中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2100050495
最近更新日期： Date of Last Refreshed on：	2022-05-02 17:23:09
注册时间： Date of Registration：	2021-08-28 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	该研究尚未获得伦理委员会批准，请于批准后再开始纳入参试者，并与我们联系上传批件。自体肿瘤浸润淋巴细胞(TIL)治疗转移/复发的晚期实体瘤单中心、单臂Ib期临床研究
Public title：	Single-center, single-arm phase Ib clinical study of autologous tumor-infiltrating lymphocytes (TIL) in metastatic/recurrent advanced solid tumors
注册题目简写：
English Acronym：
研究课题的正式科学名称：	自体肿瘤浸润淋巴细胞(TIL)治疗转移/复发的晚期实体瘤单中心、单臂Ib期临床研究
Scientific title：	Single-center, single-arm phase Ib clinical study of autologous tumor-infiltrating lymphocytes (TIL) in metastatic/recurrent advanced solid tumors
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：	杨振兴	研究负责人：	李景丰、陈誉
Applicant：	Yang Zhenxing	Study leader：	Li Jingfeng, Chen Yu
申请注册联系人电话： Applicant telephone：	+86 13801896162	研究负责人电话： Study leader's telephone：	+86 13859089836
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：	zhenxing.yang@grit-bio.com	研究负责人电子邮件： Study leader's E-mail：	13859089836@136.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：	上海市张衡路1077号2028室	研究负责人通讯地址：	福建省福州市福马路420号
Applicant address：	1077 Zhangheng Road, Shanghai	Study leader's address：	420 Fuma Road, Fuzhou, Fujian
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：	上海沙砾生物科技有限公司
Applicant's institution：	Shanghai Grit Biotechnology Inc.
研究负责人所在单位：
Affiliation of the Leader：

是否获伦理委员会批准：	否
Approved by ethic committee：	No
伦理委员会批件文号： Approved No. of ethic committee：		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：
Name of the ethic committee：
伦理委员会批准日期： Date of approved by ethic committee：	2013-08-26 00:00:00
伦理委员会联系人：
Contact Name of the ethic committee：
伦理委员会联系地址：
Contact Address of the ethic committee：
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：

福建省肿瘤医院

Primary sponsor：

Fujian Cancer Hospital

研究实施负责（组长）单位地址：

福建省福州市福马路420号

Primary sponsor's address：

420 Fuma Road, Fuzhou, Fujian

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	福建	市(区县)：	福州
Country：	China	Province：	Fujian	City：	Fuzhou
单位(医院)：	福建省肿瘤医院	具体地址：	福马路420号
Institution hospital：	Fujian Cancer Hospital	Address：	420 Fuma Road

经费或物资来源：

上海沙砾生物科技有限公司

Source(s) of funding：

Shanghai Grit Biotechnology Inc.

研究疾病：

晚期实体瘤

Target disease：

Advanced Solid Tumor

研究疾病代码：

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

探索性研究/预试验

Study phase：

0

研究设计：

单臂

Study design：

Single arm

研究目的：

1.主要研究目的：评价GT201 自体肿瘤浸润淋巴细胞(TIL)疗法在转移或复发的晚期实体瘤治疗中的安全性和耐受性。 2.次要研究目的：（1）监测GT201 TIL疗法的药效及药代动力学：回输细胞在患者体内的存续时间、扩增状况以及效应能力；（2）基于RECIST v1.1和iRECIST标准，评价GT201 TIL疗法在转移或复发的晚期实体瘤治疗中的有效性。

Objectives of Study：

1. Main research purpose: to evaluate the safety and tolerability of GT201 autologous tumor-infiltrating lymphocyte (TIL) therapy in the treatment of metastatic or recurrent advanced solid tumors. 2. Secondary research purposes: (1) Monitor the pharmacodynamics and pharmacokinetics of GT201 TIL therapy: the persistence time, expansion status and effector capacity of the reinfused cells in the patient; (2) To evaluate the efficacy of GT201 TIL therapy in the treatment of metastatic or recurrent advanced solid tumors based on RECIST v1.1 and iRECIST criteria.

药物成份或治疗方案详述：

Description for medicine or protocol of treatment in detail：

纳入标准：

1.自愿加入研究，签署知情同意书，愿意而且能够遵守研究方案；
2.年龄18～70周岁（以签署知情同意当日计算）；
3.被诊断为:
（1）经组织病理学或细胞学确诊的肝细胞癌（根据中国肝癌分期（CNLC分期）II-III期，或巴塞罗那临床肝癌（BCLC）分期分类为B/C期），且不适合进行手术或局部治疗者；和经组织病理学确诊的（肝内）胆管细胞；
（2）不可根治性切除的复发或转移性的黑色素瘤（III～IV期）；
（3）其他不可根治性切除的复发/转移性的晚期实体瘤；
4.前序治疗要求：
（1）需经过TACE（肝动脉化疗栓塞术）和系统治疗（靶向或免疫治疗）进展；
（2）需经下方列举的至少二线治疗后，疾病进展：任何用于治疗复发或转移的黑色素瘤的系统化疗（如达卡巴嗪）或辅助化疗结束6个月内疾病进展、靶向药物（如BRAF抑制剂、BRAF+MEK抑制剂联用）、免疫检查点抑制剂（如PD-1单克隆抗体）；
（3）经至少一次前序标准治疗，疾病进展；且目前已无可选择的有效治疗手段（有效治疗手段参考各癌种最新版诊疗指南）；
5.至少有一个未接受过放射治疗的、未接受过其他局部疗法的、可切除的肿瘤病灶（优选浅表淋巴结），且至少能分离出体积≥0.5cm^3的组织块（可单一病灶来源或多个病灶合并）用于制备自体肿瘤浸润淋巴细胞；尽可能微创处理；
6. 肿瘤取样后，还至少有一个符合RECIST v1.1标准定义的可测量病灶，且该病灶没有接受过放疗或其他局部疗法（除非这些疗法早于3个月前发生，且该病灶显示出进展）；
7.东部肿瘤协作组(ECOG)体能状态评分为0或1，且队列1还需满足Child-Pugh肝功能评级为A级（< 7分）；
8.预期生存时间≥12周；
9.重要器官的功能符合下列要求（手术前14天内不允许使用任何血液成分及细胞生长因子治疗）： 
（1）血常规检查：（在检测前14天内未接受细胞因子或输血治疗）绝对中性粒细胞计数（ANC）≥1.5×10^9/L, 淋巴细胞计数（LC）≥0.5×10^9/L, 血小板计数（PLT）≥80×10^9/L, 血红蛋白（Hb）≥ 90g/L；
（2）肝功能检查（队列1按肝转移的要求）： AST、ALT 和碱性磷酸酶 ≤2.5×ULN，总胆红素（TBIL）≤1.5×ULN，但当合并下列情况时，可放宽标准：
1）若确诊肝转移的：AST和/或ALT ≤5×ULN；
2）若经证实肝或骨转移的：碱性磷酸酶≤5×ULN；
3）若确诊Gilbert综合征：总胆红素≤3.0 mg/dL；
（3）肾功能检查：肌酐清除率（CrCL）≥45 mL/min（可采用Cockcroft-Gault公式），或血清肌酐在正常范围内；
（4）凝血功能检查：APTT≤1.5×ULN，同时INR或PT≤1.5×ULN；
（5）心脏彩超检查：左室射血分数（LVEF）≥50%；
（6） 肺功能检查：FEV1≥60%；
10.非手术绝育的育龄期女性，需同意在研究治疗期间和研究治疗期结束后1年内采用至少一种经医学认可的避孕措施（如宫内节育器，避孕药或避孕套）进行避孕；非手术绝育的育龄期女性受试者在细胞回输前的7天内血清HCG检查必须为阴性；
11. 在肿瘤取样前，既往治疗引起的不良反应已经恢复（CTCAE 5.0 ≤1）或能够满足试验方案中规定的检测值（除外2度外周神经病变、脱发、皮肤白斑\激素替代治疗可控的甲状腺功能减退以及胰岛素控制良好的I型糖尿病）；如果在之前的免疫检查点抑制剂疗法中有记录2级以上的腹泻或结肠炎，则需在肿瘤取样前确保6个月的无症状状态（或者经结肠镜评估安全）；
12.在肿瘤取样之前，必须有上一次治疗后疾病进展的影像学记录。

Inclusion criteria

1. Voluntarily join the research, sign the informed consent form, and be willing and able to abide by the research protocol;
2. Aged 18 to 70 years (calculated on the day of signing the informed consent);
3. Diagnosed as:
(1) Hepatocellular carcinoma confirmed by histopathology or cytology (classified as stage II-III according to Chinese liver cancer stage (CNLC stage), or stage B/C according to Barcelona clinical liver cancer (BCLC) stage), and not suitable for surgery or local therapy; and histopathologically confirmed (intrahepatic) bile duct cells;
(2) Unresectable recurrent or metastatic melanoma (stage III-IV);
(3) Other unresectable recurrent/metastatic advanced solid tumors;
4. Pre-treatment requirements:
(1) Progress through TACE (hepatic arterial chemoembolization) and systemic therapy (targeted or immunotherapy);
(2) Disease progression after at least second-line therapy listed below: disease progression within 6 months after the end of any systemic chemotherapy (such as dacarbazine) or adjuvant chemotherapy for the treatment of recurrent or metastatic melanoma, targeted drugs (such as BRAF inhibitors, BRAF+MEK inhibitor combination), immune checkpoint inhibitors (such as PD-1 monoclonal antibodies);
(3) The disease has progressed after at least one pre-sequence standard treatment; and there is no effective treatment option available at present (for effective treatment, please refer to the latest edition of the diagnosis and treatment guidelines for various cancer types);
5. At least one resectable tumor lesion (preferably superficial lymph node) that has not received radiotherapy and other local therapy, and at least a tissue block with a volume of >=0.5cm^3 can be isolated (from a single lesion or a combination of multiple lesions) for the preparation of autologous tumor-infiltrating lymphocytes; minimally invasive treatment is possible;
6. After tumor sampling, there is at least one measurable lesion that meets the definition of RECIST v1.1 criteria, and the lesion has not received radiotherapy or other local therapy (unless these therapies occurred earlier than 3 months ago and the lesion showed progression);
7. The Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1, and cohort 1 also needs to meet the Child-Pugh liver function rating of A (< 7 points);
8. Expected survival time >= 12 weeks;
9. The function of vital organs meets the following requirements (the use of any blood components and cell growth factor therapy is not allowed within 14 days before surgery):
(1) Routine blood test: (without receiving cytokines or blood transfusion within 14 days before the test) absolute neutrophil count (ANC) >= 1.5x10^9/L, lymphocyte count (LC) >= 0.5x10^9/L, platelet count (PLT) >= 80x10^9/L, hemoglobin (Hb) >= 90g/L;
(2) Liver function test (cohort 1 according to the requirements of liver metastasis): AST, ALT and alkaline phosphatase <=2.5xULN, total bilirubin (TBIL) <=1.5xULN, however, the criteria may be relaxed when the following circumstances are combined:
1) If liver metastases are diagnosed: AST and/or ALT <= 5xULN;
2) If confirmed liver or bone metastasis: alkaline phosphatase<=5xULN;
3) If Gilbert syndrome is diagnosed: total bilirubin <= 3.0 mg/dL;
(3) Renal function test: creatinine clearance (CrCL) >= 45 mL/min (Cockcroft-Gault formula can be used), or serum creatinine is within the normal range;
(4) Coagulation function test: APTT <= 1.5xULN, and INR or PT<=1.5xULN;
(5) Cardiac ultrasound examination: left ventricular ejection fraction (LVEF) >= 50%;
(6) Pulmonary function test: FEV1 >= 60%;
10. Non-surgical sterilization females of childbearing age need to agree to use at least one medically approved contraceptive method (such as intrauterine device, contraceptives or condoms) for contraception during the study treatment period and within 1 year after the end of the study treatment period; Non-surgical sterilized female subjects of childbearing age must have a negative serum HCG test within 7 days before cell reinfusion;
11. Before tumor sampling, the adverse reactions caused by previous treatment have recovered (CTCAE 5.0 <= 1) or can meet the detection value specified in the test protocol (Except 2nd degree peripheral neuropathy, alopecia, vitiligo, hypothyroidism controllable by hormone replacement therapy and type I diabetes mellitus with good insulin control); if grade 2 or higher diarrhea or colitis was documented on prior immune checkpoint inhibitor therapy, ensure asymptomatic status for 6 months (or be safe as assessed by colonoscopy) prior to tumor sampling;
12. Prior to tumor sampling, there must be an imaging record of disease progression after the last treatment.

排除标准：

1.肝性脑病或活动性的中枢神经系统（CNS）转移的患者（稳定期脑转移患者，临床判断2周内无需药物治疗，无激素依赖者除外）；
2.手术和/或放疗未能解除脊髓压迫的情况不能入组（经治的患者，手术取样前，临床证据显示症状已经缓解≥1周，可以入组）；
3.由研究者判断的伴有无法控制的肿瘤相关疼痛者。需要止痛药物治疗的受试者必须在进入研究时已经有稳定的止痛治疗方案；适合姑息放疗的症状性病灶应该在进入研究前完成治疗；
4.患有间质性肺炎或筛选时具有临床意义的活动性肺炎，或其他严重影响肺功能的呼吸系统疾病；
5.任何活动性的自身免疫性疾病、自身免疫性疾病史、或需要全身性类固醇激素或免疫抑制药物治疗的疾病（＞10 mg/天的泼尼松或等价激素）；
6.显著临床意义的心血管疾病史者，包括但不局限于：(1) 充血性心衰（NYHA 分级＞2级）；(2) 不稳定性心绞痛；(3) 过去3个月中发生过心肌梗塞； (4) 任何需要治疗或者干预的室上性心律失常或室性心律失常；
7.入组前5个月内发生的动/静脉血栓事件，如脑血管意外、深静脉血栓及肺栓塞等；
8.入组前1年内有活动性肺结核感染者，或超过1年以前有活动性肺结核感染病史但未经正规治疗者；
9.需使用系统抗感染治疗的活动性感染（局部使用抗生素除外）或在筛选期间发生原因不明发热>38.5℃者，肿瘤热除外；
10.有免疫缺陷病史，包括HIV血清检测阳性；
11.活动性乙肝或丙肝患者。HBsAg或HBcAb阳性患者如果HBV DNA检测小于所在研究中心检测正常值下限可参与本研究。HCV抗体阳性患者如果HCV RNA检测小于所在研究中心检测正常值下限可参与本研究。携带者参加研究，需酌情安排抗病毒治疗，并在研究期间定期复查进行核酸拷贝数定量检测；
12.存在难治性或顽固性癫痫、药物不能控制的腹水、门静脉癌栓、胃底或食管静脉曲张致消化道出血、门脉高压致出血风险增高、活动性消化道出血等情形；
13.入组前4周内使用减毒活疫苗，或预计研究期间需要使用减毒活疫苗；
14.入组前四周内使用长半衰期的抗血管生成药物，如VEGF贝伐珠单抗；
15.既往接受过同种异体骨髓移植或实体器官移植的患者;
16.对研究中拟使用药物（包括但不限于自体肿瘤浸润淋巴细胞、环磷酰胺、氟达拉滨、白细胞介素-2，二甲基亚砜（DMSO），人血清白蛋白(HSA)，右旋糖酐-40（dextran-40），抗生素（β-内酰胺类抗生素，庆大霉素））的任何成分有过敏反应病史;
17.已知有精神疾病、酗酒、吸毒或药物滥用等情况；
18.任何可导致产生合理怀疑以至禁止使用试验药物、或影响研究结果解读、或使患者处于高风险的治疗并发症的疾病或病症（任何其它疾病、代谢功能紊乱、体检结果或实验室检查异常结果）；
19.哺乳期妇女；
20.其他研究者评估可能影响受试者安全性的情况。

Exclusion criteria：

1. Patients with hepatic encephalopathy or active central nervous system (CNS) metastasis (patients with stable brain metastasis, no need for drug treatment within 2 weeks according to clinical judgment, except for those without hormone dependence);
2. Surgery and/or radiotherapy fails to relieve spinal cord compression and cannot be included in the group (patients who have been treated can be enrolled if clinical evidence shows that their symptoms have been relieved for >=1 week before surgical sampling);
3. Patients with uncontrolled tumor-related pain as judged by the investigator. patients requiring analgesic medication must have a stable analgesic regimen at the time of entry into the study; symptomatic lesions suitable for palliative radiotherapy should be treated prior to entry into the study;
4. Suffering from interstitial pneumonia or clinically significant active pneumonia at the time of screening, or other respiratory diseases that seriously affect lung function;
5. Any active autoimmune disease, history of autoimmune disease, or disease requiring systemic steroid hormones or immunosuppressive drugs (>10 mg/day of prednisone or equivalent hormones);
6. History of significant clinically significant cardiovascular disease, including but not limited to: (1) congestive heart failure (NYHA class>2); (2) unstable angina; (3) myocardial infarction occurred in the past 3 months; (4) any supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention;
7. Arterial/venous thrombotic events that occurred within 5 months before enrollment, such as cerebrovascular accident, deep vein thrombosis and pulmonary embolism;
8. Those who have active pulmonary tuberculosis infection within 1 year before enrollment, or those who have a history of active pulmonary tuberculosis infection more than 1 year ago but have not received regular treatment;
9. Active infection requiring systemic anti-infective treatment (except topical antibiotics) or unexplained fever >38.5℃ during screening, except tumor fever;
10. A history of immunodeficiency, including HIV seropositive;
11. Active hepatitis B or C patients. HBsAg or HBcAb positive patients can participate in this study if the HBV DNA test is less than the lower limit of the normal value in the research center. HCV antibody-positive patients can participate in this study if the HCV RNA detection is less than the lower limit of the normal value detected by the research center. Carriers participating in the study should arrange antiviral treatment as appropriate, and conduct regular review during the study period for quantitative nucleic acid copy number detection;
12. Refractory or intractable epilepsy, ascites that cannot be controlled by drugs, portal vein tumor thrombus, gastrointestinal bleeding caused by fundus or esophageal varices, increased risk of bleeding caused by portal hypertension, active gastrointestinal bleeding, etc.;
13. Use of live attenuated vaccines within 4 weeks before enrollment, or use of live attenuated vaccines during the study period;
14. Use anti-angiogenic drugs with long half-life, such as VEGF bevacizumab, within four weeks before enrollment;
15. Patients who have received allogeneic bone marrow transplantation or solid organ transplantation in the past;
16. History of allergic reaction to any component of the drug to be used in the study (including but not limited to autologous tumor-infiltrating lymphocytes, cyclophosphamide, fludarabine, interleukin-2, dimethyl sulfoxide (DMSO), human serum albumin (HSA), dextran-40 (dextran-40), antibiotics (beta-lactam antibiotics, gentamicin));
17. Known mental illness, alcoholism, drug use or drug abuse;
18. Any disease or condition that may lead to a reasonable suspicion that prohibits the use of an investigational drug, or affects the interpretation of study results, or puts patients at high risk for treatment complications (any other disease, metabolic disorder, physical examination result or abnormal laboratory test result);
19. Lactating patients;
20. Other investigators evaluate situations that may affect the safety of the patient.

研究实施时间：

Study execute time：

从 From 2021-10-01 00:00:00至 To 2024-10-01 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2021-10-01 00:00:00 至 To 2023-10-01 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	30
Group：	Experimental group	Sample size：	30
干预措施：	回输自体肿瘤浸润淋巴细胞(TIL)	干预措施代码：
Intervention：	Infusion of autologous tumor-infiltrating lymphocytes (TILs)	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	福建	市(区县)：	福州
Country：	China	Province：	Fujian	City：	Fuzhou
单位(医院)：	福建省肿瘤医院	单位级别：	三甲
Institution hospital：	Fujian Cancer Hospital	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	安全性和耐受性	指标类型：	主要指标
Outcome：	safety and tolerance	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	客观缓解率	指标类型：	主要指标
Outcome：	objective response rate	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	疾病控制率	指标类型：	主要指标
Outcome：	disease control rate	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	无进展生存期	指标类型：	主要指标
Outcome：	progression-free survival	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	响应期	指标类型：	主要指标
Outcome：	response period	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	总生存期	指标类型：	主要指标
Outcome：	overall survival	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：

标本中文名：	肿瘤组织	组织：
Sample Name：	tumor tissue	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：

正在进行

Recruiting

年龄范围：

Participant age：

最小 Min age	18	岁 years
最大 Max age	70	岁 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）：

非随机

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

Non-randomization.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：	N/A
Blinding：	N/A
试验完成后的统计结果（上传文件）：	点击下载
Calculated Results after the Study Completed(upload file)：	download

是否共享原始数据： IPD sharing	否No
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）：	未说明请阅读网页注册指南中关于“原始数据共享”的内容。
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	Not stated
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：	病例报告表
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	CRF
数据与安全监察委员会： Data and Safety Monitoring Committee：	暂未确定/Not yet
注册人： Name of Registration：	2021-08-28 12:19:08