Toripalimab Plus Concurrent Chemo-radiotherapy for Unresectable Locally Recurrent Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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Through multicenter, open-label, randomised clinical trials, we intend to demonstrate that concurrent and adjuvant PD-1 treatment added to concurrent chemo-radiotherapy could further decrease the rate of disease progression and improve the survival outcome of patients with unresectable locally recurrent nasopharyngeal carcinoma compared with those treated with concurrent chemo-radiotherapy alone.

Detailed Description
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Through multicenter, open-label, randomised clinical trials, patients with unresectable locally recurrent nasopharyngeal carcinoma are randomized into concurrent chemo-radiotherapy plus concurrent and adjuvant PD-1 treatment group and concurrent chemo-radiotherapy alone group. The efficacy and safety of patients between these two groups are compared.

Official Title
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A Multicenter Randomized Clinical Phase 3 Trial of Toripalimab Plus Concurrent Chemo-radiotherapy vs Concurrent Chemo-radiotherapy Alone for Unresectable Locally Recurrent Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma, Chemotherapy, Radiotherapy, PD-1 Treatment

Intervention / Treatment
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* Drug: Toripalimab plus concurrent chemo-radiotherapy
* Drug: Concurrent chemo-radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed recurrent nasopharyngeal carcinoma. The recurrence time is more than 12 months from the end of the first course of radiotherapy. Tumor staged as rT2-4N0-3M0，rII-IVa (according to the 8th AJCC edition). Subjects must have a measurable disease by CT or MRI per RECIST 1.1 criteria. Karnofsky scale (KPS)≥70. Normal bone marrow function. Normal liver and kidney function: total bilirubin, AST and ALT levels of no more than 2.5 times the upper normal limit; creatinine clearance rate of at least 60 mL/min or creatinine of no more than 1.5 times the upper normal limit. Given written informed consent. Exclusion Criteria: Resectable nasopharyngeal diseases: rT2 (the tumour is confined in the superficial parapharyngeal spacer and is more than 0.5cm from the internal carotid artery) and rT3 (the tumour is confined in the base wall of the sphenoid sinus and is more than 0.5cm from the internal carotid artery and cavernous sinus). The patients are suffering from severe nasopharyngeal necrosis, radiation induced brain injury, and fibrosis of the neck et. al, who are evaluated as unsuitable for secondary radiotherapy by the researchers. Has known allergy to large molecule protein products or any compound of study therapy. Has known subjects with other malignant tumors. Has any active autoimmune disease or history of autoimmune disease. Has a history of psychiatric substance abuse, alcoholism, or drug addiction. The laboratory examination value does not meet the relevant standards within 7 days before enrollment Received a systematic glucocorticoid therapy within 4 weeks of the first dose of study medication. Has a known history of active TB (bacillus tuberculosis) within 1 year; patients with adequately treated active TB with 1 year. Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1) or CTLA-4 agent. Has active autoimmune disease (e.g., uveitis, enteritis, hepatitis, hypophysitis, nephritis, vasculitis, hyperthyroidism, and asthma requiring bronchodilator therapy). Patients with skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia) will be allowed to enroll. Has a known history of human immunodeficiency virus (HIV). Has hepatitis B surface antigen (HBsAg) positive with HBV DNA copy number of ≥1000cps/ml or hepatitis C virus (HCV) antibody positive Has received a live vaccine within 4 weeks of planned start of study therapy Pregnancy or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Toripalimab plus concurrent chemo-radiotherapy arm<br>Concurrent chemo-radiotherapy plus concurrent and adjuvant toripalimab. | Drug: Toripalimab plus concurrent chemo-radiotherapy<br>* Toripalimab: 240 mg, intravenous injection over 60 minutes (Q3W); 2 cycles of toripalimab are concurrently used during radiotherapy and other 9 cycles of toripalimab are used after the end of radiotherapy. (A total of 11 cycles). Concurrent cisplatin chemotherapy: cisplatin is given at a dose of 100 mg/m2 via a continuous intravenous infusion during radiotherapy and starts on the 1st day of radiotherapy for 2 cycles. 1 cycles per 3 weeks. IMRT: PTVnx#60.0Gy/27Fr/2.22Gy; PTVnd# 60-64Gy/27Fr/2.22-2.37Gy; PTV1#54Gy/27Fr/2.00Gy<br>|
| Active Comparator: Concurrent chemo-radiotherapy arm<br>Concurrent chemo-radiotherapy alone. | Drug: Concurrent chemo-radiotherapy<br>* Concurrent cisplatin chemotherapy: cisplatin is given at a dose of 100 mg/m2 via a continuous intravenous infusion during radiotherapy and starts on the 1st day of radiotherapy for 2 cycles. 1 cycles per 3 weeks. IMRT: PTVnx#60.0Gy/27Fr/2.22Gy; PTVnd# 60-64Gy/27Fr/2.22-2.37Gy; PTV1#54Gy/27Fr/2.00Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress-free survival (PFS) | Defined as time from randomization to locoregional or distant metastasis relapse or death from any cause, whichever occurred first. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Defined as the time interval from randomization to death due to any cause. | 3 years | 
| Distant Metastasis-Free Survival (DMFS) | Defined as the time interval from randomisation to the date of first distant metastases. | 3 years | 
| Locoregional Relapse-Free Survival (LRRFS) | Defined as the time from randomisation to the date of first locoregional relapse. | 3 years | 
| Incidence of treatment related acute complications | The proportion of patients with treatment related acute complications according to NCI-CTC5.0 criteria and RTOG criteria. | up to 1 years | 
| Incidence of treatment related late complications | The proportion of patients with treatment related late complications according to NCI-CTC5.0 criteria and RTOG criteria. | up to 3 years | 
| Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0) | Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0) before treatment, during treatment, after treatment. | up to 3 years | 
| Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35) | Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35) before treatment, during treatment, after treatment. | up to 3 years |