A Phase II Clinical Trial of Chemotherapy With or Without Endostar® Continuous Intravenous Infusion in Refractory NPC

Study Overview
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Brief Summary
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We define refractory nasopharyngeal carcinoma as the following: recurrence with radiation brain injury after radiotherapy, recurrence after the second or more courses of radiotherapy, standard treatment failure after recurrence, and first-line treatment failure after multiple distant metastasis. There is no standard treatment for refractory nasopharyngeal carcinoma. Platinum plus 5-Fu is the classic regimen for primary treatment of nasopharyngeal carcinoma. Endostatin is a multiple targeted angiogenesis inhibitor acting on tumor associated neovascular endothelial cells, normalizing the morphology and function of tumor vasculature, and indirectly leading to the quiescence or reduction of tumors. The purpose of this phase II clinical trial is to determine the efficacy and safety of nedaplatin plus continuous low dose 5-Fu intravenous infusion combined with endostar® (Recombinant Human Endostatin Injection) continuous intravenous infusion compared with nedaplatin plus continuous low dose 5-Fu intravenous infusion alone in refractory nasopharyngeal carcinoma. The study hypothesis is that nedaplatin plus continuous low dose 5-Fu intravenous infusion combined with endostar® continuous intravenous infusion is effective and safe in refractory nasopharyngeal carcinoma.

Detailed Description
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With the extension of survival time in nasopharyngeal carcinoma(NPC), more and more patients suffer from recurrence with radiation brain injury after radiotherapy, recurrence after the second or more courses of radiotherapy, standard treatment failure after recurrence, and first-line treatment failure after multiple distant metastasis. We define these four types as refractory nasopharyngeal carcinoma[1-2] due to the complex and high risk of treatment and poor prognosis. For recurrence and metastasis NPC, the objective response rate ranges from 25% to 46.4% with platinum-based, or 5-Fu-based, or gemcitabine-based salvage chemotherapy[2--5]. At present, there is no standard treatment for refractory nasopharyngeal carcinoma. Most patients in this trial were pretreated with cisplatin-based chemotherapy. Nedaplatin has the equivalent antitumor effect with cisplatin and less renal toxicity and gastrointestinal toxicity in the treatment of NPC[6]. In addition, nedaplatin does not have the cross tolerance with cisplatin. After cisplatin failure, nedaplatin(80-100 mg/m2) still work in NPC treatment[3]. 5-Fu is a classic, effective, and safe chemotherapeutic drug in NPC treatment. Low dose continuous intravenous infusion of 5-Fu(300mg/m2/d, 6 weeks) is a effective regimen for recurrent and metastasis NPC with low toxicity[4]. Endostatin is a multiple targeted angiogenesis inhibitor acting on tumor associated neovascular endothelial cells, normalizing the morphology and function of tumor vasculature, and indirectly leading to the quiescence or reduction of tumors[7-9]. Anti-angiogenic therapy might optimally require that endothelial cells be exposed to steady blood levels of the inhibitor, and blood levels of certain angiogenesis inhibitors (such as endostatin) that are too high or too low will be ineffective[7,10]. Endostar® is recombinant human endostatin injection with better medicinal properties, stability and curative effect. Hoekman K. etc conducted a phase I clinical pharmacokinetic study in advanced cancer and the results showed that continuous intravenous pump of endostar® is safe[11]. Moreover, endostar® combined with chemotherapy can improve the outcome of the chemotherapy alone and does not increase the treatment related toxicity, such as in advanced non-small-cell lung cancer[12], advanced cervical cancer[13], advanced gastric cancer[14] and also metastasis NPC[15]. Given that the patients in this trial have the following features: had received standard radical treatment, poor tolerance of treatment due to the toxicity after many courses of chemotherapy, and the present treatment goal is palliative therapy. Therefore, the treatment principle in this trial is using low toxicity, well tolerance treatment regimen to relieve and control tumor, improve the quality of life, and further to prolong the survival time. Based on above background and considering the Efficacy and tolerability, we use nedaplatin plus continuous low dose 5-Fu intravenous infusion as chemotherapy regimen, and administrate endostar® in continuous intravenous infusion. This phase II randomized controlled trial is to investigate the efficacy and safety of nedaplatin plus continuous low dose 5-Fu intravenous infusion combined with endostar® (Recombinant Human Endostatin Injection) continuous intravenous infusion compared with nedaplatin plus continuous low dose 5-Fu intravenous infusion alone in refractory nasopharyngeal carcinoma.

Official Title
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A Multi-institutional, Randomized Controlled, Phase II Clinical Trial on Comparison of Efficacy and Safety of Nedaplatin Plus 5-Fu Combined With and Without Endostar® Continuous Intravenous Infusion in Refractory Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Recombinant Human Endostatin Injection (Endostar)
* Drug: Fluorouracil (5-Fu)
* Drug: Nedaplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have provided a signed Informed Consent Form. Histologically confirmed diagnosis of refractory nasopharyngeal carcinoma (the best), or when histology is difficult to obtained, the following clinical diagnosis of refractory nasopharyngeal carcinoma must be confirmed: clear and directional clinical symptoms, at least two kinds of imaging diagnosis on the basis of magnetic resonance (MR), and clear and directional signs. Age: 18-70 years old. Without dysfunction of heart, lung, liver, kidney, and hematopoiesis, and normal electrocardiogram. Karnofsky Performance Scores ≥ 50, Life expectancy ≥ 3 months, tolerance to at least two cycles of chemotherapy. At least one measurable tumor based on RECIST 1.1 ( longest diameter: ≥20 mm by CT or magnetic resonance (MR) scan) No history of serious allergic to biologic agents No history of other malignant tumors, except cured cervical carcinoma in situ and basal skin cancer. Exclusion Criteria: Having the serious cardiovascular disease or other serious complications. Woman in pregnancy and breast-feeding. Allergic to intervention drugs and dextran. Patients participated in clinical trials of other drugs within 4 weeks. Use of other chemotherapy drugs, biological treatment, and Chinese medicine anti-cancer drugs at the same time.

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: Nedaplatin+5-Fu+Endostar<br>Drug: Recombinant Human Endostatin Injection (Endostar) Endostar, 15mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total Drug: Fluorouracil (5-Fu) 5-Fu, 200mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total Drug: Nedaplatin Nedaplatin, 80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total | Drug: Recombinant Human Endostatin Injection (Endostar)<br>* 15mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total<br>* Other names: Endostar;Drug: Fluorouracil (5-Fu)<br>* 200mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total<br>* Other names: 5-Fu;Drug: Nedaplatin<br>* 80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total<br>* Other names: Nedaplait;|
| Active Comparator: Nedaplatin+5-Fu<br>Drug: Fluorouracil (5-Fu) 5-Fu, 200mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total Drug: Nedaplatin Nedaplatin, 80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total | Drug: Fluorouracil (5-Fu)<br>* 200mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total<br>* Other names: 5-Fu;Drug: Nedaplatin<br>* 80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total<br>* Other names: Nedaplait;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective response (OR) rate based on Recist 1.1 edition | include complete remission and partial remission | From the date of first drug administration, evaluation of response was performed every cycle during the treatment and then every 3 months after the completion of the treatment up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | include complete remission, partial remission, and progressive disease | From the date of first drug administration, evaluation of response was performed every cycle during the treatment and then every 3 months after the completion of the treatment up to 36 months | 
| Progress Free Survival (PFS) | 3 years PFS | From the date of first drug administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Overall Survival (OS) | 3 years OS | From the date of first drug administration until the date of death, assessed up to 36 months | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) | Safety evaluation according to NCI Common Terminology Criteria (CTC) 4.0 | From the date of first drug administration, evaluation was performed every cycle during the treatment and then every 3 months after the completion of the treatment up to 36 months, using NCI CTCAE version 4.0 | 
| Quality of life | Quality of life evaluation according to EORTC quality of life questionnaire (QLQ)-C30 | From the date of first drug administration, evaluation was performed every cycle during the treatment and then every 3 months after the completion of the treatment up to 36 months, using EORTC quality of life questionnaire (QLQ)-C30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory Nasopharyngeal Carcinoma, Endostar, 5-Fu