Phase II Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Combined With CCRT in NPC Patients

Study Overview
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Brief Summary
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This is a randomized Phase II trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with concurrent cisplatin chemoradiotherapy versus cisplatin concurrent chemoradiotherapy plus placebo in treating patients with high risk locoregionally advanced nasopharyngeal carcinoma.

Detailed Description
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Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. For locoregionally advanced NPC, especially for the high risk NPC (plasma EBV DNA ≥ 1500 copies/ml), the incidence of treatment failure is still high. Although concurrent chemoradiotherapy (CCRT) can improve the treatment outcomes of these patients, approximately 25% of locoregionally advanced NPCs still develop relapse and metastasis. Hence, there is an urgent need for novel therapies to improve survival and reduce treatment-related toxicity in NPC patients. Accumulating evidence shows that PD-1 antibody is effective for treating recurrent/metastastic NPC patients. This is a Phase II randomized trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with CCRT versus CCRT plus placebo in treating patients with high risk NPC (Stage III-IVa, AJCC 8th and EBV DNA ≥ 1500 copies/ml).

Official Title
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Randomized, Placebo-controlled, Double-blind Phase II Clinical Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Immunotherapy Combined With Concurrent Chemoradiotherapy for High-risk Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Cisplatin+Toripalimab
* Drug: Cisplatin+placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, including WHO II or III Original clinical staged as III-IVa （according to the 8th AJCC edition） No evidence of distant metastasis (M0) Plasm EB Virus DNA≥1500copies/ml Male and no pregnant female Satisfactory performance status: ECOG (Eastern Cooperative OncologyGroup) scale 0-1 WBC ≥ 4×109 /L and PLT ≥4×109 /L and HGB ≥90 g/L With normal liver function test (ALT、AST ≤ 2.5×ULN, TBIL≤ 2.0×ULN) With normal renal function test ( creatinine clearance ≥60 ml/min) Exclusion Criteria: Patients have evidence of relapse or distant metastasis Histologically confirmed keratinizing squamous cell carcinoma (WHO I) Receiving radiotherapy or chemotherapy previously The presence of uncontrolled life-threatening illness 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. Suffered from other malignant tumors (except the cure of basal cell carcinoma or uterine cervical carcinoma in situ) previously. Patients who have been treated with inhibitors of immune regulation (CTLA-4, PD-1, PD-L1, etc.). Patients with immunodeficiency disease and history of organ transplantation. Patients who have used large doses of glucocorticoids, anti-cancer monoclonal antibodies, and other immunosuppressive agents within 4 weeks. HIV positive. Patients with significantly lower heart, liver, lung, kidney and bone marrow function. Severe, uncontrolled medical conditions and infections. At the same time using other test drugs or in other clinical trials. Refusal or inability to sign informed consent to participate in the trial. Other treatment contraindications. Emotional disturbance or mental illness, no civil capacity or limited capacity for civil conduct. Hepatitis B surface antigen (HBsAg) positive and HBVDNA ≥1000cps/ml. Patients with positive HCV antibody test results can only be included in the study when the polymerase chain reaction of HCV RNA is negative.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant and Adjuvant Toripalimab+CCRT<br>Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: Toripalimab Toripalimab 240mg every 2 weeks with a total of 2 cycles as neoadjuvant anti-PD-1 immunotherapy; Toripalimab240mg every 3 weeks with a total of 8 cycles as adjuvant anti-PD-1 immunotherapy 2 weeks after CCRT Other Names:anti-PD-1 antibody, JS001 | Drug: Cisplatin+Toripalimab<br>* chemotherapy and monoclonal antibody<br>* Other names: DDP+ JS001;|
| Placebo Comparator: Neoadjuvant and Adjuvant Placebo+CCRT<br>Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: placebo placebo 240mg every 2 weeks with a total of 2 cycles as neoadjuvant treatment; placebo 240mg every 3 weeks with a total of 8 cycles as adjuvant treatment 2 weeks after CCRT. | Drug: Cisplatin+placebo<br>* chemotherapy<br>* Other names: DDP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress-free survival (PFS) | Defined from date of randomization to date of first documentation of progression or death due to any cause, whichever occurred first. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Defined as the time from randomisation to death. | 2 years | 
| Locoregional Relapse-Free Survival (LRRFS) | Defined as the time from the randomisation to documented locoregional recurrence or death due to any cause. | 2 years or until the date of the last follow-up visit. | 
| Distant Metastasis-Free Survival (DMFS) | Defined as the time from randomisation to documented distant metastasis or death due to any cause. | 2 years | 
| Objective Response Rate （ORR） | An objective response is defined as either a confirmed CR or a PR, as determined by the investigator using RECIST v1.1Response Evaluation Criteria in Solid Tumors (RECIST) from the National Cancer Institute (NCI). | After the completion of the neoadjuvant PD-1 antibody and chemoradiotherapy treatment | 
| Incidence rate of adverse events (AEs) | 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 | 2 years | 
| Correlation between the plasma EBV DNA level and PFS | The plasma EBV DNA level of the patients will be assessed. | 2 years | 
| Correlation between pre-treatment PD-L1 expression level and PFS | Pre-treatment PD-L1 expression level is evaluated centrally by means of immunohistochemical testing. | 2 years | 
| Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS | TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play important roles in the tumor microenvironment. | 2 years | 
| Change of QoL (quality of life) | QoL scores were assessed by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30) before neoadjuvant PD-1 antibody, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy. | 1 year | 
| Number of subjects with major pathologic response (MPR) | Major pathologic response rate (MPR) is defined as > 90% decrease in viable tumor. | 21-28 days |