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出境医 / 临床实验 / Autologous CAR-T/TCR-T Cell Immunotherapy for Solid Malignancies

Autologous CAR-T/TCR-T Cell Immunotherapy for Solid Malignancies

Study Description
Brief Summary:
This is a single arm, open-label, uni-center, phase I-II study to evaluate the safety and effectiveness of CAR-T/TCR-T cell immunotherapy in treating with different malignancies patients.

Condition or disease Intervention/treatment Phase
Esophagus Cancer Hepatoma Glioma Gastric Cancer Biological: CAR-T/TCR-T cells immunotherapy Phase 1 Phase 2

Detailed Description:
The study is a multi-target gene-modified immunotherapy. CAR-T/TCR-T cells include four different tumor-specific antibody.They are as following:anti-NY-ESO-1 antibody foresophagus cancer;anti-DR5 antibody for hepatoma;;anti-EGFR vIII antibody for hepatoma and glioma;anti-Mesothelin antibody for gastric cancer.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: EGFRvIII/DR5/NY-ESO-1/Mesothelin CAR-T/TCR-T Cells Immunotherapy for Solid Malignancies
Actual Study Start Date : September 1, 2019
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : December 1, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: CAR-T/TCR-T cells immunotherapy
Enrolled patients will receive CAR-T cell immunotherapy with several different specific Chimeric antigen receptors aiming at different antigens respectively by infusion.
 Biological: CAR-T/TCR-T cells immunotherapy
According to tumor burden and other conditions, patients will be treated with cyclophosphamide or fludarabine,then,CAR-T cells will be infused 48-72 hours later.
Outcome Measures
Primary Outcome Measures :
  1. Number of Participants With Adverse Events evaluated with NCI CTC AE, version 4.0 [ Time Frame: 48 months ]
    Safety evaluation


Secondary Outcome Measures :
  1. Clinical response [ Time Frame: 48 months ]
    Clinical response to T-cell infusion, especially change of tumor volume will be evaluated by comparing disease identified by computed tomography, magnetic resonance imaging.


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

Inclusion Criteria:

  1. Patients must be willing to sign an informed consent.
  2. Male or female patients aged 18 to 70 years .
  3. Estimated survival of ≥ 12 weeks.
  4. Pathological sections with positive expression of NY-ESO-1, Mesothelin, EGFRvIII and DR5 was confirmed by biopsy IHC test within 12 months.If NY-ESO-1 is positive expression ,positive HLAA*0201 is required at the same time.
  5. Solid tumor must have at least one measureable disease according to RECIST 1.1.
  6. Routine blood test#hemoglobin>=90 g/L; platelet>=50×10^9/L.
  7. Liver function:ALT and AST≤2.5 times upper limits of normal (If the tumor infiltration is the main cause of abnormal liver function ,ALT and AST≤5 times upper limits of normal); bilirubin<2.0 mg/dL.
  8. Renal function:BUN: 9-20mg / dl; serum creatinine≤ 1.5 times upper limits of normal; endogenous creatinine clearance rate≥50 ml/min .
  9. Negative serum antibody for EBV, CMV, HIV , syphilis, HBVa nd HCV.
  10. Cardiac function: stable hemodynamic and left ventricular ejection fraction (LVEF)>=55%.
  11. ECOG score:0-1.
  12. Adequate venous access for apheresis, and no other contraindications for leukapheresis .
  13. Women of child-bearing age must have evidence of negative pregnancy test. Subjects of reproductive potential must agree to use acceptable birth control methods within 1 year after treatment, as described in protocol.
  14. Subjects with hypertension/diabetes must be stable blood pressure/blood glucose or ≤CTCAE 1 level 2 weeks before the screening.

In addition to the above criteria for inclusion, the following criteria shall be met according to the indications:

Patients with glioblastoma：

  1. First disease progression or disease recurrence (≥ 1 cm and ≤ 5 cm) of a supratentorial WHO grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease.
  2. EGFRvIII, the target antigen, must be identified on tumor tissue by IHC or PCR, i.e. EGFRvIII positive via pathology report.
  3. Insensitivity to chemoradiotherapy or chemoradiotherapy failure after operation molecular pathology.
  4. Refused to receive radiotherapy or chemotherapy treatment.

Patients with liver cancer

  1. DR5 or EGFRvIII positive via pathology report.
  2. Untreatable by surgery ; Or postoperative recurrence ;Or no effective treatment.
  3. Liver function：child-pugh A grade or child-pugh B grade.

Patients with gastric cancer

  1. Mesothelin positive via pathology report.
  2. The pathological stage：IIIA～IV.
  3. chemoradiotherapy failure
  4. Refused or unable to get surgery.

Patients with esophageal cancer

  1. NY-ESO-1 positive via pathology report and HLA-A*0201 positive in blood.
  2. Refuse or unable to get surgery.
  3. Postoperative recurrence or chemoradiotherapy failure.

Exclusion Criteria:

  1. ECOG≥2.
  2. malignant tumor cells with T cell origin via pathology test.
  3. Organ failure: stage III or IV congestive heart failure; Renal failure and uremia; respiratory failure; disturbance of consciousness.
  4. Acute or chronic GVHD after allogeneic hematopoiesis; Or being treated for GVHD; Or hormone or immunosuppressant used within 30 days
  5. steroid hormoneswere used before and after blood collection and infusion
  6. Patients with HIV infection or active hepatitis
  7. Uncontrolled active infection.
  8. Enrolled to other clinical study in the last 4 weeks.
  9. Patients with systemic auto-immune disease or immunodeficiency.
  10. Patients with neuropathy or psychosis, including dementia or epilepsy, or history of psychotropic substance abuse, or other substantial lesions that may increase central neurotoxicity.
  11. Concomitant with the second tumor or other malignant tumors.
  12. Patients with bone metastases are at risk of a pathological fracture resulting in paraplegia or life threatening.
  13. Live attenuated vaccine was administered within 4 weeks prior to blood collection.
  14. Blood oxygen saturation is maintained by oxygen inhalation.
  15. Received major surgery within 2 weeks prior to screening ;Or Plan to receive surgery during study or within 2 weeks after injection.
  16. Other patients that researchers considered unsuitable for inclusion.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: ZHONG HUA YANG +8618938688105 ext +8618938688105 zh.yang@bindebio.com

Locations
Layout table for location information
China, Henan
Henan Provincial People's Hospital Recruiting
Zhengzhou, Henan, China, 450052
Contact: Shuangyin Han    +8613203710057    hansyzzu@163.com   
Contact: Chun-Xiao Ma    +8615038287266    chxma@126.com   
Principal Investigator: Shuangyin Han         
Principal Investigator: Chun-Xiao Ma         
Sponsors and Collaborators
Shenzhen BinDeBio Ltd.
Henan Provincial People's Hospital
Tracking Information
First Submitted Date  ICMJE May 6, 2019
First Posted Date  ICMJE May 8, 2019
Last Update Posted Date February 4, 2021
Actual Study Start Date  ICMJE September 1, 2019
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019) 		Number of Participants With Adverse Events evaluated with NCI CTC AE, version 4.0 [ Time Frame: 48 months ]
Safety evaluation
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2019) 		Clinical response [ Time Frame: 48 months ]
Clinical response to T-cell infusion, especially change of tumor volume will be evaluated by comparing disease identified by computed tomography, magnetic resonance imaging.
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 Autologous CAR-T/TCR-T Cell Immunotherapy for Solid Malignancies
Official Title  ICMJE EGFRvIII/DR5/NY-ESO-1/Mesothelin CAR-T/TCR-T Cells Immunotherapy for Solid Malignancies
Brief Summary This is a single arm, open-label, uni-center, phase I-II study to evaluate the safety and effectiveness of CAR-T/TCR-T cell immunotherapy in treating with different malignancies patients.
Detailed Description The study is a multi-target gene-modified immunotherapy. CAR-T/TCR-T cells include four different tumor-specific antibody.They are as following:anti-NY-ESO-1 antibody foresophagus cancer;anti-DR5 antibody for hepatoma;;anti-EGFR vIII antibody for hepatoma and glioma;anti-Mesothelin antibody for gastric cancer.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Esophagus Cancer
  • Hepatoma
  • Glioma
  • Gastric Cancer
Intervention  ICMJE Biological: CAR-T/TCR-T cells immunotherapy
According to tumor burden and other conditions, patients will be treated with cyclophosphamide or fludarabine,then,CAR-T cells will be infused 48-72 hours later.
Study Arms  ICMJE Experimental: CAR-T/TCR-T cells immunotherapy
Enrolled patients will receive CAR-T cell immunotherapy with several different specific Chimeric antigen receptors aiming at different antigens respectively by infusion.
Intervention: Biological: CAR-T/TCR-T cells immunotherapy
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: May 6, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2021
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients must be willing to sign an informed consent.
  2. Male or female patients aged 18 to 70 years .
  3. Estimated survival of ≥ 12 weeks.
  4. Pathological sections with positive expression of NY-ESO-1, Mesothelin, EGFRvIII and DR5 was confirmed by biopsy IHC test within 12 months.If NY-ESO-1 is positive expression ,positive HLAA*0201 is required at the same time.
  5. Solid tumor must have at least one measureable disease according to RECIST 1.1.
  6. Routine blood test#hemoglobin>=90 g/L; platelet>=50×10^9/L.
  7. Liver function:ALT and AST≤2.5 times upper limits of normal (If the tumor infiltration is the main cause of abnormal liver function ,ALT and AST≤5 times upper limits of normal); bilirubin<2.0 mg/dL.
  8. Renal function:BUN: 9-20mg / dl; serum creatinine≤ 1.5 times upper limits of normal; endogenous creatinine clearance rate≥50 ml/min .
  9. Negative serum antibody for EBV, CMV, HIV , syphilis, HBVa nd HCV.
  10. Cardiac function: stable hemodynamic and left ventricular ejection fraction (LVEF)>=55%.
  11. ECOG score:0-1.
  12. Adequate venous access for apheresis, and no other contraindications for leukapheresis .
  13. Women of child-bearing age must have evidence of negative pregnancy test. Subjects of reproductive potential must agree to use acceptable birth control methods within 1 year after treatment, as described in protocol.
  14. Subjects with hypertension/diabetes must be stable blood pressure/blood glucose or ≤CTCAE 1 level 2 weeks before the screening.

In addition to the above criteria for inclusion, the following criteria shall be met according to the indications:

Patients with glioblastoma：

  1. First disease progression or disease recurrence (≥ 1 cm and ≤ 5 cm) of a supratentorial WHO grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease.
  2. EGFRvIII, the target antigen, must be identified on tumor tissue by IHC or PCR, i.e. EGFRvIII positive via pathology report.
  3. Insensitivity to chemoradiotherapy or chemoradiotherapy failure after operation molecular pathology.
  4. Refused to receive radiotherapy or chemotherapy treatment.

Patients with liver cancer

  1. DR5 or EGFRvIII positive via pathology report.
  2. Untreatable by surgery ; Or postoperative recurrence ;Or no effective treatment.
  3. Liver function：child-pugh A grade or child-pugh B grade.

Patients with gastric cancer

  1. Mesothelin positive via pathology report.
  2. The pathological stage：IIIA～IV.
  3. chemoradiotherapy failure
  4. Refused or unable to get surgery.

Patients with esophageal cancer

  1. NY-ESO-1 positive via pathology report and HLA-A*0201 positive in blood.
  2. Refuse or unable to get surgery.
  3. Postoperative recurrence or chemoradiotherapy failure.

Exclusion Criteria:

  1. ECOG≥2.
  2. malignant tumor cells with T cell origin via pathology test.
  3. Organ failure: stage III or IV congestive heart failure; Renal failure and uremia; respiratory failure; disturbance of consciousness.
  4. Acute or chronic GVHD after allogeneic hematopoiesis; Or being treated for GVHD; Or hormone or immunosuppressant used within 30 days
  5. steroid hormoneswere used before and after blood collection and infusion
  6. Patients with HIV infection or active hepatitis
  7. Uncontrolled active infection.
  8. Enrolled to other clinical study in the last 4 weeks.
  9. Patients with systemic auto-immune disease or immunodeficiency.
  10. Patients with neuropathy or psychosis, including dementia or epilepsy, or history of psychotropic substance abuse, or other substantial lesions that may increase central neurotoxicity.
  11. Concomitant with the second tumor or other malignant tumors.
  12. Patients with bone metastases are at risk of a pathological fracture resulting in paraplegia or life threatening.
  13. Live attenuated vaccine was administered within 4 weeks prior to blood collection.
  14. Blood oxygen saturation is maintained by oxygen inhalation.
  15. Received major surgery within 2 weeks prior to screening ;Or Plan to receive surgery during study or within 2 weeks after injection.
  16. Other patients that researchers considered unsuitable for inclusion.
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: ZHONG HUA YANG +8618938688105 ext +8618938688105 zh.yang@bindebio.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03941626
Other Study ID Numbers  ICMJE 2019BDB016
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 Shenzhen BinDeBio Ltd.
Study Sponsor  ICMJE Shenzhen BinDeBio Ltd.
Collaborators  ICMJE Henan Provincial People's Hospital
Investigators  ICMJE Not Provided
PRS Account Shenzhen BinDeBio Ltd.
Verification Date February 2021

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

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