Radiotherapy Plus Nimotuzumab or Cisplatin in Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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This is a phase III randomized clinical trial of definitive radiotherapy plus EGFR blocker nimotuzumab versus radiotherapy plus cisplatin(CCRT) for nasopharyngeal carcinoma (NPC) patients with favorable response to induction chemotheray(IC), determining whether radiotherapy combined with nimotuzumab was non-inferior to CCRT and may provide new evidence for individualized comprehensive treatment of locoregionally advanced NPC.

Detailed Description
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Currently, 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). However, although induction chemotherapy combined with cisplatin based concurrent radiotherapy (CCRT) can significantly improve the survival of patients, the side effects during radiotherapy are more serious. Previous studies have demonstrated that with a cut-off point of 1500 copies/mL, NPC patients could be segregated into a low-risk subgroup and a high-risk subgroup. Besides, our previous results showed that patients with plasma Epstein-Barr virus (EBV) DNA= 0 copy/mL and complete response/partial response (CR/PR) after induction chemotherapy had a significantly lower risk of disease progression than patients with plasma EBV DNA>0 copy/mL and stable disease /progressive disease (SD/PD),according to Response Evaluation Criteria in Solid Tumors (RECIST). As for these low-risk and chemotheray sensitive patients, it can be considered to reduce the current standard treatment intensity without affecting the survival rate of patients, which reduces the side effects of patients and improve the their life qualities. Epidermal growth factor (EGFR) is an important therapeutic target for nasopharyngeal carcinoma. A retrospective study suggested that there was no significant difference in the 3-year overall survival between NPC patients who received nimotuzumab / cetuximab plus radiotherapy and those who received standard CCRT. Besides, in terms of hepatorenal toxicity, anti-EGFR drugs showed better safety compared with traditional cisplatin chemotherapy. Up to now, randomized clinical trial about the application of nimotuzumab after IC is still limited. This is a phase III randomized clinical trial of definitive radiotherapy plus EGFR blocker nimotuzumab versus radiotherapy plus cisplatin for NPC patients with favorable response after IC, determining whether radiotherapy combined with nimotuzumab was non-inferior to CCRT after IC and may provide new evidence for individualized comprehensive treatment of locoregionally advanced NPC.

Official Title
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A Randomized Non-inferiority Trial of Radiotherapy Plus Nimotuzumab or Cisplatin in Patients With Favorable Response to Induction Chemotherapy for Low-risk Locoregionally Advanced-Staged Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: RT plus Nimotuzumab
* Drug: RT plus Cisplatin


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 (except N3)(according to the 8th American Joint Committee on Cancer[AJCC] edition) Patients with pre-treatment plasma EBV DNA<1500 copies/mL Patients with plasma EBV DNA= 0 copy/mL and CR/PR 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RT plus Nimotuzumab<br>Patients with pretreatment plasma EBV DNA<1500 copy/ml and up to CR/PR according to RECIST and the EBV DNA reduced to undectable(0 copy/mL ) 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 nimotuzumab (200mg, once a week during radiotherapy, a total of 7 weeks) | Drug: RT plus Nimotuzumab<br>* Nimotuzumab (200mg, once a week during radiotherapy, a total of 7 weeks)<br>|
| Active Comparator: RT plus Cisplatin<br>Patients with pretreatment plasma EBV DNA<1500 copy/ml and up to CR/PR according to RECIST and the EBV DNA reduced to undectable(0 copy/mL ) 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) ) | Drug: RT plus Cisplatin<br>* concurrent cisplatin (100mg/m2, every three weeks,D1,D22,D43 of intensity modulated radiotherapy )<br>* Other names: Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-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) | 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 | 
| Change of QoL | QoL scores were assessed for each scale by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30) before induction chemotherapy, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy | 1 years | 
| Change of EORTC quality of life questionnaire(QLQ) Head and Neck score | QoL scores were assessed by using EORTC quality of life questionnaire(QLQ) Head and Neck. The QLQ-H&N35 is composed of seven multi-item symptom scales (pain, swallowing, sensation, speech, eating from a social,perspective, social interactions, and sexuality) and 11 single-item symptom scales (teeth, opening mouth,dry mouth, sticky saliva,coughing, felt ill, pain medication use, nutritional supplementation, feeding tube requirement, weight loss, and weight gain). All of the scales and items ranged in score from 0 to 100. A high score for a functional or global QoL scale represents a relatively high/healthy level of functional or global QoL, whereas a high score for a symptom scale or item represents a high number of symptoms or problems.All of the scores mentioned above were assessed at the below time point:before induction chemotherapy, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy | 1 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 |