This is a single-arm, open-label and early exploratory clinical study, with the purpose to study the safety, tolerability and initial clinical efficacy of GC012F Injection in the treatment of refractory GMG and to evaluate the PK, PD characteristics and immunogenicity in subjects with refractory GMG infused with GC012F Injection.
Subjects or their legal representative voluntary signing the ICF, and willing and able to follow the procedure in this study.
Aged between 18 and 75 years old (including 75), no gender limitation;
Patients with confirmed refractory GMG, and the clinical classification according to MGFA is IIa-IVb (including IIa, IIb, IIIa, IIIb, IVa and IVb) at screening;
At screening, the MG-ADL score must be ≥6, with ocular symptoms accounting for less than 50% of the total score, and QMG must be ≥11;
Subjects have a history of severe hypersensitivity or allergy;
Any contraindication for fludarabine, cyclophosphamide and any component of the investigational product;
Administration of intravenous immunoglobulin or plasmapheresis or immunoadsorption treatment within 4 weeks prior to infusion;
Use of B-cell targeting drugs, including but not limited to rituximab, Belimumab, and Telitacicept, within 6 months prior to apheresis;
Sequential
GC012F injection
DrugSubjects will be infused with GC012F Injection within 48-72 hours after lymphodepletion pretreatment, the infusion dose (CAR-T cells) and groups are as follows: 1. Dose group 1: 1 × 10\^5/kg; 2. Dose group 2: 2 × 10\^5/kg; 3. Dose group 3: 3 × 10\^5/kg; Note: For subjects weighing ≤70 kg: number of infused CAR-T cells = (1, 2 or 3) (±20%) × 10\^5 × body weight(kg); for subjects weighing \>70 kg: number of infused CAR-T cells (fixed doses of GC012F Injection) = (1, 2 or 3) (±20%) × 10\^5 × 70 kg.
Primary endpoints
1、DLT incidence; DLT is defined as any of the following conditions associated with GC012F Injection occurring within 28 days post cell infusion: 1. Neurotoxicity: Grade 3 and 4, which cannot recover to Grade 2 or lower within 7 days after therapeutic intervention; 2. CRS: Grade 4, which cannot recover to Grade 2 or lower within 3 days after therapeutic intervention; 3. Non-hematological toxicity: Grade 3 and Grade 4, involving heart, lung and kidney, which cannot recover to Grade 2 or lower within 28 days after therapeutic intervention; Grade 5; 4. Hematological toxicity: Grade 4, which cannot recover to Grade 2 or lower within 3 days after therapeutic intervention. The predictable complication for chemotherapeutics is not included as a DLT in this study.
Primary endpoints
Abnormal results of physical examination, vital signs, laboratory tests, electrocardiography and echocardiography, and the frequency and severity of AEs. The grading criteria for adverse event severity were based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0
Secondary endpoints
Disease activity index in 24 weeks after infusion including but not limited to: * The improvement and proportion of subjects on MG-ADL score and QMG score from baseline to 24 weeks post-infusion; MG-ADL total score of 24 points. The higher the score, the more serious the impact of the disease on daily life. * The improvement and proportion of subjects on MGC from baseline to 24 weeks post-infusion; MGC total score of 50 points. The higher the score, the more serious the impact of the life * The mean change of PRO (including MG-QoL15r scores) from baseline to 24 weeks post-infusion; The higher the score, the more serious the impact of the life * The change of MGFA post-intervention status from baseline to 24 weeks post infusion; * The decrease of titer of pathogenic antibody levels and proportion of subjects from baseline to 24 weeks post-infusion;
Secondary endpoints
PK parameters of CAR-T cells in peripheral blood (i.e. Cmax, Tmac, AUC, etc.) 1. GC012F CAR gene copy number in peripheral blood on D-1,D4,D7,D10,D14,D28,D56,D84,D168,D168+84D,D672+84D,OR withdraw 2. GC012F CAR-T cell count in peripheral blood on D-1,D4,D7,D10,D14,D28,D56,D84,D168,D168+84D,D672+84D,OR withdraw 3. Anti-GC012F antibody in peripheral blood on D-1,D28,D56,D84,D168,D168+84D,D672+84D,OR withdraw 4. Lymphocyte subpopulations in peripheral blood and B cell related tests 5. Tissue or bone marrow (if required) cell cluster related tests 6. Tissue or bone marrow (if required) CAR-T gene-related tests 4.5.6 are on D-1,D7,D14,D28,D56,D84,D168,D168+84D,D672+84D,OR withdraw 7. sBCMA in peripheral blood on D-1,D7,D14,D28,D56,D84,D168,D168+84D,D672+84D,OR withdraw 8. RCL and Lentivirus insertion siteon D-1 M1/3/6/12/18/24, twice a year for 3-5 years and once a year for 6-15 years
Secondary endpoints
Levels of cytokine in peripheral blood \[IL-2, IL-6, IL8,IL-10, IL-15, IL-17, IFN-γ, TNF-α, MCP-1and GM-CSF (if applicable), lymphocyte subsets and free BCMA in peripheral blood after GC012F infusion;
Exploratory endpoints
The detection rate of CAR-T antibody in peripheral blood from baseline to 24 weeks post GC012F infusion;
Exploratory endpoints
The change of patients and serum immunoglobulin concentration (including IgG, IgM, IgA and IgE) from baseline to 24 weeks post GC012F infusion
Exploratory endpoints
Detection rate of RCL.
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Chongbo Zhao
Lead sponsor
Huashan Hospital
Sponsor institution
Gracell Biotechnologies (Shanghai) Co., Ltd.
Collaborator
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