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Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Idiopathic Inflammatory Diseases of the Nervous System (CARTinNS)

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ClinicalTrials.gov Identifier: NCT04561557
Recruitment Status : Recruiting
First Posted : September 23, 2020
Last Update Posted : July 28, 2021
Sponsor:
Collaborator:
Nanjing IASO Biotherapeutics Co.,Ltd
Information provided by (Responsible Party):
Wei Wang, Tongji Hospital

Brief Summary:
Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder characterized by recurrent attacks of optic neuritis and myelitis. A strong humoral response with autoantibodies produced by plasma cells (effector B cells) against aquaporin-4 (AQP4) water channels on astrocytes has been identified as the main characteristic of NMOSD physiology. B-cell maturation antigen (BCMA) is expressed on the surface of plasma cells, thus making it an ideal target for targeted therapies. Chimeric antigen receptor (CAR) T cells against BCMA offers another potential therapeutic option to eliminate plasma cells in patients with AQP4-IgG-seropositive NMOSD who still suffer recurrent attacks from conventional treatments. In the current study, the safety and efficacy of a novel CAR-T cell therapy using CT103A cells, are evaluated in patients with relapsed/refractory NMOSD.

Condition or disease Intervention/treatment Phase
Autoimmune Diseases Autoimmune Diseases of the Nervous System Neuromyelitis Optica Spectrum Disorder Biological: CT103A cells Drug: Cyclophosphamide and fludarabine Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Clinical Trial to Evaluate the Safety and Efficacy of CT103A Cells for the Treatment of Relapsed/Refractory Antibody-associated Idiopathic Inflammatory Diseases of the Nervous System
Actual Study Start Date : September 22, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: CAR T cells therapy,Dose level 1: 0.5 × 10^6 CAR-T cells/Kg

The tolerability and safety of CT103A cells will be assessed in an initial dose of 0.5×10^6 CAR-T cells/Kg and three subjects will be enrolled firstly. If no dose-limiting toxicity (DLT) occurs and at least one subject benefits from the treatment, there will be two options for the investigator based on the available data: 1) three more subjects will be enrolled in the 0.5 × 10^6 CAR-T cells/Kg group and DLT will be evaluated in a total of six subjects; 2) another three subjects will be treated with 1 × 10^6 CAR-T cells/Kg instead of 0.5 × 10^6 CAR-T cells/Kg.

If DLT occurs in one of the first three subjects, three more subjects will be enrolled in this cohort to reach the total subjects of six.

Biological: CT103A cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×106 CAR+ T cells/kg will be infused on day 0.

Drug: Cyclophosphamide and fludarabine

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.


Experimental: CAR T cells therapy,Dose level 2: 1 × 10^6 CAR-T cells/Kg
If neither DLT nor efficacy is shown in the first three subjects, the dose of CAR-T cells will be increased to 1 × 106 CAR-T cells/kg to assess DLT.
Biological: CT103A cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×106 CAR+ T cells/kg will be infused on day 0.

Drug: Cyclophosphamide and fludarabine

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.


Experimental: CAR T cells therapy,Dose level 3: 0.25 × 10^6 CAR-T cells/Kg
If DLT occurs in two subjects, whether to test the safety and efficacy in 0.25 × 10^6 CAR-T cells/kg group will be determined by the investigator based on the initial data of efficacy, PK and PD.
Biological: CT103A cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×106 CAR+ T cells/kg will be infused on day 0.

Drug: Cyclophosphamide and fludarabine

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.





Primary Outcome Measures :
  1. Types and incidence of dose-limiting toxicity (DLT) after CT103A cells infusion [ Time Frame: 3 months after CT103A cells infusion ]
    To evaluate the DLT occurred within 3 months after CT103A infusion

  2. Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms. [ Time Frame: 2 years after CT103A cells infusion ]
    To evaluate the AEs occurred within 2 years after CT103A infusion


Secondary Outcome Measures :
  1. Decrease of concentration of AQP4-IgG titers in the serum after CT103A infusion [ Time Frame: 3 months after CT103A cells infusion ]
    the decrease of concentration of AQP4-IgG titers in serum after CT103A infusion will be compared with baseline

  2. CT103A cells proliferation in patients with relapse/refractory NMOSD [ Time Frame: 2 years after CT103A cells infusion ]
    Copy number of CT103A detected by PCR and concentration of CT103A detected by flow cytometry in peripheral blood will be analyzed.


Other Outcome Measures:
  1. Concentration of soluble BCMA in peripheral blood after CT103A cells [ Time Frame: 2 years after CT103A cells infusion ]
    the changes of concentration of soluble BCMA in the peripheral blood after CT103A infusion.

  2. Concentration of AQP4-IgG titers in the serum and cerebrospinal fluid (CSF) after CT103A infusion [ Time Frame: 2 years after CT103A cells infusion ]
    Changes of concentration of AQP4-IgG titers in the serum and CSF after CT103A

  3. Time to first relapse (day) of NMOSD after CT103A cells infusion [ Time Frame: 2 years after CT103A cells infusion ]
    Time from CT103A infusion to the first relapse of NMOSD

  4. Annualized relapse rate (ARR) [ Time Frame: 2 years after CT103A cells infusion ]
    the number of attacks divided by observed year after CT103A cells infusion

  5. Accumulated total active MRI lesions [ Time Frame: 2 years after CT103A cells infusion ]
    the number of accumulate total active MRI lesions after CT103A infusion

  6. Expanded Disability Status Scale (EDSS) score [ Time Frame: 2 years after CT103A cells infusion ]
    EDSS and its associated functional system (FS) score provide a system for quantifying disability and monitoring changes in the level of disability over time. EDSS is a scale for assessing neurologic impairment in multiple sclerosis (MS). It consists of 7 FS (visual FS, brainstem FS, pyramidal FS, cerebellar FS, sensory FS, bowel and bladder FS, and cerebral FS) which are used to derive EDSS score ranging from 0 (normal neurological exam) to 10 (death from MS). A negative change from baseline indicates improvement. A participant was considered to have a worsening in overall EDSS score of at least 2 if baseline EDSS score was 0, or at least 1 point if baseline EDSS score is 1 to 5, or at least 0.5 point if baseline EDSS score is 5.5 or more.

  7. Modified Rankin Scale [ Time Frame: 2 years after CT103A cells infusion ]
    Modified Rankin Scale (mRS) is a profoundly valid and reliable measure of disability and is broadly utilized for assessing stroke outcomes and degree of disability. We characterized a favorable outcome as mRS ranging from zero up to two, while unfavorable outcome ranging for 3 up to 6.

  8. Visual Evoked Potential (VEP) [ Time Frame: 2 years after CT103A cells infusion ]
    VEP waveforms were evaluated using either present baseline - reproducible positive-negative-positive complex of substantial amplitude (≥2 µV) that appeared 100-200 ms after pulse stimulus onset; marginal Baseline - low amplitude (<2 µV) reproducible P100 waveform; or absent baseline - no repeatable response present. Any activity of <0.5 µV was not considered a response. Best derivation for each particular patient was used for monitoring electroretinogram (ERG) recording and confirming the stimulation.

  9. Visual acuity, [ Time Frame: 2 years after CT103A cells infusion ]
    Acuity test is used to determine the number of letters that can be read on a standardized low-contrast Landolt C Broken Rings Chart held at a distance of 3 meters. Binocular score is the number of letters read correctly on an eye chart using both eyes simultaneously. The total score ranges from 0-70. Higher score indicates better vision.

  10. 36-item Short Form Generic Health Survey (SF-36) score [ Time Frame: 2 years after CT103A cells infusion ]
    SF-36 will used to understand the health related quality-of -life of the subjects after CT103A infusion. The eight health concepts: limitations in physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems; bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities because of emotional problems; vitality (energy and fatigue); and general health perceptions will be searched. These outcomes will be grouped as physical component summary and mental component summary. The norm data is 0-100, the health related quality of life is increases as the scores are increased. The average score is 50.

  11. EuroQol-five dimensions (EQ-SD) score [ Time Frame: 2 years after CT103A cells infusion ]
    Health status is measured with the EuroQuality of Life Five Dimensions (EQ-5D) after CT103A infusion, which includes five dimensions and is used to evaluate the quality of life of sepsis survivors. They are mobility, self-care, usual activities, discomfort or pain and depression or anxiety. Levels are coded 1-5 and a total score is then generated. Results for the demographic measured will be displayed as a percentage value.

  12. Visual analogue scale (VAS) pain score [ Time Frame: 2 years after CT103A cells infusion ]
    usual visual analog scale (VAS) of pain is used to evaluate pain after CT103A infusion (line from 0: no pain to 10:worst pain)

  13. Annual hospitalization rates [ Time Frame: 2 years after CT103A cells infusion ]
    The number of In-patient hospitalization is defined as a stay in hospital that goes beyond midnight of the first day of admission.

  14. Cytokines release after CT103A infusion [ Time Frame: 2 years after CT103A cells infusion ]
    Changes of concentration( pg/mL) of cytokines ( such as ferritin, CRP, IL-6 and procalcitonin) will be analyzed after CT103A cells infusion.

  15. Immunogenicity of CT103A cells [ Time Frame: 2 years after CT103A cells infusion ]
    Anti-drug antibodies (ADA) against CAR on CT103A cells will be analyzed after CT103A cells infusion.

  16. Detection of RCL [ Time Frame: 2 years or until CAR is undetectable after CT103A cells infusion ]
    Levels of replication competent lentivirus (RCL) will be monitored after CT103A cells infusion.

  17. Profiling of lymphocytes subtypes [ Time Frame: 2 years after CT103A cells infusion ]
    Changes in subtypes of lymphocytes( proportion of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells, and ratio of CD4+ T/CD8+T) will be analyzed after CT103A cells infusion.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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. Subjects with relapsed/refractory NMOSD that previously met the diagnostic criteria of NMOSD by 2015 International Panel for NMO Diagnosis (IPND):

    a. Subjects must be diagnosed as AQP4-IgG-positive NMOSD defined by 2015 criteria of IPND NMOSD and meet the following requirements: i. At least one kind of immunosuppressant has been used for more than one year with poorly-controlled symptoms; ii. Clinical evidence of at least two relapses in the last 12 months or three relapses in the last 24 months and one relapse in the preceding 12 months before screening.

  2. All acute toxic reactions resolved to baseline or ≤ grade 1 assessed using NCI-CTCAE v5.0 except the ones adjudicated by the investigator to pose no risks on subjects.
  3. Enrolled subjects must have satisfactory organ function and laboratory findings as defined by the following:

    1. Blood tests: absolute neutrophil count ≥ 2×109/L (or normal lower limit set by the central lab of the institution), platelets ≥ 100 × 109/L, and hemoglobin ≥ 100 g/L;
    2. Liver function: total serum bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 1.5x the institutional normal upper limit (ULN);
    3. Kidney function: CrCl ≥ 60 ml/min/1.73m2 (according to the following Cockcroft-Gault formula);
    4. Electrolytes: blood potassium ≥ 3.0 mmol/L; blood calcium ≥ 2.0 mmol/L, blood magnesium ≥ 0.5 mmol/L;
    5. Coagulation function: fibrinogen ≥ 1.0 g/L; APTT ≤ ULN + 10s; PT ≤ ULN + 3s.
  4. Blood oxygen saturation > 91% in resting state.
  5. Echocardiography suggests LVEF≥ 50%.
  6. Expected life expectancy ≥ 12 weeks as assessed by the investigator.
  7. After signing the informed consent form, subjects and their partners must be willing to use effective and reliable method of contraception, devices or medicines, within one year after CT103A cells infusion (excluding contraception safety periods).
  8. Subjects must provide written informed consent before the study begin.

Exclusion Criteria:

  1. Patients do not have adequate mononuclear cells without mobilization for CAR-T cell manufacturing.
  2. History of autoimmune hemolytic disease.
  3. History of solid organ transplantation.
  4. Patients were treated with alemtuzumab within 6 months prior to apheresis. Patients were treated with fludarabine or cladribine within 3 months prior to apheresis.
  5. Patients with Papovaviruses infection.
  6. Patients have been diagnosed with malignancies in the last 2 years prior to screening except for non-melanoma skin cancer, stage I cancers with complete resection and low risk of relapse, localized prostate cancer post-treatments, biopsy-confirmed in situ cervical cancer, or squamous epithelial lesion by PAP smear.
  7. Chronic and active hepatitis B (HBV), hepatitis C (HCV), Human Immunodeficiency Virus (HIV) infection, CMV or syphilis infections concurrently.
  8. Known history of primary immunodeficiency (innate or acquired).
  9. Patients with severe impaired cardiac function, including but not limited to the following: unstable angina, myocardial infarction (within 6 months before enrollment), congestive heart failure (≥Grade III by NYHA), severe ventricular arrhythmia.
  10. Cerebrovascular accidents, including transient ischemic attack or stroke history, occurred within 6 months before enrollment.
  11. Major operation or surgical treatment caused by any reason within 4 weeks before enrollment.
  12. Any serious and/or uncontrolled comorbidities which may interfere with the evaluation during the study in the opinion of the investigator
  13. Previous treatments:

    1. History of thymectomy within 12 months prior to CT103A infusion;
    2. Corticosteroids (>20mg per day of prednisone or the equivalent) were used within 10 days before PBMC collection or 30 days before CT103A infusion; physiological replacement, topical use and local inhalers are allowed;
    3. Immunosuppressants were used within 10 days before PBMC collection or 30 days before CT103A infusion;
    4. Patients were treated with rituximab within 5 months before signing ICF signature;
    5. Patients were treated with immunoglobin within 4 weeks before infusion;
    6. Patients were treated with plasma exchange or double filtration within 4 weeks before infusion.
  14. History of psychoactive drug abuse and failed to withdraw, or have a history of psychiatric disorders.
  15. Habitual intake and incapable of withdrawal of grapefruit juice or overdose of tea, coffee and/or caffeinated drinks during the study.
  16. Prone to allergies or history of serious allergy.
  17. Pregnant or lactating women.
  18. Patients with other conditions adjudicated by the investigator as unsuitable for enrollment.

Criteria for lymphodepletion and CAR-T cells infusion:

Before lymphocyte depletion and CAR-T cells infusion, patients are evaluated and those meeting the following criteria cannot be included:

  1. Blood tests: neutrophil count < 2 × 109/L, platelet count < 100 × 109/L, or hemoglobin < 100 g/L (not applicable before infusion);
  2. Oxygen inhalation is required to maintain blood oxygen saturation ≥ 91%;
  3. Patients have the following conditions, including but not limited to: new arrhythmia cannot be controlled by drugs; hypotension requiring pressor drugs; bacterial, fungal or viral infection requiring intravenous antibiotic treatment; creatinine clearance rate < 50 ml/min ;
  4. Patients require maintenance support treatment within one week to meet the criteria for lymphodepletion or CAR T cell infusion.
  5. Cell infusion is delayed > 7 days after lymphodepletion for any reason;
  6. Patients with other conditions adjudicated by the investigator as unsuitable for lymphodepletion or cell infusion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04561557


Contacts
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Contact: Chuan Qin, MD 86-27-83663337 qinchuan712@126.com
Contact: Chuan Qin, MD 86-27-83663332 chuanqin@tjh.tjmu.edu.cn

Locations
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China, Hubei
Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China, 430000
Contact: Chuan Qin, PhD    86-27-83663337    qinchuan712@126.com   
Contact: Chuan Qin, MD    86-27-83663333    chuanqin@tjh.tjmu.edu.cn   
Principal Investigator: Wei Wang, MD         
Sub-Investigator: Bitao Bu, MD         
Sub-Investigator: Min Zhang, MD         
Sub-Investigator: Daishi Tian, MD         
Sub-Investigator: Chuan Qin, MD         
Sub-Investigator: Jianfeng Zhou, MD         
Sub-Investigator: Chunrui Li, MD         
Sub-Investigator: Di Wang, MD         
Sponsors and Collaborators
Tongji Hospital
Nanjing IASO Biotherapeutics Co.,Ltd
Investigators
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Principal Investigator: Wei Wang, MD Tongji Hospital
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Responsible Party: Wei Wang, Professor of Neurology, President of Tongji Hospital, Tongji Hospital
ClinicalTrials.gov Identifier: NCT04561557    
Other Study ID Numbers: CAR-T treating NMOSD
First Posted: September 23, 2020    Key Record Dates
Last Update Posted: July 28, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Wei Wang, Tongji Hospital:
Adoptive T Cell Therapy
Chimeric antigen receptor
B-cell maturation antigen (BCMA)
Aquaporin-4 antibody (AQP4-IgG)
Neuromyelitis optica spectrum disorder (NMOSD)
Additional relevant MeSH terms:
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Neuromyelitis Optica
Nervous System Diseases
Autoimmune Diseases of the Nervous System
Autoimmune Diseases
Immune System Diseases
Myelitis, Transverse
Demyelinating Autoimmune Diseases, CNS
Optic Neuritis
Optic Nerve Diseases
Cranial Nerve Diseases
Demyelinating Diseases
Eye Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists