GC012F Injection in the Treatment of Refractory Generalized Myasthenia Gravis(24103)

This study is a single-arm, open-label, early-stage exploratory clinical study designed to evaluate safety, tolerability and preliminary efficacy of GC012F injection in the treatment of subjects with refractory GMG,the PK, PD characteristics and immunogenicity of GC012F injection in subjects were evaluated.

This trial is divided into:screening period, apheresis day, baseline period, lymphodepletion pretreatment period, infusion day, safety and efficacy follow-up period, long-term follow-up period and withdrawal visits.Eligible subjects will undergo apheresis collection and then receive the CAR-T infusion after the manufacturing of the products. Subjects in the lymphodepletion cohort will receive the conditioning regimen and then receive CAR-T cell infusion (per the schedule of assessment). Subjects who meet the cell infusion criteria will receive CAR-T cell infusion at the doses levels which were specified in the protocol, and the dose levels could be adjusted according to safety and clinical efficacy.

In this study, the infusion dose of CAR-T cells was set up in one dose group: 3×10^5/kg. About 6 participants are planned to be included. The subjects will be monitored for DLT for 28 days after the infusion of GC012F injection. For the first 3 patients to receive GC012F infusion, if ≤1/3 of the patients develop a DLT at a given dose level, the additional 3 patients will be enrolled in this cohort. If 2/3 or more DLTs occur at this dose level, subsequent subjects may be given a backup dose group of 2.0×10^5/kg or 1.0×10^5/kg after discussion between the investigator and the collaborator.

In the completion dose group of all subjects ,after the DLT observation period, DLTs will be observed for this dose group , all clinical study data collected during the period, especially safety data, were evaluated by the investigator discuss with the collaborator whether to add new subjects to the dose group or explore higher doses group.

After CAR-T cell infusion, subjects will be followed up for safety, cell proliferation, survival, and efficacy until the subject progresses on the disease, or withdraws from the study and refuses to accept follow-up , or dies, or withdraws informed consent, or is lost to follow-up (whichever occurs first).

Inclusion criteria

• To be enrolled, subjects must meet all of the following criteria:

• Subjects or their legal representatives voluntarily sign a written informed consent and are willing and able to comply with the procedures of the study;
• Subjects aged 18-75 years old (both inclusive), male or female;
• Subjects with confirmed refractory gMG of classes IIa - IVb by MGFA clinical classification (including classes IIa, IIb, IIIa, IIIb, IVa and IVb) at screening;
• Subjects with the Myasthenia Gravis - Activities of Daily Living (MG-ADL) score of ≥6, the proportion of ocular symptoms of <50% of the total score, and the Quantitative Myasthenia Gravis (QMG) score of ≥11;
• Subjects with poor response and/or who do not respond to the conventional therapies, that means subjects who are still at risk of relapse or exacerbation after conventional therapies with hormones, immunosuppressants (e.g., azathioprine, mycophenolate mofetil, tacrolimus, cyclosporin A, cyclophosphamide, methotrexate, etc.), or biological agents (e.g., rituximab);
• For patients who are taking corticosteroids, the dose of prednisone should not exceed 30 mg/day (or an equivalent dose of other corticosteroids), and the dose must be stable for at least 4 weeks before infusion;
• The laboratory test results during the screening period meet the following criteria:

• Neutrophil count ≥ 1.0×10^9/L; Hemoglobin ≥ 8.0 g/dL; Platelet count≥50×10^9/L;
• Alanine aminotransferase ≤ 3× upper limit of normal (ULN); Aspartate aminotransferase ≤ 3×ULN; total bilirubin (TBIL) < 2× ULN (for subjects with Gilbert's syndrome), direct bilirubin (DBIL)) ≤ 1.5×ULN
• Creatinine clearance (19.3 Appendix 3) ≥ 30 mL/min;
• Activated partial thromboplastin time (APTT) ≤ 1.5×ULN, prothrombin time (PT)≤ 1.5×ULN;
• Subject's left ventricular ejection fraction (LVEF) is ≥ 50% by echocardiography, with no evidence of pericardial effusion as determined;
• Female subjects of child-bearing age must:

• At screening, a negative serum β human chorionic gonadotropin β-hCG pregnancy test result confirmed by the investigator;
• Who agree to avoid breastfeeding during the study period until at least 1 year after the infusion of GC012F Injection or until two consecutive flow cytometry tests show the absence of CAR-T cells (whichever occurs later).
• Male subjects with sexual partners and female subjects of potential child-bearing age shall agree to take effective contraceptive measures (e.g., oral contraceptive pills, intrauterine device or condom) from the screening period until at least 2 years after the infusion of GC012F Injection or until two consecutive flow cytometry tests show the absence of CAR-T cells (whichever occurs later). Male subjects must agree to use condoms during sexual contact with pregnant women or females of child-bearing age within at least 2 years after the infusion of GC012F Injection, even if a successful vasectomy has been performed;
• Subjects for whom venous access available for blood collection can be established, and with no contraindications to leukocyte collection.

Exclusion criteria

• Participants who meet any of the following criteria are not included in the study:

• Have a history of severe hypersensitivity or allergy;
• Contraindications or hypersensitivity to fludarabine, cyclophosphamide and any component of the test drug;
• Subjects who have received intravenous immunoglobulin or plasma exchange therapy or immunoadsorption therapy within 4 weeks prior to infusion;
• Received CD20-targeted drugs within 6 months prior to apheresis;
• Received Tacrolimus, Cyclosporine, Azathioprine, Mycophenol Mofetil within 1 week before apheresis;
• Treatment with neonatal Fc receptor (FcRn) antagonists within 1 week prior to apheresis;
• Patients who have received complement inhibitors (e.g., eculizumab, etc.) within 1 weeks before apheresis ;
• Subjects with any of the following heart diseases:

• Class III or Class IV congestive heart failure based on New York Heart Association (NYHA) Functional Classification;
• Unstable angina, myocardial infarction or coronary artery bypass grafting (CABG) within 6 months prior to screening;
• Clinically significant ventricular arrhythmia or a history of unexplained syncope not due to vasovagal reaction or dehydration; or a QTc interval >480 ms at screening;
• Has a history of severe non-ischemic cardiomyopathy;
• Severe cardiovascular abnormalities (such as brain natriuretic peptide (BNP)/troponin and other indices) and the investigator judges that such subjects are not eligible for enrollment.
• Subjects with other uncontrolled malignancies. The following conditions will be excluded: early-stage tumors that have been treated by radical surgery (carcinoma in situ or grade 1 tumors, or non-ulcerative primary melanoma with a depth of <1 mm and with no involvement of lymph nodes), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in situ, or breast cancer in situ that has been treated by potential radical treatment;
• Serious underlying medical conditions, such as:

• Viral, bacterial, fungal, or other infections that are uncontrollable or requiring systemic intravenous therapy (including tuberculosis infection with clear evidence of disease activity) as demonstrated by evidence;
• Dementia or mental status changes as demonstrated by significant clinical evidence;
• History of any central nervous system (CNS) or neurodegenerative diseases, (e.g., Epilepsy, Convulsion, Paralysis, Aphasia, Stroke, Severe brain injury, Dementia, Parkinson's disease, Mental Illness).
• Positive result for any of the following tests:

• Positive test result of human immunodeficiency virus (HIV) antibody;
• Positive test result of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) (HBV DNA copy number will be detected for HBcAb- or HBsAb-positive patients. If the copy number is lower than the lower limit of detection, patients can be enrolled under the premise of standardized antiviral therapy);
• Positive test result of hepatitis C virus (HCV) antibody with the copy number of HCV RNA higher than the lower limit of detection; or with known history of hepatitis C without completion of antiviral therapy for ≥24 weeks;
• Positive test result of Syphilis antibody.
• Prior treatment with a CAR-T product for any target;
• Previous organ or allogeneic bone marrow transplantation;
• Subjects who have undergone surgery within 2 weeks prior to lymphodepletion pretreatment or plan to undergo surgery during the study (except subjects who schedule for local anesthesia surgery, but the surgery cannot be performed within 2 weeks after infusion);
• Received live attenuated vaccine within 4 weeks prior to lymphodepletion pretreatment;
• Subjects who have received study drugs in other clinical trials within 4 weeks prior to signing the informed consent form, or whose ICF signing date is within 5 half-lives of the last dose they had taken in other clinical trial (whichever is longer);
• Pregnant females or lactating females who do not agree to give up breastfeeding, during the period of participation in this study or men with a family plan within 1 year of receiving study treatment and females;
• Subjects with suicidal intentions at present based on the Columbia-Suicide Severity Rating Scale (C-SSRS), i.e., the answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on "Suicide" in the C-SSRS is "Yes", or who have a history of suicidal behavior at present;
• According to the researcher's judgment, there are circumstances that may prevent the subject from participating in the full trial, confuse the trial results, or participation in this study is not in the best interests of subjects.