肿瘤细胞治疗研究
英文原题：Bispecific CD19/CD22 CAR-T for Treatment of Children and Young Adults With r/r B-ALL
⚠ 该试验的登记信息已有 44 个月未更新， 页面上显示的「进行中（不再招募）」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 I/II 期注册临床试验，评估 CD19CAR-T 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 50 例。试验地点：其他 · 莫斯科（共 1 个中心）。登记号：NCT04499573。
不限性别 · ≥ 3 Months 且 ≤ 25 Years
纳入标准： * 能够提供知情同意（适用于>14岁的患者）。对于<18岁的受试者，其法定监护人必须提供知情同意 * 通过流式细胞术检测，白血病细胞上CD19或CD22的表达必须大于50% * 患者纳入研究时，骨髓或髓外部位存在可测量的肿瘤细胞团块 * 复发或难治性CD19和CD22表达B细胞ALL患者： * 诱导治疗失败 * 高危组患者第2疗程化疗后MRD ≥ 0.1%。 * 急性淋巴细胞白血病首次骨髓或联合复发，1疗程二线治疗后未达CR或MRD ≥ 0.1% * ALL第二次及以后复发 * 造血干细胞移植后ALL复发或MRD ≥ 0.1%（alloHSCT后>60天）必须没有可用的替代获批治愈性疗法 * 患者临床体能状态：Karnofsky >50%或Lansky >50% * 患者预期寿命>4周 * 患者已从既往化疗、免疫治疗或放疗的急性毒性效应中恢复 * 患者绝对血液初始（CD45RA+）T淋巴细胞计数 ≥ 50/mm3 * 患者心功能左心室射血分数经MUGA或心脏MRI大于或等于40%，或经ECHO缩短分数大于或等于28%，或经ECHO左心室射血分数大于或等于50%。 * 同意接受最长5年长期随访的患者（若接受了CD19/CD22 CAR-T细胞输注） * 2021年3月修订：健康的HLA相合相关或单倍体相合供者（仅用于HSCT队列） 排除标准： * 白血病细胞群CD19和CD22表达均<50% * 活动性（可检测到病毒血症）乙型肝炎、丙型肝炎或HIV感染 * 血氧饱和度≤90% * 胆红素>3倍正常上限 * 肌酐>3倍正常上限 * 活动性急性GVHD总体分级≥2级（Seattle标准） * 需要全身性类固醇治疗的中度/重度慢性GVHD（NIH共识） * 具有>3级CNS疾病临床体征（癫痫发作性疾病、瘫痪、失语、脑血管病、缺血/出血、严重脑损伤、痴呆、小脑疾病、器质性脑综合征、精神病、协调或运动障碍） * 妊娠或哺乳期女性。 * 活动性（未缓解）严重感染
Inclusion Criteria: * Ability to give informed consent (for patients \> 14 years old). For subjects \< 18 years old their legal guardian must give informed consent * CD19 or CD22 expression must be detected on greater than 50% of leukemic cells by flow cytometry * Presence of a measurable mass of tumor cells in the bone marrow or extramedullary sites at the time of patient's inclusion in the study * Patients with relapsed or refractory CD19 and CD22-expressing B-cell ALL: * Induction failure * MRD ≥ 0,1% after 2nd chemotherapy course for high-risk group patients. * First bone marrow or combined relapse of acute lymphoblastic leukemia, no CR or MRD ≥ 0,1% after 1-course 2nd line therapy * Second and further relapse of ALL * Relapse or MRD ≥ 0,1% of ALL after hematopoietic stem cell transplant (\> 60 days post alloHSCT)o There must be no available alternative approved curative therapies * Patient Clinical Performance Status: Karnofsky \>50% or Lansky \>50% * Patient Life Expectancy \> 4 weeks * Patients recovered from acute toxic effects of prior chemotherapy, immune- or radiotherapy * Patient absolute blood naïve (CD45RA+) T-lymphocyte count ≥ 50/mm3 * Patient cardiac function left ventricular ejection fraction greater than or equal to 40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO. * Patients who agree to long-term follow up for up to 5 years (if received CD19/CD22 CAR-T cell infusion) * March 2021 amendment: Healthy HLA-matched related or haploidentical donor (only for HSCT cohort) Exclusion Criteria: * \<50% expression of both CD19 and CD22 on the leukemic population * Active (detectable viremia) hepatitis B, C or HIV infection * Oxygen saturation ≤ 90% * Bilirubin \>3x upper norma limit * Creatinine \>3x upper norma limit * Active acute GVHD overall grade ≥2 (Seattle criteria) * Moderate/severe chronic GVHD (NIH consensus) requiring systemic steroids * Clinical signs of grade \> 3 CNS disorders (seizure disorder, paresis, aphasia, cerebrovascular, ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) * Pregnant or lactating women. * Active (unresolved) severe infection
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 grade 3-5 SAE · Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
\- incidence of grade 3-5 SAE (according CTCAE v.5.0) · 1 month；incidence of grade 3-5 Severe Cytokine Release Syndrome · Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
\- incidence of grade 3-5 Severe Cytokine Release Syndrome (according ASTCT consensus) · 1 month；incidence of grade 3-5 ICANS · Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
\- incidence of grade 3-5 ICANS (according to ASTCT consensus) · 1 month；Rate of complete remission · Efficacy:
\- Rate of complete remission among all enrolled patients (Intent-to-Treat population) · 1 month；Rate of MRD-negative remission · Efficacy:
\- Rate of MRD-negative remission among all patients (Intent-to-treat population) · 1 month；March 2021 amendment: incidence of graft failure before day 100 (only for HSCT cohort) · Safety: · 100 days
次要终点：Duration of MRD-negative remission；Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)；Duration of B-cell aplasia and hypogammaglobulinemia；Overall survival；Safety and adverse effects long-term；March 2021 amendment: Incidence of chronic GVHD (only for HSCT cohort)
干预： 1. 患者（队列1和2）或供者（队列3）白细胞分离术 2. 药物治疗： * 氟达拉滨 120 mg/m2 * 环磷酰胺 750 mg/m2 * 依托泊苷 450 mg/m2 * 阿糖胞苷 900 mg/m2 * 地塞米松 30 mg/m2 * 托珠单抗 8 mg/kg BW 3. 生物制剂： 队列1和2：自体CD19/CD22 CAR-T淋巴细胞，剂量0.15 - 1.5х106/kg 队列3：异体CD19/CD22 CAR-T淋巴细胞，剂量0.1х106/kg + 来自单倍体或相合相关供者的异体HSCT
本研究的目的是在复发/难治性B系急性淋巴细胞白血病的儿童和年轻成人患者队列中，评估自体CD19/CD22 CAR-T淋巴细胞的安全性和有效性。
The purpose of this study is to evaluate the safety and efficiency of autologous CD19/CD22 CAR-T lymphocytes in a cohort of pediatric and young adult patients with relapsed /refractory B-lineage acute lymphoblastic leukemia
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