Early Exploratory Clinical Study of GC012F Injection in Refractory Idiopathic Inflammatory Myopathy
This is a single-arm, open-label, early exploratory clinical study to evaluate the safety and efficacy of GC012F Injection in subjects with refractory idiopathic inflammatory myopathy and to assess the pharmacokinetic and pharmacodynamic profiles. This study consists of screening period, apheresis period, baseline period, lymphodepleting preconditioning period, pre-infusion evaluation period, CAR-T cell infusion period and follow-up period. Eligible subjects will undergo apheresis and receive infusion following the manufacture of the CAR-T product. Subjects will receive lymphodepleting preconditioning before CAR-T cell infusion and will be assessed before infusion. If the criteria for cell infusion are met, CAR-T cell infusion will be performed and the infusion dose in the same group or subsequent treatment groups may be adjusted according to the safety and clinical response. A total of 1 dose group will be set for CAR-T cell infusion dose in this study: 3 × 10\^5/kg. Approximately 12 subjects are planned to be enrolled. Subjects will be monitored for dose-limiting toxicity (DLT) within 28 days following the infusion of GC012F Injection. For the first 3 patients receiving infusions of GC012F, 3 additional patients will be included in this cohort if no more than 1/3 of the patients experience DLTs at a given dose level. If 2/3 or more DLTs occur at this dose level, a spare dose of 2.0 × 10\^5/kg or 1.0 × 10\^5/kg may be administered to subsequent subjects following discussion between the investigator and the partner. If no more than 1 out of the first 6 subjects experiences a DLT, 6 additional subjects will be enrolled. Once 2 subjects experience DLTs, the investigator and the partner will discuss and decide whether to use a spare dose group of 2.0×10\^5/kg or 1.0×10\^5/kg. After the first 3 subjects have all completed the 28-day DLT observation period, the Safety Monitoring Committee (SMC) will conduct an assessment based on clinical safety and pharmacokinetic data (if available). Subsequently, the SMC may, depending on the safety profile and study progress, request an increased frequency of safety committee assessments and reviews. After completing the DLT observation period for all subjects in this dose group, all clinical study data collected during the DLT observation period for this dose group, especially safety data, will be assessed, and whether to add new subjects to this dose group and whether to explore a different dose group will be decided upon discussion between the investigator and the partner. Following CAR-T cell infusion, subjects will be followed for safety, cell proliferation and survival, and efficacy until the subject withdraws from the study and refuses subsequent follow-up, or dies, or withdraws consent, or is lost to follow-up, whichever occurs first.
• 1\) The subject or his/her legally acceptable representative voluntarily signs the written informed consent form and is willing and able to comply with the procedures of this study; 2) Aged 18 to 70 years (inclusive) at the time of signing informed consent, male or female; 3) Patients should meet the following criteria:
‣ Subjects with suspected or confirmed idiopathic inflammatory myopathy (IIM) based on the 2017 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria and at least one proximal limb muscle strength of less than or equal to Grade 4; patients with immune-mediated necrotizing myopathy (IMNM) may be included if he/she meets other inclusion criteria and does not meet all exclusion criteria and the investigator assesses that the patient has no safety instability;
⁃ Active myositis on muscle biopsy or muscle magnetic resonance imaging (MRI) within the screening period or within 6 months prior to screening;
⁃ Positive (+ or above) for at least one myositis-specific antibody (MSA) or myositis-associated antibody (MAA) (including anti-TIF-1γ, NXP-2, Mi-2α, Mi-2β, MDA-5, SAE-1/2, SRP, HMGCR, Jo-1, PL-7, PL-12, HA, EJ, OJ, KS, Zo, PM-Scl100, PM-Scl75, SSA/Ro-52, SSB/LA, Ku, RNA-PIII, cN1A, etc.);
⁃ At screening, the subject must have moderate to severe IIM, defined as manual muscle testing (MMT) \< 142 and 2 of the following criteria are met:
• PGA (VAS) ≥ 2 cm (VAS 10 cm scale);
∙ PtGA (VAS) ≥ 2 cm (VAS 10 cm scale);
∙ Health assessment questionnaire (HAQ) \> 0.25;
∙ Increase in one or more muscle enzymes (CK, LDH, AST, ALT) is ≥ 1.5 × ULN;
∙ Extramuscular global assessment (Myositis Disease Activity Assessment Tool \[MDAAT\]) ≥ 2.0 cm (VAS 10 cm scale); 4) Muscle enzyme increased (CK) ≥ 2 × ULN; 5) Inadequate response or intolerance to corticosteroids and at least 2 immunosuppressants and/or biologic agents; 6) If the patient is taking corticosteroids, the dose of prednisone should not exceed 40 mg/day (or equivalent dose of other corticosteroids) within 3 weeks before apheresis, and the dose is not uptitrated within 3 weeks before apheresis and not changed within 4 weeks before infusion (Note: under the premise that the subject's disease under study is controlled, the investigator may consider reducing the dose of corticosteroids before apheresis, lymphodepletion, and infusion); 7) Life expectancy ≥3 months; 8) Laboratory test results must meet the following criteria at screening (except for those related to the corresponding disease under study):
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‣ Neutrophil count \> 1.0 × 10\^9/L, Hemoglobin ≥ 80g/L, platelet count ≥ 50 × 10\^9/L;
⁃ Alanine aminotransferase ≤ 3 × upper limit of normal (ULN); aspartate aminotransferase ≤ 3 × ULN (unless the increases in alanine aminotransferase and/or aspartate aminotransferase are assessed by the investigator as related to polymyositis \[PM\] or dermatomyositis \[DM\]); total bilirubin (TBIL) \< 2 × ULN (direct bilirubin \[DBIL\] ≤ 1.5 × ULN for subjects with Gilbert's syndrome);
⁃ Creatinine clearance ≥ 60 ml/min;
⁃ Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN;
⁃ Left ventricular ejection fraction (LVEF) ≥ 50% as diagnosed by echocardiogram, with no evidence of pericardial effusion as determined; 9) Women of childbearing potential must:
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‣ Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result at screening as confirmed by the investigator;
⁃ Agree to avoid breastfeeding during the study period and until at least 2 years after infusion of GC012F Injection, or until two consecutive flow cytometry tests indicate that CAR-T cells are no longer present (whichever occurs later); 10) Male subjects with sexual partners and female subjects of childbearing potential must agree to use highly effective contraception methods (e.g., oral contraceptives, intrauterine devices, or condoms) starting from screening and continuing for at least 2 years after GC012F Injection infusion or until two consecutive flow cytometry tests indicate that CAR-T cells are no longer present (whichever occurs later). Male subjects must agree to use condoms during any sexual contact with pregnant women or women of childbearing potential for at least 2 years after GC012F Injection infusion, even if they have undergone successful vasoligation.
‣ 11\) The required venous access for collection can be set up, with no contraindications for leukapheresis.