CAR T-cell Therapy Targeting CD19 and BCMA in Patients With Relapse/Refractory Autoimmune Diseases

Официальное название

A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA in Patients With Relapse/Refractory Autoimmune Diseases

Обзор

CAR T-cell Therapy Targeting CD19 and BCMA in Patients With Relapse/Refractory Autoimmune Diseases

Подробное описание

This is an investigator-initiated trial to evaluate the safety and efficacy ofuniversal allogeneic anti-CD19/BCMA CAR T-cells in Patients With Relapse/Refractory Autoimmune Diseases.

Study intervention consists of a single infusion of universal allogeneic CART-cells administered intravenously after a lymphodepleting therapy regimen consisting of fludarabine and cyclophosphamide.

Interim analysis will be performed when participants finish the visit 12 and 24 weeks after CAR T-cell infusion.

Вмешательства

• Биопрепарат UCAR T-cell
  universal allogeneic anti-CD19/BCMA CAR T-cells

Первичные конечные точки

• The number and severity of dose-limiting toxicity (DLT) events [Срок оценки: Within 28 Days After UCAR T-cell Infusion]
• The total number, incidence, and severity of AEs [Срок оценки: Up to 12 Months After UCAR T-cell Infusion]
• Clinical response of R/R AIDs [Срок оценки: Up to 24 Months After UCAR T-cell Infusion]

Критерии участия

Критерии включения

Common Inclusion Criteria:

• Age ≥ 18 years old (inclusive), regardless of gender.
• Positive expression of CD19 or BCMA on peripheral blood B cells confirmed by flow cytometry.
• Functional requirements for major organs are as follows（Except for abnormalities related to autoimmune disease activity）: 1) Bone marrow function must meet: A. Neutrophil count ≥ 1×109/L (no colony-stimulating factor treatment within 2 weeks before examination); B. Hemoglobin ≥ 60g/L; 2) Liver function: Alanine aminotransferase (ALT) ≤ 3×ULN (excluding ALT elevation due to inflammatory myopathy), aspartate aminotransferase (AST)≤3×Upper limit of normal (ULN) (excluding AST elevation due to inflammatory myopathy), TBIL≤2×ULN (or ≤ 3.0×ULN for subjects with Gilbert syndrome); 3) Renal function: creatinine clearance rate (CrCl) ≥ 30ml/minute (calculated by Cockcroft/Gault formula, acute CrCl decrease due to the target disease is excluded; LN is exluded).
• ECOG score 0-2.
• Female subjects of childbearing potential and male subjects with partners of childbearing potential must use medically approved contraception or abstinence during the study treatment period and for at least 6 months after the end of the study treatment; Female subjects of childbearing potential must have a negative Human chorionic gonadotropin (HCG) test within 7 days before study enrollment and not be lactating.
• Willing to participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up.

Disease-Specific Inclusion Criteria

Refractory/Relapsed Systemic Lupus Erythematosus:

• SLE meeting the 2019 the American College of Rheumatology (ACR) /European League Against Rheumatism (EULAR) and classification criteria.
• Disease activity score SLEDAI-2000 ≥ 8; or with significant organ involvement, such as lupus nephritis (histologically confirmed active nephritis of class III or IV, with or without class V, with an NIH activity index > 2, evidence of increased chronicity index; urine protein-to-creatinine ratio > 1.0 g/g, or 24-hour urinary protein > 1.0 g).
• Definition of refractory or relapsing disease: lack of response after more than 6 months of conventional therapy, or recurrence of disease activity after remission. Conventional therapy is defined as treatment with glucocorticoids in combination with one or more of the following immunomodulatory agents: cyclophosphamide, antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biologics such as rituximab, belimumab, and telitacicept.

Refractory/Relapsed/Progressive Systemic Sclerosis:

• Scleroderma fulfilling the 2013 ACR classification criteria.
• Positive scleroderma-related antibodies.
• Presence of diffuse cutaneous sclerosis or active interstitial lung disease (high-resolution computed tomography (HRCT) showing ground-glass opacities).
• Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids , and any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
• Definition of progressive: Rapid skin progression (mRSS increase > 25%); or progression of lung disease (forced vital capacity (FVC) decrease by 10%, or FVC decrease by more than 5% with diffusing capacity of the lung for carbon monoxide (DLCO) decrease by 15%).

Note: Meeting either criterion 4 or 5 is sufficient.

Refractory/Relapsed/Progressive Inflammatory Myopathy:

• Inflammatory myopathy fulfilling the 2017 EULAR/ACR classification criteria (including Dermatomyositis (DM), Polymyositis (PM), Anti-Synthetase Syndrome (ASS), and Necrotizing Myopathy (NM)).
• Muscle involvement with Manual Muscle Testing-8 (MMT-8) score less than 142 and at least two abnormalities found among the following five core measurements (Physician Global Assessment (PhGA), Patient Global Assessment (PtGA), or extramuscular disease activity score ≥ 2; Health Assessment Questionnaire (HAQ) total score ≥ 0.25; muscle enzyme levels ≥ 1.5×ULN);
• Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids , and any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
• Definition of progressive: Rapid progression of interstitial lung disease within a short period.

Note: Meeting either criterion 4 or 5 is sufficient.

Refractory/Relapsed ANCA-Associated Vasculitis:

• ANCA-Associated Vasculitis fulfilling 2022 ACR/EULAR criteria, including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis.
• Positive ANCA-associated antibodies (MPO-ANCA or PR3-ANCA positive).
• The Birmingham Vasculitis Activity Scale (BVAS) ≥ 15 points (a total score of 63 points), indicating active vasculitis.
• Definition of refractory/relapsed: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission., or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.

Refractory/Relapsed Connective Tissue Disease-associated thrombocytopenia

• Diagnosis of connective tissue disease established according to the latest classification criteria, including but not limited to systemic lupus erythematosus, primary Sjögren's syndrome, antiphospholipid syndrome, and undifferentiated connective tissue disease.
• Confirmed diagnosis of connective tissue disease-associated thrombocytopenia, with platelet count <30 × 10\^9/L, or <50 × 10\^9/L accompanied by a bleeding tendency.
• Bone marrow morphology consistent with immune thrombocytopenia.
• Prior treatment with at least one course of corticosteroid pulse therapy, or high-dose corticosteroids in combination with one or more immunosuppressants (including biologics) for at least 3 months, without achieving partial remission, or inability to maintain efficacy during steroid tapering.

Критерии исключения

• Subjects with a history of severe drug allergies or allergic tendencies.
• Presence or suspicion of uncontrolled or treatment-required fungal, bacterial, viral, or other infections.
• Subjects with central nervous system diseases caused by autoimmune diseases or non-autoimmune diseases (including epilepsy, psychosis, organic brain syndrome, cerebral vascular accidents, encephalitis, central nervous system vasculitis).
• Subjects with insufficient cardiac function.
• Subjects with congenital immunoglobulin deficiencies.
• History of malignancy within five years.
• Subjects with end-stage renal failure(LN is excluded).
• Subjects who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA >ULN; subjects positive for hepatitis C virus (HCV) antibody and peripheral blood HCV RNA; individuals positive for human immunodeficiency virus (HIV) antibody; individuals positive for syphilis testing.
• Subjects with psychiatric disorders and severe cognitive impairments;
• Subjects who have participated in other clinical trials within the past 3 months prior to enrollment.
• Subjects who have received immunosuppressive agents or biologics with therapeutic effects for indications within 5 half-life prior to enrollment.
• Pregnant women or women planning to conceive.
• Subjects whom the investigator believes have other reasons that make them unsuitable for inclusion in this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Institute of Hematology & Blood Diseases Hospital — Тяньцзинь

Идентификаторы

NCT: NCT06941129 · IIT2024107

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗