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出境医 / 临床实验 / 4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3

4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3

Study Description
Brief Summary:
A Phase I Clinical Study of 4th generation Chimeric Antigen Receptor T Cells Targeting Glypican-3 ( CAR-GPC3 T Cells) in Patients with Advanced Hepatocellular Carcinoma

Condition or disease Intervention/treatment Phase
Advanced Hepatocellular Carcinoma Drug: CAR-GPC3 T Cells Phase 1

Detailed Description:

This is a phase I open-label, single and multiple infusion, dose escalation/cohort expansion study to evaluate the safety, cell pharmacokinetics, and preliminary efficacy of CAR-GPC3 T cells, infused intravenously in subjects who have been diagnosed with GPC3 positive advanced hepatocellular carcinoma and refractory or intolerant to current standard systemic treatment.

Primary objectives:

•To evaluate the safety and tolerability of CAR-GPC3 T cells infused intravenously at escalating doses in patients with advanced hepatocellular carcinoma.

Secondary objectives:

  • To evaluate the cellular pharmacokinetics of CAR-GPC3 T cells
  • To evaluate the overall safety and tolerability of infusion of CAR-GPC3 T cells
  • To investigate the preliminary efficacy of CAR-GPC3 T cells in the treatment of advanced hepatocellular carcinoma
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Clinical Study of 4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3 ( CAR-GPC3 T Cells) in Patients With Advanced Hepatocellular Carcinoma
Actual Study Start Date : July 23, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: CAR-GPC3 T Cells
The subjects enrolled will be sequentially assigned to Part 1 at 3 dose levels via typical 3+3 dose escalation method and then Part 2, cohort expansion stage, 3 cohorts of CAR T therapy combination with currently available treatment for HCC. stage Part 1: Dose escalating: 3 dose level Part 2: 3 cohorts Cohort 1. Combination with tyrosine kinase inhibitors Cohort 2. Combination with PD-1 / PD-L1 monoclonal antibody Cohort 3. Combination with the drugs may benefit for patient at investigator's discretion
Drug: CAR-GPC3 T Cells
Pretreatment with fludarabine and cyclophosphamide CAR-GPC3 T Cells infusion

Outcome Measures
Primary Outcome Measures :
  1. Dose limited toxicity and Maximum Tolerated Dose [ Time Frame: After 28 days of single infusion ]
    Safety and tolerability


Secondary Outcome Measures :
  1. Number of cells [ Time Frame: Through week 52 or the second timepoint of cells undetectable ]
    1.the number of cell copies and cell persistence duration in peripheral blood) Pharmacokinetics is the "Implantation endpoint" which is defined as the number of copies of the CAR-GPC3 DNA in peripheral blood detected at each visit after infusion until any two consecutive test results are negative or below the detection limit. Duration of CAR-GPC3 T Cell persistence is the period from the day of infusion to the first negative test result or result lower than the detection limit

  2. Number of participants with treatment-related adverse events [ Time Frame: Through study completion, an average of 3 years ]

    Adverse events occurring through18 weeks and 52weeks post infusion, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc.

    Adverse events occurring through18 weeks and 52weeks post infusion, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc.


  3. Antitumor efficacy-Progression-free survival (PFS) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the day when the subject receives the first study treatment to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first

  4. Antitumor efficacy-Duration of response (DOR) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause.

  5. Antitumor efficacy-Duration of disease control (DDC) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first evaluation of CR, PR, or SD to the first evaluation of PD or any cause of death

  6. Antitumor efficacy-Overall survival (OS) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first study treatment to any cause of death

  7. Antitumor efficacy-Objective response rate (ORR) [ Time Frame: Through study completion, an average of 3 years ]
    The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%). In the event of PR or CR, the subjects should confirm it no less than 4 weeks after the first evaluation

  8. Antitumor efficacy-Disease control rate (DCR) [ Time Frame: Through study completion, an average of 3 years ]
    The number of cases in which response (PR + CR) and stable disease (SD) are achieved from the start of cell infusion/the total number of evaluable cases (%).


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 18 to 75 years, male or female;
  2. Patients with advanced hepatocellular carcinoma (HCC) diagnosed by histopathology or cytology who are not suitable for surgery or local treatment, have developed progressive disease or intolerability after standard systemic therapies (including but not limited to systemic chemotherapy, molecular targeted therapy);
  3. According to BCLC, the patients are classified into Grade C or Grade B unsuitable for local treatment/progressive disease after local treatment;
  4. In tumor tissue samples GPC3 is detected positive by immunohistochemistry (IHC);
  5. According to RECIST 1.1, patients have at least one evaluable target lesion, defined as: the longest diameter of non-lymph node lesion ≥ 10 mm, or the shortest diameter of lymph node lesion ≥ 15 mm); hepatic lesions require arterial phase contrast enhancement;
  6. Expected survival is > 12 weeks;
  7. Cirrhosis status Child-Pugh score:≤7;
  8. ECOG Performance Status score: 0 to 1 point;
  9. If the patient is HBsAg positive or HBcAb positive, HBV-DNA should be <200 IU/ml. HBsAg positive patients must receive antiviral treatment according to the 2015 China Edition of Guideline for Chronic Hepatitis B Prevention and Treatment;
  10. Subjects should have adequate organ functions before screening and pre-treatment (at baseline);
  11. Have venous accesses for pheresis;
  12. Subjects of childbearing age must undergo a serum pregnancy test within 14 days before the initiation of the study and the result must be negative. In addition, they should be willing to use a reliable method of contraception during the trial (within 52 weeks after cell infusion); male subjects whose spouses are women of childbearing age should undergo sterilization surgery or agree to use a reliable method of contraception during the trial;
  13. Understand and sign informed consent.

Exclusion Criteria:

  1. Pregnant or breast-feeding women;
  2. HCV-RNA, HIV antibodies or Syphilis Serological tests are positive;
  3. Any uncontrollable active infection, including but not limited to active tuberculosis;
  4. Subjects have clinically significant thyroid dysfunction determined by investigator (serum thyroid hormone assays TT4, TT3, FT3, FT4, and serum thyroid stimulating hormone TSH) which is not suitable for entering into the study;
  5. Previous or present hepatic encephalopathy;
  6. Current clinically significant ascites, which is defined as ascites that are physically positive or require intervention (e.g., puncture or medication) for control (those whose imaging result shows ascites requiring no intervention may be included);
  7. Imaging results:≥50% of the liver is replaced by tumor or portal vein main tumor thrombus, or tumor thrombus invasion of mesenteric vein / inferior vena cava;
  8. Patients with known active autoimmune diseases which require to be treated with immunosuppressive agents including biological agents;
  9. The side effects caused by the previous treatment of the subjects did not return to CTCAE ≤1; except hair loss and other tolerable events determined by investigator;
  10. Patients who had received systemic steroids or other immunosuppressive agents within 2 weeks before collection of mononuclear cells, except those who had recently used or are currently using inhaled steroids;
  11. Allergic to immunotherapy and related drugs;
  12. Subjects have untreated or symptomatic brain metastases;
  13. Subjects have central or extensively metastases in lung;
  14. Subjects with unstable or active ulcers and gastrointestinal bleeding currently;
  15. Patients with a history of organ transplantation or waiting for organ transplantation (including liver transplantation);
  16. Subjects who have undergone antitumor therapy within 2 weeks prior to apheresis;
  17. Previously received any chimeric antigen receptor-modified T-cells (CAR-T) , TCR T immunotherapy;
  18. Subjects who have undergone PD-1/PD-L1 therapy within 3 months prior to screening;
  19. Subjects who have undergone major surgery or significant trauma within 4 weeks prior to apheresis, or who are expected to undergo major surgery during the study;
  20. There are no other serious diseases that may limit subjects' participation in this trial;
  21. Prior to pretreatment and infusion,the subject has a central nervous system disease sign or an abnormal neurological test result with clinical significance;
  22. Prior to pretreatment, subjects developed, including but not limited to, new arrhythmias that could not be controlled with drugs, hypotension requiring pressor agent, bacterial, fungal or viral infections that required intravenous antibiotics. Creatinine clearance rate <50mL/min; The investigator judges that the subject is not suitable for continuing the trial. Subjects who use antibiotics to prevent infection can continue the trials if judged by the investigator;
  23. According to the investigators' evaluation, patients are unable or unwilling to comply with the requirements of the study protocol.
Contacts and Locations

Contacts
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Contact: Weijia Fang +86 15088681610 weijiafang@zju.edu.cn
Contact: Qihan Fu +86 15088681610

Locations
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China, Zhejiang
First affiliated hospital, Zhejiang University Recruiting
Hangzhou, Zhejiang, China, 310006
Contact: Weijia fang, MD         
Principal Investigator: Tingbo Liang, MD         
Sponsors and Collaborators
Zhejiang University
Carsgen Therapeutics, Ltd.
Investigators
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Principal Investigator: Tingbo Liang The First Affiliated Hospital, Zhejiang University
Tracking Information
First Submitted Date  ICMJE June 2, 2019
First Posted Date  ICMJE June 10, 2019
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE July 23, 2019
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
Dose limited toxicity and Maximum Tolerated Dose [ Time Frame: After 28 days of single infusion ]
Safety and tolerability
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Number of cells [ Time Frame: Through week 52 or the second timepoint of cells undetectable ]
    1.the number of cell copies and cell persistence duration in peripheral blood) Pharmacokinetics is the "Implantation endpoint" which is defined as the number of copies of the CAR-GPC3 DNA in peripheral blood detected at each visit after infusion until any two consecutive test results are negative or below the detection limit. Duration of CAR-GPC3 T Cell persistence is the period from the day of infusion to the first negative test result or result lower than the detection limit
  • Number of participants with treatment-related adverse events [ Time Frame: Through study completion, an average of 3 years ]
    Adverse events occurring through18 weeks and 52weeks post infusion, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc. Adverse events occurring through18 weeks and 52weeks post infusion, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc.
  • Antitumor efficacy-Progression-free survival (PFS) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the day when the subject receives the first study treatment to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first
  • Antitumor efficacy-Duration of response (DOR) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause.
  • Antitumor efficacy-Duration of disease control (DDC) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first evaluation of CR, PR, or SD to the first evaluation of PD or any cause of death
  • Antitumor efficacy-Overall survival (OS) [ Time Frame: Through study completion, an average of 3 years ]
    The period from the first study treatment to any cause of death
  • Antitumor efficacy-Objective response rate (ORR) [ Time Frame: Through study completion, an average of 3 years ]
    The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%). In the event of PR or CR, the subjects should confirm it no less than 4 weeks after the first evaluation
  • Antitumor efficacy-Disease control rate (DCR) [ Time Frame: Through study completion, an average of 3 years ]
    The number of cases in which response (PR + CR) and stable disease (SD) are achieved from the start of cell infusion/the total number of evaluable cases (%).
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 4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3
Official Title  ICMJE A Phase I Clinical Study of 4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3 ( CAR-GPC3 T Cells) in Patients With Advanced Hepatocellular Carcinoma
Brief Summary A Phase I Clinical Study of 4th generation Chimeric Antigen Receptor T Cells Targeting Glypican-3 ( CAR-GPC3 T Cells) in Patients with Advanced Hepatocellular Carcinoma
Detailed Description

This is a phase I open-label, single and multiple infusion, dose escalation/cohort expansion study to evaluate the safety, cell pharmacokinetics, and preliminary efficacy of CAR-GPC3 T cells, infused intravenously in subjects who have been diagnosed with GPC3 positive advanced hepatocellular carcinoma and refractory or intolerant to current standard systemic treatment.

Primary objectives:

•To evaluate the safety and tolerability of CAR-GPC3 T cells infused intravenously at escalating doses in patients with advanced hepatocellular carcinoma.

Secondary objectives:

  • To evaluate the cellular pharmacokinetics of CAR-GPC3 T cells
  • To evaluate the overall safety and tolerability of infusion of CAR-GPC3 T cells
  • To investigate the preliminary efficacy of CAR-GPC3 T cells in the treatment of advanced hepatocellular carcinoma
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Hepatocellular Carcinoma
Intervention  ICMJE Drug: CAR-GPC3 T Cells
Pretreatment with fludarabine and cyclophosphamide CAR-GPC3 T Cells infusion
Study Arms  ICMJE Experimental: CAR-GPC3 T Cells
The subjects enrolled will be sequentially assigned to Part 1 at 3 dose levels via typical 3+3 dose escalation method and then Part 2, cohort expansion stage, 3 cohorts of CAR T therapy combination with currently available treatment for HCC. stage Part 1: Dose escalating: 3 dose level Part 2: 3 cohorts Cohort 1. Combination with tyrosine kinase inhibitors Cohort 2. Combination with PD-1 / PD-L1 monoclonal antibody Cohort 3. Combination with the drugs may benefit for patient at investigator's discretion
Intervention: Drug: CAR-GPC3 T Cells
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: June 5, 2019)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2022
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Aged 18 to 75 years, male or female;
  2. Patients with advanced hepatocellular carcinoma (HCC) diagnosed by histopathology or cytology who are not suitable for surgery or local treatment, have developed progressive disease or intolerability after standard systemic therapies (including but not limited to systemic chemotherapy, molecular targeted therapy);
  3. According to BCLC, the patients are classified into Grade C or Grade B unsuitable for local treatment/progressive disease after local treatment;
  4. In tumor tissue samples GPC3 is detected positive by immunohistochemistry (IHC);
  5. According to RECIST 1.1, patients have at least one evaluable target lesion, defined as: the longest diameter of non-lymph node lesion ≥ 10 mm, or the shortest diameter of lymph node lesion ≥ 15 mm); hepatic lesions require arterial phase contrast enhancement;
  6. Expected survival is > 12 weeks;
  7. Cirrhosis status Child-Pugh score:≤7;
  8. ECOG Performance Status score: 0 to 1 point;
  9. If the patient is HBsAg positive or HBcAb positive, HBV-DNA should be <200 IU/ml. HBsAg positive patients must receive antiviral treatment according to the 2015 China Edition of Guideline for Chronic Hepatitis B Prevention and Treatment;
  10. Subjects should have adequate organ functions before screening and pre-treatment (at baseline);
  11. Have venous accesses for pheresis;
  12. Subjects of childbearing age must undergo a serum pregnancy test within 14 days before the initiation of the study and the result must be negative. In addition, they should be willing to use a reliable method of contraception during the trial (within 52 weeks after cell infusion); male subjects whose spouses are women of childbearing age should undergo sterilization surgery or agree to use a reliable method of contraception during the trial;
  13. Understand and sign informed consent.

Exclusion Criteria:

  1. Pregnant or breast-feeding women;
  2. HCV-RNA, HIV antibodies or Syphilis Serological tests are positive;
  3. Any uncontrollable active infection, including but not limited to active tuberculosis;
  4. Subjects have clinically significant thyroid dysfunction determined by investigator (serum thyroid hormone assays TT4, TT3, FT3, FT4, and serum thyroid stimulating hormone TSH) which is not suitable for entering into the study;
  5. Previous or present hepatic encephalopathy;
  6. Current clinically significant ascites, which is defined as ascites that are physically positive or require intervention (e.g., puncture or medication) for control (those whose imaging result shows ascites requiring no intervention may be included);
  7. Imaging results:≥50% of the liver is replaced by tumor or portal vein main tumor thrombus, or tumor thrombus invasion of mesenteric vein / inferior vena cava;
  8. Patients with known active autoimmune diseases which require to be treated with immunosuppressive agents including biological agents;
  9. The side effects caused by the previous treatment of the subjects did not return to CTCAE ≤1; except hair loss and other tolerable events determined by investigator;
  10. Patients who had received systemic steroids or other immunosuppressive agents within 2 weeks before collection of mononuclear cells, except those who had recently used or are currently using inhaled steroids;
  11. Allergic to immunotherapy and related drugs;
  12. Subjects have untreated or symptomatic brain metastases;
  13. Subjects have central or extensively metastases in lung;
  14. Subjects with unstable or active ulcers and gastrointestinal bleeding currently;
  15. Patients with a history of organ transplantation or waiting for organ transplantation (including liver transplantation);
  16. Subjects who have undergone antitumor therapy within 2 weeks prior to apheresis;
  17. Previously received any chimeric antigen receptor-modified T-cells (CAR-T) , TCR T immunotherapy;
  18. Subjects who have undergone PD-1/PD-L1 therapy within 3 months prior to screening;
  19. Subjects who have undergone major surgery or significant trauma within 4 weeks prior to apheresis, or who are expected to undergo major surgery during the study;
  20. There are no other serious diseases that may limit subjects' participation in this trial;
  21. Prior to pretreatment and infusion,the subject has a central nervous system disease sign or an abnormal neurological test result with clinical significance;
  22. Prior to pretreatment, subjects developed, including but not limited to, new arrhythmias that could not be controlled with drugs, hypotension requiring pressor agent, bacterial, fungal or viral infections that required intravenous antibiotics. Creatinine clearance rate <50mL/min; The investigator judges that the subject is not suitable for continuing the trial. Subjects who use antibiotics to prevent infection can continue the trials if judged by the investigator;
  23. According to the investigators' evaluation, patients are unable or unwilling to comply with the requirements of the study protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Weijia Fang +86 15088681610 weijiafang@zju.edu.cn
Contact: Qihan Fu +86 15088681610
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03980288
Other Study ID Numbers  ICMJE CISLD-4
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 TingBo Liang, Zhejiang University
Study Sponsor  ICMJE Zhejiang University
Collaborators  ICMJE Carsgen Therapeutics, Ltd.
Investigators  ICMJE
Principal Investigator: Tingbo Liang The First Affiliated Hospital, Zhejiang University
PRS Account Zhejiang University
Verification Date October 2019

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