Concurrent and Adjuvant PD1 Treatment Combined With Chemo-radiotherapy for High-risk 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 chemo-radiotherapy could further decrease the rate of disease progression and improve the survival outcome of high risk patients with nasopharyngeal carcinoma compared with those treated with chemo-radiotherapy alone.

Detailed Description
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Through multicenter, open-label, randomised clinical trials, high risk patients with nasopharyngeal carcinoma (staged as II-III with SD/PD according to RECIST criteria or EBV DNA of >0 copies/mL after 3 cycles of GP induction chemotherapy and staged as IVa) are randomized into camrelizumab plus chemo-radiotherapy arm and chemo-radiotherapy arm. The efficacy and safety of patients between these two arms are compared.

Official Title
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A Multicenter Randomized Clinical Phase 3 Trial of Induction Chemotherapy Plus Concurrent Chemo-radiotherapy With or Without Camrelizumab for High Risk Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Cancer, Chemotherapy, Radiotherapy, PD-1 Therapy

Intervention / Treatment
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* Drug: Camrelizumab plus chemo-radiotherapy
* Drug: Chemo-radiotherapy alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-keratinizing nasopharyngeal carcinoma (differentiated or undifferentiated type, i.e., WHO type II or type III). Staged as T4N0-2M0,T1-4N3M0 (stage IVa) at diagnosis (according to the 8th AJCC edition). Staged as T1-3N1-2M0, T2-3N0M0 (stage II-III) with SD/PD according to RECIST criteria or EBV DNA of >0 copies/mL after 3 cycles of GP induction chemotherapy. Aged between 18-70 years. 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: Histologically confirmed keratinized squamous cell carcinoma (WHO type I) or basal squamous cell carcinoma. Recurrent or metastatic nasopharyngeal carcinoma. Staged as II-III which is evaluated as PR or CR and EBV DNA of 0 copies/mL after 3 cycles of GP induction chemotherapy. 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: Camrelizumab plus chemo-radiotherapy arm<br>3 cycles of gemcitabin and cisplatin induction chemotherapy plus concurrent chemo-radiotherapy with concurrent and adjuvant camrelizumab therapy. | Drug: Camrelizumab plus chemo-radiotherapy<br>* Camrelizumab: 200 mg, intravenous injection over 60 minutes (Q3W); 2 cycles of camrelizumab are concurrently used during radiotherapy and camrelizumab are maintained for 1 year after the end of radiotherapy. Gemcitabine plus cisplatin induction chemotherapy: gemcitabine is injected intravenously at the dose of 1000 mg/m2 on the 1st and 8th day (within 30 minutes) for 3 cycles; cisplatin is injected intravenously at the dose of 80 mg/m2 on the 1st day, for 3 cycles. 1 cycles per 3 weeks. 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#69.96Gy/33Fr/2.12Gy; PTVnd#69.96Gy/33Fr/2.12Gy; PTV1#59.4Gy/33Fr/1.8Gy; PTV2#54Gy/33Fr/1.64Gy<br>|
| Active Comparator: Chemo-radiotherapy arm<br>3 cycles of gemcitabin and cisplatin induction chemotherapy plus concurrent chemo-radiotherapy. | Drug: Chemo-radiotherapy alone<br>* Gemcitabine plus cisplatin induction chemotherapy: gemcitabine is injected intravenously at the dose of 1000 mg/m2 on the 1st and 8th day (within 30 minutes) for 3 cycles; cisplatin is injected intravenously at the dose of 80 mg/m2 on the 1st day, for 3 cycles. 1 cycles per 3 weeks. 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#69.96Gy/33Fr/2.12Gy; PTVnd#69.96Gy/33Fr/2.12Gy; PTV1#59.4Gy/33Fr/1.8Gy; PTV2#54Gy/33Fr/1.64Gy<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 |