Concurrent Chemoradiotherapy With Nimotuzumab for High Risk Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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This is the first phase II randomized clinical trial of concurrent chemoradiotherapy with or without EGFR blocker Nimotuzumab for high risk advanced nasopharyngeal carcinoma(NPC) , determining whether concurrent chemoradiotherapy(CCRT) combined with nimotuzumab can improve the survival rate of high-risk patients and may provide new evidence for individualized comprehensive treatment of locally advanced NPC.

Detailed Description
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Currently, although NCCN(National Comprehensive Cancer Network) guidelines recommend induction chemotherapy combined with concurrent chemoradiotherapy as IIA level-evidenced treatment for locally advanced nasopharyngeal carcinoma (stage II-IVa),there is still about 20-30% of patients with locally advanced nasopharyngeal carcinoma experienced recurrence and metastasis after radical treatment. Our previous results showed that patients with plasma Epstein-Barr virus(EBV) DNA> 0 copy/mL or stable disease/progressive disease(SD/PD) after induction chemotherapy had a significantly higher risk of disease progression than patients with plasma EBV DNA=0 copy/mL and complete response/partial response(CR/PR),according to Response Evaluation Criteria in Solid Tumors (RECIST). As for these high-risk patients, the urgent clinical problem to be solved is whether increased treatment intensity during concurrent chemoradiotherapy can improve their survival rates. Epidermal growth factor (EGFR) is an important therapeutic target for nasopharyngeal carcinoma.Multiple retrospective studies have shown that chemoradiotherapy combined with the EGFR blocker nimotuzumab improved the survival rate of patients with locally advanced nasopharyngeal carcinoma compared with chemoradiotherapy alone. However, phase II randomized clinical trial about the incorporation of nimotuzumab into concurrent chemoradiotherapy is still limited. This is the first phase II randomized clinical trial of concurrent chemoradiotherapy with or without Nimotuzumab for high risk locally advanced NPC patients, determining whether concurrent chemoradiotherapy combined with nimotuzumab can improve the survival rate of high-risk patients and may provide new evidence for individualized comprehensive treatment of locally advanced nasopharyngeal carcinoma.

Official Title
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Randomized Phase II Trial of Concurrent Chemoradiotherapy With or Without Nimotuzumab for High Risk Nasopharyngeal Carcinoma After Induction Chemotherapy

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: CCRT+Nimotuzumab
* Drug: CCRT alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70, regardless of sex. Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, type of WHO II or III, clinical stage II-IVa (according to the 8th American Joint Committee on Cancer[AJCC] edition) Patients with plasma EBV DNA> 0 copy/mL or SD/PD according to RECIST after two cycle induction chemotherapy ECOG (Eastern Cooperative Oncology Group) score: 0-1 Women in their reproductive years should ensure that they use contraception during the study period. Hemoglobin (HGB) ≥90 g/L, white blood cell (WBC) ≥4×109 /L, platelet (PLT) ≥100×109 /L. Liver function: Alanine transaminase(ALT), Aspartate aminotransferase(AST)< 2.5 times the upper limit of normal value (ULN), total bilirubin <2.0×ULN. Renal function: serum creatinine <1.5×ULN 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: Histologically confirmed keratinizing squamous cell carcinoma (WHO I) Receiving radiotherapy or chemotherapy or targeted therapy previously 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 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.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCRT + Nimotuzumab<br>Patients whose plasma EBV DNA> 0 copy/mL or SD/PD according to RECIST after two cycle induction chemotherapy( TPF :Paclitaxel liposome135mg/m2 d1+DDP 25mg/m2 d1-d3+ 5-fu 750mg /m2/day civ120h, every 3 weeks for 2 courses) will have concurrent cisplatin (100mg/m2, every three weeks,D1,D22,D43 of intensity modulated radiotherapy) + nimotuzumab (200mg, once a week during radiotherapy, a total of 7 weeks) | Drug: CCRT+Nimotuzumab<br>* concurrent cisplatin (100mg/m2, every three weeks,D1,D22,D43 of intensity modulated radiotherapy) + Nimotuzumab (200mg, once a week during radiotherapy, a total of 7 weeks)<br>* Other names: Nimotuzumab;|
| Active Comparator: CCRT alone<br>Patients whose plasma EBV DNA> 0 copy/mL or SD/PD according to RECIST after two cycle induction chemotherapy( TPF :Paclitaxel liposome135mg/m2 d1+DDP 25mg/m2 d1-d3+ 5-fu 5-fu 750mg /m2/day civ120h, every 3 weeks for 2 courses) will have concurrent cisplatin (100mg/m2, every three weeks,D1,D22,D43 of intensity modulated radiotherapy) ) | Drug: CCRT alone<br>* concurrent cisplatin (100mg/m2, every three weeks,D1,D22,D43 of intensity modulated radiotherapy )<br>|

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 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) the last follow-up. | 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. | 2 years | 
| Locoregional Relapse-Free Survival (LRFS) | Defined from date of randomization to date of first documentation of locoregional relapse or the date of death from any cause or until the date of the last follow-up visit | 2 years | 
| Distant Metastasis-Free Survival (DMFS) | Defined from date of randomization to date of first documentation of distant metastases or the date of death from any cause or until the date of the last follow-up visit | 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 Response Evaluation Criteria in Solid Tumors (RECIST1.1) from the National Cancer Institute (NCI) | Three months after the completion of the CCRT with or without Nimotuzumab treatment | 
| Incidence rate of adverse events (AEs) | Analysis of acute and late adverse events (AEs) are evaluated. Numbers of patients of treatment-related adverse events(acute toxicity) as assessed by CTCAE v5.0.Numbers of patients of late radiation toxicities were assessed using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. | 2 years | 
| Evaluate EGFR expression level and EGFR Gene Copy Number as a predictive marker for survival outcomes | Pre-treatment EGFR expression level and EGFR Gene Copy Number is evaluated by means of immunohistochemical testing and fluorescent in situ hybridization (FISH), respectively. | 2 years | 
| Correlation between the frequency of EGFR-specific T cells after treatment and survival outcomes | The frequency of anti-EGFR specific T cells is evaluated centrally by means of flow cytometry | 2 years | 
| Plasma EBV DNA copy number | Plasma EBV DNA copy number in both arms was assessed by Quantitative real time polymerase chain reaction(qRT-PCR) at pretreatment, after two cycle induction chemotherapy, during CCRT and follow up time . The predictive value of plasma EBV DNA copy number was assessed by survival analysis. | 2 years |