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注册号： Registration number：	ChiCTR-OIC-17013249
最近更新日期： Date of Last Refreshed on：	2017-11-05 12:39:58
注册时间： Date of Registration：	2017-11-05 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	PD-1抗体SHR-1210治疗微卫星高度不稳定（MSI-H）晚期实体瘤的单臂单中心开放性临床研究
Public title：	A single arm and single center open clinical study of PD-1 antibody SHR-1210 in the microsatellite highly unstable (MSI-H) advanced solid tumor
注册题目简写：
English Acronym：
研究课题的正式科学名称：	PD-1抗体SHR-1210治疗微卫星高度不稳定（MSI-H）晚期实体瘤的单臂单中心开放性临床研究
Scientific title：	A single arm and single center open clinical study of PD-1 antibody SHR-1210 in the microsatellite highly unstable (MSI-H) advanced solid tumor
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：	高勇	研究负责人：	高勇
Applicant：	Yong Gao	Study leader：	Yong Gao
申请注册联系人电话： Applicant telephone：	+86 17717372156	研究负责人电话： Study leader's telephone：	+86 13310167477
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：	nade@163.com	研究负责人电子邮件： Study leader's E-mail：	drgaoyong@163.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：	上海浦东新区即墨路150号上海东方医院十楼西肿瘤科	研究负责人通讯地址：	上海浦东新区即墨路150号上海东方医院十楼西肿瘤科
Applicant address：	150 JiMo Road, Pudong New Area, Shanghai, China	Study leader's address：	150 JiMo Road, Pudong New Area, Shanghai, 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：	上海市东方医院
Applicant's institution：	Shanghai East Hospital
研究负责人所在单位：	上海市东方医院
Affiliation of the Leader：	Shanghai East Hospital

是否获伦理委员会批准：	是/Yes
Approved by ethic committee：	Yes
伦理委员会批件文号： Approved No. of ethic committee：	2017-027	伦理委员会批件附件： Approved file of Ethical Committee：	查看附件View
批准本研究的伦理委员会名称：	上海市东方医院药物临床试验伦理委员会
Name of the ethic committee：	Shanghai East Hospital Medical Ethics Committee
伦理委员会批准日期： Date of approved by ethic committee：	2017-09-14 00:00:00
伦理委员会联系人：	鲍思蔚
Contact Name of the ethic committee：	Siwei Bao
伦理委员会联系地址：	上海浦东新区即墨路150号上海东方医院
Contact Address of the ethic committee：	150 JiMo Road, Pudong New Area, Shanghai, China
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 021-38804518-22198	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：

上海东方医院

Primary sponsor：

Shanghai East Hospital

研究实施负责（组长）单位地址：

上海浦东新区即墨路150号上海东方医院十楼西肿瘤科

Primary sponsor's address：

150 JiMo Road, Pudong New Area, Shanghai, 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)：	上海	市(区县)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	上海市东方医院	具体地址：	上海浦东新区即墨路150号上海东方医院
Institution hospital：	Shanghai East Hospital	Address：	150 JiMo Road, Pudong New Area, Shanghai

经费或物资来源：

科室经费

Source(s) of funding：

Expenditure of department

Target disease：

the microsatellite highly unstable (msi-h) advanced solid tumor

Target disease code：

研究类型：

观察性研究

Study type：

Observational study

研究所处阶段：

II期临床试验

Study phase：

2

研究设计：

单臂

Study design：

Single arm

研究目的：

主要研究目的：评价SHR-1210治疗MSI-H晚期实体瘤的有效性（ORR、PFS、mOS）。次要研究目的：评价SHR-1210的安全性。探索性研究目的： 1. 评价SHR-1210疗效与肿瘤组织MSI-H和PD-L1之间的关系。 2. 采用测序技术评价肿瘤组织MSI-H与SHR-1210疗效之间的关系，建立疗效预测模型。

Objectives of Study：

Main objective: to evaluate the efficacy of SHR-1210 in treatment of msi-h advanced solid tumor (ORR, PFS, mOS). Secondary research objective: to evaluate the safety of SHR-1210. Exploratory research purpose: 1. Evaluation of the effect of SHR-1210 and the relationship between the tumor tissue MSI-H and PD-L1. 2. Use sequencing technology to evaluate the relationship between tumor tissue MSI-H and SHR-1210 efficacy, and establish a model of efficacy prediction.

药物成份或治疗方案详述：

给药方法为SHR-1210 200mg/次，每周期第1天给药，每2周为一个给药周期，给药至确证的疾病进展、毒性不可耐受、受试者主动要求退出或研究者判断受试者需要退出研究。

Description for medicine or protocol of treatment in detail：

Dosing method of SHR - 1210 is 200 mg every time at day 1 of each cycle, every 2 weeks for a cycle, dosing untill the disease progression or not tolerance of toxicity or subjects volunteered to exit or researchers determine subjects need to exit.

纳入标准：

1. 年龄≥18岁且≤75岁，男女均可；
2. 经组织学或细胞学确诊的恶性实体肿瘤，且局部晚期不可切除或伴远处转移；且经第三方进行肿瘤组织检测证实具有MSI-H或dMMR。
3. 接受一线系统化疗（方案为相应肿瘤标准一线化疗）或根治性同步放化疗（可以包含以铂类或紫衫类为基础）治疗失败的患者。治疗失败的定义：接受一线系统化疗或根治性同步放化疗治疗期间或治疗后疾病进展，必须有影像学证据或临床证据（如新发恶性胸腹水）证明疾病进展。对于新辅助/辅助治疗（化疗或放化疗），如果在治疗期间或停止治疗后6个月内发生疾病进展，应将其算作一线治疗失败；
4. 根据实体瘤疗效评价标准（RECIST1.1），至少具有一个可测量病灶，可测量病灶应未接受过放疗等局部治疗（位于既往放疗区域内的靶病灶，如果证实发生进展，并符合RECIST1.1标准，也可选做靶病灶。）；
5. 须提供组织样品进行分子病理分析，优选新近取得的组织，无法提供新近取得组织的患者可提供存档保存的5um厚的石蜡切片10张；
6. ECOG：0～1；
7. 预期生存期≥12周；
患者必须满足以下所有入选标准才可入组本研究：
1. 年龄≥18岁且≤75岁，男女均可；
2. 经组织学或细胞学确诊的恶性实体肿瘤，且局部晚期不可切除或伴远处转移；且经第三方进行肿瘤组织检测证实具有MSI-H或dMMR。
3. 接受一线系统化疗（方案为相应肿瘤标准一线化疗）或根治性同步放化疗（可以包含以铂类或紫衫类为基础）治疗失败的患者。治疗失败的定义：接受一线系统化疗或根治性同步放化疗治疗期间或治疗后疾病进展，必须有影像学证据或临床证据（如新发恶性胸腹水）证明疾病进展。对于新辅助/辅助治疗（化疗或放化疗），如果在治疗期间或停止治疗后6个月内发生疾病进展，应将其算作一线治疗失败；
4. 根据实体瘤疗效评价标准（RECIST1.1），至少具有一个可测量病灶，可测量病灶应未接受过放疗等局部治疗（位于既往放疗区域内的靶病灶，如果证实发生进展，并符合RECIST1.1标准，也可选做靶病灶。）；
5. 须提供组织样品进行分子病理分析，优选新近取得的组织，无法提供新近取得组织的患者可提供存档保存的5um厚的石蜡切片10张；
6. ECOG：0～1；
7. 预期生存期≥12周；
8. 重要器官的功能符合下列要求（开始研究治疗前2周不允许使用任何血液成分及细胞生长因子）：
a. 中性粒细胞绝对计数（ANC）≥1.5×109/L
b. 血小板≥75×109/L；
c. 血红蛋白≥9g/dL；
d. 血清白蛋白≥2.8g/dL；
e. 胆红素≤1.5倍ULN，ALT和AST≤2.5倍ULN；如存在肝脏转移，则ALT和AST≤5倍ULN；
f. 肌酐清除率≥50mL/min；
9. 具有生育能力的女性受试者应在接受首次研究药物给药之前的72小时内进行尿液或血清妊娠试验，并证明为阴性，并且愿意在试验期间至末次给予SHR-1210后3个月内采用有效方法避孕。对于伴侣为育龄妇女的男性受试者，应在试验期间和末次给予SHR-1210后3个月内采用有效方法避孕；
10. 受试者自愿加入本研究，签署知情同意书，依从性好，配合随访。

Inclusion criteria

1. Aged 18 to 75 years old, male or female;
2. A malignant solid tumor diagnosed by histology or cytology, with a partial advanced stage can not resection or metastasis; And the detection of tumor tissue by a third party confirmed MSI-H or dMMR;
3. Treatment of failed patients with first-line system chemotherapy (with the treatment of first-line chemotherapy for tumor standard) or radical concurrent chemoradiotherapy (which can contain platinum-type or purple unlined upper class).Definition of treatment failure: accept a wire system during chemotherapy or radical chemoradiation therapy or disease progression after treatment, there must be a radiographic evidence or clinical evidence (such as new hair malignant chest water) prove that disease progression.For neoadjuvant/adjuvant therapy (chemotherapy or radiotherapy), if the disease progresses within 6 months after treatment or cessation of treatment, it should be considered a first-line treatment failure;
4. According to therapeutic effect evaluation standard of solid tumor (RECIST1.1), with at least one measurable lesions, measurable lesions should be not received radiotherapy, etc, in the usual radiation area of the target lesions, if confirm progress, and meet RECIST1.1 standard, can also be selected as a target lesions);
5. Tissue samples should be provided for molecular pathologic analysis, choose the newly acquired organization. if newly acquired tissue could not be provided, the patients could provide the acquired tissue with 10 sheets of paraffin sections that were preserved in the archive;
6. ECOG 0-1;
7. The expected survival period is greater than 12 weeks;
8. The function of vital organs meets the following requirements (no blood ingredients and cell growth factors are allowed to be used for the first 2 weeks of treatment):
The neutrophil absolute count (ANC) ≥1.5 x 10^9/L;
Platelets ≥ 75 x 10^9/L;
Hemoglobin ≥ 9g/dL;
Serum albumin ≥2.8g/dL;
Bilirubin is less than or equal to 1.5 times ULN, ALT and AST are less than or equal to 2.5 times ULN; If there is a liver metastasis, ALT and AST are less than or equal to 5 times ULN;
Creatinine clearance rate ≥ 50mL/min;
9. Women with fertility should be carried out within 72 hours of urine or serum pregnancy test before accepting first study drug dosage, and prove to negative, and willing to use effective methods of contraception to the last dose of SHR - 1210 after three months during the study. For male subjects with a partner of childbearing age, effective method of contraception should be adopted during the study and within three months of the last dose of SHR-1210.

排除标准：

具有以下任何一项的患者不能入组本研究
1. 首次使用研究药物前5年内已诊断为其他恶性肿瘤，除外经有效治疗的皮肤基底细胞癌、皮肤鳞状细胞癌和/或经有效切除的原位宫颈癌和/或乳腺癌；
2. 有中枢神经系统转移；
3. 患有任何活动性自身免疫病或有自身免疫病病史（如间质性肺炎、葡萄膜炎、肠炎、肝炎、垂体炎、血管炎、心肌炎、肾炎、甲状腺功能亢进、甲状腺功能降低（激素替代治疗正常后可纳入））；患有白癜风或在童年期哮喘已完全缓解且成人后无需任何干预可纳入，需要支气管扩张剂进行医学干预的哮喘患者则不可纳入；
4. 患有未能控制的心脏临床症状或疾病，如：（1）NYHA II级以上心力衰竭（2）不稳定型心绞痛（3）1年内发生过心肌梗死（4）有临床意义的室上性或室性心律失常需要临床干预的患者；
5. 有活动性感染或在筛选期间、首次给药前发生原因不明发热＞38.5℃（经研究者判断，受试者因肿瘤产生的发热可以入组）；
6. 已知有间质性肺病或活动性非感染性肺炎病史或证据；
7. 患有先天或后天免疫功能缺陷（如HIV感染者）、活动性乙肝（HBV-DNA≥104拷贝数/ml）或丙肝（丙肝抗体阳性，且HCV-RNA高于分析方法的参考值）；
8. 既往曾接受过其他PD-1抗体治疗或其他针对PD-1/PD-L1的免疫治疗；
9. 已知对大分子蛋白制剂，或对任何SHR-1210成分过敏；
10. 首次使用研究药物前14天内，要求使用皮质类固醇（＞10mg/天泼尼松疗效剂量）或其他免疫抑制剂进行系统治疗的受试者。在没有活动性自身免疫疾病的情况下，允许吸入或局部使用类固醇和剂量＞10mg/天泼尼松疗效剂量的肾上腺皮质激素替代；
11. 首次使用研究药物前4周内接受过抗肿瘤单克隆抗体（mAb）、化疗、靶向小分子治疗或放疗，或者之前接受的药物所引起的不良事件尚未恢复（即≤1级或达到基线水平）。注：发生≤2级神经病变或≤2级脱发的受试者除外，如果受试者接受过重大手术，则在开始治疗之前其手术干预所造成的毒性反应和/或并发症必须充分恢复。
12. 首次使用研究药物前4周内（已进入随访期的受试者以末次使用试验性药物或器械时间计算）或正在参加其他临床研究；
13. 首次使用研究药物前4周内接种过活疫苗，允许接受针对季节性流感，注射用药的灭活病毒疫苗，但是不允许接受经鼻使用药的减毒活流感疫苗；
14. 妊娠期或哺乳期妇女；
15. 经研究者判断，受试者有其他可能导致其被迫中途终止研究的因素，如患有其他严重疾病（含精神疾病）需要合并治疗，实验室检查值严重异常，家庭或社会因素，可能影响到受试者安全或试验资料收集的情况。

Exclusion criteria：

Patients with any of the following cannot be enrolled in the study:
1. subjects has been diagnosed as other malignant tumor five years before first use of the study drug, except for the effective treatment of basal cell carcinoma, squamous cell carcinoma of the skin and/or the effective removal of cervical cancer in situ and/or breast cancer;
2. CNS metastases;
3. subjects have a history of any active autoimmune disease or autoimmune disease(e.g., interstitial pneumonia, uveitis, enteritis, hepatitis, the pituitary gland inflammation, vasculitis, myocarditis, nephritis, thyroid function, thyroid function decrease (hormone replacement therapy after the normal accepted)).Patients with vitiligo or asthma in childhood have been fully relieved and adults without any intervention can be included, Patients with asthma who need bronchial amplifiers for medical intervention are not included;
4. Subjects Have failed to control the heart of the clinical symptoms or disease, such as: (1) the NYHA class II heart failure (2)unstable angina pectoris (3)myocardial infarction occurred within 1 year (4) Patients with clinically significant ventricular or ventricular arrhythmia requiring clinical intervention;
5. With active infection or unexplained fever > 38.5 dgree C occurred during the screening or before the first time to give medicine (the investigator determined that the subjects were allowed to enter the group due to the fever caused by the tumor);
6. History or evidence of interstitial pulmonary disease or active non-infectious pneumonia;
7. Sbujects with congenital or acquired immunodeficiency （such as HIV infection), active hepatitis b (hbv-dna is greater than 104 copies/ml) or hepatitis c (positive for hepatitis c antibody, and HCV-RNA is higher than the reference value of analytical method);
8. Other PD-1 antibody therapy or other immunotherapy for PD-1 / PD-l1 have been accepted;
9. Known to be allergic to macromolecular proteins or to any SHR-1210 ingredients;
10. Subjects who were treated with corticosteroids (> 10mg/day prednisone) or other immunosuppressive agents were required for the first 14 days prior to the first use of the research drug.In the absence of active autoimmune disease, inhalation or partial use of steroids and doses of > 10mg/day prednisone in the efficacy dose of adrenocortical hormone replacement;
11. Subjects had used antitumor monoclonal antibody (mAb), chemotherapy, targeted small molecules or radiation therapy within 4 weeks before first use of study drugs, or adverse events caused by previously accepted drugs have not recovered (grade 1 or baseline level) or less.Note: Subjects with no more than 2 levels of neuropathy or 2 levels of hair loss were excluded.If the subjects underwent major surgery, the toxicity and/or complications of their surgical intervention must be fully restored prior to treatment;
12. Subjects are participating in other clinical studies or subjects has participated in other clinical studies for the first four weeks before the first use of the study drug (the participants who have been in the follow-up period were evaluated with the last use of experimental drugs or equipment);
13. A live vaccine was administered within four weeks of the first study of the drug.It is allowed to accept the inactivated virus vaccine against seasonal influenza and inactivated virus vaccine for injection, but it is not allowed to accept the attenuated live influenza vaccine with the nasal use;
14. Women during pregnancy or lactation;
15. Judged by investigator, the subjects had other factors that could lead to the termination of the study such as with other serious disease (including mental illness) need to merge treatment, serious abnormal laboratory values, family and social factors maybe affect the safety or data collection.

研究实施时间：

Study execute time：

从 From 2017-11-06 00:00:00至 To 2018-11-06 00:00:00

征募观察对象时间：

Recruiting time：

从From 2017-11-06 00:00:00 至 To 2018-11-06 00:00:00

干预措施：

Interventions：

组别：	SHR-1210 200mg	样本量：	50
Group：	SHR-1210 200mg	Sample size：	50
干预措施：	SHR-1210 200mg IV	干预措施代码：
Intervention：	SHR-1210 200mg IV	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	上海	市(区县)：	上海
Country：	China	Province：	Shanghai	City：	SHANGHAI
单位(医院)：	上海东方医院	单位级别：	三级甲等
Institution hospital：	Shanghai East Hospital	Level of the institution：	Tertiary A hospital

测量指标：

Outcomes：

指标中文名：	客观缓解率	指标类型：	主要指标
Outcome：	ORR	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：	次要指标
Outcome：	PFS	Type：	Secondary 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：	次要指标
Outcome：	mOS	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	生活质量评分	指标类型：	次要指标
Outcome：	EORTC QLQ-C30	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	不良事件	指标类型：	次要指标
Outcome：	AE	Type：	Secondary 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：	肿瘤组织	组织：
Sample Name：	tumor tissue	Tissue：
人体标本去向	使用后保存	说明
Fate of sample：	Preservation after use	Note：

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：

正在进行

Recruiting

年龄范围：

Participant age：

最小 Min age	17	岁 years
最大 Max age	75	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）：

单臂研究，无随机

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

Single arm study, No random

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：
Blinding：
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	Yes
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）：	无
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	Nothing
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：	本临床试验采用的是病例记录表(Case Record Form, CRF)
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	This clinical trial uses a CRF (Case Record Form,CRF)
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2017-11-05 12:39:58