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Combination CAR-T Cell Therapy Targeting Hematological Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03125577
Recruitment Status : Unknown
Verified September 2019 by Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute.
Recruitment status was:  Recruiting
First Posted : April 24, 2017
Last Update Posted : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute

Tracking Information
First Submitted Date  ICMJE April 19, 2017
First Posted Date  ICMJE April 24, 2017
Last Update Posted Date September 19, 2019
Actual Study Start Date  ICMJE July 15, 2017
Actual Primary Completion Date July 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
Safety of fourth generation anti CD19 and CD20/CD22/CD30/CD38/CD70/CD123 CAR-T cells in patients with relapsed B cell malignancies using CTCAE 4 standard to evaluate the level of adverse events standard to evaluate the level of adverse events [ Time Frame: 24 weeks ]
physiological parameter (for safety, measuring cytokine response, fever, symptoms)
Original Primary Outcome Measures  ICMJE
 (submitted: April 19, 2017)
Safety of fourth generation anti CD19 and CD20/CD22/CD38/CD123 CAR-T cells in patients with relapsed B cell malignancies using CTCAE 4 standard to evaluate the level of adverse events standard to evaluate the level of adverse events [ Time Frame: 24 weeks ]
physiological parameter (for safety, measuring cytokine response, fever, symptoms)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
Anti tumor activity of fourth generation anti CD19 and CD20/CD22/CD30/CD38/CD70/CD123 CAR-T cells in patients with relapsed or refractory B cell malignancies [ Time Frame: 1 year ]
scale of CAR copies and leukemic cell burden (for efficacy)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2017)
Anti tumor activity of fourth generation anti CD19 and CD20/CD22/CD38/CD123 CAR-T cells in patients with relapsed or refractory B cell malignancies [ Time Frame: 1 year ]
scale of CAR copies and leukemic cell burden (for efficacy)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination CAR-T Cell Therapy Targeting Hematological Malignancies
Official Title  ICMJE Combination CAR-T Therapy of 4SCAR19 Plus 4SCAR20, 22, 38, 70 and 123 Targeting Hematological Malignancies
Brief Summary The study will evaluate safety and efficacy of a combination of 4th generation chimeric antigen receptor gene-modified T cells targeting CD19 (4SCAR19) and CD20 (4SCAR20), CD22 (4SCAR22), CD30 (4SCAR30), CD38 (4SCAR38), CD70 (4SCAR70) or CD123 (4SCAR123) for patients with B cell malignancies. Clinical response and development of a standardized lentiviral vector and cell production protocol will be investigated. This is a phase I/II trial enrolling patients from multiple clinical centers.
Detailed Description

Background:

T cells modified with lentiviral chimeric antigen receptor (CAR) gene have been studied in different clinical settings. Recent successes suggest that increased costimulatory signaling in the CAR design is critical for long term efficacy. Several clinical reports indicate that many patients still relapse and developed CD19-negative cancer cells after CD19 targeted therapy. Thus, to prevent the target escapes and improve the therapeutic effects, CAR gene-modified T cells targeting CD20, CD22, CD30, CD38, CD70 or CD123 are considered to apply together with CD19 CAR-T cells.

Activation of T cell response to high tumor burden may induce a severe response. To increase safety, a novel design using an inducible caspase 9 fusion gene has been incorporated in the CAR gene. A 4th generation CAR lentiviral vector (4SCAR) carrying multiple costimulatory signals for CD28/CD137/CD27 plus an inducible apoptotic caspase 9 gene has been established. This study aims to evaluate the activities of a combination of CAR gene-modified T cells to target cancer cells based on specific CD19/CD20/CD22/CD30/CD38/CD70/CD123 single chain antibody gene designs (4SCAR19/20/22/30/38/70/123).

Objective:

To evaluate safety and efficacy of administrating 4SCAR19, 4SCAR20, 4SCAR22, 4SCAR30, 4SCAR38, 4SCAR70 and 4SCAR123 T cells to patients with mixed CD19 positive and negative B cell malignancies following a cyclophosphamide/fludarabine based conditioning regimen.

Eligibility:

Patients older than 6-month-old with CD19 positive or negative B cell malignancies that have recurred after or refractory to standard therapy and is deemed incurable using standard treatment.

Design:

Participants will be screened based on cancer cell phenotype analyzed using flow cytometry or immunohistochemical staining methods. Peripheral blood mononuclear cells (PBMC) will be obtained through apheresis. On Day -5 to -7, T cells from PBMC will be activated and enriched, which will be followed by 4SCAR19, 4SCAR20, 4SCAR22, 4SCAR30, 4SCAR38, 4SCAR70 and 4SCAR123 lentiviral transduction. The total cell preparation time is approximately 5-7 days. Participants will receive a preparative conditioning regimen comprising cyclophosphamide/fludarabine to prepare their immune system to accommodate the modified CAR T cells. The preparative regimen will depend on the immune condition of patients, which is consistent with standard chemotherapy conditioning regimen. Participants will receive an infusion of the modified 4SCAR19 and 4SCAR20/22/30/38/70/123 T cells and closely followed up for treatment-related responses. Participants will be continuously monitored for CAR T cells and clinical responses in a preset timeline.

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 B-cell Malignancies
Intervention  ICMJE
  • Biological: 4SCAR19 and 4SCAR22
    4SCAR19 and 4SCAR22
  • Biological: 4SCAR19 and 4SCAR38
    4SCAR19 and 4SCAR38
  • Biological: 4SCAR19 and 4SCAR20
    4SCAR19 and 4SCAR20
  • Biological: 4SCAR19 and 4SCAR123
    4SCAR19 and 4SCAR123
  • Biological: 4SCAR19 and 4SCAR70
    4SCAR19 and 4SCAR70
  • Biological: 4SCAR19 and 4SCAR30
    4SCAR19 and 4SCAR30
Study Arms  ICMJE Experimental: 4SCAR19 and 4SCAR20/CD22/CD30/CD38/CD70/CD123
Patients who have relapsed and refractory B cell malignancies after chemotherapy will be treated with CD19 and CD20/CD22/CD30/CD38/CD70/CD123-specific gene-engineered T cells.
Interventions:
  • Biological: 4SCAR19 and 4SCAR22
  • Biological: 4SCAR19 and 4SCAR38
  • Biological: 4SCAR19 and 4SCAR20
  • Biological: 4SCAR19 and 4SCAR123
  • Biological: 4SCAR19 and 4SCAR70
  • Biological: 4SCAR19 and 4SCAR30
Publications * Nair S, Wang JB, Tsao ST, Liu Y, Zhu W, Slayton WB, Moreb JS, Dong L, Chang LJ. Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Ralpha Signaling. Curr Gene Ther. 2019;19(1):40-53. doi: 10.2174/1566523218666181116093857.

*   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 Unknown status
Estimated Enrollment  ICMJE
 (submitted: April 19, 2017)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Actual Primary Completion Date July 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. age older than 6 months.
  2. malignant B cell surface expression of CD19/CD20/CD22/CD30/CD38/CD70/CD123 molecules.
  3. the KPS score over 80 points, and survival time is more than 1 month.
  4. greater than Hgb 80 g/L.
  5. no contraindications to blood cell collection.

Exclusion Criteria:

  1. accompanied with other active diseases, the treatment is difficult to assess patient response.
  2. bacteria, fungus, or virus infection, unable to control.
  3. living with HIV.
  4. active HBV and HCV infection.
  5. pregnant and nursing mothers.
  6. under systemic steroid treatment within a week of the treatment.
  7. prior failed CAR-T treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03125577
Other Study ID Numbers  ICMJE GIMI-IRB-17005
Has Data Monitoring Committee No
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
Current Responsible Party Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Shenzhen Geno-Immune Medical Institute
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lung-Ji Chang, PhD Shenzhen Geno-Immune Medical Institute
PRS Account Shenzhen Geno-Immune Medical Institute
Verification Date September 2019

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