肿瘤细胞治疗研究
英文原题：An Exploratory Clinical Study Evaluating the Safety and Efficacy of Intravenous Anti-CD20/CD30-CAR-T Cell Infusion in Relapsed/Refractory Lymphoma Patients.
⚠ 该试验的登记信息已有 26 个月未更新， 页面上显示的「尚未开始招募」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 CAR-T 细胞治疗 B 细胞恶性肿瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 12 例。登记号：NCT06519344。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
纳入标准：
(1) 自愿参加临床研究；本人或法定监护人完全理解并知情同意，签署知情同意书（ICF）；愿意并能够遵守所有试验程序。
(2) 年龄在18至70岁之间。
(3) 经现行标准治疗（包括异基因或自体造血干细胞移植）后难治或复发，且不适合二次造血干细胞移植等其他治疗选择的患者。难治/复发淋巴瘤定义为：
1. 对一线治疗无应答（原发难治性疾病，不包括对一线治疗不耐受的受试者）：
- 一线治疗后疾病进展（PD）评估
* 一线治疗至少4个周期（例如4个周期RCHOP）后最佳疗效为疾病稳定（SD），且末次给药后SD维持时间不超过6个月。
2. 对二线或后续治疗无应答：
* 最近治疗方案的最佳疗效为PD
* 末线治疗至少2个周期后最佳疗效为SD，且末次给药后SD维持时间不超过6个月。
3. 自体干细胞移植（ASCT）后难治：
* ASCT后≤12个月内疾病进展或复发（复发受试者必须有活检证实的复发）
* 如ASCT后接受挽救治疗，受试者必须对末线治疗无应答或在末线治疗后复发。
* 经两线或以上系统性治疗后疾病复发或难治。
(4) 靶抗原符合以下标准的淋巴瘤患者：
* CD20/CD30双阳性淋巴瘤
* 抗CD19-CAR-T细胞治疗后复发，且CD20阳性的淋巴瘤
* 从未接受过抗CD19-CAR-T细胞治疗，且CD20阳性的淋巴瘤
* CD30阳性霍奇金淋巴瘤。
(5) 纳入的淋巴瘤亚型：
* DLBCL-NOS（弥漫大B细胞淋巴瘤，非特指型）
* 原发纵隔大B细胞淋巴瘤（PMBCL）
* 转化型滤泡性淋巴瘤（TFL），既往接受过滤泡性淋巴瘤化疗，随后转化为DLBCL，疾病难治
* 套细胞淋巴瘤
* 高级别B细胞淋巴瘤
* 慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）
* 霍奇金淋巴瘤（HL）。
(6) ECOG体能状态评分≤2。
(7) 预期生存期至少12周。
(8) 静脉通路充足（用于单次采集），且无血细胞分离的其他禁忌症。
(9) 筛选期实验室检查符合要求，且在接受生长因子前7天内未进行血液学评估（长效粒细胞集落刺激因子（G-CSF/PEG-CSF）需间隔2周）：
* 中性粒细胞绝对计数≥1.0×10^9/L；
* 血红蛋白≥60 g/L（7天内未输注红细胞）；
* 血小板≥50×10^9/L（CLL适应症不受限）；
* 血清总胆红素≤1.5×正常值上限（ULN）；或若肿瘤侵及肝组织，≤3× ULN；
* 天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）≤2.5× ULN，若肿瘤侵及肝组织，AST/ALT ≤5× ULN；
* 肌酐<1.5× ULN且估算肾小球滤过率≥60 mL/分钟。
(10) 左心室射血分数≥45%，超声心动图（ECHO）显示无具有临床意义的心包积液（微量或生理性积液除外），且心电图无具有临床意义的发现。
(11) 在未补氧的情况下，基线血氧饱和度>92%。
(12) 有生育能力的女性必须血清或尿妊娠试验结果为阴性（已接受手术绝育或已绝经至少2年的女性不被视为具有生育能力）。
排除标准：
以下是临床研究受试者排除标准的翻译：
1. 脑MRI显示存在中枢神经系统淋巴瘤的证据；活动性原发性中枢神经系统DLBCL，除非CNS受累已得到有效治疗（即受试者无症状）且入组前的局部治疗间隔>4周。
2. 活动性中枢神经系统疾病，如癫痫、脑血管缺血/出血、痴呆、小脑疾病，或任何累及中枢神经系统的自身免疫性疾病。
3. 有CD19+恶性肿瘤以外的恶性肿瘤病史或合并恶性肿瘤。
4. 有临床显著的心脏疾病，或药物无法控制的心律失常。
5. 存在或疑似存在需要静脉注射抗生素的未受控制的真菌、细菌、病毒或其他感染；允许存在单纯性尿路感染和无并发症的细菌性咽炎。
6. 乙型肝炎（乙型肝炎表面抗原阳性且乙型肝炎DNA >1000拷贝/mL）和丙型肝炎（丙型肝炎抗体阳性）。
7. 存在任何留置导管或引流管（例如经皮肾造瘘管、Foley导尿管、胆汁引流管、胸腔/腹腔/心包导管）；允许使用Port-A-Cath®或Hickman®导管等专用中心静脉通路装置。
8. 既往使用以下药物：
1) 单采前1天内使用Ibrutinib。2) 单采前2天内使用Idelalisib（口服PI3Kδ抑制剂）。3) 单采前72小时内使用短效靶向治疗（如酪氨酸激酶抑制剂）。
4) 单采前 4 天内使用 Venetoclax（BCL-2 抑制剂）。5) 单采前 14 天内使用长效生长因子（如 pegfilgrastim），或单采前 5 天内使用短效生长因子或动员剂（如粒细胞集落刺激因子 (G-CSF)/filgrastim）。
6) 入组前 7 天内接受药理剂量的糖皮质激素治疗（>5 mg/day prednisone 或等效药物）或其他免疫抑制药物治疗。
7) 入组前 14 天内接受放射治疗。8) 入组前 14 天内使用全身性细胞毒性药物，包括每日或每周低剂量维持化疗（例如 cyclophosphamide、fludarabine、bendamustine、chlorambucil、methotrexate、vinblastine）。
如果单采后进行桥接治疗，则桥接治疗与 CAR-T 细胞输注之间必须至少间隔 7 天。
9) 入组前4周内接受过抗PD1或抗PDL1治疗。10) 入组前4周内接种过疫苗。11) 入组前4周内接受过供者淋巴细胞输注（DLI）。12) 入组前3个月内接受过免疫刺激或免疫抑制治疗（如干扰素-α、干扰素-β、IL-2、来那度胺、依法利珠单抗、阿仑妥单抗、环孢素或甲氨蝶呤）。
(9) 活动性GVHD，按CIBMTR急性GVHD分级系统分级≥2级，或需要全身性类固醇治疗且剂量超过生理剂量。
(10) 过去2年内有导致终末器官损害或需要全身性免疫抑制剂/疾病修饰药物治疗自身免疫性疾病的病史，如克罗恩病、类风湿关节炎、系统性红斑狼疮。
(11) 过去12个月内有心肌梗死、心脏血管手术或支架植入、不稳定型心绞痛或其他具有临床意义的心脏疾病病史。
(12) 有伴骨髓衰竭的遗传性综合征病史，如范可尼贫血、Costello综合征、Shwachman-Diamond综合征。
(13) 入组前6个月内患有需要全身抗凝治疗的有症状深静脉血栓形成或肺栓塞。需要预防性抗凝治疗的受试者允许入组。
(14) 存在并发或既往恶性肿瘤病史（不包括皮肤基底细胞癌、乳腺/宫颈原位癌，以及过去五年内未经治疗即得到有效控制的其他恶性肿瘤）。
(15) 筛选前30天内使用过其他研究性药物。
(16) 妊娠期或哺乳期有生育能力的女性。已行手术绝育或绝经至少2年的女性不被视为具有生育能力。
(17) 参与者不愿意自同意治疗起至淋巴细胞清除化疗完成或CAR-T细胞输注后12个月内（以较长者为准）采取避孕措施。
(18) 任何可能潜在干扰研究治疗安全性或疗效评估的医疗活动。
(19) 根据研究者判断，不太可能完成方案要求的所有研究访视或操作（包括随访），或无法遵守研究参与要求的受试者。
Inclusion Criteria:
(1) Voluntary participation in the clinical study; complete understanding by self or legally authorized guardian, informed of the study, and signing the Informed Consent Form (ICF); willing and able to comply with all trial procedures.
(2) Age between 18 and 70 years.
(3) Patients refractory or relapsed after current standard treatments (including allogeneic or autologous hematopoietic stem cell transplantation), and unsuitable for other treatment options such as second hematopoietic stem cell transplantation. Refractory/relapsed lymphoma is defined as:
1. No response to first-line therapy (primary refractory disease, excluding subjects intolerant to first-line therapy):
\- Progression of Disease (PD) assessment after first-line treatment
* Best response of Stable Disease (SD) after at least 4 cycles of first-line treatment (e.g., 4 cycles of RCHOP), with SD maintenance duration not exceeding 6 months after the last dose.
2. No response to second-line or subsequent therapies:
* PD as best response to the most recent treatment regimen
* Best response of SD after at least 2 cycles of last-line treatment, with SD maintenance duration not exceeding 6 months after the last dose.
3. Refractory post autologous stem cell transplantation (ASCT):
* Disease progression or relapse ≤12 months after ASCT (relapsing subjects must have biopsy-proven relapse)
* If salvage therapy is performed post-ASCT, subjects must have had no response or relapse after the last-line treatment.
* Relapsed or refractory disease after two or more lines of systemic therapy.
(4) Lymphoma patients with target antigens meeting the following criteria:
* CD20/CD30 double-positive lymphomas
* Relapse after anti-CD19-CAR-T cell therapy, and CD20-positive lymphomas
* Never received anti-CD19-CAR-T cell therapy, CD20-positive lymphomas
* CD30-positive Hodgkin lymphoma.
(5) Included lymphoma subtypes:
* DLBCL-NOS (Diffuse Large B-Cell Lymphoma, not otherwise specified)
* Primary mediastinal large B-cell lymphoma (PMBCL)
* Transformed follicular lymphoma (TFL), previously treated with follicular lymphoma chemotherapy, subsequently transformed into DLBCL, refractory disease
* Mantle cell lymphoma
* High-grade B-cell lymphoma
* Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
* Hodgkin lymphoma (HL).
(6) ECOG performance status ≤2.
(7) Expected survival of at least 12 weeks.
(8) Adequate venous access (for single collection), and no other contraindications for blood cell separation.
(9) Laboratory requirements at screening, with no hematologic evaluation within 7 days of receiving growth factors (long-acting granulocyte colony-stimulating factor (G-CSF/PEG-CSF) requires a 2-week interval):
* Absolute neutrophil count ≥1.0×10\^9/L;
* Hemoglobin ≥60 g/L (without red blood cell transfusion within 7 days);
* Platelets ≥50×10\^9/L (CLL indication unrestricted);
* Serum total bilirubin ≤1.5× upper limit of normal (ULN); or ≤3× ULN if liver tissue invasion by tumor;
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5× ULN, AST/ALT ≤5× ULN if liver tissue invasion by tumor;
* Creatinine \<1.5× ULN and estimated glomerular filtration rate ≥60 mL/minute.
(10) Left ventricular ejection fraction ≥45%, echocardiogram (ECHO) showing no clinically significant pericardial effusion (excluding minimal or physiological effusions), and no clinically significant findings on electrocardiogram.
(11) Baseline oxygen saturation \>92% without supplemental oxygen.
(12) Women of childbearing potential must have a negative serum or urine pregnancy test result (women who have undergone surgical sterilization or who are at least 2 years postmenopausal are not considered of childbearing potential).
Exclusion Criteria:
Here is the translation of the exclusion criteria for participants in a clinical study:
1. Evidence of central nervous system lymphoma on brain MRI; active primary central nervous system DLBCL, unless CNS involvement has been effectively treated (i.e., participant is asymptomatic) and there has been a local treatment interval of \>4 weeks prior to enrollment.
2. Active central nervous system diseases such as epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any autoimmune diseases with central nervous system involvement.
3. History of or concurrent malignancies other than CD19+ malignancies.
4. Clinically significant cardiac disease, or arrhythmias not controlled by medication.
5. Presence or suspicion of uncontrolled fungal, bacterial, viral, or other infections requiring intravenous antibiotics; simple urinary tract infections and uncomplicated bacterial pharyngitis are allowed.
6. Hepatitis B (positive hepatitis B surface antigen and hepatitis B DNA \>1000 copies/mL) and hepatitis C (positive hepatitis C antibody).
7. Presence of any indwelling catheters or drainage tubes (e.g., percutaneous nephrostomy tube, Foley catheter, bile drainage tube, pleural/peritoneal/pericardial catheter); specialized central venous access devices like Port-A-Cath® or Hickman® catheters are allowed.
8. Use of the following medications prior to:
1\) Ibrutinib within 1 day before apheresis. 2) Idelalisib (oral PI3Kδ inhibitor) within 2 days before apheresis. 3) Short-acting targeted therapy (such as tyrosine kinase inhibitors) within 72 hours before apheresis.
4\) Venetoclax (BCL-2 inhibitor) within 4 days before apheresis. 5) Long-acting growth factors (such as pegfilgrastim) within 14 days before apheresis, or short-acting growth factors or mobilizing agents (such as granulocyte colony-stimulating factor (G-CSF)/filgrastim) within 5 days before apheresis.
6\) Pharmacologic doses of corticosteroid therapy (\>5 mg/day prednisone or equivalent) and other immunosuppressive drugs within 7 days before enrollment.
7\) Radiotherapy within 14 days before enrollment. 8) Systemic cytotoxic drugs within 14 days before enrollment, including daily or weekly low-dose maintenance chemotherapy (e.g., cyclophosphamide, fludarabine, bendamustine, chlorambucil, methotrexate, vinblastine).
If bridging therapy is administered post-apheresis, there must be at least a 7-day interval between bridging therapy and CAR-T cell infusion.
9\) Anti-PD1 or anti-PDL1 therapy within 4 weeks before enrollment. 10) Vaccination within 4 weeks before enrollment. 11) Donor lymphocyte infusion (DLI) within 4 weeks before enrollment. 12) Immunostimulatory or immunosuppressive therapy within 3 months before enrollment (such as interferon-α, interferon-β, IL-2, lenalidomide, efalizumab, alemtuzumab, cyclosporine, or methotrexate).
(9) Active graft-versus-host disease (GVHD) using the CIBMTR acute GVHD grading system ≥ grade 2 or requiring systemic steroids greater than physiological doses.
(10) History in the past 2 years of autoimmune diseases causing end-organ damage or requiring systemic immunosuppressive/disease-modifying agents, such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus.
(11) History in the past 12 months of myocardial infarction, cardiac vascular procedures or stent implantation, unstable angina, or other clinically significant cardiac diseases.
(12) History of genetic syndromes with bone marrow failure, such as Fanconi anemia, Costello syndrome, Shwachman-Diamond syndrome.
(13) Symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation therapy within 6 months before enrollment. Subjects requiring prophylactic anticoagulation are allowed.
(14) History of concurrent or prior malignancies (excluding basal cell carcinoma of the skin, in situ carcinoma of the breast/cervix, and other malignancies effectively controlled without treatment within the past five years).
(15) Use of other investigational medicinal products within 30 days before screening.
(16) Pregnant or lactating women of childbearing potential. Women who have undergone surgical sterilization or who are at least 2 years postmenopausal are not considered of childbearing potential.
(17) Participants unwilling to use contraception from agreeing to treatment until completion of lymphocyte depletion chemotherapy or CAR-T cell infusion within 12 months (whichever is longer).
(18) Any medical activities that could potentially interfere with the safety or efficacy evaluation of the study treatment.
(19) According to the investigator's judgment, participants who are unlikely to complete all study visits or procedures required by the protocol (including follow-ups), or comply with the requirements of participating in the 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：Incidence of dose-limiting toxicity · The proportion of patients receiving CAR-T cells who encounter dose-limiting toxicities(DLTs). Safety evlauations are performed in accordance with the NCI-CTCAE version 5.0 standards(Cytokine Release Syndrome and neurotoxicity will be graded based on ASTCT/ASBMT grading criteria). · Up to 28 days from CAR-T infusion
anti-CD20/CD30-CAR-T 细胞输注。输注剂量：计划输注剂量如下：第一剂量组为 3E5 cells/kg；第二剂量组为 1E6 cells/kg；第三剂量组为 3E6 cells/kg。输注剂量指 CAR 阳性细胞的数量。 给药方式：anti-CD20/CD30-CAR-T 细胞通过输液泵以约 2-5 mL/分钟的速度静脉输注，建议输注时间少于 30 分钟。
本研究是一项单中心、开放标签、单次给药的临床试验，针对淋巴细胞清除预处理后的复发/难治性B细胞肿瘤患者，采用抗CD20/CD30-CAR-T细胞疗法。 在本研究阶段，采用传统的“3+3”试验设计进行剂量递增。
This study is a single-center,open-label,single-dose clinical trial of anti-CD20/CD30-CAR-T cell therapy in relapsed/refractory B-cell tumor patients after lymphocyte depletion pre-treatment. In this study phase,a traditional "3+3"trial design is employed for dose escalation.
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