BCT301 in Treating Refractory/Recurrent IgG4-related Disease

Clinical Study to Evaluate the Safety and Efficacy of BCT301 Cell Injection in Patients With Refractory/Recurrent IgG4-Related Disease

This is an investigator initiated trial to assess the safety and efficacy of BCT301 cell Injection (CAR-iT cells derived from chemically induced pluripotent stem cells) in patients with refractory/recurrent IgG4-related disease.

This is a single-arm, open-label, single-center clinical study in which all patients receive a unified treatment regimen. The primary objective is to evaluate the safety and tolerability of BCT301 Cell Injection in patients with refractory/recurrent IgG4-RD. Secondary objective is to evaluate the improvement in disease activity in patients with refractory/recurrent IgG4-RD treated with BCT301 Cell Injection. Six subjects with refractory/recurrent IgG4-RD meeting the inclusion/exclusion criteria are planned to be enrolled and will receive a single infusion of 1.8 × 10^8 BCT301 Cell Injection to evaluate the safety, efficacy, and PK/PD characteristics following BCT301 Cell Injection infusion. The study flow consists of a screening period, a lymphodepletion pretreatment period, a treatment period, and a follow-up period. Patients without relapse or deterioration after BCT301 Cell Injection infusion and not requiring protocol-prohibited treatment will undergo a primary follow-up of up to 360 days.

Inclusion Criteria:

• Voluntarily participate in this trial and sign the informed consent form;
• Male or female patients aged 18 to 75 years (inclusive), with body weight ≥ 40 kg;
• Women of childbearing potential must have a negative serum pregnancy test before the start of the trial and agree to use effective contraception during the trial and until the last follow-up; male subjects whose partners are of childbearing potential agree to use effective contraception during the trial and until the last follow-up;
• Confirmed diagnosis of IgG4-related disease meeting the classification criteria for IgG4-RD (the 2020 updated version of the comprehensive diagnostic criteria for IgG4-RD established in Japan) or the 2019 ACR/EULAR classification criteria for IgG4-RD; and with at least one of the following organ involvements: pancreas, bile ducts, kidneys, lungs, heart or pericardium, aorta and great vessels, retroperitoneal fibrosis, sclerosing mediastinitis, dura mater, or pituitary gland;
• Clinically meets the criteria for refractory/recurrent IgG4-RD: disease remains active, or relapses after remission, or progresses despite systemic treatment with standard-of-care regimens-glucocorticoids, immunosuppressants (cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine, etc.)-or biologic agents;
• Currently receiving one or more of the following stable-dose standard therapies:
• If the patient is receiving glucocorticoid therapy, the following conditions must be met: at screening and during the screening period, the maximum glucocorticoid dose is 30 mg/day of prednisone (or equivalent). The glucocorticoid dose must remain stable for ≥ 7 days prior to screening; during the screening period, glucocorticoid dose adjustments must not exceed 5 mg/day of prednisone (or equivalent);
• If the patient is receiving immunomodulators/immunosuppressants: initiation of drug therapy must be ≥ 12 weeks prior to screening. A stable drug dose must be maintained for ≥ 4 weeks prior to screening and during the screening period;
• If biologic agents (e.g., belimumab or telitacicept) were used before the screening period, they must be discontinued for at least 5 half-lives before screening; if anti-CD20 monoclonal antibody therapy was used before the screening period, an interval of 6 months is required before screening;
• IgG4-RD Responder Index (RI) ≥ 2, with disease in an active state;
• Peripheral blood B cells show positive CD19 expression by flow cytometry;
• Major organ function must meet the following requirements (conditions caused by the immune disease itself are exempt):
• Bone marrow hematopoietic function must meet: a. White blood cell count ≥ 3 × 10^9/L; b. Neutrophil count ≥ 1 × 10^9/L (no colony-stimulating factor treatment within 2 weeks prior to the examination); c. Hemoglobin ≥ 70 g/L;
• Hepatic function: Alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 3 × ULN, total bilirubin (TBIL) ≤ 2 × ULN (excluding Gilbert syndrome, for which total bilirubin ≤ 3.0 × ULN);
• Renal function: Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula);
• Coagulation function: International normalized ratio (INR) < 1.5 × ULN, prothrombin time (PT) < 1.5 × ULN;
• Cardiac function: Good hemodynamic stability.

Exclusion Criteria:

• The patient must not participate in this study if any of the following criteria are met:
• 1) Diseases that, after evaluation by the investigator, are considered inappropriate for participation in this study, for example life-threatening conditions;
• 2) Reduced organ functional reserve not caused by the primary disease:
• Neutrophil count < 1 × 10^9/L; lymphocyte count < 0.3 × 10^9/L; hemoglobin < 70 g/L; platelet count < 50 × 10^9/L;
• ALT > 3 × ULN; AST > 3 × ULN; total bilirubin > 2 × ULN;
• Creatinine clearance < 40 mL/min, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m², or serum creatinine > 2.5 mg/dL;
• Left ventricular ejection fraction ≤ 45% as diagnosed by echocardiography;
• Blood oxygen saturation ≤ 92%;
• 3) History of alcohol abuse or drug abuse within the past 24 weeks;
• 4) History of malignancy other than B-cell lymphoma within the past 5 years (excluding non-melanoma skin cancer, surgically cured cervical cancer, etc.);
• 5) Presence of infection with human immunodeficiency virus (HIV), agammaglobulinemia, T-cell deficiency virus, syphilis, chronic hepatitis B or C, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), etc.;
• 6) Known active tuberculosis (TB) infection or bacterial infection;
• 7) History of myocardial infarction, coronary angioplasty or stent placement, unstable angina, active arrhythmia, or other clinically significant cardiac disease requiring clinical intervention within 6 months before the start of screening;
• 8) History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before the start of screening;
• 9) Known severe allergic reactions to cell-therapy-related components or their excipients, or to other immunotherapeutic agents;
• 10) Prior organ transplantation requiring long-term immunosuppressive medication;
• 11) Known simultaneous participation in other clinical trials affecting the disease or treatment;
• 12) Prior treatment with CD19- and/or BCMA-targeted therapy or any CAR-T cell product targeting any antigen; unless, as assessed by the investigator, the prior treatment has clearly failed (including failure to achieve remission after treatment, remission duration below the required standard, or disease progression), the current disease state is suitable for treatment in this study, and there is no clear evidence that toxicity related to prior treatment may affect the safety of this study;
• 13) Severe psychiatric illness and severe cognitive impairment;
• 14) Pregnant or lactating women, or women planning pregnancy;
• 15) Any condition considered by the investigator to be inappropriate for enrollment in this clinical trial.