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Treatment of Relapsed and/or Refractory AQP4-IgG Seropositive NMOSD by Tandem CAR T Cells Targeting CD19 and CD20

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: NCT03605238
Recruitment Status : Withdrawn (It was hard to recruit patients)
First Posted : July 30, 2018
Last Update Posted : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
Wei Shihui, Chinese PLA General Hospital

Tracking Information
First Submitted Date  ICMJE June 29, 2018
First Posted Date  ICMJE July 30, 2018
Last Update Posted Date September 19, 2019
Estimated Study Start Date  ICMJE August 15, 2018
Estimated Primary Completion Date August 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 21, 2018)
Occurrence of study related adverse events [ Time Frame: From baseline to 12 months after ]
defined as >= Grade 3 signs/symptoms, laboratory toxicities, and clinical events that are possibly, likely, or definitely related to study treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2018)
  • Annualized relapse rate (ARR) of NMOSD Attacks [ Time Frame: Baseline, 12 months ]
    Compare annualized relapse rate before and one year after initial CAR-T administration.
  • Change in Expanded Disability Status Scale (EDDS) Score [ Time Frame: Baseline, 12 months ]
    The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.
  • Change in Best Corrected Visual Acuity (Log MAR) [ Time Frame: Baseline, 12 months ]
    Visual acuity assessment through Snellen's test chart.
  • Change in peripapillary retinal nerve fibre layer(pRNFL) [ Time Frame: Baseline, 12 months ]
    Compared pRNFL before and one year after initial CAR-T administration.
  • Change in macular ganglion cell-inner plexiform layers (mGCIPL) [ Time Frame: Baseline, 12 months ]
    Compared mGCIPL before and one year after initial CAR-T administration.
  • Change in Flash Visual Evoked Potential (FVEP) [ Time Frame: Baseline, 12 months ]
    Compared FVEP before and one year after initial CAR-T administration.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 21, 2018)
  • in vivo existence of tanCART19/20 [ Time Frame: Baseline, 12 months ]
    RT-PCR (reverse transcription polymerase chain reaction) analysis of whole blood will be used to detect and quantify survival of tanCART-19/20 TCR (T-cell receptor) zeta:CD137 and TCR zeta cells over time.
  • Determination of serum immunoglobulins [ Time Frame: Baseline, 12 months ]
    Compare serum IgG level before and one year after initial CAR-T administration.
  • Determination of serum AQP4 antibodies [ Time Frame: Baseline, 12 months ]
    Compare serum AQP4-ab titers before and one year after initial CAR-T administration.
  • Determination of serum cytokines [ Time Frame: Baseline, 12 months ]
    Compare serum cytokines before and one year after initial CAR-T administration.
  • Counts of peripheral blood B cell subsets [ Time Frame: Baseline, 12 months ]
    Compare peripheral blood B cells before and one year after initial CAR-T administration.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Treatment of Relapsed and/or Refractory AQP4-IgG Seropositive NMOSD by Tandem CAR T Cells Targeting CD19 and CD20
Official Title  ICMJE Clinical Study of CD19/CD20 tanCAR T Cells in Relapsed and/or Refractory AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders (NMOSD)
Brief Summary CAR-T therapy was proposed and has been recently used for cancer treatment. It has been hailed for its promising remission rates after early stage clinical trials for acute lymphoblastic leukemia. However, CAR-T therapy is seldom used for autoimmune diseases. Researchers only use it for the treatment of systemic lupus erythematosus (SLE). Neuromyelitis optica spectrum disorders (NMOSD), that include the neuromyelitis optica (NMO), are a group of inflammatory disorders of the central nervous system characterized by episodes of immune-mediated demyelination and axonal damage mainly involving optic nerves and spinal cord. NMO is characterized by the presence of an anti-Aquaporin-4 (AQP4) antibody, which can only be produced by differentiation of B cells to plasma cells. Because these anti-AQP4 antibodies may be pathogenic, B cells recognizing AQP4 may be directly involved in the disease process as well. B cells also play a role as potent antigen presenting cells in NMO. NMO has the characteristics of high recurrence rate and poor prognosis. In the conventional treatment options, NMOSD could be treated with corticosteroids and immunosuppressive drugs immunosuppressant (e.g. azathioprine, mycophenolate mofetil, rituximab). But these drugs could barely completely cure NMOSD. And now, chimeric antigen receptor modified T cell infusion maybe an effective treatment to solve these problems. The rationale for using CAR-T therapy in NMOSD is based on the known roles of B cells, antibody production and plasma cells in the pathophysiology of NMOSD. The strongest evidence of the importance of B cells in NMO comes from studies of B cell depletion, most commonly with anti-CD20 monoclonal antibody, rituximab. Emerging evidence indicates that peripheral B cells are activated during a relapse and plasmablast production of anti-AQP4 antibodies spikes. The investigators infuse tanCART19/20 to completely deplete B cells. The purpose of this study is to assess the safety and efficacy of this tanCART19/20 in the treatment of NMOSD.
Detailed Description

This study is being conducted to assess anti-CD19/20 CAR T cells safety and efficacy in treating patients with AQP4-IgG seropositive NMOSD.

PRIMARY OBJECTIVES:

I. To assess the safety of the tanCART-19/20 cells in treating NMOSD patients. II. Determine duration of in vivo survival of tanCART-19/20 cells.

SECONDARY OBJECTIVES:

I. To assess the efficacy of the tanCART-19/20 cells in treating NMOSD patients.

II. The secondary outcome measures: annual relapse rate (ARR), Expanded Disability Status Scale Score(EDDS), Best Corrected Visual Acuity (Log MAR), Spectral-Domain Optical Coherence Tomography (SD-OCT), Flash Visual Evoked Potential (FVEP) and Immunological assessments.

OUTLINE: Patients receive anti-CD19/20-CAR (coupled with CD137 and CD3 zeta signalling domains) vector-transduced autologous T cells on days 0 in the absence of unacceptable toxicity. The infusion dose is 1E5-2E6 CAR positive T cells/kg, and dose escalation methods obey the traditional 3+3 design (three doses groups: 1-2E5, 3-6E5, 1-2E6 CAR-T cells).

After completion of study treatment, patients are followed intensively for 6 months, every 6 months for 2 years, and annually thereafter for 3 years.

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 Neuromyelitis Optica Spectrum Disorder
Intervention  ICMJE Biological: Corticosteroids & tanCART19/20
Twelve days of high-dose IV methylprednisolone (1000mg×3 days, 500mg×3 days, 240mg×3 days, 120mg×3 days) before anti-CD19/20 CAR T cells infusion. The dose is 1E5~2E6 anti-CD19/20-CAR positive T cells. The cells infusion process may last for 30 min.
Study Arms  ICMJE Experimental: Corticosteroids & tanCART19/20
Twelve days of high-dose IV methylprednisolone to reduce acute inflammation, then infuse anti-CD19/20-CAR retroviral vector-transduced autologous derived T cells only once.
Intervention: Biological: Corticosteroids & tanCART19/20
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 Withdrawn
Actual Enrollment  ICMJE
 (submitted: September 17, 2019)
0
Original Estimated Enrollment  ICMJE
 (submitted: July 21, 2018)
9
Estimated Study Completion Date  ICMJE August 15, 2020
Estimated Primary Completion Date August 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Clinical diagnosis of neuromyelitis optica spectrum disorders (NMOSD) patients.
  2. Patients with AQP4-IgG seropositive by cell-based assay.
  3. Patients with corticosteroid treatment combined immunosuppressant (azathioprine or mycophenolate mofetil or rituximab) still recurrence.
  4. Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to the Screening.
  5. Best corrected visual acuity(BCVA)<20/60.
  6. Normal bone marrow reserve function: neutrophils>1 500/mm3, Hemoglobin > 10g/dL, Platelet count > 100 000/mm3.
  7. Normal liver and kidney function: Creatinine < 2.5 mg/dl, ALT (alanine aminotransferase)/AST (aspartate aminotransferase) < 3x normal, Bilirubin < 2.0 mg/dl.
  8. Successful test expansion of tanCART19/20 cells.
  9. Adequate venous access for apheresis, and no other contraindications for leukapheresis.
  10. Voluntary informed consent is given.

Exclusion Criteria:

  1. Pregnant or lactating women (The safety of this therapy on unborn children is not known, Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion).
  2. Any serious, uncontrolled diseases (including, but not limit to, uncontrolled active infection, active hepatitis B or hepatitis C infection, HIV infection, unstable angina pectoris, congestive heart failure, serious arrhythmia).
  3. Concurrent use of systemic steroids or immunosuppressant in the last two weeks.
  4. Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD137 costimulation.
  5. Other patients who are not suitable for CAR-T therapy judged by the biotherapy physician.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years 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 NCT03605238
Other Study ID Numbers  ICMJE CHN-PLAGH-NO-S2018-002-02
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
Responsible Party Wei Shihui, Chinese PLA General Hospital
Study Sponsor  ICMJE Chinese PLA General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Quangang Xu, PhD Chinese PLA General Hospital
Principal Investigator: Huanfen Zhou, PhD Chinese PLA General Hospital
PRS Account Chinese PLA General Hospital
Verification Date August 2019

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