肿瘤细胞治疗研究
英文原题：Orphan Indications for CD19 Redirected Autologous T Cells
Orphan Indications for CD19 Redirected Autologous T Cells
这是一项 II 期注册临床试验，评估细胞治疗用于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：招募中。计划入组 133 例。试验地点：美国 · 费城（共 1 个中心）。登记号：NCT04276870。
不限性别 · ≥ 0 Years 且 ≤ 29 Years
纳入标准： 1. 开始任何研究程序前须取得签署的知情同意书； 2. 男女患者均可，须有CD19阳性B-ALL病历记录： a. 队列A和B：不论初治或复发B-ALL治疗反应如何，须符合以下特征之一：队列A，核型证实低二倍体（染色体数<45）；队列B，细胞遗传学证实t(17;19)染色体易位。 b. 队列C：新诊断KMT2A重排婴儿B-ALL，且按以下标准判定为极高危：诊断时年龄<3个月；或诊断时年龄<6个月且白细胞>300,000×10⁹/L，或诱导治疗中泼尼松反应不佳；或接受2个标准婴儿ALL治疗疗程后MRD阳性>0.01（或PCR>10⁴）。 c. 队列D：首次或之后发生CNS复发，且本次复发尚未接受颅脑XRT或HSCT； 3. 骨髓、外周血、脑脊液（CSF）或肿瘤组织须有CD19肿瘤表达证据； 4. 年龄0–29岁； 5. 器官功能充分：血清肌酐按年龄和性别符合方案界值（0至<2岁：男女均≤0.6 mg/dL；2至<6岁：≤0.8；6至<10岁：≤1.0；10至<13岁：≤1.2；13至<16岁：男性≤1.5、女性≤1.4；≥16岁：男性≤1.7、女性≤1.4）；肝功能ALT≤5×ULN，总胆红素≤3×ULN。若医生研究者认为或肝活检确认异常直接由ALL肝浸润所致，可接受超出此范围的结果；肺储备至少符合呼吸困难≤1级且缺氧<3级；如医生研究者认为有临床需要，则肺功能检查（PFT）校正贫血后的DLCO≥40%；超声心动图左室短轴缩短率（LVSF）≥28%或左心室射血分数（LVEF）≥45%；无法定量时，心脏科医生可出具超声显示心室功能定性正常的意见； 6. 体能状态充分，Lansky或Karnofsky评分≥50； 7. 有生育能力者同意采取可接受的避孕方式。 排除标准： 1. CNS复发患者当前复发已接受颅脑XRT或BMT； 2. 活动性乙肝或丙肝； 3. HIV感染； 4. 活动性急性或慢性GVHD且需要全身治疗； 5. 细胞输注或细胞采集时同时使用全身性类固醇，或治疗医生认为采集期间/输注后可能需要类固醇治疗；细胞采集/输注之外因疾病治疗使用类固醇者允许；生理替代剂量氢化可的松或吸入性类固醇允许； 6. 治疗过程中进展的CNS3疾病，或可能增加CNS毒性风险的脑实质病灶； 7. 妊娠期或哺乳期女性； 8. 未控制的活动性感染。
Inclusion Criteria:
1. Signed informed consent form must be obtained prior to any study procedure.
2. Male and female patients with documented CD19+ B-ALL
a.Cohort A \& B: Patients, regardless their response to initial or relapsed B ALL therapy, with the following characteristics: i.Cohort A: Subjects with confirmation of a hypodiploid karyotype (chromosome number fewer than 45) ii.Cohort B: Subjects with cytogenetic confirmation of the chromosomal translocation t(17;19) (Cohort B) b.Cohort C: Infants w/ newly diagnosed KMT2A rearranged B-ALL classified as very high risk by the following criteria: i.Age \< 3 months at diagnosis ii.Age \< 6 months and WBC \> 300,000x109/L at diagnosis or a poor prednisone response in induction iii.MRD positive \> 0.01 (or PCR \> 104) after 2 courses of standard infant ALL therapy.
c.Cohort D: Subjects in a first or greater CNS relapse, prior to therapy with cranial XRT or HSCT for the current relapse
3. Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor tissue.
4. Age 0 to 29 years
5. Adequate organ function defined as:
1. A serum creatinine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL) Age Male Female 0 to \< 2 years 0.6 0.6 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1.0 1.0 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4
≥ 16 years 1.7 1.4
2. Adequate liver function:
i.ALT≤ 5 x ULN; ALT ii.Total bilirubin ≤ 3 x ULN iii.ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to ALL infiltration of the liver.
c.Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and \< Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the physician-investigator.
d.Left Ventricular Shortening Fraction (LVSF) ≥ 28%, or Left Ventricular Ejection Fraction (LVEF) ≥ 45% by echocardiogram. In cases where quanitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualititatively normal ventricular function wll suffice.
6. Adequate performance status defined as Lansky or Karnofsky score ≥ 50
7. Subjects of reproductive potential must agree to use acceptable birth control methods
Exclusion Criteria:
1. For subjects with a CNS relapse, prior cranial XRT or BMT for the current relapse is an exclusion.
2. Active hepatitis B or active hepatitis C.
3. HIV Infection.
4. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
5. Concurrent use of systemic steroids at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
6. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
7. Pregnant or nursing (lactating) women.
8. Uncontrolled active 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：Event-free survival (EFS) · 1 year event-free survival (EFS), where events include no response, relapse, death due to any cause · One year
次要终点：EFS Rate 1；To further evaluate the safety of CART19 in the target patient populations；EFS rate 2；MRD conversion；Relapse Free survival 1；Relapse Free survival 2；Relapse Free survival 3；Relapse Free survival 4
当前复发未接受颅脑放疗（XRT）或骨髓移植（BMT）的患者。
这是一项开放标签、4个队列的II期研究，评估CART19治疗儿童及青年患者的疗效。患者包括低二倍体（队列A）或t(17;19) B-ALL（队列B）、KMT2A重排且极高危的婴儿B-ALL（队列C），以及当前复发未接受颅脑放疗（XRT）或骨髓移植（BMT）的CNS复发患者（队列D）。
This is an open-label, four-cohort, phase 2 study to determine the efficacy of CART19 in pediatric and young adult patientswith hypodiploid (Cohort A) or t(17;19) B-ALL (Cohort B), infants with very high risk KMT2A B-ALL (Cohort C), and in patients with central nervous system (CNS) relapse who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) (Cohort D).
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