Radiotherapy Omitting Prophylactic Neck Irradiation With Neoadjuvant and Adjuvant Toripalimab in Nasopharyngeal Carcinoma

A Single-arm, Phase II Trial of Radiotherapy Without Prophylactic Neck Irradiation in Combination With Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab for Nasopharyngeal Carcinoma

This single-arm, phase 2 trial evaluates the efficacy and safety of de-escalated radiotherapy (restricted to the primary tumor, omitting prophylactic neck irradiation) combined with neoadjuvant and adjuvant toripalimab immunotherapy, and concurrent chemotherapy in patients with nasopharyngeal carcinoma staged N0 or N1, where nodal involvement is strictly confined to the retropharyngeal lymph nodes.

The goals of this clinical trial includes: ① To assess the regional relapse-free survival (RRFS) and safety after radiotherapy without prophylactic neck irradiation in combination with neoadjuvant and adjuvant PD-1 antibody toripalimab and cisplatin concurrent chemotherapy for N0-1 (restricted to retropharyngeal lymph nodes) patients with nasopharyngeal carcinoma; ② To evaluate the impact of radiotherapy without prophylactic neck irradiation on 2-year overall survival (OS), 2-year progress-free survival (PFS), 2-year distant metastasis-free survival (DMFS), and 2-year locoregional relapse-free survival (LRRFS) for N0-1 ( limited to retropharyngeal lymph nodes) patients with nasopharyngeal carcinoma; ③ To explore the impact of radiotherapy without prophylactic neck irradiation on toxicities and quality of life; ④ To explore the relationship between clinical factors and the impact of neoadjuvant and adjuvant PD-1 antibody, radiotherapy without prophylactic neck irradiation on the survival of patients; ⑤ To explore the biomarkers of sensitivity to immunotherapy, chemotherapy and radiotherapy for patients with nasopharyngeal carcinoma and the underlying mechanism.

For these purposes, we plan to prospectively enroll T2N0-1 and primary gross tumor volume (GTV) greater than 30.0 cm3 or T3-4N0-1 stage NPC patients, whose N1 restricted to retropharyngeal lymph nodes from one center in China. The patients will receive 2 cycles of neoadjuvant PD-1 antibody (toripalimab monotherapy, 240 mg, every two weeks, intravenous infusion) followed by concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy (IMRT), and adjuvant toripalimab (240 mg intravenously) once every 3 weeks for up to eight cycles. All participants will be treated with IMRT restricted to primary tumor without prophylactic neck irradiation. The clinical outcomes, safety, complications, and quality of life will be explored in the RT without prophylactic neck irradiation.

Inclusion Criteria:

1. Age: 18 Years to 70 Years;

2. Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, including WHO II or III

3. Satisfactory performance status: ECOG (Eastern Cooperative OncologyGroup) scale 0-1

4. TNM stage based on AJCC 9th edition with N0-1 (retroperitoneal lymph nodes only), and either one following criteria:

   1. T2 and primary gross tumor volume (GTV) greater than 30.0 cm3;
   2. T3-4;

5. Patients' lymph node without adverse features (no central necrosis, no muscle/skin invasion, no lymph node fusion).

6. Male and no pregnant female

7. Normal bone marrow function: white blood cell count > 4×10^9/L, hemoglobin > 90g/L, platelet count > 100×10^9/L;

8. Normal liver function: total bilirubin (TBIL) < upper limit of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) < 1.5 × ULN;

9. Normal kidney function: creatinine clearance rate ≥ 60 ml/min;

10. Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule;

Exclusion Criteria:

1. Patients have evidence of relapse or distant metastasis
2. Histologically confirmed keratinizing squamous cell carcinoma (WHO I)
3. Patients with positive cervical lymph nodes
4. Patients who have been treated with inhibitors of immune regulation (CTLA-4, PD-1, PD-L1, etc.).
5. Receiving radiotherapy or chemotherapy previously
6. Patients with active immunodeficiency disease and history of immunodeficiency disease
7. Anti-human immunodeficiency virus (HIV) positive or diagnosed with acquired immune deficiency syndrome (AIDS)
8. Chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day) or any other form of immunosuppressive therapy. Subjects who used inhaled or topical corticosteroids were eligible.
9. Active tuberculosis: active tuberculosis in the past 1 year should be excluded regardless with treatment, history of active tuberculosis over 1 year should be excluded except that previous regulatory anti-tuberculosis treatment is proved.
10. HBV DNA >2000 cps/ml (or HBV DNA > 2000 IU/ml); or HCV RNA >1000 cps/ml; Hepatitis B surface antigen (HBsAg) positive and HCV antibody positive.
11. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
12. Suffered from other malignant tumors (except the cure of basal cell carcinoma or uterine cervical carcinoma in situ) previously.
13. Uncontrolled heart disease, for example: 1) heart failure (NYHA level ≥ 2), 2) unstable angina, 3) myocardial infarction in past 1 year, 4) supraventricular or ventricular arrhythmia requiring treatment or intervention.
14. Patients with significantly lower heart, liver, lung, kidney and bone marrow function.
15. Severe, uncontrolled medical conditions and infections.
16. At the same time using other test drugs or in other clinical trials.
17. Refusal or inability to sign informed consent to participate in the trial.
18. Other treatment contraindications.
19. Emotional disturbance or mental illness, no civil capacity or limited capacity for civil conduct.