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：	ChiCTR2400086753
最近更新日期： Date of Last Refreshed on：	2024-07-10 09:14:03
注册时间： Date of Registration：	2024-07-10 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	全基因组测序联合动态循环肿瘤细胞对初始不可切除的大肠癌肝转移转化治疗的临床价值评估
Public title：	Clinical value evaluation of whole genome sequencing combined with dynamic circulating tumor cells in the conversion therapy of initial unresectable colorectal cancer liver metastasis
注册题目简写：
English Acronym：
研究课题的正式科学名称：	动态循环肿瘤细胞监测在初始不可切除的大肠癌肝转移转化治疗及手术治疗中的临床价值评估
Scientific title：	Clinical value evaluation of dynamic circulating tumor cells in the conversion therapy of initial unresectable colorectal cancer liver metastasis
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：	何晨翔	研究负责人：	李俊
Applicant：	He Chenxiang	Study leader：	Li Jun
申请注册联系人电话： Applicant telephone：	+86 152 5155 3590	研究负责人电话： Study leader's telephone：	+86 189 3056 0396
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：	421709023@qq.com	研究负责人电子邮件： Study leader's E-mail：	lijundfgd1@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：	上海市静安区延长中路301号	研究负责人通讯地址：	上海市静安区延长中路301号
Applicant address：	301 Yanchang Middle Road, Jing'an District, Shanghai	Study leader's address：	No. 301 Yanchang Middle Road, Jing'an District, Shanghai
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：	同济大学附属第十人民医院
Applicant's institution：	The 10th People's Hospital affiliated to Tongji University
研究负责人所在单位：	同济大学附属第十人民医院
Affiliation of the Leader：	The 10th People's Hospital affiliated to Tongji 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：	SHSY一 IEC-5.0/24K29/P01	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：	上海市第十人民医院伦理委员会
Name of the ethic committee：	Ethics Committee of Shanghai Tenth People's Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2024-02-27 00:00:00
伦理委员会联系人：	孙奋勇
Contact Name of the ethic committee：	Sun Fenyong
伦理委员会联系地址：	同济大学附属第十人民医院
Contact Address of the ethic committee：	The 10th People's Hospital affiliated to Tongji University
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 21 6630 1604	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：

同济大学附属第十人民医院

Primary sponsor：

The 10th People's Hospital affiliated to Tongji University

研究实施负责（组长）单位地址：

上海市静安区延长中路301号

Primary sponsor's address：

301 Yanchang Middle Road, Jing'an District, Shanghai

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)：	同济大学附属第十人民医院	具体地址：	上海市静安区延长中路301号
Institution hospital：	The 10th People's Hospital affiliated to Tongji University	Address：	301 Yanchang Middle Road, Jing'an District, Shanghai

经费或物资来源：

上海市第十人民医院研究型医师项目

Source(s) of funding：

Shanghai Tenth People’s Hospital Research Physician Project

研究疾病：

结直肠癌肝转移

Target disease：

circulating tumor cells

研究疾病代码：

Target disease code：

研究类型：

预后研究

Study type：

Prognosis study

研究所处阶段：

诊断试验新技术临床试验

Study phase：

Diagnostic New Technique Clincal Study

研究设计：

队列研究

Study design：

Cohort study

研究目的：

本研究旨在深入理解结直肠癌肝转移（Colorectal Liver Metastases, CRLM）的分子机制和治疗响应，特别是针对“同时转移”和“异时转移”两种不同临床情况的患者。通过全面分析治疗前后、复发时以及不同肝转移部位的肿瘤样本，研究将探讨肿瘤异质性、克隆进化、治疗抵抗性以及潜在的新型治疗靶点。最终目标是为CRLM患者提供个性化的治疗策略，改善治疗效果，延长患者生存期，并提高生活质量。

Objectives of Study：

This study aims to gain a deeper understanding of the molecular mechanisms and treatment responses of colorectal liver metastases (CRLM), especially for patients with two different clinical conditions: "simultaneous metastasis" and "metachronous metastasis". By comprehensively analyzing tumor samples before and after treatment, at the time of recurrence, and at different liver metastasis sites, the study will explore tumor heterogeneity, clonal evolution, treatment resistance, and potential novel therapeutic targets. The ultimate goal is to provide personalized treatment strategies for patients with CRLM, improve treatment effects, extend patient survival, and improve quality of life.

药物成份或治疗方案详述：

1）研究内容1：全基因组测序与循环肿瘤细胞分析： A）对象：选择2024年4月起在上海市第十人民医院接受治疗的75例初始不可切除的CRLM患者，包括同时性和异时性转移。 B）在转化治疗前后采集患者的外周静脉全血，提取循环肿瘤细胞，通过手术或者活检获得配对的原发及转移灶肿瘤样本，进行全基因组测序，分析肿瘤相关的遗传变异和突变负荷。通过比较治疗前后的全基因组测序结果的变化，评估转化治疗的分子响应，识别可能预测治疗反应和疗效的分子标志物。比较治疗前后的肿瘤亚克隆，探索肿瘤在治疗前后进化的共同路径，发现对于治疗敏感或耐受的亚克隆并研究其机制。追踪循环肿瘤细胞在治疗前后的变化，可以观察肿瘤的发展过程，进一步形成跟踪疾病最小残留（MRD）的有效指标，可望在更早的时间发现肿瘤复发。 2）研究内容2：影像学与分子标志物的相关性研究： A）对象：上述75例CRLM患者。 B）结合影像学检查（如CT、MRI、PET-CT）结果，分析肿瘤的形态学变化与分子标志物（包括基因组和CTC组数据）的相关性。确定影像学特征与分子变化之间的关联，开发基于分子和影像学特征的综合预测模型，以提高治疗反应的预测准确性。 3）研究内容3：治疗前后肿瘤组织的多区域采样与分析： A）对象：上述75例CRLM患者。 B）在治疗前后对原发肿瘤和肝转移灶进行多区域活检，获取组织样本进行基因组和转录组分析。评估肿瘤异质性对治疗反应的影响，探索不同肿瘤区域的分子差异，为局部治疗策略提供依据。用转录组数据计算肿瘤免疫微环境，探索治疗前后免疫微环境的变化以及与治疗效果相关的特征因素。 4）研究内容4：临床数据的综合分析： A）对象：上述75例CRLM患者。 B）收集患者的详细临床数据，包括病理特征、治疗历程、生存期和生活质量评估。整合临床数据与分子数据，探索影响CRLM患者预后的因素，为制定个体化治疗方案提供参考。通过机器学习方法建立治疗方案和治疗效果的预测模型。

Description for medicine or protocol of treatment in detail：

1) Research content 1: Whole genome sequencing and circulating tumor cell analysis: A) Subjects: 75 patients with initially unresectable CRLM who were treated at Shanghai Tenth People's Hospital from April 2024 onwards, including synchronous and metachronous metastases. B) Collect peripheral venous whole blood from patients before and after conversion therapy, extract circulating tumor cells, obtain paired primary and metastatic tumor samples through surgery or biopsy, perform whole genome sequencing, and analyze tumor-related genetic variations and mutation loads. By comparing the changes in whole genome sequencing results before and after treatment, evaluate the molecular response to conversion therapy and identify molecular markers that may predict treatment response and efficacy. Compare tumor subclones before and after treatment, explore the common path of tumor evolution before and after treatment, discover subclones that are sensitive or resistant to treatment and study their mechanisms. Tracking the changes in circulating tumor cells before and after treatment can observe the development process of the tumor, further form an effective indicator for tracking the minimum residual disease (MRD), and it is expected to detect tumor recurrence at an earlier time. 2) Research content 2: Correlation study between imaging and molecular markers: A) Subjects: The above 75 CRLM patients. B) Combined with the results of imaging examinations (such as CT, MRI, PET-CT), analyze the correlation between tumor morphological changes and molecular markers (including genomic and CTC group data). Determine the association between imaging features and molecular changes, and develop a comprehensive prediction model based on molecular and imaging features to improve the prediction accuracy of treatment response. 3) Research content 3: Multi-regional sampling and analysis of tumor tissue before and after treatment: A) Subjects: the above 75 CRLM patients. B) Perform multi-regional biopsies on primary tumors and liver metastases before and after treatment, and obtain tissue samples for genomic and transcriptomic analysis. Evaluate the impact of tumor heterogeneity on treatment response, explore molecular differences in different tumor regions, and provide a basis for local treatment strategies. Calculate the tumor immune microenvironment using transcriptomic data, explore changes in the immune microenvironment before and after treatment, and explore characteristic factors related to treatment effects. 4) Research content 4: Comprehensive analysis of clinical data: A) Subjects: the above 75 CRLM patients. B) Collect detailed clinical data of patients, including pathological characteristics, treatment history, survival, and quality of life assessment. Integrate clinical data with molecular data to explore the factors that affect the prognosis of CRLM patients and provide reference for the development of individualized treatment plans. Use machine learning methods to establish a prediction model for treatment plans and treatment effects.

纳入标准：

Inclusion criteria

1) Age 18-70 years old (including the cut-off value), male or female;
2) Expected survival ≥3 months;
3) KPS score ≥ 60 points, and there are no contraindications for various biochemical indicators;
4) ECOS PS 0 points;
5) Liver function Child-Pugh class A;
6) The primary disease is confirmed by pathology to be colorectal cancer, and the liver lesion is confirmed to be liver metastatic tumor by imaging examination or biopsy pathology;
7) Dynamic contrast-enhanced MRI of the liver was performed before surgery, and CRLM was assessed as unresectable at initial diagnosis (according to the eighth edition of TNM staging, the T stage of the tumor is T1-T3; there is no distant organ metastasis);
8) Imaging shows that the metastasis is limited to the liver, and there is no tumor thrombus or extrahepatic metastasis in blood vessels, bile ducts and other parts; a single tumor, the diameter of the tumor is > 5 cm; or multiple tumors, the number of tumors is > 5, and the maximum diameter is > 4 cm;
9) Pregnant women who are not pregnant or breastfeeding should take contraceptive measures within 6 months after the end of treatment;
10) Laboratory tests within 1 week before treatment (including conversion therapy and surgery) must meet the following standards:
A) Routine blood tests:
a) Hemoglobin (Hb) ≥90 g/L;
b) Neutrophil count (ANC) ≥1.5×109/L;
c) Platelet count (PLT) ≥75×109/L;
B) Biochemical examination:
a) Albumin (ALB) ≥35 g/L;
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN;
c) Total bilirubin (TBIL) ≤1.5×ULN;
d) Creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (Ccr) ≥ 60 mL/min;
C) Electrolytes are basically normal or normal after treatment;
D) Urinary protein <2+ or 24-hour urine protein quantitative test ≤1.0 g/L (for patients with urine protein ≥2+, a 24-hour urine protein quantitative test must be ≤1.0 g/L before they can be selected);
E) Coagulation function:
a) International standard ratio (INR) or prothrombin time (PT) ≤ 1.2 × ULN;
b) Activated partial coagulation time (APTT) ≤1.5×ULN;
F) T3 and T4 levels ≤2×ULN｡

排除标准：

1）病理确诊为肝细胞癌,肝细胞-肝内胆管癌混合型或其他非胆管细胞恶性肿瘤; 2）预计生存期<3个月; 3）复发性CRLM; 4）取样前4周内接触过任何抗生素、益生元、益生菌、类固醇或免疫抑制剂； 5）既往或现患其他恶性肿瘤,除外接受了切除手术的非黑色素皮肤癌,宫颈原位癌和甲状腺乳头状癌; 6）活动性肺结核:患者入组前1年内存在活动性的结合感染,或入组前发生过肺结核,未接受抗结核治疗或结核处于活动期; 7）活动性或疑似自身免疫性疾病,仅接受激素替代治疗的甲状腺功能减退和未接受全身系统性治疗的皮肤病患者可以纳入; 8）间质性肺疾病或非感染性肺炎需要口服或静脉应用类固醇类药物; 9）长期应用全身激素治疗（每天使用的药物剂量相当于强的松>10mg）或其他类型的免疫抑制治疗,外用或口服皮质类固醇激素可以纳入 10）需治疗的急性感染性疾病; 11）HIV阳性; 12）既往有精神类药物､酒精或药物滥用史; 13）既往3个月有明显的出血症状或明确的出血倾向; 14）对试验用药过敏或可疑过敏者; 15）高血压患者经降压药物治疗后血压控制不佳（收缩压≥140 mmHg或舒张压≥90 mmHg）; 16）有肝转移之外的其他部位转移或合并结肠癌以外的肿瘤; 17）存在难以控制的肝性脑病,腹水,Gilbert综合征,硬化性胆管炎等;合并其他脏器功能障碍预计不能耐受手术或肝切除者; 18）其他任何研究者认为不能入组者

Exclusion criteria：

1) Pathologically diagnosed as hepatocellular carcinoma, mixed hepatocellular-intrahepatic cholangiocarcinoma or other non-cholangiocytic malignant tumors; 2) Expected survival period <3 months; 3) Recurrent CRLM; 4) Contact with any antibiotics, prebiotics, probiotics, steroids or immunosuppressants within 4 weeks before sampling; 5) Formerly or currently suffering from other malignant tumors, except for non-melanotic skin cancer, cervical carcinoma in situ and papillary thyroid cancer that have undergone resection surgery; 6) Active pulmonary tuberculosis: The patient has active combined infection within 1 year before enrollment, or has had pulmonary tuberculosis before enrollment, has not received anti-tuberculosis treatment, or the tuberculosis is in the active stage; 7) Patients with active or suspected autoimmune diseases, hypothyroidism who only receive hormone replacement therapy, and skin diseases who do not receive systemic treatment can be included; 8) Interstitial lung disease or non-infectious pneumonia requires oral or intravenous steroids; 9) Long-term application of systemic hormone therapy (daily dosage equivalent to prednisone >10 mg) or other types of immunosuppressive therapy, topical or oral corticosteroids can be included 10) Acute infectious diseases requiring treatment; 11) HIV positive; 12) Previous history of psychotropic drugs, alcohol or drug abuse; 13) Have obvious bleeding symptoms or clear bleeding tendency in the past 3 months; 14) Those who are allergic or suspected of being allergic to the trial drug; 15) Hypertensive patients have poor blood pressure control after antihypertensive drug treatment (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg); 16) Metastasis to other sites other than liver metastasis or combined with tumors other than colon cancer; 17) Those who have uncontrollable hepatic encephalopathy, ascites, Gilbert syndrome, sclerosing cholangitis, etc.; who are combined with other organ dysfunction and are not expected to tolerate surgery or liver resection; 18) Anyone else who the researcher thinks cannot be included in the group

研究实施时间：

Study execute time：

从 From 2024-02-01 00:00:00至 To 2026-12-31 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2024-07-20 00:00:00 至 To 2025-02-28 00:00:00

干预措施：

Interventions：

组别：	结直肠癌肝转移同时性转移（研究内容1、2）	样本量：	40
Group：	Simultaneous colorectal cancer liver metastasis	Sample size：	40
干预措施：	采血	干预措施代码：
Intervention：	Haemospasia	Intervention code：

组别：	结直肠癌肝转移同时性、异时性转移（研究内容3）	样本量：	75
Group：	Simultaneous and heterochronous colorectal cancer liver metastasis	Sample size：	75
干预措施：	组织活检	干预措施代码：
Intervention：	Tissue biopsy	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)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	同济大学附属第十人民医院	单位级别：	三甲
Institution hospital：	The 10th People's Hospital affiliated to Tongji University	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	转化治疗客观反应率	指标类型：	主要指标
Outcome：	object response rate, 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：	总生存期	指标类型：	次要指标
Outcome：	overall Survival, OS	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	化疗不良事件	指标类型：	次要指标
Outcome：	Adverse events of chemotherapy	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：	血液	组织：	肝转移肿瘤
Sample Name：	Blood	Tissue：	Liver metastatic tumor
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：	肝转移肿瘤	组织：	肝转移肿瘤
Sample Name：	Liver metastatic tumor	Tissue：	Liver metastatic tumor
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：

尚未开始

Not yet 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）：

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	是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）：	2025年4月，原始数据上传到临床试验公共管理平台
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	Original data is uploaded to the clinical trial management public platform in April 2025
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：	病例记录表
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Case Record Form
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：	2024-07-10 09:13:58