This study is a single-arm, open, 2-stage (dose-escalation phase and dose-expansion phase), multi-center, phase I clinical trial to evaluate the safety and tolerance of SYS6020 injection in the participants with refractory systemic myasthenia gravis, and determine the recommended dose (RD) for subsequent studies of the product, and to preliminarily evaluate the clinical efficacy of the product, as well as to explore the pharmacokinetics and immunogenicity of the product in vivo.
The dose-escalation phase and dose-expansion phase include 7 periods, and they are respectively in sequence as follows: the screening period, apheresis period, pre-dosing assessment, SYS6020 injection infusion, DLT observation period, the primary follow-up period (6 months), and the long-term follow-up period (5 years). The DLT observation period is 28 days after receiving SYS6020 injection. The participants will not undergo lymphodepleting chemotherapy.
The efficacy and safety profile of the participants will be continuously assessed during the trial. Efficacy measurement includes the MG-ADL, QMG, MGC, MG-QoL 15R scale, MGFA clinical classification, and MGFA post-intervention state (MGFA PIS) grading scales, as well as self-antibodies, etc. Safety measurement includes vital signs, physical examination, laboratory tests, cytokines, and ECG, etc. The adverse events and concomitant therapy will be continuously collected during the trial. In addition, during the study period, blood samples will be collected from participants who have received SYS6020 treatment for PK/PD test, and immunogenicity test.
For the dose-escalation phase, 3 to 5 dose levels are proposed to be explored. The Safety Monitoring Committee (SMC) will discuss the safety data and make a decision if the next SYS6020 injection could be initiated or dose-escalation could be initiated. After the completion of the dose-escalation phase, the recommended doses would be determined for dose-expansion phase. For the dose-expansion phase, further safety and efficacy data will be collected among the participants who will receive the recommended dose of SYS6020 injection.
1) The ages ≥18 and ≤ 70 years old;
2) Diagnosed as generalized myasthenia gravis (GMG), the clinical classification of MGFA II-IVa;
3) Diagnosed as refractory myasthenia gravis (refractory MG) ；
4) QMG score >11 in the screening period and before apheresis;
1) Have been known to have allergic reactions, hypersensitivity, intolerance or contraindications to SYS6020（including its active ingredient and excipient dextran 40） or the drugs potentially used in the study, or who have had a previous history of severe allergic reactions;
2) Participants with major chronic diseases that are not well-controlled and considered to increase the participant's risk potentially by the investigator;
3) Participants with other autoimmune diseases that require systemic treatment. Participants with stable autoimmune thyroid diseases who have a normal thyroid function and are at a stable therapeutic dose are allowed to be enrolled.
4) Participants with a severe recurrent infection during the screening period, or any active infection that the investigator considers may affect the patient's participation;
Sequential
SYS6020 injection
Biological/VaccineThe SYS6020 is an injection of autologous CAR-T cells that have been temporarily transfected with LNP-mRNA targeting BCMA. Before each dosing, the infusion eligibility of SYS6020 is assessed by the investigator, and the eligible participants will receive 3 dosing SYS6020 injection treatment. The dosing interval is 7 days according to the protocol design.
SYS6020 injection
Biological/VaccineThe SYS6020 is an injection of autologous CAR-T cells that have been temporarily transfected with LNP-mRNA targeting BCMA. Before each dosing, the infusion eligibility of SYS6020 is assessed by the investigator. The eligible participants will receive SYS6020 injection treatment twice weekly for 3 weeks, for a total of 6 doses.
SYS6020 injection
Biological/VaccineThe SYS6020 is an injection of autologous CAR-T cells that have been temporarily transfected with LNP-mRNA targeting BCMA. Before each dosing, the infusion eligibility of SYS6020 is assessed by the investigator. The eligible participants will receive SYS6020 injection treatment once weekly for 6 weeks, for a total of 6 doses.
7
Treatment groupsSee each treatment group below.
The frequency and the grade of DLT and the incidence of adverse events and serious adverse events. (For the dose-escalation phase)
For the dose-escalation phase, the primary objective is to evaluate the safety of SYS6020, as measured by the frequency and nature of Dose-limiting toxicity (DLT) and the incidence of all adverse events and serious adverse events. DLT is defined as any adverse event related to SYS6020 that occurs within 28 days after the infusion of SYS6020 and that meets certain criteria.
Response rate at 6 months after dosing （For the dose-expansion phase)
Response is defined as a ≥3-point reduction from baseline in the MG-ADL total score at Month 6
The proportion of MG-ADL score sdecline≥2
The proportion of participants achieving a decline of 2 points or more in MG-ADL from baseline to 6 months and 12 months after dosing (as dose-escalation phase endpoints only);
the proportion of QMG score decline≥2
The proportion of participants achieving a decline of 2 points or more in QMG from baseline to 6 months and 12 months after dosing (as dose-escalation phase endpoints only);
The proportion of MGC score decline≥3
The proportion of participants achieving a decline of 3 points or more in MGC from baseline to 6 months and 12 months after dosing (as dose-escalation phase endpoints only); The proportion of participants achieving a decline of 3 points or more in MGC from baseline to 6 months and 12 months after dosing (as dose-expansion phase endpoints only)
The mean change of MG-ADL score and QMG score decline ≥3
The proportion of participants achieving a decline of 3 points or more in both MG-ADL and QMG from baseline to 6 months and 12 months after dosing (as dose expansion phase endpoints only);
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