肿瘤细胞治疗研究
英文原题：CD19 CAR-T Consolidation Therapy for Acute Lymphoblastic Leukemia
这是一项 I/II 期注册临床试验，评估 CD19T 细胞治疗急性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 40 例。试验地点：中国 · 苏州（共 1 个中心，其中中国 1 个）。登记号：NCT03984968。
不限性别 · ≥ 15 Years 且 ≤ 65 Years
纳入标准： * 签署知情同意书时年龄15–65岁。 * 确诊为新诊断的费城染色体阳性CD19阳性B-ALL。 * Karnofsky体能状态评分≥60，或ECOG体能状态评分≤2。 * 研究期间无法找到合适供者接受异基因造血干细胞移植，或因其他原因不适合接受该移植。 * 能够并愿意遵守研究访视安排及方案全部要求。 * 自愿签署知情同意书。 排除标准： * 无法长期耐受任何酪氨酸激酶抑制剂（包括第一代和第二代TKI）。 * 存在ABL激酶结构域突变，需要长期接受第三代TKI治疗。 * 肝功能不足：AST和/或ALT>正常值上限（ULN）的3倍，且直接胆红素>ULN的1.5倍。 * 肾功能不足：血清肌酐>1.6 mg/dL。 * 国际标准化比值（INR）或部分凝血活酶时间（PTT）>ULN的1.5倍。 * 左心室射血分数<50%。 * 正在接受慢性免疫抑制剂治疗。 * 研究者判断存在会使受试者面临过度风险或干扰研究的显著合并症或疾病，例如肝硬化、脓毒症、近期严重创伤等。 * 已知HIV阳性。 * 有卒中、不稳定型心绞痛、心肌梗死或需药物/机械控制的室性心律失常病史。 * 除ALL外还患有第二种恶性肿瘤。 * 妊娠或哺乳期，或拒绝采取有效避孕措施。 * 研究者认为不适合参加本试验的其他禁忌情况。
Inclusion Criteria: * 15-65 years of age at the time of signing informed consent * Diagnosed as de novo Philadelphia chromosome-positive CD19+ B-ALL * Karnofsky performance status ≥ 60 or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Unable to find a suitable donor or for other reasons to undergo allogeneic hematopoietic stem cell transplantation during the study * Ability and willingness to adhere to the study visit schedule and all protocol requirements * Voluntarily sign informed consent forms Exclusion Criteria: * Unable to tolerate any kind of TKIs (including the first- and second-generation tyrosine kinase inhibitors) for a long period. * Subjects who have positive mutation(s) of the ABL kinase domain and require the third-generation tyrosine kinase inhibitors for long-term therapies. * Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 × upper limit of normal (ULN) and direct bilirubin \> 1.5 × ULN * Inadequate renal function defined by serum creatinine \> 1.6 mg/dL * International ratio (INR) or partial thromboplastin time (PTT) \> 1.5 x ULN * Left ventricular ejection fraction \< 50% * Ongoing treatment with chronic immunosuppressants * Significant comorbid conditions or diseases which, in the judgment of the investigator, would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, recent significant traumatic injury, and other conditions * Known human immunodeficiency virus (HIV) positivity * Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control * Subjects with second malignancies in addition to ALL * Pregnant or lactating women, or subjects refusing to take effective contraception measures * Other contraindications that are considered inappropriate to participate in this trial
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：Phase 1 Incidence of adverse events (AEs) and abnormal laboratory test results · AEs will be assessed according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE5.0). · 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months)；Phase 2 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells · Complete molecular response (CMR) was defined as the absence of a detectable BCR-ABL1 transcript with a sensitivity of 0.01%. · 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months)
次要终点：Phase 1 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells.；Phase 1 The range of biologically active doses and optimal biological doses of CD19+ feeding T cells.；Phase 1 Overall survial (OS)；Phase 1 Relapse free survival（RFS）；Phase 2 Incidence of adverse events (AEs) and abnormal laboratory test results；Phase 2 Overall survial (OS)；Phase 2 Relapse free survival（RFS）
这是一项单臂、开放标签、单中心Ⅰ/Ⅱ期研究，旨在评估CD19 CAR-T细胞（ssCART-19）联合经基因工程改造表达CD19的自体T细胞（CD19阳性滋养细胞，FTC）作为巩固治疗，用于新诊断费城染色体阳性CD19阳性B细胞急性淋巴细胞白血病（B-ALL）患者的安全性和疗效。研究依次包括筛查、淋巴细胞单采、诱导治疗及联合酪氨酸激酶抑制剂的巩固化疗。达到完全缓解后，患者接受2至4个周期ssCART-19：先进行1个周期ssCART-19输注（CAR-T1），随后进行1至3个周期ssCART-19联合CD19阳性FTC输注（CAR-T2至CAR-T4）。FTC用于模拟白血病细胞，预计可促进ssCART-19在体内扩增并维持。Ⅰ期将探索FTC的生物活性剂量范围：在第1天ssCART-19输注2小时后给予FTC，并于第8天按相同剂量再次给药，剂量为5×10^6/kg、3.25×10^6/kg或2×10^6/kg。主要终点为输注后6个月内的不良事件；次要终点包括6个月内分子学缓解，以及2年无进展生存和总生存。Ⅱ期将在最佳生物学剂量下扩大研究，主要终点为完全分子学缓解，次要终点为无复发生存、总生存和不良事件。
This is a single-arm, open-label, single-center, phase I/II study to determine the safety and efficacy of CD19 CAR-T(ssCART-19) combined with autologous T cells engineered to express CD19, namely CD19+ feeding T cells (FTCs), as consolidation therapy in patients diagnosed with de novo Philadelphia chromosome-positive CD19+ B-ALL. The study will contain the following sequential phases: screening, lymphocyte apheresis, induction, and consolidation chemotherapies combined with tyrosine kinase inhibitors. Once in complete response, patients will receive two to four cycles of ssCART-19s, namely one cycle of ssCART-19 infusion (CAR-T1) followed by one to three cycles of ssCART-19 and CD19+ FTC infusion (CAR-T2-4). The role of CD19+ FTCs is to mimic leukemia cells. Therefore, they are expected to stimulate in vivo expansion and persistence of ssCART-19. Considering the limited number of lymphocytes obtained by a single apheresis from patients and cost-efficacy, in addition to safety, we will explore the range of biologically active doses of FTCs in a phase I study. Based on preclinical data, FTCs' stimulation of ssCART-19 at a ratio of 1:1 could achieve the best activation response, so a 5×10\^6/kg dosage of FTCs was set as the initial dosage in the study, and lower doses were also evaluated. In phase I, FTCs will be administered at the dose of 5×10\^6/kg, 3.25×10\^6/kg, or 2×10\^6/kg two hours after ssCART-19 infusion on day 1 and once again administered at the same dose on day 8. After ssCART-19 and FTCs infusion, adverse events (AEs) as the primary endpoints will be recorded for 6 months; efficacy as the secondary endpoint will be assessed by detecting molecular response for 6 months, PFS, and OS for 2 years. In phase II, we will expand the study at optimal biological doses of FTCs and further evaluate the efficacy and safety of the innovative combination therapy of ssCART-19 and FTCs. The primary endpoint was the complete molecular response (CMR). The secondary endpoints were RFS, OS, and adverse events (AEs) of the patients.
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