肿瘤细胞治疗研究
英文原题：A Study of CAR T-Cells in Relapsed/Refractory Hematologic Malignancy
⚠ 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。
这是一项早期 I 期注册临床试验，评估抗 CD19CAR-T 细胞治疗淋巴瘤、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 9 例。试验地点：中国 · 南通（共 1 个中心，其中中国 1 个）。登记号：NCT06756321。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
纳入标准：
* 患者必须符合以下所有标准方可入组本研究：
1. 自愿参加临床研究。本人或法定监护人充分了解本研究，签署知情同意书（ICF），且愿意并能够遵循并完成所有试验程序。
2. 年龄 ≥ 18岁且 < 70岁。
3. 经当前标准治疗（包括异基因或自体造血干细胞移植）后难治或复发的受试者，且不适合其他治疗选择，如第二次干细胞移植。复发/难治性淋巴瘤的定义包括以下情况之一：
a. 复发/难治性B细胞急性淋巴细胞白血病（ALL）定义为以下之一：
i) 原发难治性疾病。
ii) 首次复发且初始缓解持续时间 ≤ 12个月。
iii) 接受两线或以上系统性治疗后复发或难治性疾病。
iv) 异基因移植后复发或难治性疾病，前提是入组时受试者距干细胞移植至少100天，且入组前至少4周未接受免疫抑制药物，低剂量类固醇（≤ 5 mg泼尼松或等效剂量）除外。
b. Ph+ B细胞ALL受试者，对酪氨酸激酶抑制剂（TKI）治疗不耐受或不符合条件，或接受至少两种不同TKI治疗后出现复发/难治性疾病，可入组。
c. 复发/难治性B细胞来源非霍奇金淋巴瘤（NHL）和霍奇金淋巴瘤（HL）定义为以下之一：
i) 一线治疗无应答（原发难治性疾病，排除对一线治疗不耐受的受试者）；
* 一线治疗后评估为疾病进展（PD）。
* 至少4个周期一线治疗（如4个周期RCHOP）后最佳疗效为SD，且末次给药后SD持续时间不超过6个月。
ii) 二线或以上治疗无应答。
* 最近治疗方案的最佳疗效为PD。
* 至少2个周期末线治疗后最佳疗效为SD，且末次给药后SD持续时间不超过6个月。
iii) 自体干细胞移植（ASCT）后难治。
* ASCT后 ≤ 12个月疾病进展或复发（复发患者必须有活检证实的复发）。
* 若ASCT后接受挽救治疗，受试者必须对末线治疗无应答或治疗后复发。
* 接受两线或以上系统性治疗后复发或难治性疾病。
4. 纳入抗CD19-CAR T细胞队列的适应症包括：
1. CD19+ ALL患者，骨髓涂片报告显示肿瘤细胞 ≥ 5%。
2. CD19+ NHL患者，符合以下亚型之一：
* 弥漫性大B细胞淋巴瘤，非特指型（DLBCL-NOS）
* 原发性纵隔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治疗，之后转化为难治性DLBCL
* 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）
5. 抗CD20/30-CAR T细胞队列入组纳入的淋巴瘤亚型：
* 既往接受过抗CD20/30-CAR T细胞治疗，入组时CD20表达阳性。
* CD20/CD30双阳性表达的淋巴瘤。
6. 抗CD30-CAR T细胞队列入组纳入的适应症：
* CD30阳性HL
* CD30阳性T细胞淋巴瘤
7. ECOG体能状态评分≤2。
8. 预期生存期至少12周。
9. 静脉通路充分（用于单采），且无其他血细胞分离禁忌症。
10. 筛选期间的实验室检查必须符合以下要求，且受试者在血液学评估前7天内未接受过细胞生长因子（长效集落刺激因子（G-CSF/PEG-CSF）需间隔2周）和血小板输注：
1. 中性粒细胞绝对计数≥1.0×10^9/L（ALL患者的情况由研究者判定）。
2. 血红蛋白≥60 g/L（最近14天内未接受红细胞输注）。
3. 血小板≥50×10^9/L（ALL患者的情况由研究者判定）。
4. 淋巴细胞绝对计数（ALC）≥0.5×10^9/L。
5. 血清总胆红素≤1.5×正常上限（ULN）。
6. 天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）≤2.5×ULN。
7. 肌酐<1.5×ULN且估算肌酐清除率≥60 mL/min。
11. 射血分数≥45%，超声心动图（ECHO）确认无心包积液（不包括少量或生理性积液），且心电图结果无临床意义。
12. 基线血氧饱和度>92%（未吸氧状态下）。
13. 有生育能力的女性必须血清或尿液妊娠试验结果为阴性（接受过手术绝育或绝经至少2年的女性不被视为有生育能力）。
排除标准：
* 受试者若符合以下任何一项标准，则不符合参加本研究的资格：
1. 伴有中枢神经系统（CNS）异常的ALL患者，包括具有临床显著神经系统改变的CNS-2和CNS-3：
1. CNS-3疾病定义为脑脊液（CSF）样本中可检测到肿瘤细胞，且白细胞≥5个/mm^3，伴或不伴神经系统改变。
2. CNS-2疾病定义为脑脊液样本中可检测到肿瘤细胞，且白细胞<5个/mm^3，并伴有神经系统改变。
注：分类为CNS-1（脑脊液中未检测到肿瘤细胞）的受试者以及无临床显著神经系统改变分类为CNS-2的受试者有资格参加本研究。
2. 脑MRI证据显示中枢神经系统淋巴瘤。活动性原发性中枢神经系统DLBL，除非CNS受累已得到有效治疗（即受试者无症状）且入组前局部治疗间隔>4周。
3. 存在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CNS的自身免疫性疾病。
4. 有其他恶性肿瘤病史或同时存在其他恶性肿瘤。
5. 有临床显著的心脏病或药物无法控制的心律失常。
6. 存在或怀疑真菌、细菌、病毒或其他感染，且未得到控制或需要静脉抗生素治疗。允许无并发症的尿路感染和无并发症的细菌性咽炎。
7. 乙型肝炎（HBsAg阳性，和/或乙型肝炎核心抗体阳性且HBV DNA >1000 copies/mL）和丙型肝炎（HCV抗体阳性）、梅毒或人类免疫缺陷病毒（HIV）感染阳性。
8. 存在任何留置或引流导管（如经皮肾造瘘管、留置Foley导尿管、胆道引流管或胸膜/腹膜/心包导管）。允许使用专用中心静脉通路装置，如Port-A-Cath®或Hickman®导管。
9. 既往用药：
1. 入组前3个月内使用氯法拉滨或克拉屈滨，或入组前3周内使用PEG-天冬酰胺酶。
2. 入组前4周内注射活疫苗。
3. 入组前28天内供者淋巴细胞输注（DLI）。
4. 入组前4周内使用任何用于治疗GVHD的药物（如钙调神经磷酸酶抑制剂、甲氨蝶呤、霉酚酸酯、雷帕霉素、沙利度胺），或入组前4周内使用免疫抑制抗体（如抗CD20、抗肿瘤坏死因子、抗白介素-6或抗白介素-6受体）。
5. 入组前4周内进行免疫刺激或免疫抑制治疗（如干扰素-α、干扰素-β、IL-2、依那西普、英夫利西单抗、他克莫司、环孢素或霉酚酸）。
6. 入组前4周内接受任何全身性免疫抑制/刺激性检查点分子治疗（如伊匹木单抗、纳武利尤单抗、帕博利珠单抗、阿替利珠单抗、OX40激动剂、4-1BB激动剂等）。
7. 入组前2周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（如环磷酰胺、异环磷酰胺、苯达莫司汀、苯丁酸氮芥、甲氨蝶呤、长春新碱等）。
8. 在白细胞分离术前14天内使用长效生长因子（如聚乙二醇化非格司亭），或在白细胞分离术前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/非格司亭、普乐沙福）。
9. 入组前2周内接受过放射治疗。
10. 入组前7天内必须避免使用药理学剂量的皮质类固醇（>5 mg/天的泼尼松或其他皮质类固醇的等效剂量）及其他免疫抑制药物。
11. 白细胞分离术前4天内使用维奈克拉（BCL-2抑制剂）。
12. 白细胞分离术前72小时内使用短效靶向治疗（如酪氨酸激酶抑制剂）。
13. 白细胞分离术前2天内使用艾代拉里斯（口服PI3Kδ抑制剂）。
14. 白细胞分离术前1天内使用来那度胺。
10. 根据CIBMTR急性GVHD分级系统，存在≥2级的活动性移植物抗宿主病（GVHD），或需要超过生理剂量的全身性类固醇治疗。
11. 有自身免疫性疾病史（如克罗恩病、类风湿关节炎或系统性红斑狼疮），导致终末器官损伤，或在过去2年内需要全身性免疫抑制/全身性疾病修饰药物治疗。
12. 入组前12个月内有心肌梗死、心脏血管成形术或支架植入术、不稳定型心绞痛或其他临床显著心脏疾病史。
13. 有与骨髓衰竭相关的遗传综合征病史，如范可尼贫血、科斯特曼综合征和Shwachman-Diamond综合征。
14. 入组前6个月内有需要全身抗凝治疗的症状性深静脉血栓或肺栓塞病史。受试者需接受预防性抗凝药物治疗。
15. 有其他恶性肿瘤病史（非黑色素瘤皮肤癌、原位乳腺癌/宫颈癌，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除外）。
16. 筛选前30天内使用过其他研究性产品。
17. 妊娠或哺乳期育龄女性。化疗对胎儿或婴儿存在潜在风险。已接受手术绝育或绝经至少2年的女性不被视为有生育潜力。
18. 男性及女性受试者不愿意从签署知情同意书时至淋巴清除性化疗或CAR T细胞输注完成后12个月（以较长者为准）期间采取避孕措施。
19. 任何可能干扰研究治疗安全性或有效性评估的医疗活动。
20. 经研究者判断，受试者不太可能完成所有方案要求的程序和随访访视，或无法遵守参与研究的要求。
Inclusion Criteria:
* Patients must meet all of the following criteria to be eligible for the study:
1. Voluntarily participate in the clinical study. The individual or the legal guardian fully understands the study, sign the informed consent form (ICF), and is willing and able to follow and complete all trial procedures.
2. Age ≥ 18 years and \< 70 years.
3. Subjects with refractory or relapsed disease after current standard treatments (including allogeneic or autologous hematopoietic stem cell transplantation) who are not suitable for other treatment options, such as a second stem cell transplant. The definitions of relapsed/refractory lymphoma include one of the following situations:
a. Relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) is defined as one of the following:
i) Primary refractory disease.
ii) First relapse if the initial remission is ≤ 12 months.
iii) Relapse or refractory disease after two or more lines of systemic therapy.
iv) Relapse or refractory disease after allogeneic transplantation, provided that at the time of enrollment, the subject is at least 100 days post-stem cell transplantation and has not received immunosuppressive drugs for at least 4 weeks prior to enrollment, except for low-dose steroids (≤ 5 mg of prednisone or equivalent).
b. Subjects with Ph+ B-cell ALL, who are intolerant to or ineligible for tyrosine kinase inhibitor (TKI) treatment, or who have relapsed/refractory disease after receiving at least two different TKI treatments, are eligible.
c. Relapsed/refractory B-cell-derived non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) defined as one of the following:
i) No response to first-line treatment (primary refractory disease, excluding subjects intolerant to first-line treatment);
* Disease progression (PD) as assessed after first-line treatment.
* Best response of SD after at least 4 cycles of first-line treatment (e.g., 4 cycles of RCHOP), with SD duration not exceeding 6 months after the last dose.
ii) No response to second-line or more treatments.
* PD as the best response to the most recent treatment regimen.
* Best efficacy of the last line of treatment as SD after at least 2 cycles, with the duration of SD not exceeding 6 months after the last dose.
iii) Refractory after autologous stem cell transplant (ASCT).
* Disease progression or relapse ≤ 12 months post-ASCT (relapsed patients must have biopsy-proven relapse).
* If salvage treatment is performed after ASCT, the subjects must have no response to or relapsed after the last line of treatment.
* Relapsed or refractory disease after two or more lines of systemic therapy.
4. Indications included for enrollment in the cohort of anti-CD19-CAR T-cells:
1. CD19+ ALL patients, with bone marrow smear reports showing tumor cells ≥ 5%.
2. CD19+ NHL patients meeting one of the following subtypes:
* Diffuse large B-cell Lymphoma, not otherwise specified (DLBCL-NOS)
* Primary mediastinal B-cell lymphoma (PMBCL)
* Transformed follicular lymphoma (TFL), previously treated for follicular lymphoma and then transformed to refractory DLBCL
* Mantle cell lymphoma
* High-grade B-cell lymphoma
* Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
5. Subtypes of lymphoma included for enrollment in the cohort of anti-CD20/30-CAR T-cells:
* Previously received anti-CD20/30-CAR T-cell therapy, with CD20 expression positive at enrollment.
* Lymphoma with dual positive expression of CD20/CD30.
6. Indications included for enrollment in the cohort of anti-CD30-CAR T-cell:
* CD30 positive HL
* CD30 positive T-cell lymphoma
7. ECOG performance status ≤ 2.
8. Expected survival of at least 12 weeks.
9. Adequate venous access (for apheresis) and no other contraindications for blood cell separation.
10. Laboratory tests during screening must meet the following requirements, and the subject must not have received cell growth factors (long-acting colony-stimulating factors (G-CSF/PEG-CSF) require a 2-week interval) and platelet transfusions within 7 days prior to hematological assessment:
1. Absolute neutrophil count ≥ 1.0×10\^9/L (the condition of ALL patients is determined by the investigator).
2. Hemoglobin ≥ 60 g/L (without red blood cell transfusion in the last 14 days).
3. Platelets ≥ 50×10\^9/L (the condition of ALL patients is determined by the investigator).
4. Absolute lymphocyte count (ALC) ≥ 0.5×10\^9/L.
5. Total serum bilirubin ≤ 1.5× the upper limit of normal (ULN).
6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN.
7. Creatinine \<1.5×ULN and estimated creatinine clearance ≥60 mL/min.
11. Ejection fraction ≥ 45%, with echocardiogram (ECHO) confirming no pericardial effusion (excluding small or physiological amounts), and electrocardiogram results with no clinical significance.
12. Baseline oxygen saturation \> 92% without supplemental oxygen.
13. Women of childbearing potential must have a negative serum or urine pregnancy test result (women who have undergone surgical sterilization or have been postmenopausal for at least 2 years are not considered of childbearing potential).
Exclusion Criteria:
* Subjects are not eligible to participate in this study if they meet any of the following criteria:
1. ALL patients with central nervous system (CNS) abnormalities, including CNS-2 and CNS-3 that are of clinically significant neurological changes:
1. CNS-3 disease is defined as detectable tumor cells in the cerebrospinal fluid (CSF) sample with ≥ 5 WBCs/mm\^3, with or without neurological changes.
2. CNS-2 disease is defined as detectable tumor cells in the CSF sample with \< 5 WBCs/mm\^3 and with neurological changes.
Note: Subjects classified as CNS-1 (no detectable tumor cells in CSF) and those with no clinically significant neurological changes classified as CNS-2 are eligible to participate in this study.
2. Brain MRI evidence shows central nervous system lymphoma. Active primary central nervous system DLBL, unless CNS involvement has been effectively treated (i.e., participants are asymptomatic) and there has been a local treatment interval of \>4 weeks prior to enrollment.
3. Presence of active central nervous system diseases, such as epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any autoimmune diseases with CNS involvement.
4. A history of or concurrent presence of other malignancies.
5. Clinically significant cardiac disease or arrhythmias that cannot be controlled with medication.
6. Presence or suspicion of fungal, bacterial, viral, or other infections that are uncontrolled or require intravenous antibiotics for treatment. Uncomplicated urinary tract infections and uncomplicated bacterial pharyngitis are allowed.
7. Positive for hepatitis B (positive for HBsAg, and/or positive for Hepatitis B core antibody and HBV DNA \>1000 copies/mL) and hepatitis C (positive for HCV antibodies), syphilis or human immunodeficiency virus (HIV) infection.
8. Presence of any indwelling or drainage catheters (such as percutaneous nephrostomy tubes, indwelling Foley catheters, bile drainage tubes, or pleural/peritoneal/pericardial catheters). The use of specialized central venous access devices, such as Port-A-Cath® or Hickman® catheters, is allowed.
9. Prior medication:
1. Use of clofarabine or cladribine within 3 months prior to enrollment, or use of PEG-asparaginase within 3 weeks prior to enrollment.
2. Injection of live vaccines within 4 weeks prior to enrollment.
3. Donor lymphocyte infusion (DLI) within 28 days prior to enrollment.
4. Any medications used for the treatment of GVHD (such as calcineurin inhibitors, methotrexate, mycophenolate, rapamycin, thalidomide) within 4 weeks prior to enrollment, or immunosuppressive antibodies (such as anti-CD20, anti-tumor necrosis factor, anti-interleukin-6, or anti-interleukin-6 receptor) used within 4 weeks prior to enrollment.
5. Immune stimulation or immunosuppressive therapy (such as interferon-α, interferon-β, IL-2, etanercept, infliximab, tacrolimus, cyclosporine, or mycophenolic acid) within 4 weeks prior to enrollment.
6. Any systemic immunosuppressive/stimulatory checkpoint molecule therapy within 4 weeks prior to enrollment (such as ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc.).
7. Use of systemic cytotoxic drugs within 2 weeks prior to enrollment, including daily or weekly low-dose maintenance chemotherapy (such as cyclophosphamide, ifosfamide, bendamustine, chlorambucil, methotrexate, vincristine, etc.).
8. Long-acting growth factors (e.g., pegylated filgrastim) within 14 days prior to leukapheresis, or short-acting growth factors or mobilizing agents (e.g., granulocyte colony-stimulating factor/filgrastim, plerixafor) within 5 days prior to leukapheresis.
9. Radiation therapy within 2 weeks prior to enrollment.
10. Use of pharmacological doses of corticosteroids (\>5 mg/day of prednisone or equivalent doses of other corticosteroids) and other immunosuppressive medications must be avoided within 7 days prior to enrollment.
11. Use of venetoclax (BCL-2 inhibitor) within 4 days prior to leukapheresis.
12. Short-acting targeted therapy (e.g., tyrosine kinase inhibitors) within 72 hours prior to leukapheresis.
13. Idelalisib (oral PI3Kδ inhibitor) within 2 days prior to leukapheresis.
14. Lenalidomide within 1 day prior to leukapheresis.
10. Active graft-versus-host disease (GVHD) ≥ grade 2 on the CIBMTR acute GVHD grading system or requires systemic steroids at doses greater than physiological levels.
11. A history of autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, or systemic lupus) resulting in end-organ injury or requiring systemic immunosuppression/systemic disease-modifying agents within the last 2 years.
12. A history of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac diseases within 12 months prior to enrollment.
13. A history of a concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, and Shwachman-Diamond syndrome.
14. A history of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months prior to enrollment. Subjects need to be on preventive anticoagulant medication.
15. A history of other malignancies (except for non-melanoma skin cancer, in situ breast/cervical cancer, and other malignant tumors that have been effectively controlled without treatment in the past five years).
16. Use of other investigational products within 30 days prior to screening.
17. Pregnant or breastfeeding women of childbearing age. Chemotherapy poses potential risks to the fetus or infant. Women who have undergone surgical sterilization or are postmenopausal for at least 2 years are not considered of childbearing potential.
18. Male and female subjects unwilling to practice birth control from the time of consent through 12 months after the completion of lymphodepleting chemotherapy or CAR T cells infusion (whichever is longer).
19. Any medical activities that may interfere with the safety or efficacy assessment of the study treatment.
20. In the investigator's judgment, the subject is unlikely to complete all protocol-required procedures and follow-up visits, or to comply with the requirements for 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：Evaluate safety and tolerability of CAR T-cells · Proportion of subjects experiencing dose-limiting toxicities (DLT) · 28 days after infusion of CAR T-cells；Evaluate the feasibility of administration of CAR T-cells · The proportion of subjects for whom the desired dose of CAR T-cells can be successfully manufactured · 12 months
次要终点：Adverse events；Incidence of cytokine release syndrome (CRS) and neurotoxicity；Evaluate cellular kinetics and persistence of CAR T-cells；Preliminary anti-tumor effect；Overall response rate (ORR)；Progression-free survival (PFS)；Overall survival (OS)；Evaluate host immunogenicity to CAR T-cells
研究产品：抗CD19-CAR T细胞、抗CD30-CAR T细胞、抗CD20/CD30-CAR T细胞。 CD19+ ALL或NHL受试者将输注抗CD19-CAR T细胞。 CD30+ HL或T细胞淋巴瘤受试者将输注抗CD30-CAR T细胞。 抗CD19-CAR T细胞治疗后复发的CD20+淋巴瘤或CD20/CD30双阳性淋巴瘤受试者将输注抗CD20/CD30-CAR T细胞。 给药途径：静脉注射。 淋巴细胞清除性化疗方案：在输注CAR T细胞前给予氟达拉滨和环磷酰胺联合方案。
本研究是一项单中心、开放标签的临床试验，旨在评估单剂量CAR T细胞在复发/难治性血液恶性肿瘤受试者中的应用。
This study is a single-center, open-label clinical trial of single-dose of CAR T-cells in subjects with relapsed/refractory hematologic malignancy.
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