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出境医 / 临床实验 / A Study of CD147-targeted CAR-T by Hepatic Artery Infusions for Very Advanced Hepatocellular Carcinoma

A Study of CD147-targeted CAR-T by Hepatic Artery Infusions for Very Advanced Hepatocellular Carcinoma

Study Description
Brief Summary:
This is a single-center, single-arm, open label and dose escalation clinical study of anti-CD147 CART cells by hepatic artery infusions in patients with advanced hepatocellular carcinoma.

Condition or disease Intervention/treatment Phase
Advanced Hepatocellular Carcinoma Biological: CD147-CART Phase 1

Detailed Description:
Patients autologous T cells are activated and then engineered to express chimeric antigen receptors (CARs) specific for CD147(CD147-CART). CAR-T cells are expanded in culture and returned to the patient by hepatic artery infusion at specific cell doses. Four CD147-CART doses patient are planned at 1-week intervals. Tumor biopsies will be obtained at the time of the initial diagnostic angiogram and during the first infusion session. Serum cytokine level and CAR-T cell number will be measured in whole treatment session.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Dose Escalation Clinical Study to Access the Safety and Clinical Activity of CD147-targeted CART by Hepatic Artery Infusions for Very Advanced Hepatocellular Carcinoma
Actual Study Start Date : May 27, 2019
Estimated Primary Completion Date : October 27, 2020
Estimated Study Completion Date : May 27, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: CD147-CART
Infusions of CD147-CART cells over the course of each week for 3 times into the hepatic artery
 Biological: CD147-CART
Three infusions of CD147-CART cells over the course of three weeks into the hepatic artery.
Other Name: anti-CD147 chimeric antigen receptor T cell
Outcome Measures
Primary Outcome Measures :
  1. Incidence and type of adverse events induced by CD147-CART hepatic artery infusions [ Time Frame: 12 weeks ]
    To assess the safety of CD147-CART (anti-CD147 CAR-T cell) hepatic artery infusions (HAI) for very advanced hepatocellular carcinoma which measured by number and type of adverse events.


Secondary Outcome Measures :
  1. DLT and MTD of CD147-CART cell hepatic artery infusions [ Time Frame: 12 weeks ]
    To determine the dose limited toxicity (DLT) and maximum tolerated dose (MTD) of CD147-CART hepatic artery infusions.

  2. Activity of CD147-CART cell hepatic artery infusions [ Time Frame: 2 years ]
    To evaluate treatment response of CD147-CART hepatic artery infusions for very advanced hepatocellular carcinoma.

  3. CD147-CART detection in extrahepatic sites [ Time Frame: 2 years ]
    Quantification of CD147-CART cells in blood samples.


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. Age ≥ 18 year and ≤ 65 years, both male and female.
  2. Advanced hepatocellular carcinoma(HCC) patient, which is untreatable by surgery or local therapy, or has postoperative progressions, failed at least one and two line of standard systemic chemotherapy, and unwilling or intolerance to targeting therapy or immune-therapy of cancer.
  3. The portal vein is not total occlusion, or collateral circulation has formed between hepatic artery and blocked portal vein.
  4. Patient with measurable HCC focus defined by mRECIST.
  5. Patient with histologically confirmed diagnosis of CD147+ hepatocellular carcinoma.
  6. Adequate venous access for apheresis, and no other contraindications for apheresis.
  7. Child-Pugh score ≤7.
  8. Eastern Cooperative Oncology Group(ECOG) performance status of 0-2.
  9. Patient with a life expectancy of greater than three months.
  10. Patients must able to understand and be willing to sign an informed consent.

Exclusion Criteria:

  1. Patients with fibrolamellar carcinoma of liver，mixed hepatocellular carcinoma or cholangiocarcinoma.
  2. Patients with severe hypohepatia including jaundice, hepatic encephalopathy, refractory ascites or hepatorenal syndrome.

  3. Patients with severe comorbidity, including any of the following.

    1. Unstable angina pectoris and/or congestive heart failure need hospitalization;
    2. Myocardial infarction or cerebrovascular accident (CVA) in the last 6 months;
    3. chronic obstructive pulmonary disease progressions or need hospitalization;
    4. severe cardiovascular, nervous system, hematological, gastrointestinal, endocrine diseases or metabolic disorders;
    5. autoimmune disease or immunodeficiency disease;
    6. acute bacterial infections or fungal infections needs intravenous injection of antibiotics during CAR-T cell therapy;
    7. tuberculosis not cured;
    8. other malignancies;
  4. Patients who have received gene therapy, cell therapy or immune therapy.
  5. Patients who have received organ transplantation.
  6. Patients who have received treatment of targeted drugs, glucocorticoid or immunosuppressive drugs within 2 weeks before enrolling in clinical trial.
  7. Patients who have received chemotherapy except for lymphocyte clearance within 2 weeks before enrolling in clinical trial.
  8. Patients who have received radiotherapy.
  9. Patients who did not recover to CTCAE(v5.0) grade 1 from adverse events （except hair）of previous anti-tumor therapy before enrolling in trial.
  10. Syphilis test (TRUST) positive, Anti-HIV positive, Anti-HCV positive with HCV-RNA level higher than the lower limit of detection(LOD), or HBcAb positive with HBV-DNA level higher than the LOD.

  11. Patients with following abnormalities:

    1. Absolute neutrophil count (ANC) < 1.5E9/L, platelet(PLT) < 50E9/L, or hemoglobin(HGB)< 80 g/dL;
    2. Prothrombin time (PT), activated partial thromboplastin time (APTT) or international normalized ratio (INR) > 1.5×ULN (upper normal value);
    3. Total bilirubin(TBIL) > 2×ULN; ALT, AST or ALP>5×ULN;
    4. Serum creatinine (Cr)≥1.5×ULN or glomerular filtration rate (GFR) < 60 mL/min·1.73m^2;
    5. left ventricular ejection fraction (LVEF) < 50%;
  12. Patients with a history of allergic reactions attributed to any agents or compounds involved in this study.
  13. Patients with a history of mental disorders.
  14. Patients with a history of drug abuse.
  15. Pregnant and lactating women.
  16. Patients of childbearing age who unwilling or unable to take birth control from during this study and 3 months post this study.
  17. Patients who receive any other investigational agents within the 3 months before enrolling in this clinical trial.
  18. Investigator considers not suitable for this trial.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Zhi-Nan Chen, PhD 86-029-84774547 znchen@fmmu.edu.cn
Contact: Kaishan Tao, Dr 86-029-84775259 taokaishan0686@163.com

Locations
Layout table for location information
China, Shaanxi
Department of hepato-biliary & Pancreato Splenic Surgery Organ Transplant Center, Xijing Hospital Recruiting
Xi'an, Shaanxi, China, 710032
Contact: Kaishan Tao, Dr       taokaishan0686@163.com   
Sponsors and Collaborators
Xijing Hospital
Tracking Information
First Submitted Date  ICMJE June 19, 2019
First Posted Date  ICMJE June 21, 2019
Last Update Posted Date August 28, 2019
Actual Study Start Date  ICMJE May 27, 2019
Estimated Primary Completion Date October 27, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2019) 		Incidence and type of adverse events induced by CD147-CART hepatic artery infusions [ Time Frame: 12 weeks ]
To assess the safety of CD147-CART (anti-CD147 CAR-T cell) hepatic artery infusions (HAI) for very advanced hepatocellular carcinoma which measured by number and type of adverse events.
Original Primary Outcome Measures  ICMJE
 (submitted: June 19, 2019) 		Safety of CD147-CART cell hepatic artery infusions delivered for very advanced hepatocellular carcinoma [ Time Frame: 12 weeks ]
To assess the safety of CD147-CART (anti-CD147 CAR-T cell) hepatic artery infusions (HAI) for very advanced hepatocellular carcinoma which measured by number and type of adverse events.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • DLT and MTD of CD147-CART cell hepatic artery infusions [ Time Frame: 12 weeks ]
    To determine the dose limited toxicity (DLT) and maximum tolerated dose (MTD) of CD147-CART hepatic artery infusions.
  • Activity of CD147-CART cell hepatic artery infusions [ Time Frame: 2 years ]
    To evaluate treatment response of CD147-CART hepatic artery infusions for very advanced hepatocellular carcinoma.
  • CD147-CART detection in extrahepatic sites [ Time Frame: 2 years ]
    Quantification of CD147-CART cells in blood samples.
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 A Study of CD147-targeted CAR-T by Hepatic Artery Infusions for Very Advanced Hepatocellular Carcinoma
Official Title  ICMJE An Open-label, Dose Escalation Clinical Study to Access the Safety and Clinical Activity of CD147-targeted CART by Hepatic Artery Infusions for Very Advanced Hepatocellular Carcinoma
Brief Summary This is a single-center, single-arm, open label and dose escalation clinical study of anti-CD147 CART cells by hepatic artery infusions in patients with advanced hepatocellular carcinoma.
Detailed Description Patients autologous T cells are activated and then engineered to express chimeric antigen receptors (CARs) specific for CD147(CD147-CART). CAR-T cells are expanded in culture and returned to the patient by hepatic artery infusion at specific cell doses. Four CD147-CART doses patient are planned at 1-week intervals. Tumor biopsies will be obtained at the time of the initial diagnostic angiogram and during the first infusion session. Serum cytokine level and CAR-T cell number will be measured in whole treatment session.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Hepatocellular Carcinoma
Intervention  ICMJE Biological: CD147-CART
Three infusions of CD147-CART cells over the course of three weeks into the hepatic artery.
Other Name: anti-CD147 chimeric antigen receptor T cell
Study Arms  ICMJE Experimental: CD147-CART
Infusions of CD147-CART cells over the course of each week for 3 times into the hepatic artery
Intervention: Biological: CD147-CART
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 19, 2019) 		34
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 27, 2022
Estimated Primary Completion Date October 27, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ≥ 18 year and ≤ 65 years, both male and female.
  2. Advanced hepatocellular carcinoma(HCC) patient, which is untreatable by surgery or local therapy, or has postoperative progressions, failed at least one and two line of standard systemic chemotherapy, and unwilling or intolerance to targeting therapy or immune-therapy of cancer.
  3. The portal vein is not total occlusion, or collateral circulation has formed between hepatic artery and blocked portal vein.
  4. Patient with measurable HCC focus defined by mRECIST.
  5. Patient with histologically confirmed diagnosis of CD147+ hepatocellular carcinoma.
  6. Adequate venous access for apheresis, and no other contraindications for apheresis.
  7. Child-Pugh score ≤7.
  8. Eastern Cooperative Oncology Group(ECOG) performance status of 0-2.
  9. Patient with a life expectancy of greater than three months.
  10. Patients must able to understand and be willing to sign an informed consent.

Exclusion Criteria:

  1. Patients with fibrolamellar carcinoma of liver，mixed hepatocellular carcinoma or cholangiocarcinoma.
  2. Patients with severe hypohepatia including jaundice, hepatic encephalopathy, refractory ascites or hepatorenal syndrome.

  3. Patients with severe comorbidity, including any of the following.

    1. Unstable angina pectoris and/or congestive heart failure need hospitalization;
    2. Myocardial infarction or cerebrovascular accident (CVA) in the last 6 months;
    3. chronic obstructive pulmonary disease progressions or need hospitalization;
    4. severe cardiovascular, nervous system, hematological, gastrointestinal, endocrine diseases or metabolic disorders;
    5. autoimmune disease or immunodeficiency disease;
    6. acute bacterial infections or fungal infections needs intravenous injection of antibiotics during CAR-T cell therapy;
    7. tuberculosis not cured;
    8. other malignancies;
  4. Patients who have received gene therapy, cell therapy or immune therapy.
  5. Patients who have received organ transplantation.
  6. Patients who have received treatment of targeted drugs, glucocorticoid or immunosuppressive drugs within 2 weeks before enrolling in clinical trial.
  7. Patients who have received chemotherapy except for lymphocyte clearance within 2 weeks before enrolling in clinical trial.
  8. Patients who have received radiotherapy.
  9. Patients who did not recover to CTCAE(v5.0) grade 1 from adverse events （except hair）of previous anti-tumor therapy before enrolling in trial.
  10. Syphilis test (TRUST) positive, Anti-HIV positive, Anti-HCV positive with HCV-RNA level higher than the lower limit of detection(LOD), or HBcAb positive with HBV-DNA level higher than the LOD.

  11. Patients with following abnormalities:

    1. Absolute neutrophil count (ANC) < 1.5E9/L, platelet(PLT) < 50E9/L, or hemoglobin(HGB)< 80 g/dL;
    2. Prothrombin time (PT), activated partial thromboplastin time (APTT) or international normalized ratio (INR) > 1.5×ULN (upper normal value);
    3. Total bilirubin(TBIL) > 2×ULN; ALT, AST or ALP>5×ULN;
    4. Serum creatinine (Cr)≥1.5×ULN or glomerular filtration rate (GFR) < 60 mL/min·1.73m^2;
    5. left ventricular ejection fraction (LVEF) < 50%;
  12. Patients with a history of allergic reactions attributed to any agents or compounds involved in this study.
  13. Patients with a history of mental disorders.
  14. Patients with a history of drug abuse.
  15. Pregnant and lactating women.
  16. Patients of childbearing age who unwilling or unable to take birth control from during this study and 3 months post this study.
  17. Patients who receive any other investigational agents within the 3 months before enrolling in this clinical trial.
  18. Investigator considers not suitable for this trial.
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: Zhi-Nan Chen, PhD 86-029-84774547 znchen@fmmu.edu.cn
Contact: Kaishan Tao, Dr 86-029-84775259 taokaishan0686@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03993743
Other Study ID Numbers  ICMJE Chen Zhinan-1
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 Chen Zhinan, Air Force Military Medical University, China
Study Sponsor  ICMJE Xijing Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Xijing Hospital
Verification Date August 2019

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

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