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出境医 / 临床实验 / Study of Adoptive Transfer of iNKT Cells Combined With TACE to Treat Advanced HCC

Study of Adoptive Transfer of iNKT Cells Combined With TACE to Treat Advanced HCC

Study Description
Brief Summary:
Hepatocellular carcinoma (HCC) is a common disease with high mortality. More than 80% patients are first diagnosed with late-stage and unresectable, their effective drugs and treatments are very limited. invariant Natural Killer T (iNKT) cell exhibit antitumor activity against malignant tumors through producing high levels of cytokines. iNKT cells are abundant in the liver, but defect in liver cancer development. iNKT cells can express homing receptors licensing them specifically to migrate liver, then play key antitumor immunity. We already did a phase I study of autologous infusion of iNKT cells in the treatment of patients with advanced HCC. Safety and feasibility of iNKT infusion was proved. The purpose of this study is to verify the effectiveness of iNKT cells infusion combined with transcatheter arterial chemoembolization (TACE) in treatment of advanced HCC.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Biological: iNKT cells Drug: Cyclophosphamide Drug: Human recombinated Interleukin-2 Procedure: TACE Phase 2 Phase 3

Detailed Description:
Patients with advanced HCC will be enrolled and divided into two groups. Patients in experimental group will be treated with TACE combined with iNKT cells infusion. TACE will be performed at 0th and 4th week. iNKT cells will be infused at 1st, 3rd, 5th, 7th, 8th and 12th week. Patients in control group will be treated with TACE at 0th and 4th week. Adverse events(AEs), overall survival (OS) time and recurrence-free survival (RFS) time, change of immune cells will be monitored.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Adoptive Transfer of Invariant Natural Killer T Cells Combined With Transcatheter Arterial Chemoembolization (TACE) to Treat Advanced Hepatocellular Carcinoma (HCC): Phase II Clinical Trial
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: TACE+iNKT for unresectable HCC
TACE combined with autologous iNKT cells infusion will be applied for patients in experimental group. TACE will be performed at 0th and 4th week. 5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week.
Biological: iNKT cells
5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week.
Other Name: invariant Natural Killer T cells

Drug: Cyclophosphamide
CTX will be administered intravenously at a dose of 750mg/m2 2 days before the first iNKT cells infusion.
Other Name: CTX

Drug: Human recombinated Interleukin-2
IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days after iNKT cells infusion.
Other Name: IL-2

Procedure: TACE
TACE will be conducted to all patients at 0th week and 4th week.
Other Name: Transcatheter Arterial Chemoembolization

TACE for unresectable HCC
TACE will be conducted at 0th week and 4th week.
Procedure: TACE
TACE will be conducted to all patients at 0th week and 4th week.
Other Name: Transcatheter Arterial Chemoembolization

Outcome Measures
Primary Outcome Measures :
  1. Overall Survival(OS) [ Time Frame: 3 months or up to death ]
    OS is the duration from the date of enrollment to the date of death due to any causes.

  2. Progression-Free Survival(PFS) [ Time Frame: 3 months or up to death ]
    PFS is the duration from the date of enrolled into clinical trial to the date of first documentation of tumor progression.

  3. Disease Control Rate (DCR) [ Time Frame: 3 months or up to death ]
    DCR is the proportion of patients who had a response rate including complete remission (CR), partial remission (PR) and disease stabilization (SD) evaluated by imaging according to the irRC standard.


Secondary Outcome Measures :
  1. Immunological Monitoring [ Time Frame: Frequencies of immune cells will be monitored at 0th, 4th, 8th and 12th week. ]
    Frequencies of immune cells such as iNKT cells, natural killer cells (NK) , regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), et al will be analyzed by flow cytometry before and after iNKT infusion.

  2. Adverse Events(AEs) [ Time Frame: The occurrence and severities of AEs will be recorded within 12-13 weeks after iNKT cells infusion. ]
    The severities of AEs will be divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03.

  3. Alpha-fetoprotein (AFP) [ Time Frame: 3 months or up to death ]
    AFP is the best-defined tumor marker for HCC, and it is widely used in clinical settings as an adjuvant diagnostic and prognostic indicator.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-80 years.
  • Patients with hepatocellular carcinoma (BCLC, stage C) proved by histopathology or proved by CT or MRI imaging system, relapsed after previous therapy and no effective therapies known at this time.
  • Life expectancy of ≥ 12 weeks.
  • WBC>3.0×10^9/L, LYMPH> 0.8×10^9/L, Hb>85g/L, PLT>50×10^9/L, Cre<1.5×the upper limit of normal value.
  • iNKT>10/mL in peripheral blood mononuclear cell (PBMC).
  • Able to understand and sign the informed consent.

Exclusion Criteria:

  • Any uncontrolled systematic disease: hypertension, heart disease, and et al.;
  • Portal vein tumor thrombus, central nervous system tumor metastasis, or combined with other tumors;
  • Receiving radiochemotherapy, local therapy, or targeting drugs within 4 weeks prior to this treatment;
  • Unstable immune systematic diseases or infectious diseases;
  • Combined with AIDS or syphilis;
  • Patients with history of stem cell or organ transplantation;
  • Patients with allergic history to related drugs and immunotherapy;
  • Patients with complications associated with liver diseases: moderate or severe pleural effusion, pericardial effusion, ascites, or gastrointestinal hemorrhage;
  • Pregnant or lactating subjects;
  • Unsuitable subjects considered by clinicians.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jun Lu, Director 86-13661381489 lujun98@ccmu.edu.cn
Contact: Jia Guo, Clinician 86-18612238992 15210775497@163.com

Locations
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China, Beijing
Beijing Youan Hospital,Capital Medical University Recruiting
Beijing, Beijing, China, 100069
Contact: Xuli Bao, Clinician    86-13161935299    bxli2001@163.com   
Sponsors and Collaborators
Beijing YouAn Hospital
Investigators
Layout table for investigator information
Study Chair: Jun Lu, Director Beijing YouAn Hospital
Tracking Information
First Submitted Date  ICMJE July 3, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date July 8, 2019
Actual Study Start Date  ICMJE March 1, 2019
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • Overall Survival(OS) [ Time Frame: 3 months or up to death ]
    OS is the duration from the date of enrollment to the date of death due to any causes.
  • Progression-Free Survival(PFS) [ Time Frame: 3 months or up to death ]
    PFS is the duration from the date of enrolled into clinical trial to the date of first documentation of tumor progression.
  • Disease Control Rate (DCR) [ Time Frame: 3 months or up to death ]
    DCR is the proportion of patients who had a response rate including complete remission (CR), partial remission (PR) and disease stabilization (SD) evaluated by imaging according to the irRC standard.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • Immunological Monitoring [ Time Frame: Frequencies of immune cells will be monitored at 0th, 4th, 8th and 12th week. ]
    Frequencies of immune cells such as iNKT cells, natural killer cells (NK) , regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), et al will be analyzed by flow cytometry before and after iNKT infusion.
  • Adverse Events(AEs) [ Time Frame: The occurrence and severities of AEs will be recorded within 12-13 weeks after iNKT cells infusion. ]
    The severities of AEs will be divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03.
  • Alpha-fetoprotein (AFP) [ Time Frame: 3 months or up to death ]
    AFP is the best-defined tumor marker for HCC, and it is widely used in clinical settings as an adjuvant diagnostic and prognostic indicator.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Adoptive Transfer of iNKT Cells Combined With TACE to Treat Advanced HCC
Official Title  ICMJE Study of Adoptive Transfer of Invariant Natural Killer T Cells Combined With Transcatheter Arterial Chemoembolization (TACE) to Treat Advanced Hepatocellular Carcinoma (HCC): Phase II Clinical Trial
Brief Summary Hepatocellular carcinoma (HCC) is a common disease with high mortality. More than 80% patients are first diagnosed with late-stage and unresectable, their effective drugs and treatments are very limited. invariant Natural Killer T (iNKT) cell exhibit antitumor activity against malignant tumors through producing high levels of cytokines. iNKT cells are abundant in the liver, but defect in liver cancer development. iNKT cells can express homing receptors licensing them specifically to migrate liver, then play key antitumor immunity. We already did a phase I study of autologous infusion of iNKT cells in the treatment of patients with advanced HCC. Safety and feasibility of iNKT infusion was proved. The purpose of this study is to verify the effectiveness of iNKT cells infusion combined with transcatheter arterial chemoembolization (TACE) in treatment of advanced HCC.
Detailed Description Patients with advanced HCC will be enrolled and divided into two groups. Patients in experimental group will be treated with TACE combined with iNKT cells infusion. TACE will be performed at 0th and 4th week. iNKT cells will be infused at 1st, 3rd, 5th, 7th, 8th and 12th week. Patients in control group will be treated with TACE at 0th and 4th week. Adverse events(AEs), overall survival (OS) time and recurrence-free survival (RFS) time, change of immune cells will be monitored.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE
  • Biological: iNKT cells
    5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week.
    Other Name: invariant Natural Killer T cells
  • Drug: Cyclophosphamide
    CTX will be administered intravenously at a dose of 750mg/m2 2 days before the first iNKT cells infusion.
    Other Name: CTX
  • Drug: Human recombinated Interleukin-2
    IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days after iNKT cells infusion.
    Other Name: IL-2
  • Procedure: TACE
    TACE will be conducted to all patients at 0th week and 4th week.
    Other Name: Transcatheter Arterial Chemoembolization
Study Arms  ICMJE
  • Experimental: TACE+iNKT for unresectable HCC
    TACE combined with autologous iNKT cells infusion will be applied for patients in experimental group. TACE will be performed at 0th and 4th week. 5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week.
    Interventions:
    • Biological: iNKT cells
    • Drug: Cyclophosphamide
    • Drug: Human recombinated Interleukin-2
    • Procedure: TACE
  • TACE for unresectable HCC
    TACE will be conducted at 0th week and 4th week.
    Intervention: Procedure: TACE
Publications * Not Provided

*   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: July 5, 2019)
144
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18-80 years.
  • Patients with hepatocellular carcinoma (BCLC, stage C) proved by histopathology or proved by CT or MRI imaging system, relapsed after previous therapy and no effective therapies known at this time.
  • Life expectancy of ≥ 12 weeks.
  • WBC>3.0×10^9/L, LYMPH> 0.8×10^9/L, Hb>85g/L, PLT>50×10^9/L, Cre<1.5×the upper limit of normal value.
  • iNKT>10/mL in peripheral blood mononuclear cell (PBMC).
  • Able to understand and sign the informed consent.

Exclusion Criteria:

  • Any uncontrolled systematic disease: hypertension, heart disease, and et al.;
  • Portal vein tumor thrombus, central nervous system tumor metastasis, or combined with other tumors;
  • Receiving radiochemotherapy, local therapy, or targeting drugs within 4 weeks prior to this treatment;
  • Unstable immune systematic diseases or infectious diseases;
  • Combined with AIDS or syphilis;
  • Patients with history of stem cell or organ transplantation;
  • Patients with allergic history to related drugs and immunotherapy;
  • Patients with complications associated with liver diseases: moderate or severe pleural effusion, pericardial effusion, ascites, or gastrointestinal hemorrhage;
  • Pregnant or lactating subjects;
  • Unsuitable subjects considered by clinicians.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jun Lu, Director 86-13661381489 lujun98@ccmu.edu.cn
Contact: Jia Guo, Clinician 86-18612238992 15210775497@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04011033
Other Study ID Numbers  ICMJE Beijing Youan Ethics[2019]034
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 LU JUN, Beijing YouAn Hospital
Study Sponsor  ICMJE Beijing YouAn Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Jun Lu, Director Beijing YouAn Hospital
PRS Account Beijing YouAn Hospital
Verification Date July 2019

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