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.
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. This study includes periods of screening, apheresis, baseline, lymphodepletion pretreatment, assessment before infusion, infusion of CAR-T cells, and Safety and efficacy follow-ups, long-term follow-ups, and withdrawal of study visits (if any). Eligible subjects will receive the apheresis and then infusion after the production of CAR-T product. Subjects will receive lymphodepletion pretreatment, and assessments prior to CAR-T cell infusion. Subjects who meet the cell infusion criteria will receive CAR-T cell infusion with the doses specified in the protocol, and the doses in the same group or subsequent group can be adjusted based on the safety and clinical efficacy. There're 3 dose groups in this study for CAR-T cell infusion: 1×10\^5/kg, 2×10\^5/kg, 3×10\^5/kg. Dose will be escalated based on "3+3" rule. 3\~6 subjects will be enrolled into each dose group, approximately 9\~18 subjects in total will be enrolled. Subjects of each dose group will be observed for DLT within 28 days (Dose-limiting toxicities (DLT) observation period) after GC012F injection infusion. After all proposed subjects in each dose group complete the 28-day DLT observation period, the Safety Monitoring Committee (SMC) will evaluate the clinical safety and pharmacokinetic data (if available). Only after obtaining the approval of SMC and collaborator may new subjects be enrolled in the next dose group. Additionally, in order to ensure the safety of CAR-T therapy, the SMC may recommend increasing the frequency of safety committee evaluations according to the safety situation and study progress (e.g., conducting an SMC assessment for each newly enrolled subject). The dose escalation rules are as follows: Each dose level will enroll 3 to 6 subjects, and only after all subjects in a dose group complete the DLT assessment, meet escalation criteria, and have undergone evaluation by the SMC (considering clinical safety and pharmacokinetic data, if available) and received collaborator approval will they proceed to the next dose level. The criteria for dose escalation are: if none of the first 3 patients in a group experience DLT during the observation period, the study may proceed to the next dose group. If one patient among the first three experiences DLT during the observation period, three additional patients will be enrolled to the same dose group. If DLT cases are ≤1 out of the total 6 enrolled patients during the DLT observation period, the study can proceed to the next dose group. If the number of DLT cases exceeds 1, dose escalation will be halted (see the table below for details) Number of DLT cases Measures 0/3 Escalation to the next dose group 1/3 Enrolled 3 additional subjects 1/6 Escalation to the next dose group ≥2/3 or ≥2/6 1. Dose escalation will be halted 2. Dose de-escalation to a lower dose level: 1. If only 3 subjects were enrolled at the dose level, 3 additional subjects will be enrolled at that dose level; 2. If there have been 6 subjects at the dose level, DLT cases are ≤1, the dose is MTD. After all subjects in a dose group have completed the DLT observation period, all clinical study data collected during that period, particularly safety data, will be assessed. Following evaluation and approval by the SMC, which will consider the clinical safety and pharmacokinetic data (if available), the collaborator will decide whether to enroll new subjects in that dose group, halt or continue dose escalation, or introduce an intermediate dose group. If more than one DLT is observed in the 1×10\^5/kg dose group, following approval by the SMC, the researchers and collaborators will discuss whether to explore a lower dose group. If no DLT is observed after escalating to 3×10\^5/kg, the decision to explore a higher dose group will be based on a comprehensive review of safety data, CAR-T cell expansion persistence parameters, and efficacy data, after SMC evaluation and approval, followed by discussions between researchers and collaborators. Given that the activity of cell-based therapies (which are long-lasting) does not show a clear dose dependency, exposure of subjects to excessively low doses may not yield clinical benefit. Therefore, this study will determine or adjust the infusion dose for patients based on the safety of the GC012F injection, parameters for CAR-T cell expansion persistence, and clinical efficacy, following assessment and agreement by the SMC along with further discussions with the researchers and collaborators. DLT assessments will be performed for evaluable subjects within 28 days post-GC012F injection. Subjects will be replaced if any of the following situations occur during the DLT assessment period: (1) subjects withdraw from the study for reasons not related to DLT, (2) prohibited medications were used prior to DLT occurrence, or (3) safety evaluations required for DLT assessment are not completed. Following CAR-T cell infusion, subjects will be monitored for safety, cell proliferation persistence, and efficacy, until disease progression, withdrawal from the study with refusal of further follow-up, death, withdrawal of informed consent, loss to follow-up, or 24 weeks post-infusion(whichever occurs first).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Subjects 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.
Huashan Hospital, affiliated to Fudan University, Shanghai,
Shanghai, Shanghai Municipality, China
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.
Time frame: Since signing the ICF until 24-week post-infusion or premature withdrawal from the study, whichever comes first.
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
Time frame: Since signing the ICF until 24-week post-infusion or premature withdrawal from the study, whichever comes first.
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;
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Time frame: Since signing the ICF until 24-week post-infusion or premature withdrawal from the study, whichever comes first.
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
Time frame: Since signing the ICF until Long-term follow-up period or withdraw
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;
Time frame: Since signing the ICF until 24-week post-infusion or premature withdrawal from the study, whichever comes first.