肿瘤细胞治疗研究
英文原题：A Dose Escalating Study of CD19/CD22/BCMA CAR-T Therapy in Relapsed/ Refractory Multiple Myeloma
⚠ 该试验的登记信息已有 22 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。
这是一项早期 I 期注册临床试验，评估 CD19CAR-T 细胞治疗多发性骨髓瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 12 例。试验地点：中国 · 上海（共 1 个中心，其中中国 1 个）。登记号：NCT06732232。
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. 能够理解并自愿签署知情同意书（ICF），且须在进行任何研究相关评估或操作前签署；
2. 年龄18至75岁；
3. 预计生存期不少于12周；
4. ECOG评分≤2分；
5. 骨髓流式细胞术结果显示BCMA抗原阳性（包括弱阳性、中度阳性和强阳性）；
6. 按照国际骨髓瘤工作组（IMWG）标准确诊为伴可测量病灶的多发性骨髓瘤，并至少符合以下一项：
1. 血清M蛋白（SPEP）≥5 g/L；
2. 24小时尿M蛋白排泄量≥0.2 g（200 mg）；
3. 血清游离轻链（sFLC）≥100 mg/L且游离轻链比值异常；
4. 骨髓细胞学检查中原始浆细胞与幼稚浆细胞比例>5%，或流式细胞术检出的单克隆浆细胞>5%。
7. 曾接受至少3种不同作用机制的治疗（包括抗CD38单克隆抗体、蛋白酶体抑制剂、免疫抑制剂等）但治疗失败，并出现复发（12个月内）、治疗困难或对最后一线治疗方案不耐受。治疗困难包括原发性治疗困难（治疗期间未达到微小缓解[MR]或出现疾病进展[PD]）或继发性治疗困难（治疗结束后60天内出现疾病进展）；
8. 肺功能无明显异常，未吸氧时血氧饱和度>92%；
9. 血生化检查符合以下标准：
1. 天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）≤正常值上限（ULN）的2.5倍；
2. 总胆红素≤ULN的1.5倍；
3. 24小时肌酐清除率≥30 mL/min；
4. 脂肪酶和淀粉酶≤ULN的2倍。
10. 血常规符合以下标准：
1. 淋巴细胞计数>0.5×10^9/L；
2. 中性粒细胞计数≥1.0×10^9/L；
3. 血红蛋白≥60 g/L；
4. 血小板≥40×10^9/L。
11. 有生育能力的男性和育龄期女性须同意从签署知情同意书起至使用研究药物后2年内采取有效避孕措施。育龄期女性包括绝经前女性及绝经后2年内的女性。筛选期间育龄期女性的血妊娠试验须为阴性。
排除标准：
* 符合以下任一情况者不得作为受试者：
1. 无症状（冒烟型）多发性骨髓瘤；
2. 仅有髓外病灶的多发性骨髓瘤；
3. 浆细胞白血病；
4. 合并淀粉样变；
5. 中枢神经系统（CNS）转移、软脑膜病或转移性中枢压迫；
6. 妊娠或哺乳期；
7. 乙型肝炎表面抗原（HBsAg）或乙型肝炎核心抗体（HBcAb）阳性者，除非HBV-DNA低于100 IU/ml或低于最低检测限；丙型肝炎病毒（HCV）抗体及HCV-RNA均阳性；HIV抗体阳性；梅毒特异性抗体阳性且甲苯胺红不加热血清试验（TRUST）阳性；巨细胞病毒（CMV）DNA阳性；
8. 有临床意义的心血管疾病，包括以下任一情况：
1. 心率校正后的QT间期（QTcF）>470毫秒；
2. 纽约心脏协会（NYHA）分级≥II级的心力衰竭；
3. 左心室射血分数（LVEF）≤50%；
4. 高血压控制不佳（收缩压≥150 mmHg和/或舒张压≥95 mmHg）；
5. 有临床意义或需要抗心律失常治疗的心律失常（如持续性室性心动过速、心室颤动、尖端扭转型室性心动过速和完全性左束支传导阻滞）；
9. 签署知情同意书前6个月内发生过不稳定型心绞痛或急性心肌梗死；
10. 既往接受过任何抗CD45或抗CD3治疗；
11. 对本研究所用药物的任何成分过敏，包括但不限于环磷酰胺、氟达拉滨等清淋药物；
12. 单采前4周内（或研究者认为更适当的5个药物半衰期内，以较长者为准）接受过任何研究药物或全身抗肿瘤治疗；
13. 治疗前5年内有其他原发性恶性肿瘤病史，但以下情况除外：
1. 已完全治疗并治愈的宫颈原位癌；
2. 局限性皮肤基底细胞癌或鳞状细胞癌。
14. 单采前4周内发生未控制的活动性感染，且需要肠外抗生素、抗病毒或抗真菌治疗；
15. 单采前1年内有活动性肺结核感染史；但活动性肺结核感染发生在1年以前，且研究者判断目前无活动性肺结核证据者除外；
16. 目前患有或既往患有间质性肺病或间质性肺炎；
17. 签署知情同意书前8周内接受过自体造血干细胞移植（ASCT），或计划在研究期间接受ASCT；
18. 既往接受过异基因干细胞治疗；研究者认为受试者的并发症或其他情况可能影响其遵守方案，或使其不适合参加本研究。
Inclusion Criteria:
* Participants must meet all of the following criteria in order to be enrolled:
1. Understand and voluntarily sign an informed consent form (ICF) before conducting any research related evaluations/procedures;
2. Age range: 18-75 years old;
3. Expected survival period is not less than 12 weeks;
4. ECOG score ≤ 2 points;
5. The bone marrow flow cytometry results showed positive BCMA antigen (including weak positive, moderate positive, and strong positive);
6. According to the IMWG criteria, a diagnosis of multiple myeloma with measurable lesions must meet at least one of the following criteria:
1. Serum M protein (SPEP) ≥ 5g/L
2. 24-hour urinary M-protein excretion rate ≥ 0.2g (200mg)
3. Serum free light chain (sFLC) ≥ 100 mg/L and abnormal free light chain ratio
4. The ratio of primitive plasma cells to immature plasma cells in bone marrow cytology examination is greater than 5%, or the flow cytometry detection of monoclonal plasma cells is greater than 5%
7. Those who have received treatment with at least three different mechanisms of action (including anti-CD38 monoclonal antibodies, protease inhibitors, immunosuppressants, etc.) but have failed, and have experienced relapse (within 12 months), difficulty in treatment, or intolerance to the last line treatment regimen, including primary difficulty in treatment (subjects who have not achieved minimal remission \[MR\] or developed disease progression \[PD\] during treatment) or secondary difficulty in treatment (subjects who develop disease progression within 60 days after completion of treatment);
8. There is no significant abnormality in lung function, and the oxygen saturation is greater than 92% in the absence of oxygen inhalation;
9. The blood biochemistry test results meet the following criteria:
1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
2. Total bilirubin ≤ 1.5 × ULN
3. 24-hour serum creatinine clearance rate ≥ 30 mL/min
4. Lipase and amylase ≤ 2 × ULN
10. The blood routine test meets the following criteria:
1. Lymphocyte count\>0.5 × 10 \^ 9/L
2. Neutrophil count ≥ 1.0 × 10 \^ 9/L
3. Hemoglobin ≥ 60g/L
4. Platelets ≥ 40 × 10 \^ 9/L
11. Men with fertility and women of childbearing age must agree to use effective contraceptive measures from the signing of the informed consent form until 2 years after the use of the study drug. Women of childbearing age include premenopausal women and women within 2 years after menopause. The blood pregnancy test for women of childbearing age must be negative during screening.
Exclusion Criteria:
* Any of the following situations cannot be selected as a subject:
1. Asymptomatic (smoking type) multiple myeloma;
2. Multiple myeloma with only extramedullary lesions present;
3. Plasma cell leukemia;
4. Merge amyloidosis;
5. Central nervous system (CNS) metastasis, leptomeningeal disease, or metastatic central compression;
6. Pregnancy or lactation period;
7. Individuals who are HBsAg positive or HBcAb positive, unless HBV-DNA is less than 100 IU/ml or below the minimum detectable value; Individuals who are positive for hepatitis C virus (HCV) antibodies and HCV-RNA; Individuals who are HIV antibody positive; Individuals who are positive for syphilis specific antibodies and have a positive TRUST (toluidine red unheated serum test) test; Individuals who test positive for Cytomegalovirus (CMV) DNA;
8. Cardiovascular diseases with clinical significance, including any of the following:
1. QT interval (QTcF) after heart rate correction:\>470 milliseconds;
2. New York Heart Association Grade II and above heart failure;
3. Left ventricular ejection fraction (LVEF) ≤ 50%;
4. Poorly controlled hypertension (systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 95 mm Hg)
5. Arrhythmias that have clinical significance or require antiarrhythmic treatment (such as persistent ventricular tachycardia, ventricular fibrillation, apical torsion tachycardia, and complete left bundle branch block);
9. Has experienced unstable angina or acute myocardial infarction within the 6 months prior to signing the ICF;
10. Previously received any anti-CD45 or anti-CD3 treatment;
11. Individuals who are allergic to any of the components of the drugs used in this study, including but not limited to Qing Lin drugs (cyclophosphamide, fludarabine), etc;
12. Received any investigational drug or systemic anti-tumor treatment within 4 weeks (or 5 half lives of the drug, whichever the researcher deems more appropriate) prior to single collection;
13. History of other primary malignant tumors within 5 years prior to treatment, except for the following situations:
1. Fully treat cured cervical carcinoma in situ;
2. Localized basal cell carcinoma or squamous cell carcinoma of the skin;
14. Any uncontrolled active infection within 4 weeks prior to single collection requires parenteral antibiotics, antiviral or antifungal treatment;
15. Individuals with a history of active pulmonary tuberculosis infection within one year prior to single sampling (excluding subjects with a history of active pulmonary tuberculosis infection more than one year ago who, according to the researcher's judgment, currently have no evidence of active pulmonary tuberculosis);
16. Accompanying or having a history of interstitial lung disease or interstitial pneumonia;
17. Subjects who receive autologous hematopoietic stem cell transplantation (ASCT) within 8 weeks of signing the ICF, or who plan to undergo ASCT during the study period;
18. Subjects who have received allogeneic stem cell therapy in the past; The researchers believe that complications or other conditions in the subjects may affect their compliance with the protocol or make them unsuitable to participate in this study.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) · Safety · [Time Frame: Day0-Day28]；Maximum tolerated dose (MTD) · Evaluate the incidence, severity, and correlation of SAE Tolerability · [Time Frame: Day0-Day28]
次要终点：Maximum Plasma Concentration(Cmax)；Maximum Plasma Concentration Time (Tmax)；Area Under Curve (AUC)；CAR positive T cells；Cytokines ( IL(interleukin)-2）；Cytokines ( IL(interleukin)-4）；Cytokines ( IL(interleukin)-6）；Cytokines ( IL(interleukin)-8）
采集受试者外周血并通过白细胞单采分离外周血单个核细胞（PBMC），用于制备CD19/CD20/BCMA CAR-T细胞。输注前第5日至第3日给予环磷酰胺和氟达拉滨进行淋巴清除。第0日受试者接受一次CD19/CD20/BCMA CAR-T细胞静脉输注治疗。
这是一项单臂、开放标签、剂量递增临床研究，旨在评估靶向CD19/CD22/BCMA的自体嵌合抗原受体T（CAR-T）细胞用于复发/难治性多发性骨髓瘤患者时的安全性和耐受性。
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologouschimeric antigen receptor T (CAR-T) cells targeting CD19/CD22/BCMA in patients with relapsed/refractory multiple myeloma.
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