Gemcitabine-based Induction Chemotherapy Combined With Concurrent Chemoradiotherapy in Locally Advanced Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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Researchers conduct the clinical trial (gemcitabine combined with cisplatin induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine for locally advanced nasopharyngeal carcinoma) to evaluate the safety and effectiveness of gemcitabine in patients with locally advanced nasopharyngeal carcinoma.

Detailed Description
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Diagnosed as locally advanced nasopharyngeal carcinoma (stage III-IV), and pathologically confirmed as a differentiated or undifferentiated non-keratinizing nasopharyngeal carcinoma, the patient is eligible to participate in the study. Patients receive gemcitabine (1000mg/m² d1,8) and cisplatin (80mg/m², d1) every 3 weeks for 2 cycles before radiotherapy. And then intensity modulated radiotherapy (IMRT) is given a total dose of GTVnx 70Gy, GTVnd 66Gy, CTV1 60Gy and CTV2 54Gy for 33 times in total, concurrently with gemcitabine. The initial dose of gemcitabine is 25mg/m² once a week for 6 times. The patients are divided into 9 groups (25mg/m², 50mg/m², 100mg/m², 200mg/m², 300mg/m², 350mg/m², 400mg/m², 450mg/m², 500mg/m²) with 6 patients in each group. Considering about 20% of the cases of dropout, withdrawal, and loss to follow-up in clinical trials, a total of 65 cases are needed in this study. The efficacy is evaluated according to the European Solid Tumor Efficacy Evaluation Standard (RECIST1.1). After induction chemotherapy, radiotherapy, and 3 months after radiotherapy, nasopharyngeal endoscopy and magnetic resonance imaging of the would be reviewed for 1 year, 2 years, and 3 years to evaluate the curative effect. The chest CT, abdominal B-ultrasound, bone scan or PETCT examinations are reviewed to exclud distant metastases. Biopsy diagnosis can be performed for patients suspected of local residual and recurrence.

Official Title
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A Multicenter and Prospective Clinical Trial of Gemcitabine-based Induction Chemotherapy Combined With Concurrent Chemoradiotherapy in Locally Advanced Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Gemcitabine combined with cisplatin induction chemotherapy
* Drug: concurrent chemoradiotherapy with gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly histologically confirmed non-keratinizing carcinoma (according to WHO histological type) Tumor staged as Ⅲ-Ⅳa (according to the 8th AJCC edition staging system) Age :18-60 Performance status: KPS > 70 Normal liver function test: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) < 1.5×upper limit of normal (ULN) concomitant with alkaline phosphatase (ALP) < 2.5×ULN, and bilirubin < ULN Renal: creatinine clearance > 60ml/min Adequate marrow: leucocyte count > 4×109/L, neutrophil count > 2×109/L, and platelet count > 100×109/L Written informed consent Exclusion Criteria: History of allergy to related drugs Prior malignancy (except adequately treated carcinoma in-situ of the cervix or basal/squamous cell carcinoma of the skin) History of previous RT (except for non-melanomatous skin cancers outside intended RT treatment volume) Prior chemotherapy or surgery (except diagnostic) to primary tumor or nodes Any severe intercurrent disease, which may bring unacceptable risk or affect the compliance of the trial, for example, unstable cardiac disease requiring treatment, renal disease, chronic hepatitis, diabetes with poor control (fasting plasma glucose > 1.5×ULN), and emotional disturbance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Interventional Model Description: The initial dose of gemcitabine is 25mg/m² once a week for 6 times. The patients are divided into 9 groups (25mg/m², 50mg/m², 100mg/m², 200mg/m², 300mg/m², 350mg/m², 400mg/m², 450mg/m², 500mg/m²) with 6 patients in each group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Induction chemotherapy + IMRT and concurrent gemcitabine<br>Patients receive gemcitabine (1000mg/m² d1,8) and cisplatin (80mg/m²,d1) every 3weeks for 2 cycles before radiotherapy, and then receive intensity modulated radiotherapy (IMRT) concurrently with gemcitabine. The initial dose of gemcitabine is 25mg/m² once a week for 6 times. Patients are divided into 9 groups (25mg/m², 50mg/m², 100mg/m², 200mg/m², 300mg/m², 350mg/m², 400mg/m², 450mg/m², 500mg/m²) with 6 patients in each group. | Drug: Gemcitabine combined with cisplatin induction chemotherapy<br>* Patients receive gemcitabine (1000mg/m² d1,8) and cisplatin (80mg/m², d1) every 3 weeks for 2 cycles before radiotherapy. And then intensity modulated radiotherapy (IMRT) is given a total dose of GTVnx 70Gy, GTVnd 66Gy, CTV1 60Gy and CTV2 54Gy for 33 times in total, concurrently with gemcitabine. The initial dose of gemcitabine is 25mg/m² once a week for 6 times. The patients are divided into 9 groups (25mg/m², 50mg/m², 100mg/m², 200mg/m², 300mg/m², 350mg/m², 400mg/m², 450mg/m², 500mg/m²) with 6 patients in each group.<br>* Other names: concurrent chemoradiotherapy with gemcitabine;Drug: concurrent chemoradiotherapy with gemcitabine<br>* followed by concurrent gemcitabine chemoradiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerance dose(MTD) | MTD is detemined by the dose that is immediately lower than the dose that produced dose limiting toxicity （DLT）. If DLT occurs in more than half of patients at a certain dose level, the test will be terminated. If DLT occurs in 2 cases,another 6 patients will be treated with this dose. If DLT does not occur in 6 cases, the dose will continue to increase. If it still occurs, the next dose is MTD. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | We determined DLT: a) grade ≥ 3 anemia; b) grade ≥ 3 thrombocytopenia; c) grade ≥ 3 neutropenia no less than 5 days, d) grade 3 febrile neutropenia (absolute neutrophil count < 1.0 x 10^9/L, fever ≥ 38.5℃) despite therapy with granulocyte colony-stimulating factor; and e) any other grades 3-4 toxicity (except alopecia and nausea). | 3 years | 
| Tumor response rates | Tumor response rate was evaluated according to the RECIST1.1. After induction chemotherapy, radiotherapy and 3 months, 1 year, 2 years, and 3 years of radiotherapy, nasal endoscope and magnetic resonance imaging results were used to evaluate the efficacy. And chest CT scanning, abdominal ultrasound, bone scan or PETCT examination were used to exclude the distant metastases. Pathologic biopsy can be performed for patients who are suspected of locally residual or recurrence. | 3 years |