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

Nasopharyngeal Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02590133
• Other study ID #: B2015-031-01
• Status: Recruiting
• Phase: Phase 2
• First received: October 27, 2015
• Last updated: December 20, 2017
• Start date: July 2015
• Est. completion date: December 2020

Study information

• Verified date: October 2017
• Source: Sun Yat-sen University
• Contact: Yun-fei Xia, Prof
• Phone: +86-13602805461
• Email: xiayf[@]sysucc.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 328
• Est. completion date: December 2020
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms

Intervention

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
• 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
• Nedaplatin
80mg/m2/d, intravenous drip on d1 and d28 each cycle, 60 days as one cycle, 6 cycles in total

Locations

Country	Name	City	State
China	Department of Radiation Oncology, Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Yun-fei Xia

Country where clinical trial is conducted

China, 

References & Publications (15)

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. — View Citation

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. — View Citation

Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007 Apr;6(4):273-86. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Overall Survival (OS)	3 years OS	From the date of first drug administration until the date of death, assessed up to 36 months
Secondary	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
Secondary	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