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出境医 / 临床实验 / Toripalimab Combined With Gemcitabine/5--fluoropyrimidine for Advanced Cholangiocarcinoma

Toripalimab Combined With Gemcitabine/5--fluoropyrimidine for Advanced Cholangiocarcinoma

Study Description
Brief Summary:
The study is a phase II clinical trial of single arm. The purpose is to evaluate the safety and efficacy of anti-PD-1 antibody Toripalimab combined with chemotherapy(gemcitabine+5-fluorine pyrimidine) in unresectable advanced cholangiocarcinoma patients.

Condition or disease Intervention/treatment Phase
Advanced Cholangiocarcinoma Drug: Toripalimab Drug: Gemcitabine Drug: 5- fluorine pyrimidine Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: All patients were given Toripalimab 3 mg/kg (day 1 and 15); Gem+5-FU (Gem 1250mg/m2+CF 200 mg/m2+5-FU400 mg/m2 intravenous drip+5-FU 2.4-3.6 g/m2 continuous intravenous drip for 48 hours), the first and fifteenth days, four weeks for a cycle, a total of four cycles. After 4 cycles, Toripalimab was maintained at 3 mg/kg Q3 w for a total of 1 year if the disease was not progressing or toxic side effects were tolerated.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Study of Toripalimab Monoclonal Antibody Combined With Gemcitabine/5--fluoropyrimidine in the Treatment of Advanced Cholangiocarcinoma
Actual Study Start Date : July 13, 2019
Estimated Primary Completion Date : May 30, 2021
Estimated Study Completion Date : December 30, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Toripalimab combined with Gem/5-FU
All patients were given Toripalimab 3 mg/kg (day 1 and 15); Gem+5-FU (Gem 1250mg/m2+CF 200 mg/m2+5-FU400 mg/m2 intravenous drip+5-FU 2.4-3.6 g/m2 continuous intravenous drip for 48 hours), the first and fifteenth days, four weeks for a cycle, a total of four cycles.After 4 cycles, Toripalimab was maintained at 3 mg/kg Q3 w for a total of 1 year if the disease was not progressing or toxic side effects were tolerated.
 Drug: Toripalimab
3mg/kg on d1 and d15 q4W*4cycles，then 3mg/kg q3w for 1 year in total

Drug: Gemcitabine
1250mg/m2 on d1 and d15 q4W*4cycles
Other Name: Gem

Drug: 5- fluorine pyrimidine
400mg/m2 intravenous injection plus 5-FU 2.4g-3.6g/m2 continuous intravenous drip for 48h on d1 and d15 q4W*4cycles
Other Name: 5-FU
Outcome Measures
Primary Outcome Measures :
  1. 6-month PFS rate [ Time Frame: 6-month after the beginning of first line systemic therapy ]
    the rate of 6-month progression free survival

  2. mPFS [ Time Frame: from the beginning of the first line systemic therapy until the date of first documented progression or date of death from any cause,whichever came first,assessed up to 24 months ]
    the median of progression free survival

  3. Toxic side effects [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    assess according to the National Cancer Institute-Common Terminology Criteria for Adverse Events 3.0


Secondary Outcome Measures :
  1. ORR [ Time Frame: from the beginning of the first line systemic therapy until the date of completion of therapy,assessed up to 13 months ]
    the objective response rate

  2. DCR [ Time Frame: from the beginning of the first line systemic therapy until the date of completion of therapy,assessed up to 13 months ]
    the disease control rate

  3. 1-year OS rate [ Time Frame: 1 year after the beginning of the first line systemic therapy ]
    the rate of 1-year overall survival

  4. mOS [ Time Frame: from the beginning of the first line systemic therapy until the date of death from any cause,assessed up to 24 months ]
    the median of overall survival


Other Outcome Measures:
  1. the value of PD-1/PD-L1 [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    to analyze the predictive value of PD-1/PD-L1 for efficacy and toxicity

  2. the value of MMR [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    to analyze the predictive value of MMR for efficacy and toxicity


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • histologically or cytologically confirmed cholangiocarcinoma
  • stage IV disease,no system therapy for advanced disease
  • one or more lesions that can be measured by imaging assessment
  • 18 to 70 years of age and life expectancy exceeds 3 months
  • adequate specimens for detection of PD-1/PD-L1 and MMR
  • karnofsky performance status(KPS) score ≥70%
  • routine blood routine, liver and kidney function and electrocardiogram were basically normal without contraindication of chemotherapy.

Exclusion Criteria:

  • dual cancers other than cholangiocarcinoma
  • metastasis of central nervous system
  • unreleased biliary obstruction
  • acute infections requiring treatment
  • non-infectious pneumonia requires glucocorticoid therapy, active autoimmune diseases, or systemic immunosuppressive therapy.
Contacts and Locations

Contacts
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Contact: Deng wenjing, master (+86)07503165905 wjdeng2011@163.com
Contact: Yu gengsheng, master (+86)07503165915 gengsheng_yu@hotmail.com

Locations
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China, Guangdong
Jiangmen central hospital Recruiting
Jiangmen, Guangdong, China, 529000
Contact: Wenjing Deng, master    +8607503165905    wjdeng2011@163.com   
Contact: Gengsheng Yu, master    +8607503165905    gengsheng_yu@hotmail.com   
Sponsors and Collaborators
Jiangmen Central Hospital
Investigators
Layout table for investigator information
Study Director: Yu gengsheng, master jiangmen cenctral hospital
Tracking Information
First Submitted Date  ICMJE June 7, 2019
First Posted Date  ICMJE June 11, 2019
Last Update Posted Date July 16, 2019
Actual Study Start Date  ICMJE July 13, 2019
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 9, 2019)
  • 6-month PFS rate [ Time Frame: 6-month after the beginning of first line systemic therapy ]
    the rate of 6-month progression free survival
  • mPFS [ Time Frame: from the beginning of the first line systemic therapy until the date of first documented progression or date of death from any cause,whichever came first,assessed up to 24 months ]
    the median of progression free survival
  • Toxic side effects [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    assess according to the National Cancer Institute-Common Terminology Criteria for Adverse Events 3.0
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 9, 2019)
  • ORR [ Time Frame: from the beginning of the first line systemic therapy until the date of completion of therapy,assessed up to 13 months ]
    the objective response rate
  • DCR [ Time Frame: from the beginning of the first line systemic therapy until the date of completion of therapy,assessed up to 13 months ]
    the disease control rate
  • 1-year OS rate [ Time Frame: 1 year after the beginning of the first line systemic therapy ]
    the rate of 1-year overall survival
  • mOS [ Time Frame: from the beginning of the first line systemic therapy until the date of death from any cause,assessed up to 24 months ]
    the median of overall survival
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 9, 2019)
  • the value of PD-1/PD-L1 [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    to analyze the predictive value of PD-1/PD-L1 for efficacy and toxicity
  • the value of MMR [ Time Frame: from the beginning of the first line systemic therapy until the end of follow-up,assessed up to 24 months ]
    to analyze the predictive value of MMR for efficacy and toxicity
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Toripalimab Combined With Gemcitabine/5--fluoropyrimidine for Advanced Cholangiocarcinoma
Official Title  ICMJE Clinical Study of Toripalimab Monoclonal Antibody Combined With Gemcitabine/5--fluoropyrimidine in the Treatment of Advanced Cholangiocarcinoma
Brief Summary The study is a phase II clinical trial of single arm. The purpose is to evaluate the safety and efficacy of anti-PD-1 antibody Toripalimab combined with chemotherapy(gemcitabine+5-fluorine pyrimidine) in unresectable advanced cholangiocarcinoma patients.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
All patients were given Toripalimab 3 mg/kg (day 1 and 15); Gem+5-FU (Gem 1250mg/m2+CF 200 mg/m2+5-FU400 mg/m2 intravenous drip+5-FU 2.4-3.6 g/m2 continuous intravenous drip for 48 hours), the first and fifteenth days, four weeks for a cycle, a total of four cycles. After 4 cycles, Toripalimab was maintained at 3 mg/kg Q3 w for a total of 1 year if the disease was not progressing or toxic side effects were tolerated.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Cholangiocarcinoma
Intervention  ICMJE
  • Drug: Toripalimab
    3mg/kg on d1 and d15 q4W*4cycles，then 3mg/kg q3w for 1 year in total
  • Drug: Gemcitabine
    1250mg/m2 on d1 and d15 q4W*4cycles
    Other Name: Gem
  • Drug: 5- fluorine pyrimidine
    400mg/m2 intravenous injection plus 5-FU 2.4g-3.6g/m2 continuous intravenous drip for 48h on d1 and d15 q4W*4cycles
    Other Name: 5-FU
Study Arms  ICMJE Experimental: Toripalimab combined with Gem/5-FU
All patients were given Toripalimab 3 mg/kg (day 1 and 15); Gem+5-FU (Gem 1250mg/m2+CF 200 mg/m2+5-FU400 mg/m2 intravenous drip+5-FU 2.4-3.6 g/m2 continuous intravenous drip for 48 hours), the first and fifteenth days, four weeks for a cycle, a total of four cycles.After 4 cycles, Toripalimab was maintained at 3 mg/kg Q3 w for a total of 1 year if the disease was not progressing or toxic side effects were tolerated.
Interventions:
  • Drug: Toripalimab
  • Drug: Gemcitabine
  • Drug: 5- fluorine pyrimidine
Publications *
  • GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117-71. doi: 10.1016/S0140-6736(14)61682-2. Epub 2014 Dec 18.
  • Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol. 2016 Oct;7(5):797-803. Review.
  • Takakura H, Domae S, Ono T, Sasaki A. The Immunological Impact of Chemotherapy on the Tumor Microenvironment of Oral Squamous Cell Carcinoma. Acta Med Okayama. 2017 Jun;71(3):219-226. doi: 10.18926/AMO/55204.
  • Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, Mueller B, Quaratino S, Sabatos-Peyton C, Petruzzelli L, Engelman JA, Dranoff G. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017 May;17(5):286-301. doi: 10.1038/nrc.2017.17. Epub 2017 Mar 24. Review.
  • Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, Nagino M, Kondo S, Nagaoka S, Funai J, Koshiji M, Nambu Y, Furuse J, Miyazaki M, Nimura Y. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010 Aug 10;103(4):469-74. doi: 10.1038/sj.bjc.6605779. Epub 2010 Jul 13.
  • Morizane C, Ueno M, Ikeda M, Okusaka T, Ishii H, Furuse J. New developments in systemic therapy for advanced biliary tract cancer. Jpn J Clin Oncol. 2018 Aug 1;48(8):703-711. doi: 10.1093/jjco/hyy082. Review.
  • Sabbatino F, Villani V, Yearley JH, Deshpande V, Cai L, Konstantinidis IT, Moon C, Nota S, Wang Y, Al-Sukaini A, Zhu AX, Goyal L, Ting DT, Bardeesy N, Hong TS, Fernandez-del Castillo C, Tanabe KK, Lillemoe KD, Ferrone S, Ferrone CR. PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma. Clin Cancer Res. 2016 Jan 15;22(2):470-8. doi: 10.1158/1078-0432.CCR-15-0715. Epub 2015 Sep 15.
  • Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014 Oct 1;20(19):5064-74. doi: 10.1158/1078-0432.CCR-13-3271. Epub 2014 Apr 8.
  • 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.
  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.
  • Gou M, Zhang Y, Si H, Dai G. Efficacy and safety of nivolumab for metastatic biliary tract cancer. Onco Targets Ther. 2019 Jan 25;12:861-867. doi: 10.2147/OTT.S195537. eCollection 2019.
  • Asaoka Y, Ijichi H, Koike K. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Nov 12;373(20):1979. doi: 10.1056/NEJMc1510353.

*   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: June 9, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2021
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • histologically or cytologically confirmed cholangiocarcinoma
  • stage IV disease,no system therapy for advanced disease
  • one or more lesions that can be measured by imaging assessment
  • 18 to 70 years of age and life expectancy exceeds 3 months
  • adequate specimens for detection of PD-1/PD-L1 and MMR
  • karnofsky performance status(KPS) score ≥70%
  • routine blood routine, liver and kidney function and electrocardiogram were basically normal without contraindication of chemotherapy.

Exclusion Criteria:

  • dual cancers other than cholangiocarcinoma
  • metastasis of central nervous system
  • unreleased biliary obstruction
  • acute infections requiring treatment
  • non-infectious pneumonia requires glucocorticoid therapy, active autoimmune diseases, or systemic immunosuppressive therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Deng wenjing, master (+86)07503165905 wjdeng2011@163.com
Contact: Yu gengsheng, master (+86)07503165915 gengsheng_yu@hotmail.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03982680
Other Study ID Numbers  ICMJE cholangiocarcinoma
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Responsible Party yu gengsheng, Jiangmen Central Hospital
Study Sponsor  ICMJE Jiangmen Central Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Yu gengsheng, master jiangmen cenctral hospital
PRS Account Jiangmen Central Hospital
Verification Date July 2019

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

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