Immunotherapy and Chemotherapy in Unresectable Recurrent Loco-regionally Advanced Nasopharyngeal Carcinoma

High dose reirradiation is usually recommended for unresectable recurrent loco-regionally advanced nasopharyngeal carcinoma. However, it potentially adds to the RT-related severe toxicities and deaths. This trial aims to investigate the feasibility of postponing or even omitting re-irradiation based on effective first-line systemic therapy with tislelizumab and chemotherapy. For patients that progressed after exposure to another PD-1 antibody,tislelizumab rechallenge is accepted as a second subgroup.In this trial, all patients will receive chemotherapy (on doctors' recommendation) and PD-1 antibody (tislelizumab 200mg every three weeks). Patients with no response to the systemic therapy will receive salvage low dose re-irradiation delivered by SBRT, while those who showed complete or partial response will continue maintenance therapy until progression, death or intolerable toxicity, and reirradiation will be postponed or omitted.

• Tislelizumab (Drug): 1. Chemotherapy (including but not limited to following): GP regimen: gemcitabine 1000mg/m2 d1, d8 + cisplatin 25 mg/m2 d1-3, every 3 weeks for 4-6 cycles; GX regimen: gemcitabine 800mg/m2 d1 + capecitabine 750 mg/m2 d1-14, every 3 weeks for 4-6 cycles. Capecitabine: 750 mg/m2 d1-14, every 3 weeks until unacceptable toxicities or patient's withdraw. 2. anti-PD-1 antibody: Tislelizumab concurrently with chemotherapy: 200mg, every 3 weeks for 12 weeks. Tislelizumab in maintenance period: 200mg every 3 weeks or 400mg every 6 weeks, until one year or disease progression, or in the case of intolerable toxicities.

Primary outcomes

• Objective response rate (ORR) [3 months]: Defined as either a confirmed CR or a PR, as determined by the investigator using RECIST v1.1Response Evaluation Criteria in Solid Tumors (RECIST) .
• Progress-free survival (PFS) [2 year]: Defined from date of enrollment to date of first documentation of progression or death due to any cause.

Secondary outcomes

• Overall survival (OS) [2 year]: Defined from date of enrollment to date of first documentation of death from Defined from date of randomization to date of first documentation of death from any cause or censored at the date of the last follow-up.
• Adverse events (AEs) [2 year]: Analysis of adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0
• Quality of life (QoL) [1 year]: QoL scores were assessed by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30).

Sex: All, ages: 15 Years to 90 Years

Inclusion Criteria:

1. Diagnosed as local recurrence ± regional recurrence after ≥1 year of radical treatment;
2. Not suitable for surgery;
3. Clinical stage rT3-4N0-2 (rII-IVa, AJCC/UICC 8th);or residual disease afer surgery.
4. ECOG score 0-1;
5. No prior treatment to rNPC, such as radiotherapy, chemotherapy, immunotherapy or biotherapy;
6. No contraindications to immunotherapy or chemoradiotherapy;
7. Adequate marrow function: WBC count ≥ 3×10E9/L, NE count ≥ 1.5×10E9/L, HGB ≥ 90g/L, PLT count ≥ 100×10E9/L;
8. Adequate liver function: ALT/AST ≤ 2.5×ULN, TBIL ≤ 2.0×ULN;
9. Adequate renal function: BUN/CRE ≤ 1.5×ULN or endogenous creatinine clearance ≥ 60ml/min (Cockcroft-Gault formula);
10. Take effective contraceptions during and two months after treatment;
11. Patients must be informed of the investigational nature of this study and give written informed consent.

Exclusion Criteria:

1. Have local necrosis in recurrent lesions, estimated with bleeding risk;
2. Unexplained fever > 38.5 ℃, except for tumor fever;
3. Treated with ≥ 5 days antibiotics one month before enrollment;
4. Have active autoimmune disease (e.g., uveitis, enteritis, hepatitis, hypophysitis, nephritis, vasculitis, hyperthyroidism, and asthma requiring bronchodilator therapy);
5. Have a known history of human immunodeficiency virus (HIV), active Hepatitis B (HBV-DNA ≥10E3copiers/ml) or hepatitis C virus (HCV) antibody positive;
6. Have ≥G3 late toxicities, except for skin, subcutaneous tissue or mucosa;
7. Have New York Heart Association (NYHA) class 3 or 4, unstable angina, myocardial -infarction within 1 year, or clinically meaningful arrhythmia that requires treatment;
8. Have known allergy to large molecule protein products or any compound of study therapy;
9. Pregnant or breastfeeding;
10. Prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical cancer, and papillary thyroid carcinoma;
11. Any other condition, including 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.

• Kong F, Zhou J, Du C, He X, Kong L, Hu C, Ying H. Long-term survival and late complications of intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma. BMC Cancer. 2018 Nov 20;18(1):1139. doi: 10.1186/s12885-018-5055-5. PMID 30453915
• Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, Peng P, Wu X, Lin Q, Xi X, Peng J, Xu M, Chen D, Lu X, Wang R, Cao X, Chen X, Lin Z, Xiong J, Lin Q, Xie C, Li Z, Pan J, Li J, Wu S, Lian Y, Yang Q, Zhao C. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016 Oct 15;388(10054):1883-1892. doi: 10.1016/S0140-6736(16)31388-5. Epub 2016 Aug 23. PMID 27567279
• Liu LT, Chen QY, Tang LQ, Zhang L, Guo SS, Guo L, Mo HY, Zhao C, Guo X, Chen MY, Qian CN, Zeng MS, Hong MH, Shao JY, Sun Y, Ma J, Mai HQ. With or without reirradiation in advanced local recurrent nasopharyngeal carcinoma: a case-control study. BMC Cancer. 2016 Oct 7;16(1):774. doi: 10.1186/s12885-016-2803-2. PMID 27717335

• Xiaoshen Wang, Principal investigator, Eye & ENT Hospital of Fudan University