ChiCTR2400082750 版本V1.0 版本创建时间2024/04/07 14:29:35 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：

ChiCTR2400082750 

最近更新日期：

Date of Last Refreshed on：

2024-04-07 14:28:51 

注册时间：

Date of Registration：

2024-04-07 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

中晚期肝细胞癌一线靶免治疗进展后加用伊匹木单抗的单臂前瞻性临床研究

Public title：

A single arm prospective clinical study on the addition of ipilimumab after the progression of first-line targeted immunotherapy for advanced hepatocellular carcinoma

注册题目简写：

English Acronym：

研究课题的正式科学名称：

中晚期肝细胞癌一线靶免治疗进展后加用伊匹木单抗的单臂前瞻性临床研究

Scientific title：

A single arm prospective clinical study on the addition of ipilimumab after the progression of first-line targeted immunotherapy for advanced hepatocellular 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：

周俊 

研究负责人：

周俊 

Applicant：

Zhou Jun 

Study leader：

Zhou Jun 

申请注册联系人电话：

Applicant telephone：

+86 139 0190 6998

研究负责人电话：

Study leader's telephone：

+86 139 0190 6998

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：

zhouj2@gobroadhealthcare.com

研究负责人电子邮件：

Study leader's E-mail：

zhouj2@gobroadhealthcare.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：

上海市浦东新区台北东路170号上海高博肿瘤医院

研究负责人通讯地址：

上海市浦东新区台北东路170号上海高博肿瘤医院

Applicant address：

Shanghai GoBroad Cancer Hospital, No. 170 Taipei East Road, Pudong New Area, Shanghai

Study leader's address：

Shanghai GoBroad Cancer Hospital, No. 170 Taipei East Road, Pudong New Area, 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：

上海高博肿瘤医院

Applicant's institution：

Shanghai GoBroad Cancer Hospital

研究负责人所在单位：

上海高博肿瘤医院

Affiliation of the Leader：

Shanghai GoBroad Cancer 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：

KY2024-005

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：

上海高博肿瘤医院医学伦理审查委员会

Name of the ethic committee：

Shanghai GoBroad Cancer Hospital Medical Ethics Review Board

伦理委员会批准日期：

Date of approved by ethic committee：

2024-02-26 00:00:00

伦理委员会联系人：

张友会

Contact Name of the ethic committee：

Zhang Youhui

伦理委员会联系地址：

上海市浦东新区台北东路170号

Contact Address of the ethic committee：

No. 170 Taipei East Road, Pudong New Area, Shanghai

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 21 6057 1204

伦理委员会联系人邮箱：

Contact email of the ethic committee：

gcplunli@gobroadhealthcare.com

研究实施负责（组长）单位：

上海高博肿瘤医院

Primary sponsor：

Shanghai GoBroad Cancer Hospital

研究实施负责（组长）单位地址：

上海市浦东新区台北东路170号上海高博肿瘤医院

Primary sponsor's address：

Shanghai GoBroad Cancer Hospital, No. 170 Taipei East Road, Pudong New Area, 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

市(区县)：

上海市

Country：

China

Province：

Shanghai

City：

Shanghai

单位(医院)：

上海高博肿瘤医院

具体地址：

上海市浦东新区台北东路170号上海高博肿瘤医院

Institution
hospital：

Shanghai GoBroad Cancer Hospital

Address：

Shanghai GoBroad Cancer Hospital, No. 170 Taipei East Road, Pudong New Area, Shanghai

经费或物资来源：

无资金赞助

Source(s) of funding：

No funding sponsorship

Target disease：

Mid to late stage hepatocellular 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：

一线靶免（PD-（L）1和抗血管生成药物）进展加用伊匹木单抗在中晚期肝细胞癌中的疗效及安全性  

Objectives of Study：

The efficacy and safety of first-line targeted immunotherapy (PD - (L) 1 and anti angiogenic drugs) combined with ipilimumab in the treatment of advanced hepatocellular carcinoma

药物成份或治疗方案详述：

本研究是一项前瞻性、开放性、单臂、探索性II期临床研究。在既往接受过全身系统性治疗的、不适合根治性手术切除的中晚期 HCC 患者中，评估中晚期肝细胞癌一线靶免治疗进展后加用伊匹木单抗的单臂前瞻性临床研究的有效性和安全性。 签署知情同意后，合格入选的受试者加用伊匹木单抗。伊匹木单抗根据公斤体重，体重<70kg，剂量为50mg或100mg，体重≥70kg，剂量为100mg或150mg， Q3W，联合PD-（L）1＋抗血管抑制剂治疗，4个周期后序贯PD-（L）1＋抗血管抑制剂治疗，直至疾病进展、死亡、毒性不能耐受、撤回知情同意、开始新的抗肿瘤治疗或方案规定的其他原因终止治疗 。 治疗过程中采用RECIST v1.1进行临床肿瘤影像学评价，自首次给药时开始，首次评估在8周内，之后每6-9周（±7天）接受1次肿瘤影像学评估。如果研究过程中，受试者出现临床疾病不稳定，可随时进行计划外影像学评估。若评估为可手术的患者（手术条件：至少接受过1次以上肿瘤评估，且疗效经研究者综合评估后判断可接受原发病灶的根治性切除）则停用相关抗血管生成药物后可进行手术治疗，在停用抗血管生成药物后，建议继续免疫治疗药物。 采用NCI-CTCAE 5.0标准从首次用药开始，至末次给药后30天，进行安全性评估。 安全性随访后受试者进入生存期随访，每45-60天随访一次，直至受试者死亡、失访或研究结束。 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

1.在任何试验相关流程实施之前，签署书面知情同意 2.年龄18-70周岁 3.ECOG PS评分为0-1 4.根据中国原发性肝癌诊疗规范（2022年版）诊断标准初次诊断为HCC 5.巴塞罗那临床肝癌（Barcelona Clinic Liver Cancer, BCLC）分期为B、 C 期 6.Child-Pugh评分A级 7.预期生存时间>3个月 8.根据RECIST1.1标准至少有1个可测量病灶 9.总三碘甲腺原氨酸（T3）或游离T3和游离甲状腺素（T4）在正常范围内。（可以接受通过甲状腺替代疗法控制）。无症状的T3，游离T3或游离T4异常的受试者可以入选 10.充分控制血压 11.具有充分的器官和骨髓功能，随机分组前7天内实验室检查值符合下列要求(获得实验室检查的前14天内不允许通过给予任何血液成分、细胞生长因子、白蛋白及其他纠正治疗的药物来满足条件)，具体如下： 1)血常规：绝对中性粒细胞计数（absolute neutrophil count, ANC）≥1.5×109/L； 血小板计数（platelet, PLT）≥50×10 9/L； 血红蛋白含量（hemoglobin, HGB）≥9.0 g/dL； 2)肝功能：血清总胆红素（total bilirubin, TBIL）≤3×正常上限（upper limit of normal value, ULN）；丙氨酸氨基转移酶（alanine aminotransferase, ALT）、天门冬氨酸氨基转移酶（aspartate transferase, AST）和碱性磷酸酶（alkaline phosphatase, ALP）≤5×ULN； 血清白蛋白≥28 g/L； 3)肾功能：血清肌酐（creatinine, Cr）≤ 1.5×ULN 或肌酐清除率（clearance of creatinine, CCr）≥ 50mL/min（Cockcroft-Gault 公式）；尿常规结果显示尿蛋白<2+；对基线时尿常规检测显示尿蛋白≥2+的患者，应进行24小时尿液采集且24小时尿蛋白定量<1g； 4)凝血功能：国际标准化比率（international normalized ratio，INR）和活化部分凝血活酶时间（activated partial thromboplastin time ，APTT）≤ 1.5倍ULN 12.对于育龄期女性受试者，应在接受首次研究药物给药（第1周期第1天）之前的3天内接受尿液或血清妊娠试验且结果为阴性。如果尿液妊娠试验结果无法确认为阴性，则要求进行血液妊娠试验。非育龄期女性定义为绝经后至少１年，或进行过手术绝育或子宫切除术； 13.如存在受孕风险，所有受试者（不论男性或女性）均需在整个治疗期间直至治疗末次研究药物给药后120天（或末次化疗药物给药后180天）内采用年失败率低于1%的避孕措施。

Inclusion criteria

1. Sign written informed consent before implementing any trial related procedures 2. Age 18-70 years old 3. ECOG PS score is 0-1 4. According to the diagnostic criteria of the Chinese Primary Liver Cancer Diagnosis and Treatment Guidelines (2022 Edition), the initial diagnosis is HCC 5. Barcelona Clinical Liver Cancer (BCLC) staging is stages B and C 6. Child Pugh rating A 7. Expected survival time>3 months 8. According to RECIST 1.1 standard, there should be at least one measurable lesion 9. Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within the normal range. (Can be controlled through thyroid replacement therapy). Asymptomatic T3, free T3, or free T4 abnormal subjects can be selected 10. Fully control blood pressure 11. It has sufficient organ and bone marrow functions, and the laboratory test values within the first 7 days of random grouping meet the following requirements (no blood components, cell growth factors, albumin, or other corrective treatment drugs are allowed to meet the conditions within the first 14 days of obtaining laboratory tests), as follows: 1) Blood routine: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; Platelet count (PLT) ≥ 50 × 10 9/L; Hemoglobin content (HGB) ≥ 9.0 g/dL; 2) Liver function: serum total bilirubin (TBIL) ≤ 3 x upper limit of normal value (ULN); Alanine aminotransferase (ALT), aspartate transferase (AST), and alkaline phosphatase (ALP) ≤ 5 × ULN; Serum albumin ≥ 28 g/L; 3) Renal function: serum creatinine (Cr) ≤ 1.5 x ULN or creatinine clearance rate (CCr) ≥ 50mL/min (Cockcroft Gault formula); The urine routine results showed that urine protein<2+; For patients whose baseline urine routine test shows urine protein ≥ 2+, 24-hour urine collection should be conducted and the 24-hour urine protein quantification should be less than 1g; 4) Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 times ULN 12. For female participants of childbearing age, they should undergo a urine or serum pregnancy test with a negative result within 3 days prior to receiving the first study drug administration (day 1 of cycle 1). If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Non reproductive age women are defined as those who have experienced at least one year after menopause, or have undergone surgical sterilization or hysterectomy 13. If there is a risk of conception, all subjects (whether male or female) must use contraceptive measures with an annual failure rate of less than 1% throughout the entire treatment period until 120 days after the last study drug administration (or 180 days after the last chemotherapy drug administration)

排除标准：

1.既往经组织学/细胞学确诊的含纤维板层肝细胞癌、肉瘤样肝细胞癌、胆管癌等成分 2.有肝性脑病病史，或有肝移植病史 3.有临床症状需要引流的胸水、腹水、心包积液 4.急性或者慢性活动性乙型肝炎或丙型肝炎感染者，乙型肝炎病毒（HBV） DNA＞2000IU/ml或104拷贝/ml；丙型肝炎病毒（HCV）RNA＞103拷贝/ml；乙肝表面抗原（HbsAg）与抗HCV抗体同时阳性 5.有中枢神经系统转移 6.既往6个月内出现过门静脉高压导致的食管或胃底静脉曲张出血事件。首次给药前3个月内已知的内镜检查存在重度（G3）静脉曲张。有门静脉高压证据（包括影像学检查发现脾大），经研究者评估出血风险高者 7.既往3个月内发生任何危及生命的出血事件，包括需要输血治疗、手术或局部治疗、持续药物治疗 8.既往6个月内动、静脉血栓栓塞事件，包括心肌梗死、不稳定型心绞痛、脑血管意外或一过性脑缺血发作、肺动脉栓塞、深静脉血栓或其它任何严重血栓栓塞的病史。植入式静脉输液港或导管源性血栓形成，或浅表静脉血栓形成，经过常规抗凝治疗后血栓稳定者除外。允许预防性使用小剂量低分子肝素（如依诺肝素40 mg/天） 9.首次给药前2周内，连续10天使用阿司匹林（＞ 325 mg/天）或其他已知可以抑制血小板功能的药物如双嘧达莫或氯吡格雷等 10.不可控制的高血压, 经最佳医学治疗后收缩压＞150mmHg或舒张压＞90 mmHg，高血压危象或高血压脑病病史 11. 症状性充血性心力衰竭（纽约心脏病协会分级II-IV级）。症状性或控制不佳的心律失常。先天性长QT综合征病史或筛查时校正的QTc＞500ms（使用Fridericia法计算） 12.严重出血倾向或凝血功能障碍，或正在接受溶栓治疗 13.既往6个月内有胃肠道穿孔和/或瘘管病史，肠梗阻病史（包括需要肠外营养的不完全肠梗阻），广泛肠切除（部分结肠切除或广泛小肠切除，并发慢性腹泻）、克罗恩氏病、溃疡性结肠炎或长期慢性腹泻 14.首次给药前3周内接受过放射治疗。对于首次给药前3周前接受放射治疗的患者，必须满足下述所有条件方可入组：目前不存在任何放疗相关的毒性反应，不需要服用糖皮质激素，排除放射性肺炎、放射性肝炎、放射性肠炎等 15.既往和目前有肺纤维化史、间质性肺炎、尘肺、药物相关肺炎、肺功能严重受损等肺部疾病 16.活动性肺结核(TB)，正在接受抗结核治疗或者首次给药前1年内接受过抗结核治疗者 17.人免疫缺陷病毒（HIV）感染者（HIV 1/2抗体阳性），已知的梅毒感染者 18.处于活动期或临床控制不佳的严重感染。在首次给药前4周内有重度感染，包括但不限于因感染、菌血症或重度肺炎并发症而住院治疗 19.首次给药前2年内发生过需要全身性治疗（例如使用缓解疾病药物、皮质类固醇或免疫抑制剂）的活动性自身性免疫疾病。允许使用替代疗法（例如甲状腺素、胰岛素或者用于肾上腺或垂体机能不全的生理性皮质类固醇等）。已知的原发性免疫缺陷病史。仅存在自身免疫抗体阳性的患者需根据研究者判断确认是否存在自身免疫性疾病 20.首次给药前4周之内使用过免疫抑制药物，不包括喷鼻、吸入性或其他途径的局部糖皮质激素或生理剂量的系统性糖皮质激素（即不超过10mg/天泼尼松或等效剂量的其他糖皮质激素）、允许因治疗哮喘、慢性阻塞性肺疾病等疾病的呼吸困难症状临时使用糖皮质激素 21.首次给药前4周之内或计划在研究期间接受减毒活疫苗 22.首次给药前4周之内接受过重大的外科手术（开颅、开胸或开腹手术）或者未愈合的伤口、溃疡或骨折。首次给药之前7天内接受过组织穿刺活检或其他小外科手术，以静脉输液为目的的静脉穿刺置管除外 23.首次给药前4周之内接受过针对肝癌的局部治疗 24.首次给药前2周内接受过具有免疫调节作用的药物（包括胸腺肽、干扰素、白介素，除外为控制胸水或腹水局部使用） 25.不受控制/无法纠正的代谢紊乱或其它非恶性肿瘤器官疾病或全身性疾病或癌症继发反应，并可导致较高医学风险和/或生存期评价不确定性 26.在首次给药前5年内诊断为其他恶性肿瘤，不包括经过根治的皮肤基底细胞癌、皮肤鳞状细胞癌和/或经过根治切除的原位癌。如果给药前5年以上诊断为其他恶性肿瘤或肝癌，需对复发转移病灶进行病理学或细胞学诊断 27.既往对其他单克隆抗体或酪氨酸激酶抑制剂产生过严重过敏反应 28.首次给药前4周内接受过其他临床试验的治疗 29.妊娠或哺乳的女性患者 30.可能会导致以下结果的其它急性或慢性疾病、精神疾病或实验室检测值异常：增加研究参与或研究药物给药的相关风险，或者干扰研究结果的解读，而且根据研究者的判断将患者列为不符合参加本研究的资格

Exclusion criteria：

1. Components such as fibroblastic hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, and cholangiocarcinoma previously confirmed by histology/cytology 2. History of hepatic encephalopathy or history of liver transplantation 3. Chest fluid, ascites, and pericardial effusion with clinical symptoms that require drainage 4. Acute or chronic active hepatitis B or hepatitis C infected individuals with hepatitis B virus (HBV) DNA>2000IU/ml or 104 copy/ml; Hepatitis C virus (HCV) RNA>103 copies/ml; Hepatitis B surface antigen (HbsAg) and anti HCV antibody are positive at the same time 5. There is central nervous system metastasis 6. There have been incidents of esophageal or gastric variceal bleeding caused by portal hypertension within the past 6 months. Severe (G3) varicose veins were found on endoscopic examination within 3 months prior to the first administration. Evidence of portal hypertension (including imaging findings of splenomegaly), assessed by researchers as high-risk for bleeding 7. Any life-threatening bleeding event that occurred within the past 3 months, including the need for blood transfusion treatment, surgery or local treatment, and continuous medication treatment 8. History of arterial and venous thromboembolism events within the past 6 months, including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other serious thromboembolism. Implantable venous infusion port or catheter-related thrombosis, or superficial venous thrombosis, except for those with stable thrombosis after routine anticoagulation treatment. Allow prophylactic use of low-dose low molecular weight heparin (such as enoxaparin 40 mg/day) 9. Within 2 weeks before the first administration, use aspirin (>325 mg/day) or other drugs known to inhibit platelet function, such as dipyridamole or clopidogrel, for 10 consecutive days 10. Uncontrollable hypertension, with systolic blood pressure>150mm Hg or diastolic blood pressure>90 mmHg after optimal medical treatment, hypertensive crisis or history of hypertensive encephalopathy 11. Symptomatic congestive heart failure (New York Heart Association classification II-IV). Symptomatic or poorly controlled arrhythmia. History of congenital long QT syndrome or corrected QTc during screening>500ms (calculated using Fridericia method) 12. Severe bleeding tendency or coagulation dysfunction, or undergoing thrombolytic therapy 13. History of gastrointestinal perforation and/or fistula within the past 6 months, history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive intestinal resection (partial or extensive intestinal resection with concurrent chronic diarrhea), Crohn's disease, ulcerative colitis, or long-term chronic diarrhea 14. Received radiation therapy within 3 weeks prior to the first administration. For patients who received radiation therapy three weeks before the first administration, all of the following conditions must be met before enrollment: currently, there are no radiation related toxic reactions, no corticosteroids need to be taken, and radiation pneumonia, radiation hepatitis, radiation enteritis, etc. are excluded 15. Previous and current history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia, severe impairment of lung function, and other lung diseases 16. Active pulmonary tuberculosis (TB), who is currently receiving anti tuberculosis treatment or has received anti tuberculosis treatment within one year before the first administration 17. Human immunodeficiency virus (HIV) infected individuals (HIV 1/2 antibody positive), known syphilis infected individuals 18. Severe infections that are active or poorly controlled clinically. Severe infection within 4 weeks prior to initial administration, including but not limited to hospitalization due to complications of infection, bacteremia, or severe pneumonia 19. Active autoimmune diseases that require systemic treatment (such as the use of disease relieving drugs, corticosteroids, or immunosuppressants) have occurred within 2 years prior to the first administration. Allow the use of alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency). A known history of primary immunodeficiency. Only patients with positive autoimmune antibodies need to confirm the presence of autoimmune diseases based on the researcher's judgment 20. Within 4 weeks before the first administration, immunosuppressive drugs have been used, excluding local corticosteroids administered through nasal spray, inhalation, or other routes, or systemic corticosteroids with physiological doses (i.e. no more than 10mg/day prednisone or equivalent doses of other corticosteroids), and temporary use of corticosteroids is allowed to treat respiratory distress symptoms such as asthma and chronic obstructive pulmonary disease 21. Within 4 weeks before the first administration or planned to receive attenuated live vaccines during the study period 22. Within 4 weeks prior to the first administration, significant surgical procedures (craniotomy, thoracotomy, or laparotomy) or unhealed wounds, ulcers, or fractures have been performed. Within 7 days prior to the first administration, tissue biopsy or other minor surgical procedures have been performed, except for venous catheterization for the purpose of intravenous infusion 23. Received local treatment for liver cancer within 4 weeks prior to initial administration 24. Received immunomodulatory drugs (including thymosin, interferon, interleukin, except for local use to control pleural or ascitic fluid) within 2 weeks before the first administration 25. Uncontrolled/uncorrectable metabolic disorders or other non malignant organ diseases or systemic diseases or secondary reactions to cancer, which can lead to higher medical risk and/or uncertainty in survival evaluation 26. Diagnosed as other malignant tumors within 5 years prior to initial administration, excluding curative skin basal cell carcinoma, skin squamous cell carcinoma, and/or curative resection of carcinoma in situ. If diagnosed with other malignant tumors or liver cancer more than 5 years before administration, pathological or cytological diagnosis of recurrent and metastatic lesions is required 27. Previous severe allergic reactions to other monoclonal antibodies or tyrosine kinase inhibitors 28. Treatment received from other clinical trials within 4 weeks prior to initial administration 29. Pregnant or breastfeeding female patients 30. Other acute or chronic diseases, mental illnesses, or abnormal laboratory test values that may lead to increased risk of study participation or drug administration, or interference with the interpretation of study results, and patients being classified as ineligible to participate in this study based on the researcher's judgment

研究实施时间：

Study execute time：

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

征募观察对象时间：

Recruiting time：

从From 2024-04-15 00:00:00 至 To 2025-04-15 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

45

Group：

Test group

Sample size：

干预措施：

签署知情同意后，合格入选的受试者在一线靶免进展加用伊匹木单抗。伊匹木单抗根据公斤体重，体重<70kg，剂量为 50mg 或 100mg，体重≥70kg，剂量为 100mg 或 150mg， Q3W，联合 PD-（L）1＋抗血管抑制剂治疗，4 个周期后序贯 PD-（L）1＋抗血管抑制剂治疗，直至疾病进展、死亡、毒性不能耐受、撤回知情同意、开始新的抗肿瘤治疗或方案规定的其他原因终止治疗, 伊匹木单抗治疗时间为 4 次。 治疗过程中采用 RECIST v1.1 进行临床肿瘤影像学评价，自首次给药时开始，6-8 周内进行首次影像学评估，之后每 6-9 周（±7 天）接受 1 次肿瘤影像学评估。 采用 NCI-CTCAE 5.0 标准从首次用药开始，至末次给药后 30 天，进行安全性评估。 安全性随访后受试者进入生存期随访，每 45-60 天随访一次，直至受试者死亡、失访或研究结束。

干预措施代码：

Intervention：

After signing informed consent, eligible participants will receive the addition of ipilimumab during first-line targeted immunotherapy. Epilimumab is administered in combination with PD - (L) 1+anti angiogenic inhibitors based on kilogram body weight, weight<70kg, dose 50mg or 100mg, weight ≥ 70kg, dose 100mg or 150mg, Q3W. After 4 cycles, sequential treatment with PD - (L) 1+anti angiogenic inhibitors is performed until disease progression, death, toxicity intolerance, withdrawal of informed consent, initiation of new anti-tumor treatment, or termination of treatment for other reasons specified in the protocol. Epilimumab treatment is administered 4 times. During the treatment process, RECIST v1.1 was used for clinical tumor imaging evaluation. The first imaging evaluation was conducted within 6-8 weeks from the initial administration, and then every 6-9 weeks (± 7 days), tumor imaging evaluation was conducted. Conduct a safety assessment using NCI-CTCAE 5.0 standard from the initial administration until 30 days after the last administration. After safety follow-up, the subjects will enter the survival follow-up period, which will be conducted every 45-60 days until the subjects die, are lost to follow-up, or the study ends.

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 

市(区县)：

 上海市 

Country：

China 

Province：

Shanghai 

City：

Shanghai 

单位(医院)：

上海高博肿瘤医院 

单位级别：

三级 

Institution
hospital：

Shanghai GoBroad Cancer Hospital

Level of the institution：

Tertiary hospital

测量指标：

Outcomes：

指标中文名：

一线靶免（PD-（L）1和抗血管生成药物）进展加用伊匹木单抗 在中晚期肝细胞癌患者的客观缓解率（ORR）

指标类型：

主要指标

Outcome：

Objective response rate (ORR) of first-line targeted immunotherapy (PD - (L) 1 and anti angiogenic drugs) combined with ipilimumab in patients with advanced hepatocellular carcinoma

Type：

Primary indicator

测量时间点：

自首次给药时开始，6-8周内进行首次影像学评估，之后每6-9周（±7天）接受1次肿瘤影像学评估；48周后每12周（±7天）进行一次肿瘤影像学评估

测量方法：

按照方案规定的影像学评估方式对靶病灶进行检测测量

Measure time point of outcome：

Starting from the first administration, the first imaging evaluation shall be conducted within 6-8 weeks, and thereafter, tumor imaging evaluation shall be conducted every 6-9 weeks (± 7 days); Perform tumor imaging evaluation every 12 weeks (± 7 days) after 48 weeks

Measure method：

Detect and measure target lesions according to the imaging evaluation method specified in the plan

指标中文名：

RECIST 1.1和mRECIST评估的无疾病进展时间（PFS）

指标类型：

次要指标

Outcome：

Disease progression free time (PFS) assessed by RECIST 1.1 and mRECIST

Type：

Secondary indicator

测量时间点：

自首次给药时开始，6-8周内进行首次影像学评估，之后每6-9周（±7天）接受1次肿瘤影像学评估；48周后每12周（±7天）进行一次肿瘤影像学评估

测量方法：

按照方案规定的影像学评估方式对靶病灶进行检测测量

Measure time point of outcome：

Starting from the first administration, the first imaging evaluation shall be conducted within 6-8 weeks, and thereafter, tumor imaging evaluation shall be conducted every 6-9 weeks (± 7 days); Perform tumor imaging evaluation every 12 weeks (± 7 days) after 48 weeks

Measure method：

Detect and measure target lesions according to the imaging evaluation method specified in the plan

指标中文名：

总生存期（OS）

指标类型：

次要指标

Outcome：

Total survival time (OS)

Type：

Secondary indicator

测量时间点：

自首次给药时开始，6-8周内进行首次影像学评估，之后每6-9周（±7天）接受1次肿瘤影像学评估；48周后每12周（±7天）进行一次肿瘤影像学评估

测量方法：

按照方案规定的影像学评估方式对靶病灶进行检测测量

Measure time point of outcome：

Starting from the first administration, the first imaging evaluation shall be conducted within 6-8 weeks, and thereafter, tumor imaging evaluation shall be conducted every 6-9 weeks (± 7 days); Perform tumor imaging evaluation every 12 weeks (± 7 days) after 48 weeks

Measure method：

Detect and measure target lesions according to the imaging evaluation method specified in the plan

指标中文名：

RECIST 1.1和mRECIST评估的疾病控制率（DCR）

指标类型：

次要指标

Outcome：

Disease Control Rate (DCR) assessed by RECIST 1.1 and mRECIST

Type：

Secondary indicator

测量时间点：

自首次给药时开始，6-8周内进行首次影像学评估，之后每6-9周（±7天）接受1次肿瘤影像学评估；48周后每12周（±7天）进行一次肿瘤影像学评估

测量方法：

按照方案规定的影像学评估方式对靶病灶进行检测测量

Measure time point of outcome：

Starting from the first administration, the first imaging evaluation shall be conducted within 6-8 weeks, and thereafter, tumor imaging evaluation shall be conducted every 6-9 weeks (± 7 days); Perform tumor imaging evaluation every 12 weeks (± 7 days) after 48 weeks

Measure method：

Detect and measure target lesions according to the imaging evaluation method specified in the plan

指标中文名：

RECIST 1.1和mRECIST评估的持续缓解率（DOR）

指标类型：

次要指标

Outcome：

Continuous response rate (DOR) evaluated by RECIST 1.1 and mRECIST

Type：

Secondary indicator

测量时间点：

自首次给药时开始，6-8周内进行首次影像学评估，之后每6-9周（±7天）接受1次肿瘤影像学评估；48周后每12周（±7天）进行一次肿瘤影像学评估

测量方法：

按照方案规定的影像学评估方式对靶病灶进行检测测量

Measure time point of outcome：

Starting from the first administration, the first imaging evaluation shall be conducted within 6-8 weeks, and thereafter, tumor imaging evaluation shall be conducted every 6-9 weeks (± 7 days); Perform tumor imaging evaluation every 12 weeks (± 7 days) after 48 weeks

Measure method：

Detect and measure target lesions according to the imaging evaluation method specified in the plan

指标中文名：

安全性

指标类型：

次要指标

Outcome：

Security

Type：

Secondary indicator

测量时间点：

研究者或合格的指定人员按试验流程图的要求评估每例受试者在研究过程中和随访期间的不良事件

测量方法：

根据NCI CTCAE（5.0版）对不良事件（AE）进行分级和记录

Measure time point of outcome：

Researchers or qualified designated personnel shall evaluate the adverse events of each subject during the study process and follow-up period in accordance with the requirements of the trial flowchart

Measure method：

Classify and record adverse events (AEs) according to NCI CTCAE (version 5.0)

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

组织

组织：

肿瘤组织（组织块或未染色切片）

Sample Name：

tissue

Tissue：

Tumor tissue(tissue blocks or unstained sections)

人体标本去向

 使用后销毁  

说明

在伦理委员会允许的情况下，凡是符合入选标准的受试者尽量在基线时提供符合要求的肿瘤组织样本（组织块或未染色切片）进行生物标记物分析。

Fate of sample：

Destruction after use  

Note：

Subject to the approval of the ethics committee, all subjects who meet the inclusion criteria should provide tumor tissue samples (tissue blocks or unstained sections) that meet the requirements for biomarker analysis at baseline as much as possible.

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

受试者需要在以下时间点提供5 ml全血标本：首次给药前、成完治疗时和确认疾病进展时，进行生物标志物研究。

Fate of sample：

Destruction after use  

Note：

The subjects are required to provide 5 ml of whole blood samples at the following time points: before initial administration, upon completion of treatment, and upon confirmation of disease progression, for biomarker studies.

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 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:

公开/Public

盲法：

无

Blinding：

None

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）：

不共享

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

NA

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：

本试验采用电子采集和管理系统进行数据采集和管理

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

This study uses an electronic collection and management system for data collection and management

数据与安全监察委员会：

Data and Safety Monitoring Committee：

无/No

注册人：

Name of Registration：

  2024-04-07 14:28:51