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：	ChiCTR2500115509
最近更新日期： Date of Last Refreshed on：	2025-12-26 16:41:47
注册时间： Date of Registration：	2025-12-26 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	艾帕洛利托沃瑞利单抗联合JAK抑制剂托法替布治疗免疫进展的晚期食管鳞癌的单臂临床研究
Public title：	A Phase II Study of Iparomlimab and Tuvonralimab(PD-1/CTLA-4 Bispecific Antibody)Plus Tofacitinib in Patients With Immunotherapy-Refractory Advanced Esophageal Squamous Cell Carcinoma
注册题目简写：
English Acronym：
研究课题的正式科学名称：	艾帕洛利托沃瑞利单抗联合JAK抑制剂托法替布治疗免疫进展的晚期食管鳞癌的单臂临床研究
Scientific title：	A Phase II Study of Iparomlimab and Tuvonralimab(PD-1/CTLA-4 Bispecific Antibody)Plus Tofacitinib in Patients With Immunotherapy-Refractory Advanced Esophageal Squamous Cell Carcinoma
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：	冯虹	研究负责人：	冯虹
Applicant：	Feng Hong	Study leader：	Feng Hong
申请注册联系人电话： Applicant telephone：	+86 531 6877 6102	研究负责人电话： Study leader's telephone：	+86 531 6877 6102
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：	zl1145268734@163.com	研究负责人电子邮件： Study leader's E-mail：	zl1145268734@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：	中国山东省济南市槐荫区经五路324号	研究负责人通讯地址：	中国山东省济南市槐荫区经五路324号
Applicant address：	No. 324, Jingwu Road, Huaiyin District, Jinan City, Shandong Province, China	Study leader's address：	No. 324, Jingwu Road, Huaiyin District, Jinan City, 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：	山东第一医科大学附属省立医院
Applicant's institution：	Shandong Provincial Hospital Affiliated to Shandong First Medical University
研究负责人所在单位：	山东第一医科大学附属省立医院
Affiliation of the Leader：	Shandong Provincial Hospital Affiliated to Shandong First Medical University

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：	SWYX:NO.2025-1052	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：	山东省立医院涉及人的生物医学研究伦理委员会
Name of the ethic committee：	The Ethics Committee for Biomedical Research Involving Humans of Shandong Provincial Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2025-08-28 00:00:00
伦理委员会联系人：	杨爱辉
Contact Name of the ethic committee：	Aihui Yang
伦理委员会联系地址：	中国山东省济南市槐荫区经五路324号
Contact Address of the ethic committee：	No. 324, Jingwu Road, Huaiyin District, Jinan City, Shandong Province, China
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 531 6877 6025	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：

山东第一医科大学附属省立医院

Primary sponsor：

Shandong Provincial Hospital Affiliated to Shandong First Medical University

研究实施负责（组长）单位地址：

中国山东省济南市槐荫区经五路324号

Primary sponsor's address：

No. 324, Jingwu Road, Huaiyin District, Jinan City, 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	市(区县)：	济南
Country：	China	Province：	Shandong	City：	Jinan
单位(医院)：	山东第一医科大学附属省立医院	具体地址：	中国山东省济南市槐荫区经五路324号
Institution hospital：	Shandong Provincial Hospital Affiliated to Shandong First Medical University	Address：	No. 324, Jingwu Road, Huaiyin District, Jinan City, Shandong Province, China

经费或物资来源：

自筹

Source(s) of funding：

self-finance

研究疾病：

食管癌

Target disease：

Esophageal Squamous Cell Carcinoma

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：

上市后药物

Study phase：

4

研究设计：

单臂

Study design：

Single arm

研究目的：

拟入组一线免疫治疗后进展的原发性耐药和继发性耐药的晚期食管鳞癌患者，探索PD-1/CTLA-4双免的免疫继续使用联合JAK抑制剂能否逆转免疫耐药，为临床中大量的免疫耐药患者提供新型治疗方案。

Objectives of Study：

A cohort of patients with advanced esophageal squamous cell carcinoma (ESCC) who experience disease progression after first-line immunotherapy—encompassing both primary and acquired resistance—is planned for enrollment. This study aims to investigate whether continued immunotherapy with combined PD-1/CTLA-4 blockade plus a JAK inhibitor can overcome established immune resistance. By addressing a major unmet clinical need, this strategy seeks to provide a novel therapeutic option for the substantial proportion of patients with ESCC who develop resistance to immune checkpoint 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：

Inclusion criteria

1. Subjects voluntarily join this study, sign the informed consent form, have good compliance, and cooperate with follow-up;
2. Patients with histopathologically confirmed recurrent or metastatic esophageal squamous cell carcinoma;
3. Disease progression after at least two cycles of PD-(L)1 inhibitor ± first-line treatment;
4. Patients with untreated brain metastases;
5. RECIST V1.1 measurable lesions can be biopsied;
6. Age 18-75 years old;
7. ECOG score of 0-1 points;
8. The function of vital organs meets the following requirements (excluding the use of any blood components and cell growth factors during the screening period): absolute neutrophil count >=1.5×10^9/L; Platelets>=100×10^9/L; Hemoglobin>=9g/dL; Serum albumin>=3g/dL; Thyroid-stimulating hormone (TSH) <=ULN (if abnormal, FT3 and FT4 levels should be investigated at the same time, if FT3 and FT4 levels are normal, they can be enrolled); Bilirubin <=1 times ULN; ALT and AST <=1.5 times ULN; AKP <= 2.5 times ULN; Serum creatinine <=1.5 times ULN or creatinine clearance >=60mL/min;
9. Non-surgically sterilized or female patients of childbearing age who need to use one medically approved contraceptive measure (such as intrauterine device, birth control pill, or condom) during the study treatment period and within 3 months after the end of the study treatment period; Non-surgically sterilized female patients of childbearing age must have a negative serum or urine HCG test within 72 hours before study enrollment; and must be non-lactating; For men, use an appropriate method of contraception during the trial and for 3 months after the last dose of the trial drug.

排除标准：

1.受试者既往使用过JAK抑制剂类药物； 2.受试者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，葡萄膜炎，肠炎，肝炎，垂体炎，血管炎，肾炎，甲状腺功能亢进，甲状腺功能降低；受试者患有白癜风；在童年期哮喘已完全缓解，成人后无需任何干预的可纳入，如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）； 3.受试者正在使用免疫抑制剂、或全身、或可吸收的局部激素治疗以达到免疫抑制目的（剂量>10mg/天泼尼松或其他等疗效激素），并在入组前2周内仍在继续使用的； 4.对其他单克隆抗体或试验用药类药物发生过重度过敏反应； 5.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）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治疗或干预; （5）QTc>450ms（男性）；QTc>470ms (女性)； 6.有大出血风险的患者：凝血功能异常（INR>1.5或PT>16s），出血倾向或正在接受溶栓或抗凝治疗；已知存在的遗传性或获得性出血及血栓倾向（如血友病人，凝血机能障碍，血小板减少，脾功能亢进等）或近6个月发生过动、静脉血栓事件； 7.受试者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度； 8.既往和目前有肺纤维化史、间质性肺炎、尘肺、放射性肺炎、药物相关肺炎、肺功能严重受损等的客观证据的患者； 9.受试者先天或后天免疫功能缺陷（如HIV感染者），或活动性肝炎（乙肝参考：HBV DNA检测值超过正常值上限；丙肝参考：HCV病毒滴度或RNA检测值超过正常值上限）； 10.首次用药前4周内使用过其它药物临床试验研究药物者； 11.受试者既往或同时患有其它恶性肿瘤； 12.受试者在研究期间可能会接受其他抗肿瘤治疗； 13.研究用药前不足4周内或可能于研究期间接种活疫苗； 14.经究者判断，受试者有其他可能导致本研究被迫中途终止的因素，如，其他的严重疾病（含精神疾病）需要合并治疗，有严重的实验室检查异常，伴有家庭或社会等因素，会影响到受试者的安全，或资料及样品的收集。

Exclusion criteria：

1. Subjects have used JAK inhibitors in the past; 2. Subjects have any active autoimmune disease or history of autoimmune disease (such as but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; Subject has vitiligo; Asthma that has been completely resolved in childhood and does not require any intervention in adulthood can be included, such as asthma requiring bronchodilators for medical intervention cannot be included); 3. Subjects are using immunosuppressants, or systemic, or absorbable topical hormone therapy for immunosuppressive purposes (dose > 10mg/day prednisone or other equivalent efficacy hormones), and continue to use them within 2 weeks before enrollment; 4. Severe allergic reactions to other monoclonal antibodies or investigational drugs; 5. Have uncontrolled cardiac clinical symptoms or diseases, such as: (1) NYHA grade 2 or above heart failure; (2) Unstable angina; (3) Myocardial infarction within 1 year; (4) Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; (5) QTc>450ms (male); QTc>470ms (female); 6. Patients at risk of major bleeding: abnormal coagulation function (INR>1.5 or PT>16s), bleeding tendency, or receiving thrombolytic or anticoagulant therapy; Known hereditary or acquired bleeding and thrombophilia (such as hemophilia patients, coagulopathy, thrombocytopenia, hypersplenism, etc.) or hyperarterial or venous thrombotic events in the past 6 months; 7. Subjects have active infection or unexplained fever >38.5 degrees during screening and before the first dose; 8. Patients with previous and current history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonitis, severe impairment of lung function, etc.; 9. Subjects with congenital or acquired immunodeficiency (such as HIV infection), or active hepatitis (hepatitis B reference: HBV DNA test value exceeds the upper limit of normal value; Hepatitis C reference: HCV virus titer or RNA detection value exceeds the upper limit of normal value); 10. Subjects who have used other investigational drugs within 4 weeks before the first dose of the study medication; 11. Subjects with a history of or concurrent other malignancies; 12. Subjects who may receive other anti-tumor treatments during the study; 13. Subjects who have received live vaccines less than 4 weeks before the study medication or may receive them during the study; 14. According to the investigator's judgment, subjects have other factors that may lead to premature termination of the study, such as other severe diseases (including psychiatric disorders) requiring concomitant treatment, significant laboratory abnormalities, or family or social factors that may affect the subject's safety or the collection of data and samples.

研究实施时间：

Study execute time：

从 From 2025-12-26 00:00:00至 To 2028-12-31 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2025-12-26 00:00:00 至 To 2027-06-30 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	26
Group：	Experimental group	Sample size：	26
干预措施：	托法替布 5mg 每天2次，2个周期联合艾帕洛利托沃瑞利 5mg/kg 每3周给药一次，直至疾病进展或满2年	干预措施代码：
Intervention：	Tofacitinib 5mg twice daily for two cycles, combined with apalolide and tovolrelli 5mg/kg once every three weeks until disease progression or 2 years have passed	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	山东	市(区县)：
Country：	China	Province：	Shangdong	City：
单位(医院)：	山东第一医科大学附属省立医院	单位级别：	三甲
Institution hospital：	Shandong Provincial Hospital Affiliated to Shandong First Medical University	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	12周时的客观缓解率	指标类型：	主要指标
Outcome：	objective response rate at 12 weeks	Type：	Primary 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 (incidence and severity of adverse events, clinically significant abnormal laboratory findings)	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：	progression-free survival	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：	overall survival	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	缓解持续时间	指标类型：	主要指标
Outcome：	duration of response	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：	无	组织：
Sample Name：	None	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		岁 years
最大 Max age		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：
Blinding：

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）：	无
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	None
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：	病例报告表和管理系统
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Case report forms and management systems
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：	2025-12-26 16:41:40