ChiCTR2100049829 版本V1.2 版本创建时间2022/04/15 07:52:38 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：

ChiCTR2100049829 

最近更新日期：

Date of Last Refreshed on：

2022-03-14 22:30:37 

注册时间：

Date of Registration：

2021-08-10 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

阿替利珠单抗和贝伐珠单抗联合TACE治疗无法手术切除肝细胞癌（BCLC B期）的临床有效性和安全性：开放、单臂探索性研究

Public title：

Efficacy and safety of TACE combined with atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma (BCLC stage-B): an open-label, single-arm, exploratory trial

注册题目简写：

English Acronym：

研究课题的正式科学名称：

阿替利珠单抗和贝伐珠单抗联合TACE治疗无法手术切除肝细胞癌（BCLC B期）的临床有效性和安全性：开放、单臂探索性研究

Scientific title：

Efficacy and safety of TACE combined with atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma (BCLC stage-B): an open-label, single-arm, exploratory trial

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：

王康 

研究负责人：

王康 

Applicant：

Wang Kang 

Study leader：

Wang Kang 

申请注册联系人电话：

Applicant telephone：

+86 18817302388

研究负责人电话：

Study leader's telephone：

+86 18817302388

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：

wangkang_md@aliyun.com

研究负责人电子邮件：

Study leader's E-mail：

wangkang_md@aliyun.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：

上海市杨浦区长海路225号

研究负责人通讯地址：

上海市杨浦区长海路225号

Applicant address：

225 Changhai Road, Yangpu District, Shanghai, China

Study leader's address：

225 Changhai Road, Yangpu District, Shanghai, 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：

中国人民解放军第二军医大学第三附属医院

Applicant's institution：

The Third Affiliated Hospital of the Second Military Medical University of the Chinese people's Liberation Army

研究负责人所在单位：

中国人民解放军第二军医大学第三附属医院

Affiliation of the Leader：

The Third Affiliated Hospital of the Second Military Medical University of the Chinese people's Liberation Army

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：

EHBHKY2021-K-015

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：

第二军医大学第三附属医院伦理学委员会

Name of the ethic committee：

Ethics Committee of the Third Affiliated Hospital of Second Military Medical University

伦理委员会批准日期：

Date of approved by ethic committee：

2021-03-01 00:00:00

伦理委员会联系人：

袁振刚

Contact Name of the ethic committee：

Yuan Zhengang

伦理委员会联系地址：

上海市杨浦区长海路225号

Contact Address of the ethic committee：

225 Changhai Road, Yangpu District, Shanghai, China

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：

中国人民解放军第二军医大学第三附属医院

Primary sponsor：

The Third Affiliated Hospital of the Second Military Medical University of the Chinese people's Liberation Army

研究实施负责（组长）单位地址：

上海市杨浦区长海路225号

Primary sponsor's address：

225 Changhai Road, Yangpu District, Shanghai, 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)：

上海

市(区县)：

Country：

China

Province：

Shanghai

City：

单位(医院)：

中国人民解放军第二军医大学第三附属医院

具体地址：

杨浦区长海路225号

Institution
hospital：

The Third Affiliated Hospital of the Second Military Medical University of the Chinese people's Liberation Army

Address：

225 Changhai Road, Yangpu District

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)：

福建省省立医院

具体地址：

东街134号

Institution
hospital：

Fujian Provincial Hospital

Address：

134 East Street

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)：

福建省肿瘤医院

具体地址：

晋安区福马路420号

Institution
hospital：

Fujian Cancer Hospital

Address：

420 Fuma Road, Jinan District

经费或物资来源：

自筹

Source(s) of funding：

Self-raised

Target disease：

unresectable hepatocellular carcinoma (BCLC stage B)

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

 II期临床试验 

Study phase：

2

研究设计：

单臂 

Study design：

Single arm 

研究目的：

主要目的：通过单臂、II期临床试验初步探索阿替利珠单抗和贝伐珠单抗联合TACE用于无法手术切除或患者拒绝接受手术切除的肝细胞癌（HCC）患者的有效性和安全性。  

Objectives of Study：

Main purpose: To investigate the preliminaryefficacy and safety of TACE combined with atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC) or HCC patients refusing surgical resection in a single-arm phase-II clinical trial.

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.年龄在18岁至70岁之间，性别不限；
2.签署知情同意书；
3.研究者认为患者有能力依从研究方案；
4.经组织学或细胞学或影像学或临床诊断为肝细胞癌（HCC）（纤维板层和混合型肝细胞/胆管癌亚型不符合入选标准）；
5.根据EASL临床实践指南（2020版）临床分期为BCLC B期；
6.疾病不适合或患者拒绝进行手术治疗和/或局部消融；
7.过去12个月内未接受过任何抗肿瘤治疗；
8.至少有1个可测量（依据RECIST1.1可测量）、未经治疗的病灶；
9.首次研究治疗前7天内的美国东部肿瘤协作组（ECOG）的体力状态（PS）评分为0或1分；
10.研究治疗前7天内Child-Pugh A 级；
11.血液学和脏器功能充足，基于开始研究治疗之前7天内获得的以下实验室检查结果（除非另有说明）：
(1)绝对中性粒细胞计数(ANC)≥1.5×10^9/L（1500/μL），无粒细胞集落刺激因子支持；
(2)淋巴细胞计数≥0.5×10^9/L（500/μL）；
(3)血小板计数≥75×10^9/L（75, 000/μL），无输血；
(4)血红蛋白≥90 g/L（9g/dL），为满足此条标准，
(5)可允许对患者输血；AST、ALT 和碱性磷酸酶（ALP）≤5倍正常值上限（ULN）；
(6)血清胆红素≤3倍正常值上限（ULN）；
(7)血清肌酐≤1.5倍正常值上限（ULN）或计算的肌酸酐清除率≥50 mL/min（使用Cockcroft-Gault 公式进行计算）；
(8)血清白蛋白≥28 g/L（2.8 g/dL）；
(9)未接受抗凝治疗的患者：INR 或aPTT≤2倍正常值上限（ULN）；
(10)尿纤维素试纸检查结果蛋白尿＜2＋（在开始研究治疗之前7天内进行）；
(11)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＜1g。
12.治疗前肿瘤组织样本（如可获得）。如果肿瘤组织可获得，则递交石蜡块中的1个福尔马林固定、石蜡包埋（FFPE）肿瘤样本（首选），或含未染色、现切、系列切片的大约10-15个载玻片，连同递交一份入组4 周内相关病理学报告。如果上文描述的FFPE 样本不可用，则也可接受任何类型的样本（包括细针抽吸活检样本、细胞团块样本[例如，源自胸膜积液的样本]和灌洗样本）。应随该样本提供一份相关病理学报告。如果肿瘤组织不可用（例如，因为既往诊断性测试而用尽），则患者仍旧有资格参与研究；
13.有活动性乙肝病毒（HBV）感染的患者：在开始研究治疗之前28天内获得的HBVDNA＜500IU/mL，且在入组研究之前至少接受14天抗HBV治疗（依据当地标准治疗进行治疗，例如恩替卡韦）且愿意在研究期间继续接受治疗；
14.育龄妇女在开始治疗前必须进行阴性妊娠试验（βHCG），育龄妇女和男子（与育龄妇女发生性关系）必须同意在治疗期间和最后一次治疗剂量给药后6个月不间断地使用有效避孕措施；
15.预期寿命大于3个月。

Inclusion criteria

1. Aged 18 to 70 years, and the gender is not limited;
2. Sign the informed consent;
3. The investigator believes that the patient has the ability to comply with the research protocol;
4. Histological or cytological or imaging or clinical diagnosis of hepatocellular carcinoma (HCC) (fibrous lamellar and mixed hepatocellular/cholangiocarcinoma subtypes do not meet the inclusion criteria);
5. According to the EASL clinical practice guidelines (2020 edition), the clinical stage is BCLC stage B;
6. The disease is not suitable or the patient refuses to undergo surgical treatment and/or local ablation;
7. Have not received any anti-tumor therapy in the past 12 months;
8. At least 1 measurable (measurable according to RECIST1.1), untreated lesions;
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 within 7 days before the first study treatment;
10. Child-Pugh Class A within 7 days before study treatment;
11. Adequate hematology and organ function, based on the following laboratory test results obtained within 7 days prior to initiation of study treatment (unless otherwise stated):
(1) Absolute neutrophil count (ANC)>=1.5x10^9/L (1500/μL), without granulocyte colony-stimulating factor support;
(2) Lymphocyte count >=0.5x10^9/L (500/μL);
(3) Platelet count >=75x10^9/L (75,000/μL), no blood transfusion;
(4) Hemoglobin >= 90 g/L (9 g/dL), in order to meet this standard,
(5) Blood transfusion can be allowed to the patient; AST, ALT and alkaline phosphatase (ALP) <= 5 times the upper limit of normal (ULN);
(6) Serum bilirubin <= 3 times the upper limit of normal (ULN);
(7) Serum creatinine <= 1.5 times the upper limit of normal (ULN) or calculated creatinine clearance rate >= 50 mL/min (calculated using the Cockcroft-Gault formula);
(8) Serum albumin>=28 g/L (2.8 g/dL);
(9) Patients not receiving anticoagulation therapy: INR or aPTT <= 2 times the upper limit of normal (ULN);
(10) Proteinuria <2+ on urine cellulose test strip (performed within 7 days before the initiation of study treatment);
(11) Patients with a baseline cellulose dipstick urine test result of >=2+ proteinuria should collect 24-hour urine, and then must confirm that the urine protein content within 24 hours is less than 1 g.
12. Pre-treatment tumor tissue samples (if available). If tumor tissue is available, submit 1 formalin-fixed, paraffin-embedded (FFPE) tumor sample in a paraffin block (preferred), or approximately 10-15 slides containing unstained, fresh-cut, serial sections radiographs, together with a relevant pathology report within 4 weeks of enrollment. If the FFPE samples described above are not available, any type of sample (including fine needle aspiration biopsy samples, cell mass samples [eg, from pleural effusions], and lavage samples) is acceptable. A relevant pathology report should be provided with the sample. If tumor tissue is not available (e.g., exhausted due to previous diagnostic testing), the patient is still eligible to participate in the study;
13. Patients with active hepatitis B virus (HBV) infection: HBVDNA < 500IU/mL obtained within 28 days before the start of study treatment, and received anti-HBV treatment for at least 14 days before entering the study (treatment according to local standard treatment, such as entecavir) and are willing to continue receiving treatment during the study;
14. Women of childbearing age must have a negative pregnancy test (βHCG) before starting treatment, and women of childbearing age and men (having sex with women of childbearing age) must agree to use uninterrupted during treatment and for 6 months after the last therapeutic dose to be effective contraceptive measures;
15. Life expectancy greater than 3 months.

排除标准：

1.对任何研究所使用的药物有禁忌症、超敏反应史或不耐受；
2.肝性脑病史；
3.已知证据显示出血素质或凝血障碍；
4.伴随出血或有高出血风险的未经治疗或未完全治疗的食管和/或胃静脉曲张患者。在入组之前，患者必须接受B超、CT、MRI或肝弹性检测，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 个月内接受过相应检查的患者无需再重复接受检查；
5.在开始研究治疗之前6个月内曾发生过食管和/或胃静脉曲张出血；
6.在开始研究治疗之前6个月内有腹腔瘘、胃肠穿孔或腹腔脓肿；
7.已知活动性结核；
8.HIV抗体检测结果为阳性；
9.在开始研究治疗之前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；
10.在开始研究治疗之前2周内口服或静脉给予治疗性抗生素。接受预防性抗生素（例如，预防尿路感染或慢性阻塞性肺病加重）的患者有资格参与研究。
11.同时感染HBV和HCV。有HCV感染病史但HCV RNA的PCR 结果为阴性的患者可认为未感染HCV；
12.血压控制不理想，收缩压≥150 mmHg，舒张压≥100 mmHg；
13.无法纠正的血清钾、钙或镁等电解质紊乱病史；
14.在开始研究治疗之前4周内接受过大手术治疗（诊断除外）或预期需在研究期间进行大手术治疗；
15.在开始研究治疗之前3个月内有重大心血管疾病（例如在开始研究治疗之前3个月内有纽约心脏学会II 级或更严重心脏病、心肌梗死或脑血管意外）、不稳定型心律失常、不稳定型心绞痛或冠心病等；
16.先天性长QT综合征病史或筛查时校正的QT间期>500ms（使用Fridericia方法计算）；
17.存在严重无法愈合的创口、溃疡或骨折；
18.特发性肺纤维化、机化性肺炎（例如，闭塞性细支气管炎）、药物性肺炎或特发性肺炎或在筛选期胸部计算机断层扫描（CT）图上可见活动性肺炎证据。允许辐射区（纤维化）曾有辐射性肺炎；
19.当前或既往自身免疫疾病或免疫缺陷，包括但不限于重症肌无力、肌炎、自身免疫性肝炎、系统性红斑狼疮、类风湿性关节炎、炎性肠病、抗磷脂抗体综合征、韦格纳肉芽肿、干燥综合征、格林-巴利综合征或多发性硬化；
20.既往同种异基因干细胞或实体器官移植；
21.在开始研究治疗之前4 周内接受过减毒活疫苗治疗，或预期在阿替利珠单抗治疗期间或阿替利珠单抗末次给药后5个月内需接种此类疫苗；
22.曾在筛选之前5年内罹患除HCC之外的恶性肿瘤，转移或死亡风险（例如，5年OS率＞90%）可忽略不计的恶性肿瘤除外，例如经过充分治疗的原位宫颈癌、非黑素瘤皮肤癌、局限性前列腺癌、原位管癌或I 期子宫癌；
23.中枢神经系统（CNS）转移灶；
24.患者不能接受随访或正参加其它临床试验；
25.研究者认为不适合入组本研究的受试者。

Exclusion criteria：

1. Have a contraindication, history of hypersensitivity, or intolerance to any of the drugs used in the study;
2. History of hepatic encephalopathy;
3. Known evidence of bleeding diathesis or coagulation disorder;
4. Patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk of bleeding. Before enrollment, patients must undergo B-ultrasound, CT, MRI, or liver elastography, and all varicose veins must be assessed for size (small to large) and treated according to local standard of care. Patients who have undergone corresponding examinations within 6 months before starting study treatment do not need to undergo repeated examinations;
5. Bleeding from esophageal and/or gastric varices occurred within 6 months prior to the initiation of study treatment;
6. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months before starting study treatment;
7. Known active tuberculosis;
8. HIV antibody test result is positive;
9. Severe infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization due to complications of infection, bacteremia or severe pneumonia;
10. Oral or intravenous therapeutic antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (eg, to prevent urinary tract infections or exacerbations of chronic obstructive pulmonary disease) are eligible to participate in the study.
11. Simultaneous infection with HBV and HCV. Patients with a history of HCV infection but negative PCR results for HCV RNA can be considered HCV-uninfected;
12. Blood pressure control is not ideal, systolic blood pressure >= 150 mmHg, diastolic blood pressure >= 100 mmHg;
13. History of uncorrectable serum potassium, calcium or magnesium electrolyte disturbances;
14. Received major surgery (except diagnosis) within 4 weeks before the start of study treatment or is expected to undergo major surgery during the study period;
15. Major cardiovascular disease within 3 months prior to initiation of study treatment (such as New York Heart Association class II or more severe heart disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment), unstable Arrhythmia, unstable angina or coronary heart disease;
16. History of congenital long QT syndrome or corrected QT interval at screening >500ms (calculated using Fridericia method);
17. There are serious wounds, ulcers or fractures that cannot be healed;
18. Idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia or evidence of active pneumonia on chest computed tomography (CT) images during screening. Radiation pneumonitis in the permissible radiation zone (fibrosis);
19. Current or past autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sj?gren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: patients with prior autoimmune-related hypothyroidism receiving thyroid hormone replacement therapy are eligible for study participation; Patients with controlled type 1 diabetes were eligible to participate in the study; only patients with dermatologically manifested eczema, psoriasis, chronic lichen simplex, or vitiligo (eg, excluding patients with psoriatic arthritis);
20. Previous allogeneic stem cell or solid organ transplantation;
21. Received a live attenuated vaccine within 4 weeks before starting study treatment, or is expected to receive such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab;
22. Malignant tumors other than HCC within 5 years prior to screening, except for those with negligible risk of metastasis or death (eg, 5-year OS rate >90%), such as adequately treated in situ cervical cancer, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer;
23. Central nervous system (CNS) metastases;
24. The patient cannot receive follow-up or is participating in other clinical trials;
25. Subjects deemed unsuitable for inclusion in this study by the investigator.

研究实施时间：

Study execute time：

从 From 2021-08-01 00:00:00至 To 2022-06-30 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2021-08-16 00:00:00 至 To 2021-12-31 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

49

Group：

Experimental group

Sample size：

干预措施：

阿替利珠单抗和贝伐珠单抗联合TACE治疗

干预措施代码：

Intervention：

atilizumab and bevacizumab combined with TACE

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)：

中国人民解放军第二军医大学第三附属医院 

单位级别：

三级甲等 

Institution
hospital：

The Third Affiliated Hospital of the Second Military Medical University of the Chinese people's Liberation Army

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：

Objective response rate

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

总体生存期

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：

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：

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：

疾病进展时间

指标类型：

次要指标

Outcome：

Time to progression

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

疾病缓解持续时间

指标类型：

次要指标

Outcome：

Duration of response

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

手术切除转化率

指标类型：

次要指标

Outcome：

Conversion rate of surgical resection

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

不良反应发生率

指标类型：

副作用指标

Outcome：

Incidence of adverse events

Type：

Adverse events

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

潜在的预测、预后生物标志物

指标类型：

附加指标

Outcome：

Potential predictive or prognostic biomarkers

Type：

Additional 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：

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 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）：

不涉及

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

Not applicable

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

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）：

可联系研究负责人

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

Data during the study are available from the study leader by request.

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：

  2021-08-10 05:20:10