肿瘤细胞治疗研究
英文原题：Safety and Efficacy of Fourth-Generation CAR-T in the Treatment of Hematologic Malignancies
⚠ 该试验的登记信息已有 21 个月未更新， 页面上显示的「招募中」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗多发性骨髓瘤、B 细胞淋巴瘤、血液系统恶性肿瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 60 例。试验地点：中国 · 广州（共 1 个中心，其中中国 1 个）。登记号：NCT06758713。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：
受试者须符合以下全部条件方可入组：
1. 自愿参加本临床研究并签署知情同意书；
2. 年龄18至75岁（含），男女不限；
3. 预计生存期至少3个月；
4. 符合以下任一疾病类型：
4.1 CD19阳性的B淋巴细胞来源血液系统恶性肿瘤；
4.2 多发性骨髓瘤；
4.3 CD7或其他靶分子阳性的非B细胞来源血液系统恶性肿瘤。
5. 筛选期间临床实验室检查符合以下标准：
1. 白细胞计数≥3.0×10^9/L；中性粒细胞绝对计数≥1.0×10^9/L；淋巴细胞计数≥0.5×10^9/L。（允许使用生长因子支持，但实验室检查前7天内不得使用生长因子。）
2. 血小板计数≥50×10^9/L（实验室检查前7天内不得接受输血支持）。注：白血病、多发性骨髓瘤和淋巴瘤患者不受上述血象要求限制。
3. 生化指标：血清总胆红素（TBIL）≤正常值上限（ULN）的2.5倍；天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）≤ULN的2.5倍；若肝功能异常主要由肿瘤浸润所致，则AST和ALT≤ULN的5倍。
6. 心功能：血流动力学稳定，左心室射血分数（LVEF）≥55%。
7. 肺部状况：无严重感染，如重症肺炎。
8. ECOG体能状态评分为0至2分。
9. 女性受试者须在整个研究期间采取有效避孕措施（如处方口服避孕药、注射避孕药、宫内节育器、双重屏障避孕、避孕贴或男性伴侣绝育）；筛选时及研究期间的血清或尿液妊娠试验均须为阴性。
排除标准：符合以下任一情况者不得入组：
1. 既往接受过靶向同一分子的CAR-T治疗；
2. 既往接受过其他靶向相同分子的免疫治疗；
3. 妊娠或哺乳期女性；
4. 既往患有其他恶性肿瘤，但以下情况除外：
1. 已接受根治性治疗，且入组前≥3年无已知活动性疾病；
2. 非黑色素瘤皮肤癌患者已接受充分治疗，且无当前疾病证据。
5. 患有严重精神障碍；
6. 患有需要免疫治疗的活动性自身免疫性疾病；
7. 既往接受过异基因造血干细胞移植；
8. 患有显著心血管疾病，包括：
a. 未控制或有症状的心律失常、充血性心力衰竭，或任何按纽约心脏协会（NYHA）功能分级为III级或IV级的心脏病；
b. 筛选前6个月内发生心肌梗死或接受冠状动脉旁路移植术；
c. 有临床意义的室性心律失常病史或无法解释的晕厥（非血管迷走性且非脱水所致）。
9. 患有活动性感染，包括乙型肝炎表面抗原（HBsAg）或乙型肝炎核心抗体（HBcAb）阳性且外周血乙型肝炎病毒（HBV）DNA滴度≥500 IU/mL；丙型肝炎病毒（HCV）抗体阳性且外周血HCV RNA阳性；人类免疫缺陷病毒（HIV）抗体阳性；梅毒初筛抗体阳性；活动性肺结核；或存在需要高级别抗生素治疗的任何显著感染；
10. 重要器官功能异常，包括：
1. 血清AST或ALT>ULN的2.5倍；若肝功能异常主要由肿瘤浸润所致，则>ULN的5倍；TBIL>ULN的2.5倍（Gilbert综合征患者除外）；
2. 血清肌酐>2.5 mg/dl；
3. 未接受抗凝治疗时，凝血酶原时间、活化部分凝血活酶时间或国际标准化比值>ULN的1.5倍。
11. 过去3个月内参加过其他临床研究，或既往接受过任何基因治疗产品；
12. 糖尿病控制不佳（筛选时糖化血红蛋白HbA1c>8%）；
13. 属于高度过敏体质或有严重过敏史，且禁忌使用环磷酰胺或氟达拉滨；
14. 可行性评估筛选显示，靶淋巴细胞转染率<10%，或在CD3/CD28共刺激条件下扩增不足（<5倍）；
15. 研究者认为不适合参加本试验。
Inclusion Criteria:
Subjects must meet all of the following criteria to be enrolled:
1\. Voluntarily participate in this clinical study and sign the informed consent form; 2. 18 to 75 years old (including cut-off value), Male and female;; 3. Expected survival of at least 3 months; 4.1 CD19-positive B lymphocyte-derived hematologic malignancies; 4.2 Multiple myeloma patients; 4.3 Non-B cell-derived hematologic malignancies patients with CD7 or other target molecules; 5. The clinical trial values during the screening period meet the following criteria:
1. White blood cell count ≥ 3.0 × 10e9/L; Absolute neutrophil ≥ 1.0 × 10e9/L; Lymphocyte count ≥ 0.5 × 10e9/L. (The growth factor support is allowed, but growth factor must not have been received within 7 days prior to laboratory testing);
2. Platelet count ≥ 50 × 10e9/L (No blood transfusion support within 7 days prior to laboratory tests.); Note: Patients with leukemia, multiple myeloma, and lymphoma are not subject to the above blood picture requirements;
3. Biochemical indicators Serum total bilirubin (TBIL) ≤ 2.5 ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN, or 5 ULN if liver dysfunction is primarily due to tumor invasion); 6. Cardiac function: Subjects must have good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 55%; 7. Lung condition: Subjects are not serious infections such as severe pneumonia; 8. ECOG activity status score: 0-2 points; 9. Female subjects must use effective contraception (such as oral prescription contraceptives, injectable contraceptives, intrauterine devices, double blockade, contraceptive patches, male partner sterilization) throughout the study period; Must have a negative serum or urine pregnancy test result at screening and throughout the study.
Exclusion Criteria:
Any one of the following conditions cannot be selected as a subject:
1. Having received CAR-T therapy targeting the same molecule;
2. Having received other immunotargeted therapy targeting the same molecules;
3. Pregnant or lactating women;
4. Subjects who have previously suffered from other malignancies, with the following exceptions:
1. Having received curative therapy, and no known active disease in the ≥ 3 years prior to the enrollment;
2. Non melanoma skin cancer subjects who have completed sufficient treatment and no evidence of thecurrent disease;
5. Subjects with a severe mental disorder;
6. Subjects with active autoimmune disease requiring immunotherapy;
7. Having received allogeneic hematopoietic stem cell transplantation;
8. Subjects with significant cardiovascular diseasesa.uncontrolled or symptomatic arrhythmias, congestive heart failure, or any heart disease with cardiac function grade 3 or grade 4 (according to the functional classification method of the New York Heart Association NYHA); b. Myocardial infarction or coronary artery bypass grafting within 6 months prior to screening); c. Clinically significant history of ventricular arrhythmia or unexplained syncope (non vaso-vagal or not due to dehydration);
9. Subjects with active infectious disease including positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) and peripheral blood Hepatitis B virus(HBV) DNA titer is ≥500IU/mL, hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive, human immunodeficiency virus(HIV) antibody positive, syphilis primary screening antibody positive, active pulmonary tuberculosis; or with any significant infection requiring high-grade antibiotics Event;
10. Subjects with dysfunction of important organssuch as organ function in the following abnormalities:
1. Serum AST or ALT \> 2.5×ULN, or \> 5ULN if liver function is predominantly due to tumor invasion; TBIL \> 2.5 × ULN, unless the subject is Gilbert's syndrome;
2. Serum creatinine\>2.5mg/dl;
3. Partial prothrombin time or activated partial thromboplastin time or international normalized ratio \> 1.5×ULN in the absence of anticoagulant therapy;
11. Participation in other clinical studies or prior treatment with any gene therapy product in the past three months;
12. Subjects with uncontrolled diabetes mellitus (glycosylated hemoglobin HbAlc \>8% at screening);13. Highly allergic constitution or history of severe allergies, and having contraindications to cyclophosphamide or fludarabine;
14\. Feasibility assessment screening demonstrated \<10% transfection of targeted lymphocytes or underamplification under CD3 / CD28 costimulation (\<5-fold); 15. Subjects who are considered unsuitable to participate in this trial by the investigator.以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Number of patients with dose-limiting toxicity (DLT) · For DLT evaluation, severity (grade) is classified according to common terminology criteria for adverse events version 4.03 (CTCAE v4.03). · Within 30 days of receiving CAR T-cells transfusion therapy；Maximum Tolerated Dose (MTD) · At least 6 subjects in the MTD dose group must complete the DLT assessment. · Within 30 days of receiving CAR T-cells transfusion therapy；Adverse Event · Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during medical tests (e.g. laboratory tests, electrocardiogram, imaging examinations or physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MeDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). · Minimum 2 years after CAR T-cells infusion (Day 1)；Recommended Phase 2 Dose (RP2D) · To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation · Through study completion, an average of 1 year；Objective response rate (ORR) · The definition of ORR is the proportion of subjects achieving sCR, CR, VGPR, or PR confirmed by efficacy reassessment after a minimum interval of three months. ORR is calculated as (sCR+CR+VGPR+PR) divided by the total number of cases of Multiple Myeloma, or (CR+PR) divided by the total number of cases of B-cell lymphoma and other hematologic malignancies, multiplied by 100%. · Through study completion, an average of 2 years
次要终点：Stringent complete response rate (sCRR)；Progression-free Survival (PFS)；Overall Survival (OS)
单次输注CAR-T细胞，剂量为0.5×10^6个CAR-T细胞/kg。
单次输注CAR-T细胞，剂量为1.5×10^6个CAR-T细胞/kg。
单次输注CAR-T细胞，剂量为5.0×10^6个CAR-T细胞/kg。
I期剂量递增研究的所有受试者完成DLT观察后，根据IIa期扩展研究的分析结果确定RP2D。
这是一项单中心、开放标签、剂量递增/扩展临床研究，旨在评估第四代CAR-T治疗的安全性和有效性，并为多发性骨髓瘤、B细胞淋巴瘤及其他血液系统恶性肿瘤患者确定CAR-T细胞的推荐剂量。
This is a single center, open-label, dose-escalation/expansion clinical study to evaluate the safety and effectiveness of Fourth-Generation CAR-T, and determine the recommended dose of the CAR T-cells for patients with Multiple Myeloma，B-cell lymphoma and other hematologic malignancies.
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