肿瘤细胞治疗研究
英文原题：A Clinical Study to Evaluate the Safety and Efficacy of CLL1 and CD38 Dual-Target CAR-T Cell Injection in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
⚠ 该试验的登记信息已有 16 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 细胞治疗急性髓系白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 37 例。试验地点：中国 · 天津（共 1 个中心，其中中国 1 个）。登记号：NCT06880354。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
纳入标准：
1. 签署知情同意书时年龄18至70岁（含界值）。
2. 根据世界卫生组织（WHO）2022年标准确诊为急性髓系白血病（AML，急性早幼粒细胞白血病[APL]除外），并符合复发/难治性AML诊断标准（参照《2023年中国复发难治性急性髓系白血病诊疗指南》）。
3. 肿瘤细胞CLL1和/或CD38表达阳性。
4. 预计生存期≥3个月。
5. 已确定异基因造血干细胞移植供者。CAR-T细胞输注后，受试者可随时接受异基因造血干细胞移植。
6. 筛选期ECOG评分为0至2分。
7. 器官功能储备充分：
1）丙氨酸氨基转移酶/天冬氨酸氨基转移酶（ALT/AST）≤正常值上限（ULN）的2.5倍；
2）血清总胆红素≤ULN的2倍；先天性胆红素血症患者除外（Gilbert综合征患者直接胆红素≤ULN的1.5倍）；
3）按Cockcroft-Gault公式计算的血清肌酐清除率>45 mL/min；
4）左心室射血分数（LVEF）≥45%；
5）室内空气下指脉氧饱和度≥92%。
8. 能够从第7天起停用糖皮质激素（地塞米松≥3 mg/日或其他激素等效剂量），并持续至CAR-T细胞输注后30天。
9. 有生育能力女性的筛选期和基线HCG（免疫荧光法）检测须为阴性。男性受试者须同意输注后至少2年内不捐献精子；有生育能力男性及其性伴侣须同意输注后至少2年内采用高效避孕措施。
10. 同意按照方案及知情同意书所述要求接受随访。
11. 自愿签署知情同意书（ICF）。
排除标准：
1. 已知对本研究所用任何药物成分过敏。
2. 有以下合并治疗史：
1）单采前7天内接受过累计剂量≥70 mg的泼尼松或等效糖皮质激素；
2）研究者评估认为存在合并症，研究治疗后12周内需要使用全身糖皮质激素（泼尼松累计剂量≥70 mg或其他糖皮质激素等效剂量）或其他免疫抑制药物；
3）单采前14天内或药物5个半衰期内（以较短者为准）接受过全身抗肿瘤治疗，包括但不限于细胞毒治疗、靶向治疗或研究性药物治疗；
4）单采前4周内接受过放疗；
5）单采前6周内接受过供者淋巴细胞输注。
3. 确诊急性早幼粒细胞白血病（APL）。
4. 既往接受过CAR-T、CAR-NK或任何其他基因修饰细胞治疗。
5. 筛选前6个月内接受过异基因造血干细胞移植。
6. 筛选时存在活动性移植物抗宿主病（GvHD），或入组前4周内存在活动性急性/慢性GvHD，或需要使用免疫抑制药物。
7. 存在需要全身治疗的活动性感染。
8. 有任何活动性恶性肿瘤病史；已治愈且无复发迹象、无病生存期超过5年的非黑色素瘤皮肤癌、宫颈原位癌、膀胱癌、乳腺癌或其他类似肿瘤除外。
9. 签署知情同意书前6个月内发生过卒中或癫痫发作。
10. 存在以下任一心脏疾病：
1）纽约心脏协会（NYHA）III级或IV级心力衰竭；
2）入组前≤6个月发生心肌梗死或接受冠状动脉旁路移植术（CABG）；
3）严重心律或传导异常，如需要临床干预的室性心律失常、II–III度房室传导阻滞，或心电图校正QTcF间期≥480 ms；
4）严重非缺血性心肌病史；
5）超声心动图或多门控采集扫描显示心功能不全（左心室射血分数<45%），或入组前6个月内有其他具有临床症状的心脏疾病；
6）临床未控制的高血压（收缩压≥150 mmHg和/或舒张压≥100 mmHg；以至少2次测量的平均值为准）。
11. 存在或既往有中枢神经系统（CNS）受累，或有急性髓系白血病中枢受累的临床表现。
12. 以下任一病毒学检查阳性：
1）人类免疫缺陷病毒抗体（HIV抗体）；
2）乙型肝炎表面抗原（HBsAg）阳性，或乙型肝炎核心抗体（HBcAb）阳性且乙型肝炎病毒（HBV）DNA拷贝数高于检测下限；
3）丙型肝炎病毒抗体阳性且HCV RNA高于检测下限；
4）梅毒螺旋体抗体（TPPA抗体）阳性。
13. 患有肺纤维化。
14. 患有活动性自身免疫性疾病（如系统性红斑狼疮、类风湿关节炎、多发性硬化、干燥综合征等）。
15. 筛选前4周内接种过减毒活疫苗。
16. 单采前4周内接受过重大手术，或计划在研究期间接受手术（诊断性活检除外）。
17. 妊娠或哺乳期女性且不同意停止哺乳；男性或女性计划在研究期间或研究治疗后2年内生育。
18. 既往治疗引起的急性副作用未恢复至1级或以下；研究者判断无安全风险的情况（如脱发、激素替代治疗后稳定的甲状腺功能减退等）除外。
19. 研究者判断任何可能妨碍受试者完成整个试验、混淆试验结果，或使其参加研究不符合最佳利益的情况。
Inclusion Criteria:
1. At the time of signing the informed consent, 18-70 years old (including the critical value);
2. Diagnosed with acute myeloid leukemia (except for APL) based on the World Health Organization (WHO) 2022 criteria and meeting the diagnostic criteria for relapsed/refractory AML (refer to the 2023 Chinese Guidelines for the Diagnosis and Treatment of relapsed refractory acute myeloid leukemia);
3. Positive expression of CLL1 and/or CD38 in tumor cells;
4. Estimated survival ≥3 months;
5. Have a confirmed donor for allogeneic hematopoietic stem cell transplantation. After the CAR-T cells were infused, subjects could undergo potential allogeneic hematopoietic stem cell transplantation at any time;
6. ECOG score of 0\~2 during the screening phase;
7. Adequate functional reserve of organs:
1. Alanine aminotransferase/aspartate aminotransferase ≤2.5× ULN;
2. Total serum bilirubin ≤2× ULN, except in subjects with congenital bilirubinemia (direct bilirubin ≤1.5× ULN in subjects with Gilbert's syndrome);
3. Serum creatinine clearance \> 45mL/min (calculated according to Cockcroft-Gault formula);
4. Left ventricular ejection fraction (LVEF) ≥45%;
5. Basal finger oxygen saturation ≥92% in room air.
8. The ability to discontinue corticosteroids (dexamethasone ≥3mg/ day or other equivalent dose of hormones) from day 7 and continue until 30 days after CAR T cell infusion;
9. Pregnant women of childbearing potential should be negative for HCG (immunofluorescence) tests during screening and baseline. Male subjects must agree not to donate sperm for at least two years after the infusion. Male subjects and his sexual partner with childbearing potential must agree to use highly effective contraception for at least 2 years after the infusion;
10. Agree to follow-up in accordance with the protocol and the requirements outlined in the informed consent form;
11. Voluntarily sign the ICF.
Exclusion Criteria:
1. Known allergy to any of the drug ingredients to be used in this study;
2. With a history of the following concomitant treatments:
1. Received a cumulative dose of prednisone (or equivalent corticosteroids). Greater than or equal to ≥ 70 mg within 7 days prior to apheresis;
2. Based on the investigator's assessment, there is a comorbidity that requires the use of systemic corticosteroids (≥ 70 mg total dose of prednisone or equivalent doses of other corticosteroids) or other immunosuppressive medications within 12 weeks after the study treatment;
3. Received systemic anti-tumor therapy within 14 days before apheresis or within five half-lives of the drug, whichever was shorter, including but not limited to cytotoxic therapy, targeted therapy, or an investigational drug treatment;
4. Received radiotherapy 4 weeks before apheresis;
5. Received donor lymphocyte infusion within 6 weeks before apheresis.
3. Acute promyelocytic leukemia was diagnosed;
4. Have previously been received CAR-T therapy, CAR-NK therapy or any other genetically modified cell therapy;
5. Received allogeneic hematopoietic stem cell transplantation within 6 months before screening phase;
6. Active graft-versus-host disease (GvHD) at the time of screening or active acute or chronic GvHD within 4 weeks of enrollment or the need for immunosuppressive drugs;
7. An active infection that requires systemic treatment;
8. Any history of active malignancy (excluding non-melanoma skin cancer, cervical carcinoma in situ, bladder cancer, breast cancer, or other similar cancers, with a disease-free survival period of more than 5 years and no signs of recurrence after curative treatment);
9. Experienced a stroke or seizure within 6 months prior to signing the ICF;
10. Presence of any heart diseases as follows:
1. New York Heart Association (NYHA) Stage III or IV heart failure;
2. Myocardial infarction or coronary artery bypass graft (CABG) ≤ 6 months prior to enrollment;
3. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree II-III atrioventricular block, and electrocardiographic corrected QTcF interval ≥480 ms;
4. History of severe non-ischemic cardiomyopathy;
5. Cardiac dysfunction (LV \<45%), as assessed by echocardiography or multigated acquisition scanning, or other clinically symptomatic cardiac disease within 6 months before enrollment;
6. Clinically uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100mmHg) (based on the mean of ≥2 measurements).
11. Active or past central nervous system involvement, or clinical manifestations of central involvement in acute myeloid leukemia;
12. Any positive results of the following virological test results:
1. Human immunodeficiency virus antibodies (HIV antibodies);
2. Hepatitis B surface antigen (HBsAg) positive; Or hepatitis B core antibody (HBcAb) positive, and hepatitis B virus (HBV) -DNA copy number higher than the lower limit of detection;
3. Hepatitis C virus antibody positive, and hepatitis C virus RNA higher than the lower limit of detection;
4. Treponema pallidum antibody (TPPA antibody).
13. There is pulmonary fibrosis;
14. With active autoimmune diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, etc.);
15. Received live attenuated vaccine within 4 weeks prior to screening;
16. Receipt of major surgery within 4 weeks prior to apheresis or a plan to receive surgeries during the study (except for diagnostic biopsy);
17. Pregnant women or nursing women who do not agree to give up breastfeeding, men and women who plan to have children during the study period or within 2 years after receiving the study treatment;
18. Acute side effects caused by previous treatment did not return to grade 1 or below (except those that the investigators judged to have no safety risk, such as hair loss, stable hypothyroidism after hormone replacement therapy, etc.);
19. According to the investigator's judgment, conditions that interfere with the subject's participation in the entire trial, confound the trial results, or make participation in the trial not in the best interest of the subject.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：Dose-Limiting Toxicity (DLT) Rate · Proportion of subjects with DLT within 28 days after infusion of CLL1/CD38 dual-target CAR-T cell injection. · 28 days；Adverse Events （AEs） · Proportion of subjects experiencing AE within 96 weeks after infusion of CLL1/CD38 dual-target CAR-T cell injection. · 96 weeks
次要终点：Complete Remission Rate (CRc)；Overall Response Rate (ORR)；MRD negative rate and MRD negative duration；Duration of Remission（DOR）；Event-free Survival (EFS)；Overall Survival (OS)；Indicators of proliferation and survival in vivo；Anti-drug Antibodies
本研究为单中心、开放标签临床研究，主要作为研究者发起的临床试验（IIT），评估CLL1和CD38双靶点CAR-T注射液用于复发/难治性急性髓系白血病（r/r AML）受试者时的安全性和初步疗效。入组患者为r/r AML患者。
这是一项单臂、开放标签的I期剂量递增临床研究，旨在评估CLL1和CD38双靶点CAR-T细胞注射液用于复发/难治性急性髓系白血病（r/r AML）受试者时的安全性和初步疗效。
This is a single-arm, open-label, phase I dose-escalation clinical study to evaluate the safety and preliminary efficacy of CLL1 and CD38 dual-target CAR T cell injection in r/r AML subjects.
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