Safety and Efficacy of BAFF-R CART for Refractory Neuroimmune Diseases
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Types and incidence of dose-limiting toxicity (DLT) after BAFF-R CART cells infusion
研究概览
简要总结
This study is a phase Ib/IIa dose-escalation study designed to evaluate the safety, tolerability, and preliminary efficacy of autologous T cells expressing chimeric antigen receptor (CAR)-targeted B-cell activating factor receptor (BAFFR) in refractory neuroimmune diseases. The study design is divided into two parts, the first of which will be given to each patient at 3 incremental dose levels to establish the maximum tolerated dose (MTD). Each disease is expected to enroll 12 patients who meet the inclusion criteria. In the second part, 15 patients per disease will be recruited to further characterize the efficacy of the MTD.
详细描述
- Phase I: Frequency, type, and severity of adverse events (according to the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE V5.0) occurring within 4 weeks after BAFF-R CART infusion;
- Phase II: Number of recurrences at 52 weeks after BAFF-R CART infusion;
- Characterization of BAFF-R CART cell expansion levels over time in subjects (peripheral blood, cerebrospinal fluid, bone marrow, etc.);
- Characteristics of BAFF-R+ B cell and antibody secreting cell (ASC) lymphocyte ablation in subjects;
- Changes in disease-related clinical scores at baseline, 24 and 52 weeks after BAFF-R CART infusion;
- Changes in the cumulative total number of MRI active lesions in MS and NMOSD patients at 24 and 52 weeks after BAFF-R CART infusion;
- Frequency, type, and severity of treatment-related laboratory index abnormalities (according to the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE V5.0);
- Characterization of changes in disease-associated antibody titers in the subject;
- Changes in vital signs (blood pressure, pulse rate, weight, ECG).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Assessed by the investigator as having a refractory neuroimmune disease;
- •Refractory neuroimmune diseases were defined as:
- •Poor symptom control on at least three immunosuppressive agents for more than one year;
- •Clinical evidence of at least two relapses within 12 months or three relapses within 24 months and one relapse within 12 months prior to screening.
- •Male study participants must agree to use contraception during the treatment period for 1 year after receiving study treatment, and sperm donation is prohibited throughout the study period;
- •In the case of females with childbearing potential, need to agree to use contraception during the treatment period and for at least 1 year after receiving study treatment. Participants must have a negative serum pregnancy test result at screening and a confirmed negative urine pregnancy test result prior to first CART treatment.
排除标准
- •Any medical or psychiatric condition that, in the opinion of the investigator, may jeopardize the study participant or affect the study participant's ability to participate in this study;
- •A history of drug or alcohol abuse within the 12 months prior to baseline, or any condition that in the opinion of the investigator is associated with poor adherence;
- •Women who are breastfeeding or pregnant, or who plan to become pregnant at any time during the 12-month time period following treatment with CART, or a history of spontaneous or induced abortion within 4 weeks prior to screening;
- •Study participants with a clinically relevant active infection (e.g., sepsis, pneumonia, or abscess) or serious infection (resulting in hospitalization or requiring antibiotic therapy) within 4 weeks prior to baseline;
- •The study participant has received a live attenuated vaccination within 8 weeks prior to baseline; or is scheduled to receive a live vaccination (including COVID-19 vaccine) within 8 weeks after treatment;
- •Study participants who have received prior treatment with rituximab within 6 months prior to baseline;
- •Study participants had received tolizumab, eculizumab within 3 months prior to baseline;
- •Study participants who have received intravenous human immunoglobulin, plasma exchange, undergone immunotherapy within 4 weeks prior to baseline;
- •Known concomitant serious underlying diseases, such as hepatic and renal impairment, hematologic disorders, previous severe cardiovascular disease, severe hypertension, diabetes mellitus, poor control of blood pressure and blood glucose;
- •Comorbid mental illness, suicidal ideation (affirmative answer (yes) to question 4 or question 5 of the Colombian Suicide Severity Rating Scale (C-SSRS) indicating a suicide attempt within the last 6 months);
- •Any of the following laboratory abnormalities during the screening period (a repeat measurement may be taken during the screening period prior to randomization to confirm results); (1) Elevated liver enzymes: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN); (2) Total bilirubin > 1.5 times the ULN; (3) Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2; (4) CD19 + B cell count <40 cells/µL;
- •Presence of a history of tuberculosis infection, high risk of acquired tuberculosis infection;
- •known immunodeficiency diseases, including human immunodeficiency virus (HIV) infection;
- •Viral hepatitis B surface antigen (HBsAg) positivity during the screening period;
- •Receiving blood transfusion therapy 4 weeks prior to baseline or during the screening period;
- •Any other condition that the investigator deems inappropriate for participation in the study.
研究组 & 干预措施
Participant Group BAFF-R CART cells
Experimental: CART cells therapy，Dose level 1: 0.5 × 10^6 CART cells/Kg The tolerability and safety of BAFF-R CART cells will be assessed in an initial dose of 0.5×10^6 CART cells/Kg and three subjects will be enrolled firstly.
Experimental: CART cells therapy，Dose level 2: 1 × 10^6 CART cells/Kg If neither DLT nor efficacy is shown in the first three subjects, the dose of CART cells will be increased to 1 × 10^6 CART cells/kg to assess DLT.
Experimental: CART cells therapy，Dose level 3: 2 × 10^6 CART cells/Kg If DLT occurs in two subjects, whether to test the safety and efficacy in 2 × 10^6 CART cells/kg group will be determined by the investigator based on the initial data of efficacy, PK and PD.
干预措施: BAFF-R CART (Drug)
结局指标
主要结局
Types and incidence of dose-limiting toxicity (DLT) after BAFF-R CART cells infusion
时间窗: Up to 3 months post BAFF-R CART cells infusion
To evaluate the DLT occurred within 3 months after BAFF-R CART cells infusion.
Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms.
时间窗: Up to 2 years post BAFF-R CART cells infusion
To evaluate the AEs occurred within 2 years after BAFF-R CART cells infusion.
次要结局
- PD-Soluble BAFF(Up to 2 years post BAFF-R CART cells infusion)
- PD-Pathogenic antibody(Up to 2 years post BAFF-R CART cells infusion)
- PD-Nfl（MS）(Up to 2 years post BAFF-R CART cells infusion)
- PK-VCN(Up to 15 years post BAFF-R CART cells infusion)
- PK-BAFF-R CAR-T cells(Up to 2 years post BAFF-R CART cells infusion)
研究者
Qiang Liu
Department of Neurology
Tianjin Medical University General Hospital