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出境医 / 临床实验 / Phase II Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Combined With CCRT in NPC Patients

Phase II Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Combined With CCRT in NPC Patients

Study Description
Brief Summary:
This is a randomized Phase II trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with concurrent cisplatin chemoradiotherapy versus cisplatin concurrent chemoradiotherapy plus placebo in treating patients with high risk locoregionally advanced nasopharyngeal carcinoma.

Condition or disease Intervention/treatment Phase
Nasopharyngeal Carcinoma Drug: Cisplatin+Toripalimab Drug: Cisplatin+placebo Phase 2

Detailed Description:

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. For locoregionally advanced NPC, especially for the high risk NPC (plasma EBV DNA ≥ 1500 copies/ml), the incidence of treatment failure is still high. Although concurrent chemoradiotherapy (CCRT) can improve the treatment outcomes of these patients, approximately 25% of locoregionally advanced NPCs still develop relapse and metastasis.

Hence, there is an urgent need for novel therapies to improve survival and reduce treatment-related toxicity in NPC patients. Accumulating evidence shows that PD-1 antibody is effective for treating recurrent/metastastic NPC patients. This is a Phase II randomized trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with CCRT versus CCRT plus placebo in treating patients with high risk NPC (Stage III-IVa, AJCC 8th and EBV DNA ≥ 1500 copies/ml).

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 138 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Placebo-controlled, Double-blind Phase II Clinical Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Immunotherapy Combined With Concurrent Chemoradiotherapy for High-risk Nasopharyngeal Carcinoma
Actual Study Start Date : December 8, 2019
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Neoadjuvant and Adjuvant Toripalimab+CCRT
Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: Toripalimab Toripalimab 240mg every 2 weeks with a total of 2 cycles as neoadjuvant anti-PD-1 immunotherapy; Toripalimab240mg every 3 weeks with a total of 8 cycles as adjuvant anti-PD-1 immunotherapy 2 weeks after CCRT Other Names:anti-PD-1 antibody, JS001
 Drug: Cisplatin+Toripalimab
chemotherapy and monoclonal antibody
Other Name: DDP+ JS001
Placebo Comparator: Neoadjuvant and Adjuvant Placebo+CCRT
Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: placebo placebo 240mg every 2 weeks with a total of 2 cycles as neoadjuvant treatment; placebo 240mg every 3 weeks with a total of 8 cycles as adjuvant treatment 2 weeks after CCRT.
 Drug: Cisplatin+placebo
chemotherapy
Other Name: DDP
Outcome Measures
Primary Outcome Measures :
  1. Progress-free survival (PFS) [ Time Frame: 2 years ]
    Defined from date of randomization to date of first documentation of progression or death due to any cause.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 2 years ]
    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. Locoregional Relapse-Free Survival (LRRFS) [ Time Frame: 2 years or until the date of the last follow-up visit. ]
    Defined from date of randomization to date of first documentation of locoregional relapse or until the date of the last follow-up visit.

  3. Distant Metastasis-Free Survival (DMFS) [ Time Frame: 2 years ]
    Defined from date of randomization to date of first documentation of distant metastases or until the date of the last followup visit.

  4. Objective Response Rate （ORR） [ Time Frame: After the completion of the neoadjuvant PD-1 antibody and chemoradiotherapy treatment ]
    An objective response is defined as either a confirmed CR or a PR, as determined by the investigator using RECIST v1.1Response Evaluation Criteria in Solid Tumors (RECIST) from the National Cancer Institute (NCI).

  5. Incidence rate of adverse events (AEs) [ Time Frame: 2 years ]
    Analysis of adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0

  6. Correlation between the plasma EBV DNA level and PFS [ Time Frame: 2 years ]
    The plasma EBV DNA level of the patients will be assessed.

  7. Correlation between pre-treatment PD-L1 expression level and PFS [ Time Frame: 2 years ]
    Pre-treatment PD-L1 expression level is evaluated centrally by means of immunohistochemical testing.

  8. Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS [ Time Frame: 2 years ]
    TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play important roles in the tumor microenvironment.

  9. Change of QoL (quality of life) [ Time Frame: 1 year ]
    QoL scores were assessed by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30) before neoadjuvant PD-1 antibody, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy.

  10. Number of subjects with major pathologic response (MPR) [ Time Frame: 21-28 days ]
    Major pathologic response rate (MPR) is defined as > 90% decrease in viable tumor.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, including WHO II or III Original clinical staged as III-IVa （according to the 8th AJCC edition）
  2. No evidence of distant metastasis (M0)
  3. Plasm EB Virus DNA≥1500copies/ml
  4. Male and no pregnant female
  5. Satisfactory performance status: ECOG (Eastern Cooperative OncologyGroup) scale 0-1
  6. WBC ≥ 4×109 /L and PLT ≥4×109 /L and HGB ≥90 g/L
  7. With normal liver function test (ALT、AST ≤ 2.5×ULN, TBIL≤ 2.0×ULN)
  8. With normal renal function test ( creatinine clearance ≥60 ml/min)

Exclusion Criteria:

  1. Patients have evidence of relapse or distant metastasis
  2. Histologically confirmed keratinizing squamous cell carcinoma (WHO I)
  3. Receiving radiotherapy or chemotherapy previously
  4. The presence of uncontrolled life-threatening illness
  5. 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.
  6. Suffered from other malignant tumors (except the cure of basal cell carcinoma or uterine cervical carcinoma in situ) previously.
  7. Patients who have been treated with inhibitors of immune regulation (CTLA-4, PD-1, PD-L1, etc.).
  8. Patients with immunodeficiency disease and history of organ transplantation.
  9. Patients who have used large doses of glucocorticoids, anti-cancer monoclonal antibodies, and other immunosuppressive agents within 4 weeks.
  10. HIV positive.
  11. Patients with significantly lower heart, liver, lung, kidney and bone marrow function.
  12. Severe, uncontrolled medical conditions and infections.
  13. At the same time using other test drugs or in other clinical trials.
  14. Refusal or inability to sign informed consent to participate in the trial.
  15. Other treatment contraindications.
  16. Emotional disturbance or mental illness, no civil capacity or limited capacity for civil conduct.
  17. Hepatitis B surface antigen (HBsAg) positive and HBVDNA ≥1000cps/ml.
  18. Patients with positive HCV antibody test results can only be included in the study when the polymerase chain reaction of HCV RNA is negative.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Qiuyan Chen, MD,PhD 86-20-87343380 chenqy@sysucc.org.cn

Locations
Layout table for location information
China, Guangdong
Sun Yat-sen Universitty Cancer Center Recruiting
Guangzhou, Guangdong, China, 510060
Contact: Hai-Qiang Mai, MD,PhD    +862087343643    maihq@sysucc.org.cn   
Principal Investigator: Hai-Qiang Mai, MD,PhD         
Sponsors and Collaborators
Sun Yat-sen University
Investigators
Layout table for investigator information
Principal Investigator: Overall Study Officials Mai, MD,PhD Sun Yat-Sen University Cancer Cente
Tracking Information
First Submitted Date  ICMJE March 28, 2019
First Posted Date  ICMJE April 23, 2019
Last Update Posted Date April 22, 2020
Actual Study Start Date  ICMJE December 8, 2019
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2019) 		Progress-free survival (PFS) [ Time Frame: 2 years ]
Defined from date of randomization to date of first documentation of progression or death due to any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: April 20, 2019) 		Progress-free survival (PFS) [ Time Frame: 2 years ]
Defined from date of registration to date of first documentation of progression or death due to any cause.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2020)
  • Overall Survival (OS) [ Time Frame: 2 years ]
    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.
  • Locoregional Relapse-Free Survival (LRRFS) [ Time Frame: 2 years or until the date of the last follow-up visit. ]
    Defined from date of randomization to date of first documentation of locoregional relapse or until the date of the last follow-up visit.
  • Distant Metastasis-Free Survival (DMFS) [ Time Frame: 2 years ]
    Defined from date of randomization to date of first documentation of distant metastases or until the date of the last followup visit.
  • Objective Response Rate （ORR） [ Time Frame: After the completion of the neoadjuvant PD-1 antibody and chemoradiotherapy treatment ]
    An objective response is defined as either a confirmed CR or a PR, as determined by the investigator using RECIST v1.1Response Evaluation Criteria in Solid Tumors (RECIST) from the National Cancer Institute (NCI).
  • Incidence rate of adverse events (AEs) [ Time Frame: 2 years ]
    Analysis of adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0
  • Correlation between the plasma EBV DNA level and PFS [ Time Frame: 2 years ]
    The plasma EBV DNA level of the patients will be assessed.
  • Correlation between pre-treatment PD-L1 expression level and PFS [ Time Frame: 2 years ]
    Pre-treatment PD-L1 expression level is evaluated centrally by means of immunohistochemical testing.
  • Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS [ Time Frame: 2 years ]
    TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play important roles in the tumor microenvironment.
  • Change of QoL (quality of life) [ Time Frame: 1 year ]
    QoL scores were assessed by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30) before neoadjuvant PD-1 antibody, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy.
  • Number of subjects with major pathologic response (MPR) [ Time Frame: 21-28 days ]
    Major pathologic response rate (MPR) is defined as > 90% decrease in viable tumor.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2019)
  • Overall Survival (OS) [ Time Frame: 2 years ]
    Defined from date of registration to date of first documentation of death from any cause or censored at the date of the last follow-up.
  • Locoregional Relapse-Free Survival (LRRFS) [ Time Frame: 2 years or until the date of the last follow-up visit. ]
    Defined from date of registration to date of first documentation of locoregional relapse or until the date of the last follow-up visit.
  • Distant Metastasis-Free Survival (DMFS) [ Time Frame: 2 years ]
    Defined from date of registration to date of first documentation of distant metastases or until the date of the last followup visit.
  • Complete Response (CR) [ Time Frame: after the completion of the chemoradiotherapy treatment (up to 9 weeks) ]
    Number of Participants with CR will be assessed according to the Modified Response Evaluation Criteria in Solid Tumors (RECIST) from the National Cancer Institute (NCI).
  • Determine the toxic effects in these patients [ Time Frame: 2 years ]
    Number of Participants with Treatment-Related Adverse Events as Assessed by standard NIH criteria during follow up will be assessed.
  • Determine the molecular expression of EBV DNA [ Time Frame: 12 weeks ]
    The molecular expression of EBV DNA of the patients will be assessed.
  • Change of QoL (quality of life) [ Time Frame: 1 year ]
    QoL scores were assessed 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Combined With CCRT in NPC Patients
Official Title  ICMJE Randomized, Placebo-controlled, Double-blind Phase II Clinical Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Immunotherapy Combined With Concurrent Chemoradiotherapy for High-risk Nasopharyngeal Carcinoma
Brief Summary This is a randomized Phase II trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with concurrent cisplatin chemoradiotherapy versus cisplatin concurrent chemoradiotherapy plus placebo in treating patients with high risk locoregionally advanced nasopharyngeal carcinoma.
Detailed Description

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. For locoregionally advanced NPC, especially for the high risk NPC (plasma EBV DNA ≥ 1500 copies/ml), the incidence of treatment failure is still high. Although concurrent chemoradiotherapy (CCRT) can improve the treatment outcomes of these patients, approximately 25% of locoregionally advanced NPCs still develop relapse and metastasis.

Hence, there is an urgent need for novel therapies to improve survival and reduce treatment-related toxicity in NPC patients. Accumulating evidence shows that PD-1 antibody is effective for treating recurrent/metastastic NPC patients. This is a Phase II randomized trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with CCRT versus CCRT plus placebo in treating patients with high risk NPC (Stage III-IVa, AJCC 8th and EBV DNA ≥ 1500 copies/ml).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Nasopharyngeal Carcinoma
Intervention  ICMJE
  • Drug: Cisplatin+Toripalimab
    chemotherapy and monoclonal antibody
    Other Name: DDP+ JS001
  • Drug: Cisplatin+placebo
    chemotherapy
    Other Name: DDP
Study Arms  ICMJE
  • Experimental: Neoadjuvant and Adjuvant Toripalimab+CCRT
    Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: Toripalimab Toripalimab 240mg every 2 weeks with a total of 2 cycles as neoadjuvant anti-PD-1 immunotherapy; Toripalimab240mg every 3 weeks with a total of 8 cycles as adjuvant anti-PD-1 immunotherapy 2 weeks after CCRT Other Names:anti-PD-1 antibody, JS001
    Intervention: Drug: Cisplatin+Toripalimab
  • Placebo Comparator: Neoadjuvant and Adjuvant Placebo+CCRT
    Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: placebo placebo 240mg every 2 weeks with a total of 2 cycles as neoadjuvant treatment; placebo 240mg every 3 weeks with a total of 8 cycles as adjuvant treatment 2 weeks after CCRT.
    Intervention: Drug: Cisplatin+placebo
Publications *
  • Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998 Apr;16(4):1310-7.
  • Langendijk JA, Leemans CR, Buter J, Berkhof J, Slotman BJ. The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol. 2004 Nov 15;22(22):4604-12.
  • Baujat B, Audry H, Bourhis J, Chan AT, Onat H, Chua DT, Kwong DL, Al-Sarraf M, Chi KH, Hareyama M, Leung SF, Thephamongkhol K, Pignon JP; MAC-NPC Collaborative Group. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):47-56. Review.
  • Twu CW, Wang WY, Chen CC, Liang KL, Jiang RS, Wu CT, Shih YT, Lin PJ, Liu YC, Lin JC. Metronomic adjuvant chemotherapy improves treatment outcome in nasopharyngeal carcinoma patients with postradiation persistently detectable plasma Epstein-Barr virus deoxyribonucleic acid. Int J Radiat Oncol Biol Phys. 2014 May 1;89(1):21-9. doi: 10.1016/j.ijrobp.2014.01.052.
  • Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012 Feb;13(2):163-71. doi: 10.1016/S1470-2045(11)70320-5. Epub 2011 Dec 7.
  • Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, Hu CS, Xu XY, Chen YY, Hu WH, Guo L, Mo HY, Chen L, Mao YP, Sun R, Ai P, Liang SB, Long GX, Zheng BM, Feng XL, Gong XC, Li L, Shen CY, Xu JY, Guo Y, Chen YM, Zhang F, Lin L, Tang LL, Liu MZ, Ma J. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016 Nov;17(11):1509-1520. doi: 10.1016/S1470-2045(16)30410-7. Epub 2016 Sep 27.
  • Leung SF, Zee B, Ma BB, Hui EP, Mo F, Lai M, Chan KC, Chan LY, Kwan WH, Lo YM, Chan AT. Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol. 2006 Dec 1;24(34):5414-8.
  • Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004 Jun 10;350(24):2461-70.
  • Economopoulou P, Agelaki S, Perisanidis C, Giotakis EI, Psyrri A. The promise of immunotherapy in head and neck squamous cell carcinoma. Ann Oncol. 2016 Sep;27(9):1675-85. doi: 10.1093/annonc/mdw226. Epub 2016 Jul 5. Review.
  • Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.
  • Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. doi: 10.1200/JCO.2013.51.4802. Epub 2013 Oct 21.
  • Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. Epub 2016 Oct 8.
  • Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.
  • Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.
  • Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331. Review.
  • Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013 Dec;14(12):1212-8. doi: 10.1038/ni.2762. Review.
  • Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014 Nov 27;515(7528):563-7. doi: 10.1038/nature14011.
  • Schoenfeld JD. Immunity in head and neck cancer. Cancer Immunol Res. 2015 Jan;3(1):12-7. doi: 10.1158/2326-6066.CIR-14-0205. Review.
  • Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 2017 Dec 20;35(36):4050-4056. doi: 10.1200/JCO.2017.73.3675. Epub 2017 Aug 24.
  • Hsu MC, Hsiao JR, Chang KC, Wu YH, Su IJ, Jin YT, Chang Y. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Mod Pathol. 2010 Oct;23(10):1393-403. doi: 10.1038/modpathol.2010.130. Epub 2010 Jul 23.
  • Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27. Erratum in: J Clin Oncol. 2018 Aug 1;36(22):2360.
  • Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, Killestein J, Polman CH, Aalberse RC, Schuurman J, van de Winkel JG, Parren PW. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009 Aug;27(8):767-71. doi: 10.1038/nbt.1553. Epub 2009 Jul 20.
  • Liu J, Blake SJ, Yong MC, Harjunpää H, Ngiow SF, Takeda K, Young A, O'Donnell JS, Allen S, Smyth MJ, Teng MW. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov. 2016 Dec;6(12):1382-1399. Epub 2016 Sep 23.
  • Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, Battafarano RJ, Velez MJ, Rekhtman N, Olah Z, Naidoo J, Marrone KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom JW, Scharpf RB, White J, Gabrielson E, Wang H, Rosner GL, Rusch V, Wolchok JD, Merghoub T, Taube JM, Velculescu VE, Topalian SL, Brahmer JR, Pardoll DM. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018 May 24;378(21):1976-1986. doi: 10.1056/NEJMoa1716078. Epub 2018 Apr 16. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 20, 2019) 		138
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2023
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, including WHO II or III Original clinical staged as III-IVa （according to the 8th AJCC edition）
  2. No evidence of distant metastasis (M0)
  3. Plasm EB Virus DNA≥1500copies/ml
  4. Male and no pregnant female
  5. Satisfactory performance status: ECOG (Eastern Cooperative OncologyGroup) scale 0-1
  6. WBC ≥ 4×109 /L and PLT ≥4×109 /L and HGB ≥90 g/L
  7. With normal liver function test (ALT、AST ≤ 2.5×ULN, TBIL≤ 2.0×ULN)
  8. With normal renal function test ( creatinine clearance ≥60 ml/min)

Exclusion Criteria:

  1. Patients have evidence of relapse or distant metastasis
  2. Histologically confirmed keratinizing squamous cell carcinoma (WHO I)
  3. Receiving radiotherapy or chemotherapy previously
  4. The presence of uncontrolled life-threatening illness
  5. 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.
  6. Suffered from other malignant tumors (except the cure of basal cell carcinoma or uterine cervical carcinoma in situ) previously.
  7. Patients who have been treated with inhibitors of immune regulation (CTLA-4, PD-1, PD-L1, etc.).
  8. Patients with immunodeficiency disease and history of organ transplantation.
  9. Patients who have used large doses of glucocorticoids, anti-cancer monoclonal antibodies, and other immunosuppressive agents within 4 weeks.
  10. HIV positive.
  11. Patients with significantly lower heart, liver, lung, kidney and bone marrow function.
  12. Severe, uncontrolled medical conditions and infections.
  13. At the same time using other test drugs or in other clinical trials.
  14. Refusal or inability to sign informed consent to participate in the trial.
  15. Other treatment contraindications.
  16. Emotional disturbance or mental illness, no civil capacity or limited capacity for civil conduct.
  17. Hepatitis B surface antigen (HBsAg) positive and HBVDNA ≥1000cps/ml.
  18. Patients with positive HCV antibody test results can only be included in the study when the polymerase chain reaction of HCV RNA is negative.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Qiuyan Chen, MD,PhD 86-20-87343380 chenqy@sysucc.org.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03925090
Other Study ID Numbers  ICMJE B2019-014-01
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hai-Qiang Mai,MD,PhD, Sun Yat-sen University
Study Sponsor  ICMJE Sun Yat-sen University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Overall Study Officials Mai, MD,PhD Sun Yat-Sen University Cancer Cente
PRS Account Sun Yat-sen University
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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