A Phase II Clinical Trial of Chemotherapy With or Without Endostar® Continuous Intravenous Infusion in Refractory NPC
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Nedaplatin+5-Fu+Endostar 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)
15mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total
Other Names:
Drug: Fluorouracil (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
Other Names:
Drug: Nedaplatin
80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total
Other Names:
|
Active Comparator: Nedaplatin+5-Fu 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)
200mg/m2/d, continuous intravenous infusion in 2ml/h for 30 days each cycle, 60 days as one cycle, 6 cycles in total
Other Names:
Drug: Nedaplatin
80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total
Other Names:
|
Outcome Measures
Primary Outcome Measures
- objective response (OR) rate based on Recist 1.1 edition [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]
include complete remission and partial remission
Secondary Outcome Measures
- Disease Control Rate (DCR) [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]
include complete remission, partial remission, and progressive disease
- Progress Free Survival (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]
3 years PFS
- Overall Survival (OS) [From the date of first drug administration until the date of death, assessed up to 36 months]
3 years OS
- Number of participants with adverse events (AEs) and serious adverse events (SAEs) [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]
Safety evaluation according to NCI Common Terminology Criteria (CTC) 4.0
- Quality of life [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]
Quality of life evaluation according to EORTC quality of life questionnaire (QLQ)-C30
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Department of Radiation Oncology, Sun Yat-Sen University Cancer Center | Guangzhou | Guangdong | China | 510060 |
Sponsors and Collaborators
- Yun-fei Xia
Investigators
- Principal Investigator: Yun-fei Xia, Prof, Sun Yat-sen University
Study Documents (Full-Text)
None provided.More Information
Publications
- Chen C, Wang FH, Wang ZQ, An X, Luo HY, Zhang L, Chen YC, Xu RH, Li YH. Salvage gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol. 2012 Nov;48(11):1146-51. doi: 10.1016/j.oraloncology.2012.05.021. Epub 2012 Jun 27.
- Fandi A, Taamma A, Azli N, Bachouchi M, Yanes B, Armand JP, Cvitkovic E. Palliative treatment with low-dose continuous infusion 5-fluorouracil in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma type. Head Neck. 1997 Jan;19(1):41-7.
- Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007 Apr;6(4):273-86. Review.
- Folkman J. Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action. Exp Cell Res. 2006 Mar 10;312(5):594-607. Epub 2005 Dec 22. Review.
- Gao Y, Huang HQ, Bai B, Cai QC, Wang XX, Cai QQ. Treatment outcome of docetaxel, capecitabine and cisplatin regimen for patients with refractory and relapsed nasopharyngeal carcinoma who failed previous platinum-based chemotherapy. Expert Opin Pharmacother. 2014 Feb;15(2):163-71. doi: 10.1517/14656566.2014.866652. Epub 2013 Dec 3.
- Hansma AH, Broxterman HJ, van der Horst I, Yuana Y, Boven E, Giaccone G, Pinedo HM, Hoekman K. Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer. Ann Oncol. 2005 Oct;16(10):1695-701. Epub 2005 Jul 12.
- Jin T, Li B, Chen XZ. A phase II trial of Endostar combined with gemcitabine and cisplatin chemotherapy in patients with metastatic nasopharyngeal carcinoma (NCT01612286). Oncol Res. 2013;21(6):317-23. doi: 10.3727/096504014X13983417587401.
- Ke QH, Zhou SQ, Huang M, Lei Y, Du W, Yang JY. Early efficacy of Endostar combined with chemoradiotherapy for advanced cervical cancers. Asian Pac J Cancer Prev. 2012;13(3):923-6.
- Kisker O, Becker CM, Prox D, Fannon M, D'Amato R, Flynn E, Fogler WE, Sim BK, Allred EN, Pirie-Shepherd SR, Folkman J. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 2001 Oct 15;61(20):7669-74.
- Peng F, Xu Z, Wang J, Chen Y, Li Q, Zuo Y, Chen J, Hu X, Zhou Q, Wang Y, Ma H, Bao Y, Chen M. Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models. PLoS One. 2012;7(4):e34646. doi: 10.1371/journal.pone.0034646. Epub 2012 Apr 9.
- Peng PJ, Ou XQ, Chen ZB, Liao H, Peng YL, Wang SY, Zhang HY, Lin Z. Multicenter phase II study of capecitabine combined with nedaplatin for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. Cancer Chemother Pharmacol. 2013 Aug;72(2):323-8. doi: 10.1007/s00280-013-2203-0. Epub 2013 Jun 1.
- Rong B, Yang S, Li W, Zhang W, Ming Z. Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer. World J Surg Oncol. 2012 Aug 24;10:170. doi: 10.1186/1477-7819-10-170. Review.
- Xu R, Ma N, Wang F, Ma L, Chen R, Chen R, Kebinu M, Ma L, Han Z, Ayixiamu, Mayier M, Su P, Naman Y, Jieensi H, Yang H, Adili A, Aili S, Liu J. Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. Onco Targets Ther. 2013 Jul 25;6:925-9. doi: 10.2147/OTT.S46487. Print 2013.
- Zhang F, Wu K, Gao F, Zhang W, Shi F, Li C. Refractory nasopharyngeal carcinoma: positron emission tomography combined with computed tomography-guided 125I seed implantation therapy after repeated traditional radiochemotherapy. Otolaryngol Head Neck Surg. 2013 Sep;149(3):417-23. doi: 10.1177/0194599813491221. Epub 2013 May 28.
- Zheng J, Wang G, Yang GY, Wang D, Luo X, Chen C, Zhang Z, Li Q, Xu W, Li Z, Wang D. Induction chemotherapy with nedaplatin with 5-FU followed by intensity-modulated radiotherapy concurrent with chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Jpn J Clin Oncol. 2010 May;40(5):425-31. doi: 10.1093/jjco/hyp183. Epub 2010 Jan 19.
- B2015-031-01