
• Concurrent cisplatin (Drug), also known as DDP: Concurrent cisplatin 100mg/m2, every 3 weeks for 2 cycles during radiation

Primary outcomes

• Progress-free survival (PFS) [3 years]: Calculated from randomization to the date of progression or death from any cause, whichever occurred first.

Secondary outcomes

• Overall survival (OS) [3 years]: Calculated from randomization to the date of death from any cause.
• Distant Metastasis-free survival (DMFS) [3 years]: Calculated from randomization to the date of first distant metastasis.
• Locoregional failure-free survival (LRRFS) [3 years]: Calculated from randomization to the date of locoregional relapse.
• Adverse events (AEs) and serious adverse events (SAEs) [3 years]: Graded according to CTCAE V5.0.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

1. Patients with histologically confirmed nasopharyngeal carcinoma.
2. Tumor staged as III-IVA (AJCC 8th, included T1-2N2-3 and/or T3-4N0-3 M0).
3. Eastern Cooperative Oncology Group performance status ≤1.
4. Adequate marrow function: neutrocyte count≥1.5×10e9/L, hemoglobin ≥80g/L and platelet count ≥80×10e9/L.
5. Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×upper limit of normal (ULN), and bilirubin ≤ 1.5×ULN.
6. Adequate renal function: creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula).
7. Patients must be informed of the investigational nature of this study and give written informed consent.
8. Women of childbearing potential (WOCBP) who are sexually active must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of study drug. Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of the study drug.

Exclusion Criteria:

1. Age > 70 or < 18.
2. Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA >1×10e3 copies/ml or 200IU/ml
3. Hepatitis C virus (HCV) antibody positive
4. Has active autoimmune disease, except type I diabetes, hypothyroidism treated with replacement therapy, and skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia).
5. Has any condition that required systemic corticosteroid (equivalent to prednisone >10mg/d) or other immunosuppressive therapy within 28 days before informed consent. Patients received systemic corticosteroid equivalent to prednisone ≤10mg/d, inhale or topical corticosteroid will be allowed.
6. Has a known history of active TB (bacillus tuberculosis) within 1 year; patients with adequately treated active TB over 1 year ago will be allowed.
7. Has a known history of interstitial lung disease.
8. Has received a live vaccine within 30 days before informed consent or will receive a live vaccine in the near future.
9. Is pregnant or breastfeeding.
10. Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer, and papillary thyroid carcinoma.
11. Has known allergy to large molecule protein products or any compound of camrelizumab.
12. Has a known history of human immunodeficiency virus (HIV) infection.
13. Any other condition, including symptomatic heart failure, unstable angina, myocardial infarction, active infection requiring systemic therapy, mental illness or domestic/social factors, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interferes with the interpretation of the results.

• Bin Zhang, M.D., Principal investigator, Wuzhou Red Cross Hospital
• Yu-fei Pan, M.D., Principal investigator, Guangxi Nanxishan Hospital
• Yi-xin Su, M.D., Principal investigator, Lingshan County People's Hospital
• Jian Zhang, M.D., Principal investigator, Laibin People's Hospital