ChiCTR2000032533 版本V1.2 版本创建时间2020/10/21 01:29:08 中国临床试验注册中心

审核状态：

Project audit state：

通过审核

Successful

注册号：

Registration number：

ChiCTR2000032533 

最近更新日期：

Date of Last Refreshed on：

2020-05-01 23:51:37 

注册时间：

Date of Registration：

2020-05-01 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

彭永海医师：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。 立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经治疗的局部晚期或转移性肝癌患者：一项前瞻性、单臂、单中心、探索性临床研究

Public title：

SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma: a prospective, single arm, single center, exploratory clinical study

注册题目简写：

English Acronym：

研究课题的正式科学名称：

立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经治疗的局部晚期或转移性肝癌患者：一项前瞻性、单臂、单中心、探索性临床研究

Scientific title：

SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma: a prospective, single arm, single center, exploratory clinical study

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：

彭永海 

研究负责人：

彭永海 

Applicant：

Yonghai Peng 

Study leader：

Yonghai Peng 

申请注册联系人电话：

Applicant telephone：

+86 13805015469

研究负责人电话：

Study leader's telephone：

+86 13805015469

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：

1208852065@qq.com

研究负责人电子邮件：

Study leader's E-mail：

1208852065@qq.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：

福建省福州市鼓楼区西二环北路156号

研究负责人通讯地址：

福建省福州市鼓楼区西二环北路156号

Applicant address：

156 West Second Ring Road North, Gulou District, Fuzhou, Fujian, China

Study leader's address：

156 West Second Ring Road North, Gulou District, Fuzhou, Fujian, 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：

中国人民解放军联勤保障部队第900医院

Applicant's institution：

The 900th Hospital of the Joint Logistic Support Force of PLA

研究负责人所在单位：

中国人民解放军联勤保障部队第900医院

Affiliation of the Leader：

The 900th Hospital of the Joint Logistic Support Force of PLA

是否获伦理委员会批准：

否/No

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：

中国人民解放军联勤保障部队第900医院

Primary sponsor：

The 900th Hospital of The Joint Logistic Support Force of PLA

研究实施负责（组长）单位地址：

福建省福州市鼓楼区西二环北路156号

Primary sponsor's address：

156 West Second Ring Road North, Gulou District, Fuzhou, Fujian, 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)：

福建省

市(区县)：

福州

Country：

China

Province：

Fujian

City：

Fuzhou

单位(医院)：

中国人民解放军联勤保障中心第900医院

具体地址：

鼓楼区西二环北路156号

Institution
hospital：

The 900th Hospital of the Joint Logistic Support Force of PLA

Address：

156 West Second Ring Road North, Gulou District

经费或物资来源：

暂无

Source(s) of funding：

not available

Target disease：

hepatic carcinoma

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：

主要研究目的： 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经过系统治疗的局部晚期或转移性肝癌患者的临床疗效。 次要研究目的： 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经过系统治疗的局部晚期或转移性肝癌患者的安全性； 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经过系统治疗的局部晚期或转移性肝癌患者的无进展生存期； 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未未经过系统治疗的局部晚期或转移性肝癌患者的一年以及两年生存率； 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经过系统治疗的局部晚期或转移性肝癌患者的疾病控制率； 评估立体定向放疗与安罗替尼诱导联合特瑞普利单抗治疗未经过系统治疗的局部晚期或转移性肝癌患者的总生存时间。  

Objectives of Study：

Primary research objective: To evaluate the Clinical Effect of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma. Secondary research objectives: To evaluate the safety of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma; To evaluate the progression-free survival of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma; To evaluate the One-year and Two-year survival rate of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma; To evaluate the disease control rate of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma; To evaluate the overall survival of SBRT and Anlotinib Hydrochloride combined with Toripalimab for the first-line treatment of patients with locally advanced or metastatic hepatic carcinoma. Objective of exploratory research: To evaluate the biomarkers for potential predictive efficacy (intestinal flora detection, PD-L1 expression, and blood TMB expression).

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. 年龄 18~75 岁；ECOG PS 评分：0~1 分；预计生存期超过 3 个月；
2. Child-Pugh 肝功能分级：A或B级（≤7分）；
3. 符合我国原发性肝癌诊断标准（2019）或通过组织学/细胞学诊断的肝细胞肝癌；
4. 巴塞罗那临床肝癌分期（BCLC 分期）B 期或 C 期，疾病不适合进行根治手术的局部晚期或转移性和/或不可切除和/或在手术和或局部治疗后出现了疾病进展的原发性肝癌；
5. 既往未接受任何针对 HCC 的系统治疗；
6. 至少有1个可测量（依据RECIST 1.1 可测量）、未经治疗的病灶；或接受过既往局部治疗（例如，射频消融、无水乙醇或醋酸注射、冷冻消融、高强度聚焦超声、经动脉栓塞化疗、经动脉栓塞等等）的患者（如果靶病灶之前未接受过局部治疗或在局部治疗范围内的靶病灶在之后出现了依据RECIST v1.1 进展的患者也可入组）；
7. 用药前患者的实验室检查值需符合以下标准：
1） 血常规：WBC ≥3.0 × 10^9/L；ANC ≥1.5 × 10^9/L；PLT ≥90 ×10^9/L；HGB ≥9.0 g/dL；
2） 肝功能：TBIL≤1.5 × ULN，AST≤2.5 × ULN，ALT≤2.5 × ULN（若为肝转移受试者，AST≤5× ULN，ALT≤5 × ULN）；
3） 肾功能：Cr≤1.5 × ULN 或 CrCl ≥50 mL/min；
4） 凝血功能：INR≤1.5，APTT≤1.5 ×ULN。
8. HBV-DNA 定量<500IU/ml（2500拷贝/ml），且在试验开始前至少14天接受抗乙肝病毒治疗并愿意在研究期间持续抗病毒治疗；HCV-RNA 定量阳性患者需接受抗病毒治疗且肝功能在NCI-CTCAE 评级1级以内；
9. 育龄妇女必须在首次用药前2周内进行血清妊娠研究，且结果为阴性。育龄妇女受试者和伴侣为育龄妇女的男性受试者须在研究期间和末次给予研究药物后180天内避孕；
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. Patients aged 18-75 years old, ECoG PS score: 0-1, estimated survival time more than 3 months;
2. Child Pugh liver function grade: A or B (< 7 points);
3. Patients who meet the diagnostic criteria of primary liver cancer in China (2019) or who are diagnosed by histology / cytology;
4. Stage B or stage C of BCLC stage in Barcelona, which is not suitable for radical operation, and which is locally advanced or metastatic and / or unresectable and / or has disease progression after operation and / or local treatment;
5. Patients who have not received any systematic treatment for HCC before;
6. At least one can be measured (according to RECIST 1.1 Measurable), untreated lesions, or patients who have received previous local treatment (e.g., radiofrequency ablation, ethanol or acetic acid injection, cryoablation, high intensity focused ultrasound, transcatheter arterial chemoembolization, transcatheter arterial embolization, etc.) (if the target has not received local treatment before or the target within the scope of local treatment appears according to RECIST later) Patients with v1.1 progression can also be included in the group;
7. The laboratory test value of patients before medication should meet the following standards:
(1) Blood routine test: WBC >= 3.0 x 10^9 / L; ANC >= 1.5 x 10^9 / L; PLT >= 90 x 10^9 / L; Hgb >= 9.0 g / dl;
(2) Liver function: TBIL <= 1.5 x ULN, AST <= 2.5 x ULN, ALT <= 2.5 x ULN (in case of liver metastasis, AST <= 5 x ULN, ALT <= 5 x ULN);
(3) Renal function: Cr <= 1.5 x ULN or CrCl >= 50 ml / min;
(4) Coagulation function: INR <= 1.5, APTT <= 1.5 x ULN;
8. The quantity of HBV-DNA was less than 500iu / ml (2500 copies / ml), and received anti HBV treatment at least 14 days before the start of the test and was willing to continue antiviral treatment during the study period; the patients with positive quantity of HCV-RNA needed to receive antiviral treatment and their liver function was within nci-ctcae grade 1;
9. Women of childbearing age must carry out the study of serum pregnancy within 2 weeks before the first drug use, and the result is negative. Women of childbearing age and male subjects with partners of women of childbearing age were required to use contraception during the study and within 180 days after the last administration of the study drug;
10. The subjects volunteered to join the study, signed the informed consent, had good compliance and cooperated with the follow-up.

排除标准：

1. 已知有纤维板层HCC、肉瘤样HCC 或混合型胆管癌和HCC伴随出血或有高出血风险的未经治疗或未完全治疗的静脉曲张患者在入组之前，患者必须接受食管胃十二指肠镜检（EGD），必须评估所有静脉曲张的规模（小型至大型），并依据当地标准治疗进行治疗。在开始研究治疗之前6个月内接受过EGD 的患者无需再重复接受此镜检；
2. 既往使用过盐酸安罗替尼胶囊、甲磺酸阿帕替尼片、甲磺酸仑伐替尼胶囊、甲苯磺酸索拉非尼片、苹果酸舒尼替尼胶囊、贝伐珠单抗等抗血管生成药物或针对 PD-1、PD-L1 等相关免疫治疗药物；
3. 5年内患者既往或同时患有其它恶性肿瘤(已治愈的皮肤基底细胞癌、前列腺原位癌和宫颈原位癌除外)；
4. 存在任何活动性自身免疫病或有自身免疫病病史(如以下，但不局限于：自身免疫性肝炎、间质性肺炎、肠炎、血管炎，肾炎；受试者需要支气管扩张剂进行医学干预的哮喘则不能纳入)；但以下患者允许入组：无需进行全身治疗的白癜风、银屑病、 脱发，控制良好的 I 型糖尿病，经替代治疗甲状腺功能正常的甲减；
5. 采用标准治疗未得到控制的高血压（血压未稳定在＜150/90 mmHg以下）；
6. 不管严重程度如何，存在任何出血体质迹象或病史的患者；在首次给药前 4 周内，出现任何出血或流血事件≥CTCAE 3 级的患者；或存在未愈合创口、骨折、胃及十二指肠活动性溃疡、溃疡性结肠炎等消化道疾病或未切除的肿瘤存在活动出血，或研究者判定的可能引起消化道出血、穿孔的其他状况；
7. 明确或怀疑有脑转移的患者。既往有脑转移病史的患者必须是已完成治疗，并且不再需要皮质激素治疗的患者可以入组；
8. 有未能良好控制的心脏临床症状或疾病，如：（1）NYHA2级以上心力衰竭（2）不稳定型心绞痛（3）24周内发生过心肌梗死（4）有临床意义的室上性或室性心律失常需要治疗或干预；
9. 存在临床上不可控制的第三间隙积液（如胸腔积液/心包积液，不需要引流积液或停止引流3天积液无明显增加的患者可以入组）；
10. 影像学（CT或者MRI）显示肿瘤侵犯大血管者或研究者判断后续研究期间肿瘤极有可能侵袭重要血管引起致命大出血者；
11. 有免疫缺陷病史，包括 HIV 检测阳性，或患有其他获得性、先天性免疫缺陷疾病，或有器官移植史和异基因骨髓移植史；
12. 活动性乙肝（定义为筛选期乙肝病毒表面抗原[HBsAg]检测结果呈阳性同时检测到 HBV-DNA 检测值高于所在研究中心检验科正常值上限）或丙肝（定义为筛选期丙肝病毒表面抗体[HCsAb]检测结果呈阳性，HCV-RNA阳性）的患者；
13. 具有明显影响口服药物吸收的因素，如无法吞咽、慢性腹泻和肠梗阻等；
14. 基线纤维素试纸尿检结果为≥ 2+蛋白尿的患者，应收集24小时尿液，然后必须证实24小时内尿蛋白含量＜1 g；
15. 对本应用的试验药物存在过敏反应者；
16. 经研究者判断，受试者有其他可能导致本研究被迫中途终止的因素。

Exclusion criteria：

1. Patients who are known to have fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC with bleeding or who are at high risk of bleeding, untreated or untreated varices, must undergo gastroduodenoscopy (EGD) prior to enrollment, must assess the size of all varices (small to large), and must be treated according to local standards. Patients who had received EGD within 6 months prior to the start of the study did not need to repeat the microscopy;
2. Patients who have used anti angiogenic drugs such as enrotinib hydrochloride capsules, apatinib mesylate tablets, lovatinib mesylate capsules, sorafenib mesylate tablets, sunitinib malate capsules, bevacizumab or immunotherapy drugs such as PD-1 and PD-L1 before;
3. Patients with other malignant tumors (except for cured skin basal cell carcinoma, prostate carcinoma in situ and cervical carcinoma in situ) within 5 years;
4. Patients with any active autoimmune disease or history of autoimmune disease (such as the following, but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; asthmatic patients who need medical intervention of bronchodilator can not be included); but the following patients are allowed to join the group: vitiligo, psoriasis, psoriasis without systemic treatment Hair loss, good control of type I diabetes, thyroid function normal hypothyroidism by replacement therapy;
5. Patients with uncontrolled hypertension were treated with standard therapy (blood pressure was not stable below 150 / 90 mmHg);
6. Patients with any physical signs or history of bleeding, regardless of the severity; within 4 weeks before the first administration, any bleeding or bleeding event >= CTCAE 3 Patients of Grade A, or patients with digestive tract diseases such as unhealed wound, fracture, gastric and duodenal active ulcer, ulcerative colitis, or patients with active bleeding due to unresected tumor, or other conditions that may cause gastrointestinal bleeding and perforation determined by researchers;
7. Patients with definite or suspected brain metastasis. Patients with previous history of brain metastasis must have completed treatment, and patients who no longer need corticosteroid treatment can be included in the group;
8. Patients with clinical symptoms or diseases of heart that can not be well controlled, such as: (1) heart failure above NYHA Level 2; (2) unstable angina pectoris; (3) myocardial infarction within 24 weeks; (4) clinically significant supraventricular or ventricular arrhythmias that need treatment or intervention;
9. Patients with clinically uncontrollable third space effusion (such as pleural effusion / pericardial effusion, patients who do not need drainage of effusion or stop drainage for 3 days without significant increase of effusion can be included in the group);
10. Imaging (CT or MRI) shows that the tumor invades the large blood vessels or the researcher judges that during the follow-up study, the tumor is likely to invade the important blood vessels and cause fatal bleeding;
11. Patients with a history of immunodeficiency, including HIV positive, or with other acquired or congenital immunodeficiency diseases, or with a history of organ transplantation and allogeneic bone marrow transplantation;
12. Patients with active hepatitis B (defined as those with positive HBsAg test results and HBV-DNA test values higher than the upper limit of normal values in the laboratory of the research center) or hepatitis C (defined as those with positive HBsAb test results and HCV-RNA test results in the screening period);
13. Patients with significant factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction;
14. For patients whose baseline cellulose test paper urinalysis result is >= 2 + albuminuria, 24-hour urine should be collected, and then it must be confirmed that the urine protein content is less than 1G within 24 hours;
15. Patients with allergic reaction to the test drug;
16. According to the judgment of the researcher, the subjects have other factors that may lead to the forced termination of the study.

研究实施时间：

Study execute time：

从 From 2020-05-01 00:00:00至 To 2024-12-31 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2020-05-01 00:00:00 至 To 2022-12-31 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

40

Group：

treatment group

Sample size：

干预措施：

立体定向放疗与安罗替尼诱导联合特瑞普利单抗

干预措施代码：

Intervention：

SBRT and Anlotinib Hydrochloride combined with Toripalimab

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)：

中国人民解放军联勤保障部队第900医院 

单位级别：

三级甲等 

Institution
hospital：

The 900th Hospital of the Joint Logistic Support Force of PLA

Level of the institution：

Tertiary A

测量指标：

Outcomes：

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：

一年生存率

指标类型：

次要指标

Outcome：

one-year survival rate

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

二年生存率

指标类型：

次要指标

Outcome：

two-year survival rate

Type：

Secondary 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：

次要指标

Outcome：

objective remission rate

Type：

Secondary 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：

次要指标

Outcome：

Disease control rate

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

安全性

指标类型：

主要指标

Outcome：

safety

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：

大便

组织：

Sample Name：

Faeces

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：

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 18 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）：

未使用

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

Not used

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）：

Calculated Results after
the Study Completed(upload file)：

是否共享原始数据：

IPD sharing

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）：

试验结束后上传原始数据到本网站

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

the original data will be Upload to this web site after the trial

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：

试验记录

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

暂未确定/Not yet

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2020-05-01 22:36:49