Clinical trial NCT06371040: Safety and Efficacy of CD19-BCMA Targeted CAR-T Therapy for Refractory Generalized Myasthenia Gravis
Official title: Evaluate the Safety and Efficacy of CD19-BCMA Targeted CAR-T Therapy for Refractory, Generalized Myasthenia Gravis: A Single-center, Open-label, Single-arm, Dose-finding Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Myasthenia Gravis
Keywords: Generalized Myasthenia Gravis
CAR-T Therapy
Lead sponsor: Tang-Du Hospital
Sponsor class: OTHER
First posted: 2024-04-17
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: CD19-BCMA Targeted CAR-T Dose 1 5.0 e5/ kg CD19-BCMA CAR-T positive T cells

CD19-BCMA Targeted CAR-T Dose 2 1.5 e6/ kg CD19-BCMA CAR-T positive T cells

CD19-BCMA Targeted CAR-T Dose 2 5 e6/ kg CD19-BCMA CAR-T positive T cells
Primary purpose: TREATMENT

Brief summary: This study is a single-center, open-label, single-arm, dose-exploration study to evaluate the safety and preliminary effectiveness of CD19-BCMA CAR-T in the treatment of refractory, generalized myasthenia gravis. The study is a dose escalation trial in adult, refractory, systemic MG patients. The Keyboard method will be used to perform dose escalation to explore the maximum tolerated dose (MTD). A total of 12 MG patients who meet the inclusion criteria are expected to be recruited.


Eligibility criteria: Inclusion Criteria:

* Study participants will be selected for this study only if they meet all of the following criteria:

  1. Age ≥18 years old and ≤80 years old;
  2. The subject signs the informed consent form, is willing and able to comply with the protocol, complete the research assessment and return for follow-up;
  3. To be diagnosed as a patient with systemic MG, the patient is required to have positive myasthenia-related antibodies (AChR-Ab, Musk-Ab or LRP4) on the basis of typical myasthenic symptoms;
  4. Evaluated by the researcher as refractory MG. Refractory MG is defined as:

     1. Treatment failed after receiving at least 2 immunosuppressants
     2. Definition of treatment failure: 1) Persistent weakness and impairment of daily activities; 2) MG aggravation and/or crisis during treatment; 3) Intolerance to immunotherapy due to side effects or comorbidities;
     3. Repeated plasma exchange (PE) or intravenous immune globulin (IVIg) treatment is required to control symptoms;
     4. The researchers believe that despite the current routine immunotherapy for patients, MG still imposes a large functional burden on patients.
  5. MGFA classification IIa\~IVa at screening and baseline;
  6. QMGS score ≥11 points or MG-ADL score ≥5 points at screening and baseline, of which the eye score accounts for no more than 50%;
  7. Male study participants must agree to take contraceptive measures during the treatment period and within 1 year after receiving study treatment, and are prohibited from donating sperm throughout the study period;
  8. If you are a woman of childbearing potential (WOCBP), you must agree to take contraceptive measures during treatment and for at least 1 year after receiving study treatment. Participants must have a negative serum pregnancy test result during screening; a negative urine pregnancy test result must be confirmed before receiving CART for the first time.

Exclusion Criteria:

* Prior to screening and the baseline visit, study participants will not be eligible for inclusion in the study if they meet any of the following criteria:

  1. The researcher believes that there is any medical or mental condition that may harm the research participant or affect the research participant's ability to participate in this study; or any condition that the researcher believes is related to poor compliance;
  2. Women who are lactating or pregnant, or women who plan to become pregnant at any time within 12 months after receiving CART treatment, or who have a history of spontaneous abortion or induced abortion within 4 weeks before screening;
  3. Study participants have clinically relevant active infections (such as sepsis, pneumonia or abscess) or serious infections (resulting in hospitalization or requiring antibiotic treatment) within 4 weeks before screening;
  4. thymoma that underwent thymectomy within 6 months before baseline or was planned to undergo thymectomy during the study, or required chemotherapy and/or radiotherapy at any time;
  5. Investigator participants have received live attenuated vaccine vaccination within 8 weeks before screening; or plan to receive live vaccine vaccination within 8 weeks after treatment;
  6. Study participants have received rituximab treatment within 6 months before screening;
  7. Have received tocilizumab or eculizumab treatment within 3 months before screening;
  8. Have received intravenous human immunoglobulin, plasma exchange, or immunotherapy within 4 weeks before screening;
  9. Those with known serious underlying diseases, such as liver and kidney damage, blood diseases, previous severe cardiovascular disease, severe hypertension, diabetes, and poor blood pressure and blood sugar control;
  10. Unresected thymoma (Note: Subjects with benign thymoma resected more than one year before screening are eligible. Benign is defined as no known metastasis on pathological examination and no intracystic or extracystic Extension. Imaging studies must be performed during the screening period to assess thymic status).
  11. Any of the following laboratory abnormalities occur during the screening period (one repeat measurement can be performed during the screening period before randomization to confirm the results)

      1. Elevated liver enzymes (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 times the upper limit of normal (ULN)).
      2. Total bilirubin\>1.5 times ULN
      3. Estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73 m2
      4. Abnormal PT or INR, or prolonged APTT \>1.5 times ULN
      5. Neutrophil count \<1000cell/ul
      6. Platelet count \<50000/mm3
      7. Hemoglobin\<8.0g/dl
  12. Those with a high-risk history of tuberculosis infection or acquired tuberculosis infection;
  13. Known immunodeficiency diseases, including human immunodeficiency virus (HIV) infection;
  14. Positive for hepatitis B surface antigen (HBsAg) during the screening period;
  15. Receive blood transfusion treatment 4 weeks before screening or during the screening period;
  16. Symptoms worsen rapidly during the lead-in period and enter crisis or pre-crisis state (MGFA IVb-V)
  17. Other circumstances in which the researcher deems it inappropriate to participate in the study.

Primary outcomes:
measure: Frequency, type, and severity of adverse events
timeFrame: From Baseline (Day 1) to Safety Follow-Up Visit (up to 4 weeks)
Secondary outcomes:
measure: Frequency, type, and severity of abnormal laboratory indicators related to treatment
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of blood pressure
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of pulse rate
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of weight
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of Myasthenia Gravis Activities of Daily Living (MG-ADL) scores
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of Quantitative Myasthenia Gravis (QMG) scores
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of Myasthenia Gravis Composite (MGC) scores
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Proportion of subjects who achieved improvement
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Time to achieve clinical improvement
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of myasthenia gravis-specific autoantibody titers
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: Changes of immunoglobulins
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
Other outcomes:
measure: Changes in proportion of peripheral blood immune cell
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 24 weeks)
measure: serum inflammatory markers levels
timeFrame: From Baseline (Day 1) up fo Follow-Up (up to 4 weeks)
Locations:
city: Xi'an
country: China
facility: Tangdu Hospital, The Fourth Military Medical University
state: Shaanxi
Study officials:
References: