ChiCTR2500111736 版本V1.0 版本创建时间2025/11/05 11:04:34 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：

ChiCTR2500111736 

最近更新日期：

Date of Last Refreshed on：

2025-11-05 11:04:28 

注册时间：

Date of Registration：

2025-11-05 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

特瑞普利单抗联合瑞戈非尼二线及以后治疗免疫经治肝细胞癌的有效性和安全性研究

Public title：

A study on the efficacy and safety of Toripalimab combined with Regorafenib in the second-line and subsequent treatment of hepatocellular carcinoma previously treated with immunotherapy

注册题目简写：

English Acronym：

研究课题的正式科学名称：

特瑞普利单抗联合瑞戈非尼二线及以后治疗免疫经治肝细胞癌的有效性和安全性研究

Scientific title：

A study on the efficacy and safety of Toripalimab combined with Regorafenib in the second-line and subsequent treatment of hepatocellular carcinoma previously treated with immunotherapy

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：

董亮亮 

研究负责人：

董亮亮 

Applicant：

Liangliang Dong 

Study leader：

Liangliang Dong 

申请注册联系人电话：

Applicant telephone：

+86 535 669 1999

研究负责人电话：

Study leader's telephone：

+86 535 669 1999

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：

liangliangdongdll@163.com

研究负责人电子邮件：

Study leader's E-mail：

liangliangdongdll@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：

烟台市芝罘区毓璜顶东路20号

研究负责人通讯地址：

烟台芝罘区毓璜顶东路20号

Applicant address：

No.20,Yantai Yuhuangding East Road,Zhifu District,Yantai,Shandong,China

Study leader's address：

No.20, Yuhuangdingdong Road, Zhifu District，Yantai，Shandong Province, 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：

烟台毓璜顶医院

Applicant's institution：

Yantai Yuhuangding Hospital

研究负责人所在单位：

烟台毓璜顶医院

Affiliation of the Leader：

Yantai Yuhuangding 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：

YYYIRB-IIT[2025]063

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：

烟台毓璜顶医院临床研究伦理委员会

Name of the ethic committee：

Yantai Yuhuangding Hospital Clinical Research Institutional Review Board

伦理委员会批准日期：

Date of approved by ethic committee：

2025-08-11 00:00:00

伦理委员会联系人：

李康琪

Contact Name of the ethic committee：

Li KangQi

伦理委员会联系地址：

烟台芝罘区毓璜顶东路20号

Contact Address of the ethic committee：

No.20, Yuhuangdingdong Road, Zhifu District，Yantai，Shandong Province, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 535 669 1999

伦理委员会联系人邮箱：

Contact email of the ethic committee：

likangqiyt@163.com

研究实施负责（组长）单位：

烟台毓璜顶医院

Primary sponsor：

Yantai Yuhuangding Hospital

研究实施负责（组长）单位地址：

烟台芝罘区毓璜顶东路20号

Primary sponsor's address：

No.20, Yuhuangdingdong Road, Zhifu District，Yantai，Shandong Province, 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)：

山东省

市(区县)：

Country：

China

Province：

Shandong

City：

单位(医院)：

烟台毓璜顶医院

具体地址：

烟台芝罘区毓璜顶东路20号

Institution
hospital：

Yantai Yuhuangding Hospital

Address：

No.20, Yuhuangdingdong Road, Zhifu District，Yantai，Shandong Province, China

经费或物资来源：

自选课题（自筹）

Source(s) of funding：

Self-selected topic（self-raised）

Target disease：

Metastatic hepatic carcinoma

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

 上市后药物 

Study phase：

4

研究设计：

单臂 

Study design：

Single arm 

研究目的：

对于接受PD-1抑制剂出现进展的晚期肝癌患者，使用特瑞普利单抗联合瑞戈非尼二线及以后治疗的安全性和有效性探索。  

Objectives of Study：

Exploration of the safety and efficacy of using teprotumumab combined with regorafenib for second-line and subsequent treatment in patients with advanced liver cancer who have experienced progression after receiving PD-1 inhibitors.

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.愿意并能够签署书面知情同意书。
2.签署知情同意书当天年龄≥18 岁且≤75 岁。
3.晚期肝细胞肝癌，经组织学/细胞学确诊或符合肝细胞肝癌临床诊断标准。
4.既往仅接受过一种含免疫检查点抑制剂方案治疗，影像学评估疾病出现进展。
5.既往接受过其他局部治疗（如手术切除、介入治疗、消融治疗、无水酒精注射、 氩氦刀治疗等）的患者可以纳入本研究。
6.肝功能符合 Child Pugh A 级（评分为 5-6 分）或 B 级（评分为 7 分）。
7.东部肿瘤协作组（ECOG）的一般状态评分为 0 或 1 分。
8.根据 RECIST 1.1 标准，CT 或 MRI 检查至少有 1 个可测量病灶。
9.符合以下标准的乙型肝炎病毒（HBV）感染得到控制（治疗）的参与者将被允许： HBV 抗病毒治疗必须至少 4 周，并且在第一剂研究干预前 HBV 病毒载量必须低 于 500 IU/mL。接受 HBV 活性治疗且病毒载量低于 500 IU/ml 的参与者应在整 个研究治疗期间继续接受相同的治疗。抗- hbc（+）、HBsAg 阴性、抗- hbs 阴 性、HBV 病毒载量低于 500 IU/mL 且不需要 HBV 抗病毒预防的参与者。
10.在研究筛查期间，必须对患者进行丙型肝炎病毒（HCV）RNA 状态的检测。本研 究允许未经治疗的慢性 HCV 感染患者进行研究。此外，对于丙肝治愈的患者， 可纳入本研究，但入组时丙肝治疗应结束 4 周以上。
11.主要器官功能基本正常，符合下列要求：骨髓：中性粒细胞绝对计数≥1.5× 109/L，血小板≥40×109/L，血红蛋白≥90g/L；肝脏：总胆红素≤2 倍正常值 上限（ULN），白蛋白≥29g/L；肾脏：血清肌酐≤1.5×ULN，或肌酐清除率≥ 50mL/min；凝血功能：国际标准化比率（INR）≤ 2，且活化部分凝血活酶时间 （APTT）≤ 1.5 倍 ULN。
12.预期生存＞3 个月。
13.育龄妇女必须同意在研究入组前，研究参与期间以及最后一次研究药物治疗后 至少 30 天内使用有效的避孕方法。育龄妇女需要在开始治疗前 72 小时内进行 血清妊娠试验。治疗或登记此试验的男性必须同意在完成 PD-1 抑制剂治疗前和 治疗 4 个月后使用适当的避孕措施。
14.筛选前4周内未参加其他临床试验；如果其他试验筛选失败病例，但是符合本试验要求者可以入组。

Inclusion criteria

1.Willing and able to sign a written informed consent form. 2.The age on the day of signing the informed consent form should be between 18 and 75 years old. 3.Advanced hepatocellular carcinoma, confirmed by histological/cytological examination or meeting the clinical diagnostic criteria for hepatocellular carcinoma; 4.Previously, only one immunotherapy checkpoint inhibitor regimen had been administered, and the imaging assessment indicated disease progression. 5.Patients who have previously received other local treatments (such as surgical resection, interventional therapy, ablation therapy, anhydrous alcohol injection, argon-helium knife therapy, etc.) can be included in this study. 6.Liver function is classified as Child Pugh grade A (with a score of 5-6) or grade B (with a score of 7). 7.The general condition score according to the Eastern Cooperative Oncology Group (ECOG) is 0 or 1. 8.According to the RECIST 1.1 standard, there is at least one measurable lesion on CT or MRI examination. 9.Participants with HBV infection who have achieved control (treatment) will be allowed to: The HBV antiviral treatment must last for at least 4 weeks, and the HBV viral load must be lower than 500 IU/mL before the first dose of the study intervention.Participants who receive HBV active treatment and have a viral load lower than 500 IU/ml should continue with the same treatment throughout the entire study treatment period. Participants with anti-hbc (+), negative HBsAg, negative anti-hbs, a viral load lower than 500 IU/mL, and no need for HBV antiviral prophylaxis. 10.During the screening process, it is necessary to test the HCV RNA status of the patients. This study allows patients with untreated chronic HCV infection to participate in the research. Additionally, patients who have been cured of hepatitis C can be included in this study, but the hepatitis C treatment should have been completed for more than 4 weeks at the time of enrollment. 11.The main organ functions are basically normal, meeting the following requirements: Bone marrow: Absolute neutrophil count >= 1.5 × 109/L, platelets >= 40 × 109/L, hemoglobin >= 90 g/L. Liver: Total bilirubin <= 2 times the upper limit of normal (ULN), albumin >= 29g/L; Kidney: Serum creatinine <= 1.5×ULN, or creatinine clearance rate >= 50mL/min; Coagulation function: International normalized ratio (INR) <= 2, and activated partial thromboplastin time (APTT) <= 1.5 times ULN. 12.Expected survival > 3 months. 13.Women of childbearing age must agree to use an effective contraceptive method at least 30 days before enrollment in the study, during the study period, and after the last administration of the study drug. Women of childbearing age need to undergo a serum pregnancy test within 72 hours before starting the treatment. Males who administer or register this test must agree to use appropriate contraceptive measures before completing PD-1 inhibitor treatment and 4 months after the treatment. 14.Participants must not have participated in any other clinical trials within the past 4 weeks. If there are cases that failed the screening in other trials but meet the requirements of this trial, they can be included.

排除标准：

1.目前正在参与并接受其他实验性治疗，或者参加了免疫检查点抑制剂研究并接受了研究治疗。
2.先前曾进行实体器官移植，诊断为免疫缺陷，或在首次试验治疗前7天内接受全身性类固醇治疗或任何其他形式的免疫抑制治疗。
3.入组前3个月内曾有食道、胃底或直肠静脉曲张出血。
4.在过去的6个月中有过肝性脑病，或者在入选时有明显的腹水。
5.有已知的活动性结核病病史。
6.对PD-1抑制剂过敏。
7.受试者同时具有其他已知的侵袭性恶性肿瘤（通过治疗目前没有肿瘤复发的 证据，且持续时间在 2 年以上者除外）。例外情况包括：皮肤基底细胞癌， 皮肤鳞状细胞癌，浅表性膀胱癌，低风险前列腺癌或原位宫颈癌。
8.既往有需要全身治疗的活动性自身免疫性疾病的患者。
9.已知有活动的非感染性肺炎的病史或任何证据。
10.有活动性感染需要全身治疗。
11.有已知的精神疾病或药物滥用障碍者。
12.妊娠或哺乳期女性。
13.有已知的人类免疫缺陷病毒（HIV）病史（HIV 1/2 抗体）。
14.计划开始研究治疗前 30 天内接种过活疫苗。
15.患有高血压，且经降压药物治疗无法获得良好控制者（收缩压>140mmHg，舒 张压>100mmHg）；患有 CTCAE 分级Ⅱ级以上心肌缺血或心肌梗塞、控制不良 的心律失常，和/或纽约心脏协会（NYHA）Ⅲ~Ⅳ级的心功能不全。
16.各种原因导致的无法平卧或无法长时间平卧的患者。
17.研究者认为妨碍患者参加本试验的其他状况。

Exclusion criteria：

1.Currently, they are participating in and undergoing other experimental treatments, or they have participated in studies on immune checkpoint inhibitors and received the treatment from those studies.
2.Previously had undergone organ transplantation, were diagnosed with immunodeficiency, or received systemic steroid treatment or any other form of immunosuppressive therapy within 7 days prior to the first trial treatment.
3.Within the previous 3 months prior to enrollment, there was a history of variceal bleeding in the esophagus, stomach, or rectum.
4.During the past 6 months, there has been hepatic encephalopathy, or at the time of enrollment, there was obvious ascites.
5.Has a known history of active tuberculosis.
6.Allergic to PD-1 inhibitors.
7.Subjects who have other known aggressive malignant tumors (excluding those with no evidence of tumor recurrence after treatment and a duration of more than 2 years). Exceptional cases include: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, low-risk prostate cancer, or in situ cervical cancer.
8.Patients with a previous history of active autoimmune diseases requiring systemic treatment.
9.Those with a known history of active non-infectious pneumonia or any evidence thereof.
10.Those with active infections requiring systemic treatment.
11.Individuals with known mental disorders or substance abuse disorders.
12.Women during pregnancy or lactation period.
13.Those with a known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies).
14.The study will begin with the examination of individuals who received live vaccines within 30 days prior to the treatment.
15.Patients with hypertension who cannot achieve good control despite treatment with antihypertensive drugs (systolic blood pressure > 140 mmHg, diastolic blood pressure > 100 mmHg).
16.Patients who are unable to lie flat or cannot remain in a flat position for a long time due to various reasons.
17.Other conditions that the researchers consider to prevent patients from participating in this trial.

研究实施时间：

Study execute time：

从 From 2025-11-01 00:00:00至 To 2028-10-31 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2025-11-15 00:00:00 至 To 2027-11-30 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

35

Group：

Treatment group

Sample size：

干预措施：

药物干预

干预措施代码：

Intervention：

Drug intervention

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 山东省 

市(区县)：

  

Country：

China 

Province：

Shandong 

City：

 

单位(医院)：

烟台毓璜顶医院 

单位级别：

三级甲等 

Institution
hospital：

Yantai Yuhuangding Hospital

Level of the institution：

Tertiary A

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：

治疗过程中及治疗结束每 6 周

测量方法：

影像学检查

Measure time point of outcome：

Every six weeks during the treatment process and after the treatment is completed

Measure method：

Imageological examination

指标中文名：

疾病控制率

指标类型：

次要指标

Outcome：

DCR

Type：

Secondary indicator

测量时间点：

治疗过程中及治疗结束每 6 周

测量方法：

影像学检查

Measure time point of outcome：

After the treatment is completed

Measure method：

Imageological examination

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：

治疗过程中及治疗结束每 6 周

测量方法：

影像学检查，生存期随访

Measure time point of outcome：

Every six weeks during the treatment process and after the treatment is completed

Measure method：

Imageological examination，follow-up visit of lifetime

指标中文名：

安全性

指标类型：

次要指标

Outcome：

Security index

Type：

Secondary indicator

测量时间点：

每周期治疗前及治疗结束后 30 天和 90 天（±3 天）。

测量方法：

实验室检查

Measure time point of outcome：

Before each cycle of treatment and 30 days and 90 days (±3 days) after the end of the treatment.

Measure method：

Laboratory examination

指标中文名：

总生存期

指标类型：

次要指标

Outcome：

OS

Type：

Secondary indicator

测量时间点：

治疗过程中及治疗结束每 6 周

测量方法：

影像学检查，生存期随访

Measure time point of outcome：

Every six weeks during the treatment process and after the treatment is completed

Measure method：

Imageological examination，follow-up visit of lifetime

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

无

组织：

Sample Name：

NA

Tissue：

人体标本去向

 其它  

说明

Fate of sample：

0thers  

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 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）：

无

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

None

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：

无

Blinding：

None

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）：

论文发表后

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

After the paper was punlished

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：

病历记录表

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：

无/No

注册人：

Name of Registration：

  2025-11-05 11:04:28