Clinical trial NCT04561557: Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Inflammatory Diseases of the Nervous System
Official title: An Open Label Clinical Trial to Evaluate the Safety and Efficacy of CT103A Cells for the Treatment of Relapsed/Refractory Antibody-associated Inflammatory Diseases of the Nervous System
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Neuromyelitis Optica Spectrum Disorder
Myasthenia Gravis
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Idiopathic Inflammatory Myopathies
Multiple Sclerosis
Autoimmune Encephalitis
Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD)
POEMS Syndrome
Keywords: Adoptive T Cell Therapy
Chimeric antigen receptor
B-cell maturation antigen (BCMA)
Autoimmune Diseases of the Nervous System
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Nanjing IASO Biotechnology Co., Ltd.
First posted: 2020-09-23
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Antibody-mediated inflammatory diseases of the nervous system (also known as autoimmune diseases of the nervous system) are autoimmune diseases in which autoimmune cells and immune molecules attack the nervous system as the main pathogenic mechanism. In the immune response, pathogenic antibodies acting on autoantigens of the nervous system are collectively referred to as autoantibodies of the nervous system, and antibody-mediated inflammatory diseases of the nervous system can occur in the central nervous system, peripheral nervous system, and neuromuscular junctions, and muscles. In this study, we will recruit eight kinds of autoimmune diseases of nervous system including Neuromyelitis Optica Spectrum Disorder (NMOSD), Myasthenia Gravis (MG), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), idiopathic inflammatory myopathyand (IIM), multiple sclerosis (MS), autoimmune encephalitis (AE), Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and POEMS Syndrome. 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 neurological autoimmune diseases driven by abnormal antibody 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 antibody-mediated idiopathic inflammatory diseases.


Eligibility criteria: Inclusion Criteria:

1. Male or female subjects aged 18-75 years (including 18 and 75 years);
2. Subjects with Relapsing/refractory Antibody-mediated inflammatory diseases of the nervous system without effective treatment, including:

   1. 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. Subjects with MG with positive abnormal antibody, MG-ADL total score ≥ 6 points, MGFA classification II-IV defined by 2020 MGFA diagnostic criteria and meet the following requirement: i. At least one kind of immunosuppressant for standardized treatment for more than 1 year, and have one of the following poor control conditions: 1) continuous inability to affect daily life; 2) Exacerbation of MG symptoms and/or crisis attacks still occur despite standard treatment; 3) Inability to tolerate immunosuppressive therapy ii. Requires plasma exchange or maintenance therapy with IV gamma globulin
   3. Subjects with CIDP with positive abnormal antibodies, INCAT disability scale with total score of 2-9 defined by 2021 EAN/PNS diagnostic criteria and meet the following requirement: i. Standardized use of at least one first-line therapy for more than 3 months (cortisol hormone therapy, gamma globulin or plasma exchange therapy) with poorly-controlled symptoms. ii. Inability to tolerate cortisol hormones, gamma globulin, and plasmapheresis because of side effects or other conditions
   4. Subjects were diagnosed with IIM defined by 2017 European League against Rheumatism/American Rheumatology (EULAR/ACR) conference Class criteria; At least one kind of cardiac enzymes (CK, AST, ALT, ALD, LDH) ≥1.5×ULN during the screening period, or Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) ≥6, or at least one other sign of active disease within the last 6 months: MRI, EMG, or muscle biopsy; positive serological tests for myositis-specific antibodies (MSA) or myositis-associated autoantibodies (MAA), or antinuclear antibody (ANA). and meet one of the following requirements:

   i. After at least 1 month of corticosteroid therapy and standardized use of at least one immunosuppressant/modulator (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, Cyclophosphamide, leflunomide, intravenous gamma globulin, etc.) for more than 3 months with poorly-controlled symptoms.

   ii. ii. Inability to tolerate the above traditional regimens due to side effects or other conditions;

   e. Subjects were diagnosed with PMS (including PPMS and SPMS) or RMS according to the 2017 revision of the McDonald diagnostic criteria；EDSS score between 2 to 7 points inclusive, at screening. Subjects with RMS should meet one of the following requirements after standard therapy: i. at least two relapses in the last two years before screening. ii. at least one relapse in the last one year before screening. iii. positive Gd-enhancing MRI in the last one year before screening.

   f. Subjects were diagnosed with POEMS syndrome according to the 2021 revised IMWG diagnostic criteria and meet all of the following requirements: i. bone marrow involvement; ii. no response to traditional regimens treatment including corticosteroid, chemotherapy, protease inhibitor or inability to tolerate the above traditional regimens; iii. Have measurable lesions (refer to the 2021 revised IMWG standard) iv. VEGF \> 2 ULN; v. ECOG score ≥1; vi. ONLS score ≥1.

   g. Subjects were diagnosed with autoimmune encephalitis according to the 2016 International Diagnostic Criteria for Autoimmune Encephalitis and meet all of the following requirements: i. at least one pathogenic antibody positive; ii. previously standardized use of corticosteroid, at least one immunosuppressant/modulator, including CD20 monoclonal antibody with poorly-controlled symptoms or intolerance; iii. onset of autoimmune encephalitis within 3 months prior to screening; iv. mRS Score ≥2 or CASE score ≥4.

   h. Subjects were diagnosed with MOGAD according to the 2023 International MOGAD Diagnostic criteria and meet all of the following requirements: i. a documented positive serum MOG Ab test using a cell-based assay (CBA); ii mRS Score ≥2; iii previously standardized use of corticosteroid, at least one immunosuppressant/modulator, including CD20 monoclonal antibody with poorly-controlled symptoms or intolerance.
3. 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.
4. Enrolled subjects must have satisfactory organ function and laboratory findings as defined by the following:i. 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; ii. Liver function: total serum bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 1.5x the institutional normal upper limit (ULN); iii. Kidney function: CrCl ≥ 60 ml/min/1.73m2 (according to the following Cockcroft-Gault formula); iv. Electrolytes: blood potassium ≥ 3.0 mmol/L; blood calcium ≥ 2.0 mmol/L, blood magnesium ≥ 0.5 mmol/L; v. Coagulation function: fibrinogen ≥ 1.0 g/L; APTT ≤ ULN + 10s; PT ≤ ULN + 3s.
5. Blood oxygen saturation \> 91% in resting state.
6. Echocardiography suggests LVEF≥ 50%.
7. Expected life expectancy ≥ 12 weeks as assessed by the investigator.
8. 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).
9. 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. MG crisis was not effectively controlled within 2 weeks before enrollment.
9. Known history of primary immunodeficiency (innate or acquired).
10. 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.
11. Cerebrovascular accidents, including transient ischemic attack or stroke history, occurred within 6 months before enrollment.
12. Major operation or surgical treatment caused by any reason within 4 weeks before enrollment.
13. Any serious and/or uncontrolled comorbidities which may interfere with the evaluation during the study in the opinion of the investigator
14. Previous treatments: History of thymectomy within 12 months prior to CT103A infusion;
15. History of psychoactive drug abuse and failed to withdraw, or have a history of psychiatric disorders.
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 \< 50 × 10\^9/L;
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.

Primary outcomes:
measure: Types and incidence of dose-limiting toxicity (DLT) after CT103A cells infusion
timeFrame: Up to 28 days post CT103A infusion
measure: Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms.
timeFrame: Up to 2 years post CT103A infusion
Secondary outcomes:
measure: PD-Soluble BCMA
timeFrame: Up to 2 years post CT103A infusion
measure: PD-Pathogenic antibody
timeFrame: Up to 2 years post CT103A infusion
measure: PD-Nfl（MS）
timeFrame: Up to 2 years post CT103A infusion
measure: PK-VCN
timeFrame: Up to 15 years post CT103A infusion
measure: PK-BCMA CAR-T cells
timeFrame: Up to 28 days post CT103A infusion
Other outcomes:
measure: NMOSD: Annualized relapse rate (ARR)
timeFrame: Up to 2 years post CT103A infusion
measure: NMOSD: Accumulated total active MRI lesions
timeFrame: Up to 2 years post CT103A infusion
measure: NMOSD: Expanded Disability Status Scale (EDSS) score
timeFrame: Up to 2 years post CT103A infusion
measure: NMOSD: Modified Rankin Scale
timeFrame: Up to 2 years post CT103A infusion
measure: NMOSD: Visual acuity
timeFrame: Up to 2 years post CT103A infusion
measure: MG: Quantitative Myasthenia Gravis Score (QMG)
timeFrame: Up to 2 years post CT103A infusion
measure: MG: Myasthenia Gravis Activities if Daily Living (MG-ADL) Score
timeFrame: Up to 2 years post CT103A infusion
measure: CIDP: Inflammatory Neuropathy Cause and Treatment (INCAT) Score
timeFrame: Up to 2 years post CT103A infusion
measure: CIDP: Medical Research Council (MRC) muscle function Score
timeFrame: Up to 2 years post CT103A infusion
measure: CIDP: Assess changes in nerve conduction test results
timeFrame: Up to 2 years post CT103A infusion
measure: IMNM: Manual Muscle Testing (MMT) Score
timeFrame: Up to 2 years post CT103A infusion
measure: IMNM: Assess the changes in serum creatine kinase levels in patients with IMNM before and after treatment.
timeFrame: Up to 2 years post CT103A infusion
measure: IMNM: Muscle MRI
timeFrame: Up to 2 years post CT103A infusion
measure: 36-item Short Form Generic Health Survey (SF-36) score
timeFrame: Up to 2 years post CT103A infusion
measure: EuroQol-five dimensions (EQ-SD) score
timeFrame: Up to 2 years post CT103A infusion
measure: Visual analogue scale (VAS) pain score
timeFrame: Up to 2 years post CT103A infusion
measure: Annual hospitalization rates
timeFrame: Up to 2 years post CT103A infusion
measure: Cytokines release after CT103A infusion
timeFrame: Up to 2 years post CT103A infusion
measure: Immunogenicity of CT103A cells
timeFrame: Up to 2 years post CT103A infusion
measure: Detection of RCL
timeFrame: Up to 2 years post CT103A infusion
measure: Profiling of cell subtypes
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Annualized Relapse Rate (ARR)
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Time to first relapse
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Number of T1 Gadolinium (Gd)
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Annualized rate of T2 lesions
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Percent Change in T2 lesions volume
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Change in EDSS
timeFrame: Up to 2 years post CT103A infusion
measure: MS: Percent of NEDA-3
timeFrame: Up to 2 years post CT103A infusion
measure: MS: 3-month CDP
timeFrame: Up to 3 months post CT103A infusion
measure: MS: 6-month CDP
timeFrame: Up to 6 months post CT103A infusion
measure: MS: Patient Reported Outcomes (PRO)
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: Overall Response Rate (ORR)
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: Hematological response rate
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: Neural response rate
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: Change in VEGF
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: PET response rate
timeFrame: Up to 2 years post CT103A infusion
measure: POEMS syndrome: Response rate of other organs
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Time to ≥1point improvement in modified Rankin score (mRS)
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Time to first relapse
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Epilepsy
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Change in CASE
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Change in MoCA
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Change in CGI
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Change in GCS
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Change in MMSE
timeFrame: Up to 2 years post CT103A infusion
measure: AE: Number of FBDS
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: Annualized relapse rate
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: Time to first relapse
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: MS: Number of T1 Gadolinium (Gd)
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: Change in EDSS
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: Change in MoCA
timeFrame: Up to 2 years post CT103A infusion
measure: MOGAD: Change in MoCA
timeFrame: Up to 2 years post CT103A infusion
measure: All patients: Change in mRS
timeFrame: Up to 2 years post CT103A infusion
Locations:
city: Wuhan
country: China
facility: Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
Study officials:
affiliation: Tongji Hospital
name: Wei Wang, MD
role: PRINCIPAL_INVESTIGATOR
References: