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：	ChiCTR2200057711
最近更新日期： Date of Last Refreshed on：	2022-11-17 22:45:28
注册时间： Date of Registration：	2022-03-15 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	BR105注射液在晚期恶性肿瘤患者的安全性、耐受性、抗肿瘤活性的开放、剂量递增及剂量扩展I期临床研究
Public title：	An open-lable, dose escalation and dose expansion, phase I study of BR105 injection to evaluate the safety, tolerability and antitmor activity in patients with advanced malignant tumors
注册题目简写：
English Acronym：
研究课题的正式科学名称：	BR105注射液在晚期恶性肿瘤患者的安全性、耐受性、抗肿瘤活性的开放、剂量递增及剂量扩展I期临床研究
Scientific title：	An open-lable, dose escalation and dose expansion, phase I study of BR105 injection to evaluate the safety, tolerability and antitmor activity in patients with advanced malignant tumors
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：	林樑	研究负责人：	朱军
Applicant：	Lin Liang	Study leader：	Zhu Jun
申请注册联系人电话： Applicant telephone：	+86 13817156157	研究负责人电话： Study leader's telephone：	+86 13910333346
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：	liang.lin@bioraypharm.com	研究负责人电子邮件： Study leader's E-mail：	zhujun3346@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：	浙江省台州市椒江区疏港大道1号	研究负责人通讯地址：	北京市海淀区阜成路52号
Applicant address：	1 Shugang Avenue, Jiaojiang District, Taizhou, Zhejiang	Study leader's address：	52 Fucheng Road, Haidian District, Beijing
申请注册联系人邮政编码： Applicant postcode：	311400	研究负责人邮政编码： Study leader's postcode：
申请人所在单位：	海正生物制药有限公司
Applicant's institution：	Hisun Biopharmaceutical Co., Ltd.
研究负责人所在单位：
Affiliation of the Leader：

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：	2022YW05+2022YW06	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：	北京肿瘤医院医学伦理委员会
Name of the ethic committee：	Ethics Committee of Beijing Cancer Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2022-02-17 00:00:00
伦理委员会联系人：	张雷
Contact Name of the ethic committee：	Zhang Lei
伦理委员会联系地址：	北京市海淀区阜成路81号
Contact Address of the ethic committee：	81 Fucheng Road, Haidian District, Beijing
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：

北京肿瘤医院

Primary sponsor：

Beijing Cancer Hospital

研究实施负责（组长）单位地址：

北京市海淀区阜成路52号

Primary sponsor's address：

52 Fucheng Road, Haidian District, Beijing

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	北京	市(区县)：
Country：	China	Province：	Beijing	City：
单位(医院)：	北京肿瘤医院	具体地址：	海淀区阜成路52号
Institution hospital：	Beijing Cancer Hospital	Address：	52 Fucheng Road, Haidian District

经费或物资来源：

海正生物制药有限公司

Source(s) of funding：

Hisun Biopharmaceutical Co., Ltd.

研究疾病：

晚期恶性肿瘤

Target disease：

Advanced malignant tumor

研究疾病代码：

Target disease code：

研究类型：

治疗研究

Study type：

Treatment study

研究所处阶段：

I期临床试验

Study phase：

1

研究设计：

单臂

Study design：

Single arm

研究目的：

Ia期：评价BR105注射液单药治疗（单次和多次给药）在晚期恶性肿瘤受试者中的安全性和耐受性，探索最大耐受剂量（MTD）。 Ib期：初步探索BR105注射液单药治疗在选定肿瘤适应症受试者中的抗肿瘤活性，确定II期临床试验推荐剂量（RP2D）。

Objectives of Study：

Phase Ia: To evaluate the safety and tolerability of BR105 injection monotherapy (single and multiple dosing) in subjects with advanced malignancies and to explore the maximum tolerated dose (MTD). Phase Ib: To initially explore the antitumor activity of BR105 injection monotherapy in subjects with selected tumor indications and to determine the recommended dose for Phase II clinical trials (RP2D).

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. Those who voluntarily sign informed consent, understand the nature, purpose and procedure of the experiment and can complete the experiment according to the scheme;
2. Aged 18-75 years (patient to the date of signing the informed consent), gender unlimited;
3. Stage Ia: patients with advanced malignant tumors or relapsed refractory malignant lymphoma who have been confirmed by histopathology or cytology and have failed standard treatment or are intolerant or have no standard effective treatment options; Phase Ib: The Phase Ib dose expansion study will be limited to specific patients based on the results of the Phase Ia trial, which will initially include patients with relapsed refractory B-cell non-Hodgkin lymphoma and patients with advanced gastric cancer;
4. Physical state score of Eastern Tumor Collaboration Group (ECOG) <=1;
5. Expected survival >=3 months;
6. According to the RECIST v1.1 or Lugano 2014 criteria, patients with stage Ia may have no measurable lesion at baseline, and patients with stage Ib may have at least one measurable lesion at baseline (bone metastases only or central nervous system (CNS) only metastases are not accepted as measurable lesions);
7. Patients who have received antitumor therapy in the past should not be enrolled until toxicity from previous therapy has returned to CTCAE v5.0 score <= level 1 or baseline (except for residual hair loss effects);
8. Have adequate organ and bone marrow function (except for patients treated with any cells, growth factors, or blood transfusions within 14 days prior to enrollment), as defined below;
(1) Neutrophil count (Neu) >= 1,500/mm^3 (1.5x10^9/L);
(2) Platelet count (PLT) >=100,000/mm^3 (100x10^9/L);
(3) Hemoglobin (HGB) >=9g/dL (90g/L);
(4) Serum creatinine (Cr) <=1.5 times x upper limit of normal (ULN) or creatinine clearance (Ccr) >= 50 ml/min;
(5) Total bilirubin (TBIL) <=1.5xULN, patients with liver metastasis or liver cancer <=2xULN;
(6) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level <=2.5xULN, patients with liver metastasis or liver cancer should be <=5xULN;
(7) International Standardized ratio (INR) <=1.5, prothrombin time (PT) and activated partial thrombin time (APTT) <=1.5xULN;
9. The serum pregnancy test results of female patients of childbearing age must be negative at the time of admission to this study; Female patients of childbearing age or male patients with a female sexual partner of childbearing age were willing to use appropriate and effective contraceptive methods such as abstinence and double barrier (e.g., condom and diaphragm), oral contraceptives, and IUD placement during the study period and for 6 months after the last test drug administration.

排除标准：

1.已知对试验用药品或其任何辅料过敏；或者对其他单克隆抗体发生过严重过敏反应；
2.既往接受过靶向抗CD47或抗SIRPα药物的治疗；
3.试验用药品首次给药前3个月内有因任何原因导致的溶血性贫血史（包括Evans综合征）或自身免疫性血小板减少史；
4.因血栓高风险正在接受溶栓或抗凝治疗者；
5.在首次研究治疗前接受过以下治疗或药物：
（1）首次试验用药品治疗前28天之内进行过重大手术，或预期在研究期间实施重大手术（因诊断需要进行的组织活检是允许的）；
（2）首次试验用药品治疗前14天之内使用过免疫抑制药物；在没有活动性自身免疫疾病的情况下，允许喷鼻和吸入性皮质类固醇或生理剂量的系统性类固醇激素（即不超过10 mg/d泼尼松或同等药物生理学剂量的其他皮质类固醇）；
（3）首次试验用药品治疗前28天内或计划在研究期间及试验用药品治疗结束后60天内接种减毒活疫苗；
（4）首次试验用药品治疗前28天内接受抗肿瘤治疗（包括化疗、放疗、免疫治疗、内分泌治疗、靶向治疗、生物治疗或者肿瘤栓塞术）；或首次试验用药品治疗前56天内使用过治疗性的放射药剂；
（5）首次试验用药品治疗前28天内参加了其他临床试验且使用了试验相关药物者；
6.有活动性自身免疫性疾病或可能复发的自身免疫性疾病病史，包括但不限于系统性红斑狼疮、银屑病、类风湿性关节炎、炎性肠道疾病、桥本氏甲状腺炎等。除外仅需替代性治疗情况的（如自身免疫性甲状腺炎所致的残留性甲状腺功能减退）；
7.合并中枢神经系统转移癌、无法控制的胸腔积液、心包积液或腹腔积液（留置导管的患者除外)；或无法控制的高钙血症；或合并脊髓压迫；
8.既往2年内患有任何其它恶性肿瘤，不包括完全治愈的宫颈原位癌，皮肤基底细胞或鳞状上皮细胞癌，其他既往经过治疗且研究者判断目前疾病状况稳定的恶性肿瘤，以及研究者判断其他恶性肿瘤可能从本试验获益的；
9.人类免疫缺陷病毒（HIV）抗体阳性；梅毒螺旋体（TP）抗体阳性；丙型肝炎病毒（HCV）抗体阳性，且丙肝病毒RNA定量检测结果大于检测下限；乙肝表面抗原（HBsAg）阳性或乙肝核心抗体（HBcAb）阳性，且乙肝病毒DNA检测结果≥1ⅹ10^3IU/ml；
10.存在严重的控制不佳的伴随疾病者，例如：充血性心力衰竭（NYHA分级II级以上），增加血栓栓塞事件的心律失常或心绞痛，近6个月内进行过冠状动脉支架置入术、血管成形术或冠状动脉旁路移植术，经过治疗未控制的高血压（收缩压≥160mmHg或舒张压≥100mmHg）等；
11.已知异体器官移植史或异体造血干细胞移植史；如果不需要免疫抑制的移植可纳入(如角膜移植、头发移植)；
12.入组前14天内出现任何需要通过静脉输注进行全身治疗的活动性感染；
13.有活动性结核病，或筛选前1年内接受过抗结核治疗；
14.存在有间质性肺病，如间质性肺炎、肺纤维化等，或非感染性肺炎；
15.目前患有影响静脉输注、静脉采血疾病者；
16.存在已知或怀疑不能够遵守研究方案的情况（如精神类药物滥用、酒精依赖、心理障碍或吸毒史）；
17.妊娠或哺乳期女性；
18.研究者认为不适合入组或可能因为其他原因不能完成本试验者。

Exclusion criteria：

1. Known allergy to the test drug or any of its excipients; Or have had a severe allergic reaction to other monoclonal antibodies;
2. Previous therapy with targeted anti-CD47 or anti-SIRPα drugs;
3. A history of hemolytic anemia (including Evans syndrome) or autoimmune thrombocytopenia from any cause within 3 months prior to initial administration of the investigatory drug;
4. Patients who are receiving thrombolytic or anticoagulant therapy due to high risk of thrombosis;
5. Received the following treatments or medications before the initial study treatment:
(1) Major surgery was performed within 28 days prior to treatment with the initial investigational drug, or major surgery is expected to be performed during the study period (tissue biopsies required for diagnosis are permitted);
(2) Use of immunosuppressive drugs within 14 days before treatment with the first experimental drug; In the absence of active autoimmune disease, intranasal and inhaled corticosteroids or systemic steroid hormones at physiological doses are permitted (i.e., no more than 10 mg/ day of prednisone or equivalent drug physiological doses of other corticosteroids);
(3) Live attenuated vaccine received within 28 days before treatment with the first investigational drug or planned during the study period and within 60 days after the end of treatment with the investigational drug;
(4) Receiving antitumor therapy (including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, targeted therapy, biotherapy or tumor embolization) within 28 days prior to treatment with the first investigational drug; Or use of therapeutic radiation within 56 days prior to treatment with the first experimental drug;
(5) Those who have participated in other clinical trials and used trial-related drugs within 28 days prior to the first investigational drug treatment;
6. A history of active or potentially recurrent autoimmune diseases, including but not limited to systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis, etc. Except for those with only alternative treatment (e.g., residual hypothyroidism due to autoimmune thyroiditis);
7. Patients with central nervous system metastases, uncontrollable pleural effusion, pericardial effusion or abdominal effusion (except patients with indwelling catheter); Or uncontrolled hypercalcemia; Or combined with spinal cord compression;
8. Any other malignancies within the previous 2 years, excluding completely cured cervical carcinoma in situ, basal cell or squamous cell carcinoma of the skin, other previously treated malignancies that the investigator determined to be stable at present, and other malignancies that the investigator determined might benefit from the study;
9. Positive for human immunodeficiency virus (HIV) antibodies; Treponema pallidum (TP) antibody positive; Hepatitis C virus (HCV) antibody positive, and HCV RNA quantitative detection results greater than the lower limit of detection; Hepatitis B surface antigen (HBsAg) positive or Hepatitis B core antibody (HBcAb) positive, and hepatitis B virus DNA detection result >=1 10^3IU/ml;
10. There are serious poorly controlled concomitant diseases, such as: congestive heart failure (NYHA Grade II or higher), arrhythmia or angina with increased thromboembolic events, coronary stenting, angioplasty, or coronary artery bypass grafting within the last 6 months, treatment of uncontrolled hypertension (systolic blood pressure >=160mmHg or diastolic blood pressure >=100mmHg);
11. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; Grafts that do not require immunosuppression can be included (e.g., corneal transplantation, hair transplantation);
12. Any active infection requiring systemic treatment by intravenous infusion during the first 14 days of enrollment;
13. Have active TB or have received anti-TB treatment within 1 year prior to screening;
14. There is interstitial lung disease, such as interstitial pneumonia, pulmonary fibrosis, etc., or non-infectious pneumonia;
15. Currently suffering from diseases affecting intravenous infusion and venous blood collection;
16. There is a known or suspected inability to comply with the research programme (e.g. psychotropic substance abuse, alcohol dependence, psychological disorder or history of drug use);
17. Pregnant or lactating patients;
18. Those who are considered unsuitable for inclusion or may not be able to complete the study for other reasons.

研究实施时间：

Study execute time：

从 From 2022-03-01 00:00:00至 To 2025-03-03 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2022-03-01 00:00:00 至 To 2023-06-30 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	162
Group：	Experimental group	Sample size：	162
干预措施：	静脉输注BR105	干预措施代码：
Intervention：	Intravenous injection of BR105	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	北京	市(区县)：
Country：	China	Province：	Beijing	City：
单位(医院)：	北京肿瘤医院	单位级别：	三级甲等
Institution hospital：	Beijing Cancer Hospital	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	耐受性	指标类型：	主要指标
Outcome：	Tolerance	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	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	抗肿瘤活性	指标类型：	主要指标
Outcome：	Antitumor activity	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	药代动力学评价	指标类型：	次要指标
Outcome：	Evaluation of pharmacokinetics	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	免疫原性评价	指标类型：	次要指标
Outcome：	Evaluation of immunogenicity	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	抗肿瘤活性评价	指标类型：	次要指标
Outcome：	Evaluation of antitumor activity	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：
Sample Name：	Blood	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：	尿液	组织：
Sample Name：	Urine	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	75	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）：

非随机

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

Non-randomization

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）：	点击下载
Calculated Results after the Study Completed(upload file)：	download

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）：	ResMan 临床试验公共管理平台, http://www.medresman.org.cn
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	ResMan， http://www.medresman.org.cn
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：	本研究采用电子病例报告表（eCRF），eCRF 是一个经验证的、符合所有法规要求的数据管理系统，内容将由研究者或受其委派并经过培训的人员通过临床电子数据采集与管理系统（EDC）填写。研究开始前eCRF在EDC系统内设置完毕，并分配给各个研究中心负责填写eCRF表的研究者和/或其授权人员每人一个账号，申办方将向研究中心提供关于相应eCRF 填写的培训和帮助文本。将由数据管理方负责病例报告表和统计分析计划书的要求创建数据管理计划。将在数据收集开始前公布数据管理计划，描述所有功能、过程和数据收集、清理以及验证的规范，并提供数据系统和数据库的上线使用。将按照数据管理第三方标准操作规程进行数据录入。将采用MedDRA和世界卫生组织（WHO）药物词典，对AE、病史和合并用药进行医学编码。申办方将监督本研究的数据管理。申办方将产生一份EDC研究规范文件，描述将对数据进行的质量检查。如果出现数据差异，申办方将要求研究中心作数据澄清，研究中心可以在EDC系统中以电子的形式解决数据疑问。当所有数据已处理、疑问已解决、医学编码已完成以及方案违背和数据列表审查发现的任何问题解决，经申办方、研究者、统计分析人员等审核确认后将锁定数据库。将按照申办方的标准程序对数据系统备份以及研究数据记录进行保存。最终数据库将根据海正生物制药有限公司的数据规范进行构建。
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	This study adopts electronic case report form (ECRF). ECRF is a verified data management system that meets all regulatory requirements. The content will be filled in by the researcher or its appointed and trained personnel through the clinical electronic data acquisition and management system (EDC). Before the start of the study, the ECRF is set up in the EDC system and assigned to the researchers and / or their authorized personnel responsible for filling in the ECRF form in each research center. The sponsor will provide the research center with training and help text on the filling in of the corresponding ECRF. The data manager will be responsible for creating the data management plan according to the requirements of the case report form and statistical analysis plan. The data management plan will be published before data collection, describing all functions, processes and specifications for data collection, cleaning and verification, and providing online use of data system and database. The data will be entered according to the standard operating procedures of the third party of data management. MedDRA and the World Health Organization (who) drug dictionary will be used to medically code AE, medical history and concomitant drugs. The sponsor will supervise the data management of this study. The sponsor will produce an EDC study specification document describing the quality checks to be performed on the data. In case of data discrepancy, the sponsor will ask the Research Center for data clarification, and the research center can solve the data query electronically in the EDC system. When all data have been processed, questions have been solved, medical coding has been completed, and any problems found in protocol violation and data list review have been solved, the database will be locked after being reviewed and confirmed by the sponsor, researchers, statistical analysts, etc. The data system backup and research data records will be saved in accordance with the standard procedures of the sponsor. The final database will be constructed according to the data specification of Haizheng biopharmaceutical Co., Ltd.
数据与安全监察委员会： Data and Safety Monitoring Committee：	无/No
注册人： Name of Registration：	2022-03-15 23:38:47