Clinical Study of the Safety and Efficacy of CD19/BCMA CAR-T Cell Therapy for Refractory/Moderate-to-severe Systemic Lupus Erythematosus
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Safety and tolerability
研究概览
简要总结
The purpose of the study is to explore the safety and efficacy of cluster of differentiation 19 (CD19)/B cell maturation antigen (BCMA) CAR-T cell therapy in refractory/moderate-to-severe systemic lupus erythematosus(SLE).
详细描述
The prognosis of patients with refractory/moderate-to-severe systemic lupus erythematosus (SLE) remains poor, due to two major therapeutic obstacles: (1) current treatment strategies including glucocorticoids, immunosuppressive agents, biological agents, are still difficult to achieve disease control, making the disease condition of some patients continue to be active or even worse; (2) some patients are unable to wean themselves off glucocorticoid and face the risk of numerous adverse effects caused by long-term glucocorticoid dependence, such as glucocorticoid-related diabetes, femoral head necrosis, hypertension, stress ulcers, and infection, etc. Therefore, there is a strong unmet clinical need for more effective treatment for patients suffering from refractory/moderate-to-severe SLE. Several preclinical and clinical studies have shown the efficacy of chimeric antigen receptor T (CAR-T) cell therapy in SLE. The aim of this study is to investigate the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of cluster of differentiation 19 (CD19)/B cell maturation antigen (BCMA) CAR-T cell therapy in refractory/moderate-to-severe SLE. Patients with refractory/moderate-to-severe SLE will be invited to participate in the study, to receive CD19/BCMA CAR-T cell intravenous infusion and follow-up visits of up to 1 years after enrollment. Given that the pretreatment chemotherapy (fludarabine,cyclophosphamide) of CAR-T therapy in current SLE clinical studies is mostly based on experiences in hematologic malignancies, which may cause severe complications such as infection, there is a lack of evidence-based rationale for patients with SLE to receive pretreatment chemotherapy. This study will explore the feasibility of CAR-T cell therapy without pretreatment chemotherapy in the treatment of refractory/moderate-to-severe systemic lupus erythematosus.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants or their legal guardians understand and voluntarily sign the informed consent form, and be able to complete all the documents, procedures, follow-up examinations and treatments specified in the study protocol, with good compliance;
- •Age range from 18 to 70 years old, regardless of gender;
- •Participants diagnosed with SLE according to the 2019 European League Against Rheumatism (EULAR)/the American College of Rheumatology (ACR) SLE criteria at least 24 weeks prior to screening;
- •Refractory/moderate-to-severe SLE needs to meet the following criteria at screening: SELENA-SLEDAI score > 6 points; PGA ≥ 1 points; BILAG-2004 organ system scores of at least 1 A or 2 B;Have received at least 12 weeks of standardized treatment for SLE prior to screening but lack efficacy;
- •Participants with fertility agree to take effective contraceptive measures throughout the study and within 3 months after the last follow-up visit.
排除标准
- •Diagnosis of active severe lupus nephritis within 8 weeks prior to screening, requiring medications prohibited by the research protocol for active nephritis, hemodialysis or prednisone ≥ 100 mg/d, or equivalent glucocorticoid therapy for ≥14 days;
- •Any attempted suicide or suicidal ideation within the past year prior to screening;
- •Presence of SLE or non-SLE related central nervous system diseases or pathological changes within 8 weeks prior to screening;
- •Previous or current diagnosis of non-SLE-related inflammatory arthropathy or skin diseases;
- •History of vital organ transplantation or hematopoietic stem cell/or bone marrow transplantation;
- •History of lymphoproliferative diseases;
- •Subjects with malignancy within 5 years prior to screening;
- •Have received plasma exchange, plasma separation, hemodialysis, or intravenous immunoglobulin (IVIG) within 14 days prior to screening;
- •Other autoimmune diseases requiring systemic therapy;
- •Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the lower limit of research institution's test range. Subjects with positive hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV) antibodies, or syphilis;
- •Active or latent tuberculosis at screening;
- •Abnormalities in major organ function at screening;
- •Previous or current diagnosis of acute or chronic illnesses unrelated to SLE with obviously unstable or uncontrollable clinical symptoms;
- •Severe lupus lung damage at screening;
- •Severe lupus cardiac damage at screening;
- •Presence of uncontrollable infections at screening, requiring antibiotic therapy;
- •Have received live/attenuated vaccination within 4 weeks prior to screening or plan to receive live/attenuated vaccination throughout the study;
- •Have received intra-articular, intramuscular or intravenous glucocorticoids within 4 weeks prior to screening;
- •Have received any commercially available Janus kinase (JAK) inhibitor or Bruton tyrosine kinase (BTK) inhibitor within 12 weeks prior to screening;
- •Have received B-cell targeted therapy prior to screening;
- •Have received a biologic agent other than B-cell targeted therapy within 5 half-lives prior to screening;
- •Previously received therapies with CAR-T cells or other genetically modified T cells;
- •Have received therapeutic dose of corticosteroids within 7 days prior to leukapheresis or within 72 hours prior to infusion;
- •Subjects that have donated blood for ≥ 400mL or had a significant blood loss equivalent to at least 400mL within 4 weeks prior to screening, or have received blood transfusion within 8 weeks, or plan to donate blood during the study period;
- •History of ≥grade 2 bleeding within 4 weeks prior to screening or need for long-term continuous anticoagulant therapy;
- •Subjects that have undergone any major surgeries within 12 weeks prior to screening, or those who are scheduled to undergo major surgery during the study period;
- •History of drug abuse within 12 weeks prior to screening;
- •Female subjects who are pregnant or lactating, or intend to conceive within 2 years after the cell infusion; male patients whose female partners intend to conceive within 2 years after the cell infusion;
- •History of any significant drug allergy or intolerance;
- •Subjects that have participated in other clinical trials within 3 months prior to screening and/or currently participated in other clinical trials (those who do not receive study drugs are excluded);
- •Presence of other circumstances that make the subjects not eligible for participation in the study, in the opinion of the researchers.
研究组 & 干预措施
CD19/BCMA CAR-T cell therapy intervention
The first 3 participants will be enrolled to receive CAR-T cell infusion without pretreatment chemotherapy. Then participants' peripheral blood samples would be collected for CAR-T cell testing. If test results showed the presence of CAR-T cells on certain time points, CAR-T cell therapy without pretreatment chemotherapy is considered feasible, and the subsequent 17 participants will receive the consistent regimen; Otherwise, the 3 participants will be re-treated with pretreatment chemotherapy and CAR-T cell infusion, and the subsequent 17 participants will receive pretreatment chemotherapy-containing regimen.
干预措施: CD19/BCMA CAR-T cell therapy (Biological)
结局指标
主要结局
Safety and tolerability
时间窗: Within 1 years after CAR-T cell infusion
Safety and tolerability will be assessed by incidence and severity of adverse events (AEs) and serious AEs (SAEs). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are graded by ASTCT criteria, other AEs are assessed by CTCAE V5.0 criteria
次要结局
- Proportion of subjects with SRI-4 response(Within 1 years after CAR-T cell infusion(month 1, month 3, month 6, month 9, month 12）)
- Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline(Within 1 years after CAR-T cell infusion(month 1, month 3, month 6, month 9, month 12）)
- Changes in the BILAG-2004 score from baseline(Within 1 years after CAR-T cell infusion(month 1, month 3, month 6, month 9, month 12）)
- Changes in the Physician Global Assessment (PGA) score from baseline(Within 1 years after CAR-T cell infusion(month 1, month 3, month 6, month 9, month 12）)
- Pharmacokinetics (PK)(Within 1 years after CAR-T cell infusion(per 3 days in month 1, per month in month 2 - month 12）)
- Pharmacodynamics (PD)(Within 1 years after CAR-T cell infusion(per 3 days in month 1, per month in month 2 - month 12）)
研究者
Qiubai Li
Director, Head of Department of Rheumatology and Immunology, Principal Investigator, Professor, Wuhan Union Hospital
Wuhan Union Hospital, China