Safety and Efficacy of Immunosuppressive CAR-DC Targeting FAP in the Treatment of End-stage Dilated Cardiomyopathy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 43
- 试验地点
- 1
- 主要终点
- The proportion of subjects with Dose-limiting toxicity (DLT)
研究概览
简要总结
To study the safety and efficacy of fibroblast activation protein (FAP)-targeted immunosuppressive chimeric antigen receptor-dendritic cell (CAR-DC) in the treatment of end-stage dilated cardiomyopathy and provide a new method for the treatment of end-stage dilated cardiomyopathy.
详细描述
This study aims to evaluate the safety and efficacy of fibroblast activation protein (FAP)-targeted immunosuppressive chimeric antigen receptor-dendritic cell (iCDC) therapy in patients with end-stage dilated cardiomyopathy, and to provide a novel therapeutic approach for this condition. This is a prospective, single-center, open-label, two-phase clinical study designed to assess the safety and preliminary efficacy of iCDC in patients with end-stage dilated cardiomyopathy.
Phase 1 employs a single-arm, 3+3 dose-escalation design. iCDC therapy will be administered at predefined dose levels to evaluate safety, dose-limiting toxicities, treatment-related adverse events, and preliminary efficacy, and to determine the safe and effective dose.
Phase 2 will expand enrollment at the safe and effective dose identified in Phase 1. Additional patients will receive iCDC therapy at this dose, and a non-randomized concurrent control group will also be enrolled. Control participants must meet the same eligibility criteria and, after providing informed consent, choose not to receive iCDC therapy but agree to participate in study follow-up. They will not undergo leukapheresis, iCDC manufacturing, or cell infusion, and will continue to receive guideline-directed standard medical therapy. The iCDC treatment group will be assessed for safety and preliminary efficacy. The concurrent control group will be followed using clinically feasible shared assessments, including echocardiography, BNP or NT-proBNP, 6-minute walk distance, NYHA functional class, INTERMACS profile, KCCQ score, worsening heart failure, hospitalization, death, and major cardiovascular events. Cardiac magnetic resonance imaging and cell therapy-specific assessments will be performed exclusively in participants receiving iCDC therapy and will not be included in between-group comparisons with the control group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 18 years old and 75 years old, diagnosed with dilated cardiomyopathy.
- •Able to verbally confirm that he/she understands the risks, benefits and treatment options of the iCDC trial. He/she or his/her legal representative provides written informed consent before participating in the clinical trial.
- •Diagnosed with Heart Failure with reduced ejection fraction (HFrEF), optimized drug therapy (under maximum tolerance of GDMT) for at least 3 months, left ventricular ejection fraction <35%, NYHA functional class ⅢB-IV, INTERMACS class 3-
- •Blood test: hematocrit >30%, lymphocytes >0.5×10^9/L, platelets >60×10^9/L.
排除标准
- •History of myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks before enrollment.
- •CRT implanted within 12 weeks before enrollment or intended to implant CRT device.
- •Previous heart transplantation or implantation of a ventricular assist device or similar device, or planned implantation of a ventricular assist device or similar device.
- •Heart failure caused by ischemic cardiomyopathy, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, long-standing hypertension, congenital structural heart disease, or uncorrected primary valvular disease.
- •Symptomatic bradycardia or second/third degree heart block.
- •Active autoimmune disease requiring immunosuppressive therapy.
- •Pulmonary Embolism (PE).
- •A history of tuberculosis.
- •History of severe renal failure or need for dialysis, creatinine >2.5 mg/dl.
- •Uncorrected thrombocytopenia or systemic coagulopathy (platelet count < 50,000, INR > 2.5, or aPTT > 2.5 times control in the absence of anticoagulation), or active bleeding and uncorrectable coagulopathy.
- •Aspartate aminotransferase or alanine aminotransferase levels greater than 5.0 times the upper limit of normal (ULN), total bilirubin >3 mg/dl.
- •History of concurrent severe infection, hepatobiliary obstruction, or malignancy.
- •Infections: Active hepatitis B (PCR-detected hepatitis B virus DNA copies > 1000), hepatitis C, syphilis, or human immunodeficiency virus (HIV) infection at screening; uncontrolled systemic fungal, bacterial, viral, or other pathogen infection.
- •Severe hemodynamic instability (eg, shock).
- •Women who are pregnant or may become pregnant.
- •Contraindications to study drugs or tests.
研究组 & 干预措施
iCDC Therapy
Participants in this arm will receive FAP-targeted immunosuppressive chimeric antigen receptor-dendritic cell (iCDC) therapy.
In Phase 1, iCDC will be administered at predefined dose levels (1×10⁵, 4×10⁵, and 8×10⁵ cells/kg) using a modified single-arm 3+3 dose-escalation design. Safety and preliminary efficacy will be evaluated at each dose level. If a given dose level is deemed safe and effective at 1 month post-treatment, it will be selected as the safe and effective dose, and no further dose escalation will be pursued. Otherwise, dose escalation may proceed to the next predefined level in accordance with the protocol.
In Phase 2, additional participants will receive iCDC therapy at the safe and effective dose identified in Phase 1.
干预措施: FAP immunosuppressive CAR-DC (Biological)
Control
Participants in this arm will be enrolled in Phase 2 as a non-randomized concurrent control group. They must meet the eligibility criteria and, after providing informed consent, elect not to receive iCDC therapy but agree to study follow-up. These participants will not undergo leukapheresis, iCDC manufacturing, or cell infusion, and will continue to receive guideline-directed standard medical therapy. They will be followed using clinically feasible shared assessments for exploratory comparison with the iCDC therapy arm.
结局指标
主要结局
The proportion of subjects with Dose-limiting toxicity (DLT)
时间窗: in 14 days after injection
The proportion of participants with treatment-related adverse events as assessed by CTCAE v5.0
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: in 14 days after injection
Incidence of iCDC treatment-emergent adverse events
次要结局
- Left ventricular ejection fraction (LVEF)(1, 3, 6, 12 months after injection)
- Left ventricular ejection fraction (LVEF)(6, 12 months after injection)
- Enhanced volume (volume%)(6 , 12 months after injection)
- INTERMACS Profile(1, 3, 6 , 12 months after injection)
- Left ventricular internal diameter end systole (LVIDs)(1, 3, 6 , 12 months after injection)
- Left ventricular internal diameter end diastole (LVIDd)(1, 3, 6 , 12 months after injection)
- Left ventricular end-systolic volume (LVESV)(6 , 12 months after injection)
- Left ventricular end-diastolic volume (LVEDV)(6 , 12 months after injection)
- NT-proBNP(1, 3, 6 , 12 months after injection)
- 6 minutes walk test (6MWT)(1, 3, 6 , 12 months after injection)
- assessment of heart failure symptom(1, 3, 6, 12 months after injection)
- Incidence of major adverse cardiovascular events (MACE)(1, 3, 6, 12 months after injection)
- incidence of adverse events(6, 12 months)