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人源化抗CD19 CAR-T治疗难治性、侵袭性非霍奇金淋巴瘤的安全性和有效性临床研究
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注册号:

Registration number:

ChiCTR1900022622 

最近更新日期:

Date of Last Refreshed on:

2019-04-19 

注册时间:

Date of Registration:

2019-04-19 

注册号状态:

预注册  

Registration Status:

Prospective registration  

注册题目:

人源化抗CD19 CAR-T治疗难治性、侵袭性非霍奇金淋巴瘤的安全性和有效性临床研究 

Public title:

hCD19 targeted Chimeric Antigen Receptor T Cells (CART) Therapy in Refractory/Relapsed non-Hodgkin's lymphoma  

注册题目简写:

 

English Acronym:

 

研究课题的正式科学名称:

人源化抗CD19 CAR-T治疗难治性、侵袭性非霍奇金淋巴瘤的安全性和有效性临床研究 

Scientific title:

hCD19 targeted Chimeric Antigen Receptor T Cells (CART) Therapy in Refractory/Relapsed non-Hodgkin's lymphoma  

研究课题代号(代码):

Study subject ID:

 

在二级注册机构或其它机构的注册号:

The registration number of the Partner Registry or other register:

 

申请注册联系人:

林敏 

研究负责人:

邹立群 

Applicant:

Min Lin 

Study leader:

Liqun Zou 

申请注册联系人电话:

Applicant telephone:

+86 15618108082 

研究负责人电话:

Study leader's telephone:

+86 13980585788 

申请注册联系人传真 :

Applicant Fax:

 

研究负责人传真:

Study leader's fax:

 

申请注册联系人电子邮件:

Applicant E-mail:

linmin@sidansai.com 

研究负责人电子邮件:

Study leader's E-mail:

linmin@sidansai.com 

申请单位网址(自愿提供):

Applicant website(voluntary supply):

 

研究负责人网址(自愿提供):

Study leader's website(voluntary supply):

 

申请注册联系人通讯地址:

上海市浦东新区张江高科哈雷路998号4号楼201 

研究负责人通讯地址:

成都市武侯区国学巷37号 

Applicant address:

Room 201, 4th Building, 998 Halei Road, Zhangjing Hi-tech park, Shanghai, China 

Study leader's address:

37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China 

申请注册联系人邮政编码:

Applicant postcode:

 

研究负责人邮政编码:

Study leader's postcode:

 

申请人所在单位:

上海斯丹赛生物技术有限公司 

Applicant's institution:

Innovative Cellular Therapeutics Co.,Ltd. 

是否获伦理委员会批准:

是 

Approved by ethic committee:

Yes 

伦理委员会批件文号:

Approved No. of ethic committee:

2018年审(89)号 

伦理委员会批件附件:

Approved file of Ethical Committee:

批准本研究的伦理委员会名称:

四川大学华西医院生物医学伦理分委会 

Name of the ethic committee:

West China Hospital of Sichuan University Medical Science Research Ethics Committee  

伦理委员会批准日期:

Date of approved by ethic committee:

2018-05-30 

伦理委员会联系人:

孙荣国 

Contact Name of the ethic committee:

Sun Rongguo 

伦理委员会联系地址:

中国四川省成都市武侯区国学巷37号四川大学华西医院老八教412室 

Contact Address of the ethic committee:

Room 412, Old 8th Teaching Building, West China Hospital, Sichuan University, 37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China  

伦理委员会联系人电话:

Contact phone of the ethic committee:

 

伦理委员会联系人邮箱:

Contact email of the ethic committee:

 

研究实施负责(组长)单位:

四川大学华西医院 

Primary sponsor:

West China Hospital, Sichuan University 

研究实施负责(组长)单位地址:

成都市武侯区国学巷37号 

Primary sponsor's address:

37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China 

试验主办单位(项目批准或申办者):

Secondary sponsor:

国家:

中国

省(直辖市):

四川省

市(区县):

成都市

Country:

China

Province:

Sichuan

City:

Chengdu

单位(医院):

四川大学华西医院

具体地址:

成都市武侯区国学巷37号

Institution
hospital:

West China Hospital, Sichuan University

Address:

37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China

经费或物资来源:

上海斯丹赛生物技术有限公司 

Source(s) of funding:

Innovative Cellular Therapeutics Co.,Ltd.  

研究疾病:

难治性、侵袭性非霍奇金淋巴瘤 

Target disease:

Refractory Aggressive Non-Hodgkin Lymphoma (NHL)  

研究疾病代码:

 

Target disease code:

 

研究类型:

观察性研究 

Study type:

Observational study 

研究所处阶段:

I期临床试验 

Study phase:

研究目的:

研究的主要目的是通过NHL受试者的客观缓解率测定评价CART的疗效。次要目的包括评估CART的安全性和耐受性以及其他疗效终点。 

Objectives of Study:

The primary objective of phase 1 is to evaluate the safety of CART regimens. The primary objective of phase 2 is to evaluate the efficacy of CART, as measured by objective response rate in subjects with NHL. Secondary objectives will include assessing the safety and tolerability of CD19CART and additional efficacy endpoints. 

药物成份或治疗方案详述:

 

Description for medicine or protocol of treatment in detail:

 

研究设计:

单臂 

Study design:

Single arm 

纳入标准:

1. 组织学证实的侵袭性B细胞NHL,包括WHO 2008定义的如下类型: o DLBCL;T细胞/富含组织细胞的大B细胞淋巴瘤;慢性炎症相关DLBCL;埃-巴尔二氏病毒(EBV)阳性的DLBCL老年人; 2. 将化疗复发性疾病定义为存在下列任何一种情形: o 对一线治疗无应答(原发性难治性疾病);但排除无法耐受一线化疗的受试者 ? 对一线治疗的最佳应答为PD ? 至少4个周期一线治疗后的最佳应答为SD(例如,4个周期的R-CHOP),SD持续时间从末次治疗用药开始不超过6个月 或 o 对二线或以后的治疗线无应答 ? 对最近治疗方案的最佳应答为PD ? 至少2个周期最后线治疗后的最佳应答为SD,SD持续时间从末次治疗用药开始不超过6个月 或 o 自体干细胞移植后难治 ? 自体干细胞移植后≤12个月,疾病进展或者复发(复发的受试者中必须进行活检证明复发) ? 如果自体干细胞移植后进行了挽救治疗,受试者必须对最后线治疗无应答或者治疗后出现复发 3. 受试者必须接受了包括至少以下治疗的充分既往治疗: o 抗CD20单克隆抗体,除非研究者确定肿瘤为CD20阴性,以及 o 包含蒽环类抗生素的化疗方案; 4. 根据修订版IWG恶性淋巴瘤疗效评价标准,至少存在1个可测量病变(Cheson 2007)。除非完成放射治疗后观察到病变进展,之前进行过照射的病变将视为可测量病变。 5. 脑部MRI未显示有CNS淋巴瘤的证据 6. 受试者计划进行白细胞去除术时,距离任何既往全身治疗须至少经过2周或5个半衰期,以较短者为准,全身抑制/刺激性免疫检查点疗法除外。受试者计划进行白细胞去除术时,距离任何既往全身抑制/刺激性免疫检查点分子治疗须至少经过3个半衰期(如,伊匹木单抗、nivolumab、pembrolizumab、atezolizumab、OX40激动剂、4-1BB激动剂等)。 7. 既往治疗产生的毒性必须稳定,并恢复至≤1级(无临床意义的毒性除外,如脱发) 8. 年龄为18岁以上65岁以下 9. 东部肿瘤协作组(ECOG)体能状态评分为0或1分 10. 中性粒细胞绝对计数≥ 1×109/L 11. 血小板计数≥75×109/L 12. 绝对淋巴细胞计数 ≥ 100/ uL 13. 肾脏、肝脏、肺和心脏功能充足,定义如下: o 肌酐清除率(按Cockcroft Gault法估计)≥60 mL/min o 血清ALT/AST ≤正常上限2.5倍 o 总胆红素 ≤正常上限1.5倍,吉尔伯特病的患者的受试者除外。 o 心脏射血分数≥50%,超声心动图检查确认未见心包积液,未见有临床意义的心电图发现 o 不存在有临床意义的胸腔积液 o 在室内时基线血氧饱和度>92% 14. 有生育能力的女性的血清或尿液妊娠试验必须为阴性(接受了绝育术或绝经后至少2年的女性可认定为不具有生育能力)  

Inclusion criteria

1. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008: (1) DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; OR (2) primary mediastinal (thymic) large B cell lymphoma; (3) transformation of follicular lymphoma to DLBCL will also be included; 2. Chemotherapy-refractory disease, defined as one or more of the following: (1) No response to first-line therapy (primary refractory disease); subjects who are intolerant to first-line therapy chemotherapy are excluded; (2) PD as best response to first-line therapy; (3) SD as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R- CHOP) with SD duration no longer than 6 months from last dose of therapy; OR (4) No response to second or greater lines of therapy; (5) PD as best response to most recent therapy regimen; (6) SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy; OR (7) Refractory post-ASCT; (8) Disease progression or relapsed ≤12 months of ASCT (must have biopsy proven recurrence in relapsed subjects); (9) if salvage therapy is given post-ASCT, the subject must have had no response to or relapsed after the last line of therapy; 3. Subjects must have received adequate prior therapy including at a minimum: (1) anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and (2) an anthracycline containing chemotherapy regimen; (3) for subjects with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL; 4. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy; 5. MRI of the brain showing no evidence of CNS lymphoma; 6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc); 7. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia); 8. Aged 18 years or older; 9. Eastern cooperative oncology group (ECOG) performance status of 0 or 1; 10. ANC ≥1000/uL; 11. Platelet count ≥75,000/uL; 12. Absolute lymphocyte count ≥100/uL; 13. Adequate renal, hepatic, pulmonary and cardiac function defined as: (1) Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min; (2) Serum ALT/AST ≤2.5 ULN; (3) Total bilirubin ≤1.5 mg/dl, except in subjects with Gilberts syndrome; (4) Cardiac ejection fraction ≥ 50% ,no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings; (5) No clinically significant pleural effusion; (6) Baseline oxygen saturation >92% on room air; 14. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). 

排除标准:

1. 具有除黑素瘤皮肤癌或原位癌(如,宫颈、膀胱、乳腺)或滤泡淋巴瘤外的恶性肿瘤病史,但至少3年未发的病者除外 2. 有Richter转换的慢性淋巴细胞白血病病史 3. 计划在CD19CART输注的6周内进行自体干细胞移植 4. 有异体基因干细胞移植史 5. 既往接受过CD19靶向治疗,但在本研究中接受CD19CART并符合再次治疗标准的受试者除外 6. 既往接受过嵌合抗原受体治疗或其他转基因T细胞治疗 7. 有氨基糖苷类的重度超敏反应史 8. 存在不可控制或需要IV抗菌剂治疗管理的真菌、细菌、病毒或其他感染。如果对活性治疗有应答,在咨询医学监查员后,允许存在单纯的尿路感染和无并发症的细菌性咽炎 9. 已知存在HIV或乙型肝炎(HBsAg阳性)或丙型肝炎病毒(抗HCV阳性)感染病史。如果通过定量PCR和/或核酸试验无法检测到病毒载量,则允许存在经过治疗的乙型肝炎或丙型肝炎病史。 10. 存在任何留置导管或引流管(如,经皮肾造口管、留置弗利氏导尿管、胆汁引流管或胸膜/腹膜/心包导管)。允许使用专用中心静脉导管,如植入式静脉给药系统或Hickman导管 11. 可检测到脑脊液恶性细胞或脑转移,或具有CNS淋巴瘤、脑脊液恶性细胞或脑转移病史的受试者 12. 存在CNS病史或疾病,如癫痫发作疾病、脑血管缺血/出血、痴呆、小脑疾病,或任何涉及CNS的自身免疫性疾病 13. 有心房或心室淋巴瘤受累的受试者 14. 入组的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具有临床意义的心脏疾病病史 15. 因肿瘤肿块的影响,需要紧急治疗,如肠梗阻或血管压迫 16. 存在重大免疫缺陷 17. 入组6个月内存在深静脉血栓或肺栓塞病史 18. 有任何可能对研究治疗的安全性或疗效评估产生干扰的疾病 19. 对本研究中的任何药物具有重度超敏反应病史 20. 开始预处理治疗方案前≤6周内注射活疫苗 21. 任何妊娠或正在哺乳中有生育能力的女性。接受了绝育术或绝经后至少2年的女性可认为不具有生育能力 22. 自签署同意书起至完成CD19CART给药后6个月不愿意采取节育措施的男性及女性受试者。 23. 根据研究者的判断,受试者不太可能完成所有方案要求的研究访视或程序,包括随访访视或依从参与研究的要求。 24. 过去2年内存在导致末端器官损伤或需要全身免疫抑制/全身疾病调节药物的自身免疫性疾病(如,克罗恩氏病、类风湿性关节炎、系统性红斑狼疮)病史 

Exclusion criteria:

1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years; 2. History of Richters transformation of CLL; 3. Autologous stem cell transplant within 6 weeks of planned CAR-C19 infusion; 4. History of allogeneic stem cell transplantation; 5. Prior CD19 targeted therapy with the exception of subjects who received CAR-C19 in this study and are eligible for re-treatment; 6. Prior chimeric antigen receptor therapy or other genetically modified T cell therapy; 7. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides; 8. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the K Medical Monitor; 9. Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti- HCV positive). A history of treated hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing; 10. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted; 11. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases; 12. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement; 13. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement; 14. History of myocardial infarction, cardiac angioplasty or stentin, unstable angina, or other clinically; significant cardiac disease within 12 months of enrollment; 15. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression; 16. Primary immunodeficiency; 17. History of deep vein thrombosis or pulmonary embolism within 6 months of enrollment; 18. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment; 19. History of severe immediate hypersensitivity reaction to any of the agents used in this study; 20. Live vaccine ≤ 6 weeks prior to start of conditioning regimen; 21. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential; 22. Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of CAR-C19; 23. In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation; 24. History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.  

研究实施时间:

Study execute time:

From2019-04-18To 2024-04-17 

干预措施:

Interventions:

组别:

Case series

样本量:

5

Group:

Case series

Sample size:

干预措施:

CART细胞

干预措施代码:

Intervention:

CART cells

Intervention code:

研究实施地点:

Countries of recruitment and research settings:

国家:

中国 

省(直辖市):

四川省 

市(区县):

成都市 

Country:

China 

Province:

Sichuan Province 

City:

Chengdu 

单位(医院):

四川大学华西医院 

单位级别:

三甲 

Institution
hospital:

West China Hospital,Sichuan University  

Level of the institution:

Tertiary A Hospital 

测量指标:

Outcomes:

指标中文名:

PET CT

指标类型:

主要指标 

Outcome:

PET CT

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

采集人体标本:

Collecting sample(s)
from participants:

标本中文名:

血液

组织:

Sample Name:

blood

Tissue:

人体标本去向

使用后销毁 

说明

Fate of sample:

Destruction after use 

Note:

征募研究对象情况:

Recruiting status:

尚未开始

Not yet recruiting

年龄范围:

Participant age:

最小 Min age 18 years
最大 Max age 65 years

性别:

男女均可

Gender:

Both

随机方法(请说明由何人用什么方法产生随机序列):

N/A

Randomization Procedure (please state who generates the random number sequence and by what method):

N/A

盲法:

N/A

Blinding:

N/A

原始数据公开时间:

The time of sharing IPD:

试验完成后6个月内公开/Within six months after the trial complete

共享原始数据的方式(说明:请填入公开原始数据日期和方式,如采用网络平台,需填该网络平台名称和网址):

上海斯丹赛生物技术有限公司官网,www.ictbio.com; ResMan

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url):

www.ictbio.com,Within six months after the trial complete; ResMan

数据采集和管理(说明:数据采集和管理由两部分组成,一为病例记录表(Case Record Form, CRF),二为电子采集和管理系统(Electronic Data Capture, EDC),如ResMan即为一种基于互联网的EDC:

EDC

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture:

EDC

数据管理委员会:

Data Managemen Committee:

无/No

注册人:

Name of Registration:

 2019-04-19
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