ChiCTR2000039748 版本V1.3 版本创建时间2021/02/13 16:11:24 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：

ChiCTR2000039748 

最近更新日期：

Date of Last Refreshed on：

2021-02-13 16:09:34 

注册时间：

Date of Registration：

2020-11-07 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

贺加贝医师：该研究尚未获得伦理委员会批准，请于批准后再开始纳入参试者，并与我们联系上传批件。 放射性粒子近距离治疗联合信迪利单抗治疗难治性实体恶性肿瘤：一项前瞻性Ⅱ期临床研究

Public title：

Radioactive particle brachytherapy combined with sintilimab in the treatment of refractory solid malignant tumors: a prospective phase II clinical study

注册题目简写：

English Acronym：

研究课题的正式科学名称：

放射性粒子近距离治疗联合信迪利单抗治疗难治性实体恶性肿瘤：一项前瞻性Ⅱ期临床研究

Scientific title：

Radioactive particle brachytherapy combined with sintilimab in the treatment of refractory solid malignant tumors: a prospective phase II clinical study

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：

贺加贝 

研究负责人：

王若雨 

Applicant：

He Jia-Bei 

Study leader：

Wang Ruo-Yu 

申请注册联系人电话：

Applicant telephone：

+86 18698612120

研究负责人电话：

Study leader's telephone：

+86 411-62893203

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：

hejiabei1128@126.com

研究负责人电子邮件：

Study leader's E-mail：

wangruoyu1963@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：

辽宁省大连市中山区解放街6号

研究负责人通讯地址：

辽宁省大连市中山区解放街6号

Applicant address：

6 Jiefang Street, Zhongshan District, Dalian, Liaoning

Study leader's address：

6 Jiefang Street, Zhongshan District, Dalian, Liaoning

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：

大连大学附属中山医院

Applicant's institution：

The Affiliated Zhongshan Hospital of Dalian University

研究负责人所在单位：

大连大学附属中山医院

Affiliation of the Leader：

The Affiliated Zhongshan Hospital of Dalian University

是否获伦理委员会批准：

否/No

Approved by ethic committee：

No

伦理委员会批件文号：

Approved No. of ethic committee：

伦理委员会批件附件：

Approved file of Ethical Committee：

批准本研究的伦理委员会名称：

Name of the ethic committee：

伦理委员会批准日期：

Date of approved by ethic committee：

2013-08-26 00:00:00

伦理委员会联系人：

Contact Name of the ethic committee：

伦理委员会联系地址：

Contact Address of the ethic committee：

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：

大连大学附属中山医院

Primary sponsor：

The Affiliated Zhongshan Hospital of Dalian University

研究实施负责（组长）单位地址：

辽宁省大连市中山区解放街6号

Primary sponsor's address：

6 Jiefang Street, Zhongshan District, Dalian, Liaoning

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

辽宁

市(区县)：

大连

Country：

China

Province：

Liaoning

City：

Dalian

单位(医院)：

大连大学附属中山医院

具体地址：

中山区解放街6号

Institution
hospital：

The Affiliated Zhongshan Hospital of Dalian University

Address：

6 Jiefang Street, Zhongshan District

经费或物资来源：

医院资助

Source(s) of funding：

Hospital funding

Target disease：

Refractory solid malignant tumor

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：

放射性粒子近距离治疗特有的高剂量梯度及持续低剂量率照射是增强照射部位免疫原性反应的最佳方法，可通过DNA损伤信号通路调节肿瘤微环境中的免疫细胞，以触发比常规外放疗更多的免疫刺激。本项研究主要的研究目的是评价放射性粒子近距离治疗联合信迪利单抗治疗难治性实体恶性肿瘤的有效性与安全性，并探索潜在预测疗效的生物靶标。  

Objectives of Study：

The unique high-dose gradient and continuous low-dose rate irradiation of radioactive particle brachytherapy are the best methods to enhance the immunogenic response of the irradiated site. It can regulate immune cells in the tumor microenvironment through DNA damage signaling pathways to trigger more immune stimulation than conventional external radiotherapy.The main purpose of this study is to evaluate the effectiveness and safety of radioactive particle brachytherapy combined with sintilimab in the treatment of refractory solid malignant tumors, and to explore potential biological targets for predicting the efficacy.

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.在实施任何试验相关流程之前，签署书面知情同意；
2.年龄≥18周岁且≤80周岁；
3.组织学或细胞学证实的恶性肿瘤，需符合以下三种情况：
1)至少两种全身系统性治疗方案后出现进展或不耐受，即≥2线治疗，定义为难治性；
2)转移病灶数量≤4个，定义为寡转移；
4.根据实体肿瘤疗效评价标准（RECIST v1.1版），至少有一处影像学可测量病灶；
5.SABT可完全放射消融其中至少一个病灶；
6.允许无症状或经局部治疗后症状稳定的脑转移患者入组，只要患者满足以下条件：
1)中枢神经系统之外有可测量病灶
2)无中枢神经系统症状或至少2周内症状无加重
3)无需糖皮质激素治疗或首次研究药物给药前3天内停用糖皮质激素治疗者
7.ECOG评分0-2分；
8.预期生存时间>3个月；
9.足够器官功能，受试者需满足如下实验室指标：
1)近14天未使用粒细胞集落刺激因子的情况下，中性粒细胞绝对值（ANC）≥1.5x10^9/L；
2)近14天未输血的情况下，血小板≥100×10^9/L；
3)近14天内无输血或使用促红细胞生成素的情况下，血红蛋白>9g/dL；
4)总胆红素≤1.5×正常值上限（ULN）；或总胆红素>ULN但直接胆红素≤ ULN
5)天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）在≤2.5×ULN（有肝转移的患者允许ALT 或AST ≤5×ULN）；
6)血肌酐≤1.5×ULN并且肌酐清除率（采用Cockcroft-Gault 公式计算）≥60 ml/min；
7)凝血功能良好，定义为国际标准化比值（INR）或凝血酶原时间（PT）≤1.5倍ULN；
8)甲状腺功能正常，定义为促甲状腺激素（TSH）在正常范围内。如基线TSH超出正常范围，如果总T3（或FT3）及FT4在正常范围内的受试者亦可入组；
9)心肌酶谱在正常范围内（如研究者综合判断为不具有临床意义的单纯实验室异常也允许入组）；
10.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；
11.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. Aged >= 18 years and <= 80 years;
3. Malignant tumors confirmed by histology or cytology shall meet the following three conditions:
1) Progression or intolerance after at least two systemic systemic treatment options, that is, >= 2 line treatment, is defined as refractory;
2) The number of metastatic lesions <= 4, which is defined as oligometastasis;
4. According to the evaluation criteria for the efficacy of solid tumors (RECIST v1.1 version), there is at least one imaging measurable lesion;
5. SABT can completely ablate at least one of the lesions;
6. Patients with brain metastases who are asymptomatic or have stable symptoms after local treatment are allowed to join the group, as long as the patients meet the following conditions:
1) There are measurable lesions outside the central nervous system
2) No symptoms of central nervous system or no worsening of symptoms for at least 2 weeks
3) Those who do not need glucocorticoid therapy or stop glucocorticoid therapy within 3 days before the first study drug
7. ECOG score 0-2 points;
8. Expected survival time> 3 months;
9. Sufficient organ function, subjects need to meet the following laboratory indicators:
1) The absolute value of neutrophils (ANC) >= 1.5 x 10^9/L when no granulocyte colony stimulating factor is used in the past 14 days;
2) In the case of no blood transfusion in the past 14 days, platelets >= 100 x 10^9/L;
3) In the past 14 days without blood transfusion or erythropoietin, hemoglobin > 9g/dL;
4) Total bilirubin <= 1.5 x upper limit of normal (ULN); or total bilirubin>ULN but direct bilirubin <= ULN;
5) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are within <= 2.5 x ULN (patients with liver metastases allow ALT or AST <= 5 x ULN);
6) Serum creatinine <= 1.5 x ULN and creatinine clearance rate (calculated by Cockcroft-Gault formula) >= 60 ml/min;
7) Good coagulation function, defined as International Normalized Ratio (INR) or Prothrombin Time (PT) <= 1.5 times ULN;
8) Normal thyroid function is defined as thyroid stimulating hormone (TSH) within the normal range. If the baseline TSH is outside the normal range, subjects whose total T3 (or FT3) and FT4 are within the normal range can also be included in the group;
9) Myocardial enzyme spectrum is within the normal range (if the investigator comprehensively judges that simple laboratory abnormalities are not clinically significant, they are also allowed to be included);
10. For female subjects of childbearing age, a urine or serum pregnancy test and the result should be negative within 3 days before 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. Women of non-bearing age are defined as at least 1 year after menopause, or have undergone surgical sterilization or hysterectomy;
11. 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% during the entire treatment period until 120 days after the last study drug administration.

排除标准：

1.既往接受过下列疗法：抗PD-1、抗PD-L1或抗PD-L2药物或者针对另一种刺激或协同抑制T细胞受体（例如，CTLA-4、OX-40、CD137）的药物；
2.接受过以下治疗：
1)治疗前3周内接受过全身性抗肿瘤治疗，如化疗、靶向治疗、免疫治疗（包括以抗肿瘤为适应症的中草药治疗）等；
2)治疗前4周内接受过任何研究性药物治疗；
3)治疗前4周内接受过大剂量免疫抑制药物（全身性糖皮质激素超过10mg/天泼尼松或其等效的剂量）；
4)治疗前4周内接受过减毒活疫苗（或计划在研究期间接受减毒活疫苗）；
5)治疗前4周内接受过大型手术，或未愈合的手术伤口、溃疡或骨折。
3.存在临床上不可控制的胸腔积液/腹腔积液（不需要引流积液或停止引流3天积液无明显增加的患者可以入组）；
4.在治疗前6个月内接受过大于30Gy的胸部放射治疗或在治疗前7天内接受过30Gy及更小剂量的姑息性放射治疗的受试者（允许骨病变或颅内病变的姑息性放射治疗）；
5.有症状的中枢神经转移和/或癌性脑膜炎。对于无症状脑转移或经过脑转移病灶治疗后症状稳定的患者，只要符合下列标准，可参与本项研究：中枢神经系统之外有可测量的病灶，无中脑、脑桥、小脑、延髓或脊髓转移，无颅内出血史，目前无需糖皮质激素治疗；
6.已知异体器官移植（角膜移植除外）或异体造血干细胞移植；
7.已知对本研究药物信迪利单抗活性成分或辅料过敏者;
8.在开始治疗前，尚未从任何干预措施引起的毒性和/或并发症中充分恢复（即，≤1级或达到基线，不包括乏力或脱发）；
9.已知人类免疫缺陷病毒（HIV）感染史（即HIV 1/2抗体阳性）；
10.未经治疗的活动性乙肝（定义为HBsAg阳性同时检测到HBV-DNA拷贝数大于所在研究中心检验科正常值上限）；
注：符合下列标准的乙肝受试者亦可入组：
1)首次给药前HBV病毒载量<1000拷贝/ml（200 IU/ml），受试者应在整个研究化疗药物治疗期间接受抗HBV治疗避免病毒再激活
2)对于抗HBc（+）、HBsAg（-）、抗HBs（-）和HBV病毒载量（-）的受试者，不需要接受预防性抗HBV治疗，但是需要密切监测病毒再激活
12.活动性的HCV感染受试者（HCV抗体阳性且HCV-RNA水平高于检测下限）；
13.首次给药之前（第1周期，第1天）30天内接种过活疫苗；
14.妊娠或哺乳期妇女；
15.存在任何严重或不能控制的全身性疾病，例如：
1)静息心电图在节律、传导或形态上出现有重大且症状严重难以控制的异常，如完全性左束支传导阻滞，Ⅱ度以上心脏传导阻滞，室性心律失常或心房颤动；
2)不稳定型心绞痛，充血性心力衰竭，纽约心脏病协会（NYHA）分级≥ 2 级的慢性心衰；
3)入组前6个月内出现心肌梗死；
4)血压控制不理想（收缩压＞140 mmHg，舒张压＞90 mmHg）；
5)首次给药前1年内存在需要糖皮质激素治疗的非感染性肺炎病史，或当前存在临床活动性间质性肺病；
6)活动性肺结核；
7)存在需要全身性治疗的活动性或未能控制的感染；
8)存在临床活动性憩室炎、腹腔脓肿、胃肠道梗阻；
9)肝脏疾病如肝硬化、失代偿性肝病、急性或慢性活动性肝炎；
10)糖尿病控制不佳（空腹血糖（FBG）＞10mmol/L）；
11)尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0 g者；
12)存在精神障碍且无法配合治疗的患者；
16.有可能干扰试验结果、妨碍受试者全程参与研究的病史或疾病证据、治疗或实验室检查值异常，或研究者认为其他不适合入组的情况研究者认为存在其他潜在风险不适合参加本研究。

Exclusion criteria：

1. Have received the following therapies in the past: anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs or for another stimulating or synergistic inhibition of T cell receptors (for example, CTLA-4, OX-40, CD137) drug;
2. Have received the following treatments:
1) Received systemic anti-tumor therapy, such as chemotherapy, targeted therapy, immunotherapy (including Chinese herbal medicine with anti-tumor indications), etc. within 3 weeks before treatment;
2) Have received any investigational drug treatment within 4 weeks before treatment;
3) Receiving large doses of immunosuppressive drugs within 4 weeks before treatment (systemic glucocorticoids exceeding 10mg/day prednisone or its equivalent dose);
4) Received live attenuated vaccine within 4 weeks before treatment (or plan to receive live attenuated vaccine during the study period);
5) Have received major surgery within 4 weeks before treatment, or have unhealed surgical wounds, ulcers or fractures.
3. There is clinically uncontrollable pleural effusion/abdominal effusion (patients who do not need to drain the effusion or stop drainage for 3 days without a significant increase in effusion can be included);
4. Subjects who have received thoracic radiotherapy of greater than 30Gy within 6 months before treatment or palliative radiotherapy of 30Gy or less within 7 days before treatment (allowing the palliative of bone lesions or intracranial lesions) Radiation Therapy);
5. Symptomatic central nerve metastasis and/or cancerous meningitis. For asymptomatic brain metastases or patients with stable symptoms after brain metastasis treatment, they can participate in this study as long as they meet the following criteria: there are measurable lesions outside the central nervous system, without midbrain, pons, cerebellum, medulla oblongata or spinal cord Metastasis, no history of intracranial hemorrhage, no glucocorticoid treatment is currently needed;
6. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
7. Those who are known to be allergic to the active ingredients or excipients of Sintilizumab;
8. Before starting treatment, have not fully recovered from toxicity and/or complications caused by any intervention (ie, ≤ Grade 1 or reach baseline, excluding fatigue or hair loss);
9. Known human immunodeficiency virus (HIV) infection history (ie HIV 1/2 antibody positive);
10. Untreated active hepatitis B (defined as HBsAg positive and the number of HBV-DNA copies detected at the same time is greater than the upper limit of the normal value of the laboratory department of the research center);
Note: Hepatitis B subjects who meet the following criteria can also be included in the group:
1) HBV viral load <1000 copies/ml (200 IU/ml) before the first administration, subjects should receive anti-HBV treatment during the entire study chemotherapy drug treatment period to avoid virus reactivation
2) Subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-) do not need to receive preventive anti-HBV treatment, but need to closely monitor virus reactivation
12. Active HCV infected subjects (HCV antibody-positive and HCV-RNA level is higher than the lower limit of detection);
13. Live vaccines have been vaccinated within 30 days before the first administration (cycle 1, day 1);
14. Pregnant or lactating women;
15. There are any serious or uncontrollable systemic diseases, such as:
1) The resting electrocardiogram has major abnormalities in rhythm, conduction, or morphology that are severe and difficult to control, such as complete left bundle branch block, heart block above Ⅱ degree, ventricular arrhythmia or atrial fibrillation;
2) Unstable angina pectoris, congestive heart failure, and chronic heart failure of New York Heart Association (NYHA) grade ≥ 2;
3) Myocardial infarction occurred within 6 months before enrollment;
4) Unsatisfactory blood pressure control (systolic blood pressure>140 mmHg, diastolic blood pressure>90 mmHg);
5) A history of non-infectious pneumonia requiring glucocorticoid treatment within 1 year before the first administration, or current clinically active interstitial lung disease;
6) Active tuberculosis;
7) There are active or uncontrolled infections that require systemic treatment;
8) There is clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction;
9) Liver diseases such as liver cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
10) Diabetes is poorly controlled (fasting blood glucose (FBG)> 10mmol/L);
11) Urine routines suggest that urine protein is ≥++, and the 24-hour urine protein quantitative is confirmed to be greater than 1.0 g;
12) Patients with mental disorders who cannot cooperate with treatment;
16. The medical history or disease evidence, abnormal treatment or laboratory test values ??that may interfere with the test results, prevent the subject from participating in the study, or the investigator believes that it is not suitable for inclusion this research.

研究实施时间：

Study execute time：

从 From 2020-11-07 00:00:00至 To 2022-11-07 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2020-11-07 00:00:00 至 To 2023-11-07 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

44

Group：

experimental group

Sample size：

干预措施：

立体定向近距离放疗（SABT）联合免疫检查点抑制剂-信迪利单抗

干预措施代码：

Intervention：

Stereotactic brachytherapy (SABT) combined with immune checkpoint inhibitor-sintilimab

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 辽宁 

市(区县)：

 大连 

Country：

China 

Province：

Liaoning 

City：

Dalian 

单位(医院)：

大连大学附属中山医院 

单位级别：

三级甲等 

Institution
hospital：

The Affiliated Zhongshan Hospital of Dalian University

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：

无进展生存期

指标类型：

主要指标

Outcome：

Progression-free survival

Type：

Primary 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：

主要指标

Outcome：

Disease control 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：

总生存期

指标类型：

主要指标

Outcome：

Overall survival

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：

肿瘤组织

组织：

Sample Name：

Tumor samples

Tissue：

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：

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：

尚未开始

Not yet recruiting

年龄范围：

Participant age：
最小 Min age 18 岁 years
最大 Max age 80 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）：

未使用

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

Not use

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：

Blinding：

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）：

通过本平台公布

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

Through this platform

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：

我们通过纸质版CRF进行数据采集及管理

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

Data collection and Managemnt from 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：

  2020-11-07 23:57:11