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：	ChiCTR2200060059
最近更新日期： Date of Last Refreshed on：	2023-03-06 11:17:30
注册时间： Date of Registration：	2022-05-16 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	放疗续贯免疫化疗治疗原发难治弥漫大B细胞淋巴瘤的开放、单臂、多中心、II期临床研究
Public title：	Hypofractionated radiotherapy followed by immunochemotherapy as salvage therapy in patients with primary refractory diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial
注册题目简写：
English Acronym：
研究课题的正式科学名称：	放疗续贯免疫化疗治疗原发难治弥漫大B细胞淋巴瘤的开放、单臂、多中心、II期临床研究
Scientific title：	Hypofractionated radiotherapy followed by immunochemotherapy as salvage therapy in patients with primary refractory diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial
研究课题代号(代码)： Study subject ID：	FMUUH-DLBCL-2201
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：	杨勇	研究负责人：	徐本华
Applicant：	Yang Yong	Study leader：	Xu Benhua
申请注册联系人电话： Applicant telephone：	+86 18813019084	研究负责人电话： Study leader's telephone：	+86 13365910602
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：	dr_yangyong1983@163.com	研究负责人电子邮件： Study leader's E-mail：	benhuaxu@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：	福建省福州市新权路29号	研究负责人通讯地址：	福建省福州市新权路29号
Applicant address：	29 Xinquan Road, Fuzhou, Fujian	Study leader's address：	29 Xinquan Road, Fuzhou, Fujian
申请注册联系人邮政编码： Applicant postcode：	350001	研究负责人邮政编码： Study leader's postcode：	350001
申请人所在单位：	福建医科大学附属协和医院
Applicant's institution：	Fujian Medical University Union Hospital
研究负责人所在单位：	福建医科大学附属协和医院
Affiliation of the Leader：	Fujian Medical University Union Hospital

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：	2022YF019-01	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：	福建医科大学附属协和医院伦理委员会
Name of the ethic committee：	Ethics Committee of Fujian Medical University Union Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2022-03-31 00:00:00
伦理委员会联系人：	林兆函
Contact Name of the ethic committee：	Lin Zhaohan
伦理委员会联系地址：	福建省福州市新权路29号
Contact Address of the ethic committee：	29 Xinquan Road, Fuzhou, Fujian
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 591 86218329	伦理委员会联系人邮箱： Contact email of the ethic committee：	Email:xhyyllwyh@163.com

研究实施负责（组长）单位：

福建医科大学附属协和医院

Primary sponsor：

Fujian Medical University Union Hospital

研究实施负责（组长）单位地址：

福建省福州市新权路29号

Primary sponsor's address：

29 Xinquan Road, Fuzhou, Fujian

试验主办单位(项目批准或申办者)：

Secondary sponsor：

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)：	福建医科大学附属协和医院	具体地址：	新权路29号
Institution hospital：	Fujian Medical University Union Hospital	Address：	29 Xinquan Road

经费或物资来源：

PD1单抗由广州誉衡生物提供

Source(s) of funding：

PD1 monoclonal antibody was provided by Guangzhou Gloria Biosciences Co., Ltd.

研究疾病：

弥漫大B细胞淋巴瘤

Target disease：

Diffuse Large B-cell Lymphoma (DLBCL)

研究疾病代码：

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：

评价放疗续贯R-GemOx联合PD-1单抗4个周期免疫化疗在原发难治DLBCL患者的完全缓解率（complete response，CR）。

Objectives of Study：

The aim of this study was to evaluate the complete response rate of hypofractionated radiotherapy followed by 4 cycles R-GemOx+PD1 monoclonal antibody in refractory DLBCL.

药物成份或治疗方案详述：

赛帕利单抗：240 mg/次，静脉滴注 45 min（不得少于 45 min）；放疗前及每周期化疗第 1 天给药，每 3周为一个给药周期。利妥昔单抗：375mg/m^2，d2，初次静脉滴注推荐起始滴注速度为50mg/h；最初60分钟过后，可每30分钟增加50mg/h，直至最大速度400mg/h。以后的滴注,利妥昔单抗滴注的开始速度可为100mg/h，每30分钟增加100mg/h，直至最大速度400mg/h。吉西他滨：1000mg/m^2，d3，氯化钠注射液是唯一被允许用于重新溶解吉西他滨无菌粉末的溶液。根据药物的溶解性，重新溶解后吉西他滨浓度不应超过40mg/ml。奥沙利铂：100mg/m^2，d3，加入250～500ml 5％葡萄糖溶液中输注2～6个小时。免疫化疗采用同步方案，每三周为一个周期，放疗后共用4个周期。直到出现下列情况为止：疾病进展、毒性不能耐受或方案规定的其他原因。

Description for medicine or protocol of treatment in detail：

Cepalizumab: 240 mg/ time, intravenously for 45 min (not less than 45 min); The drug was given before radiotherapy and on the first day of each chemotherapy cycle, and every 3 weeks was an administration cycle. Rituximab: 375mg/m^2, d2, initial intravenous infusion rate of 50mg/h is recommended; After the first 60 minutes, increase by 50mg/h every 30 minutes until the maximum speed is 400mg/h. For future infusions, rituximab infusions may be started at 100mg/h and increased by 100mg/h every 30 minutes until the maximum rate is 400mg/h. Gemcitabine: 1000mg/m^2, d3, and sodium chloride injection are the only solutions approved for re-dissolving Gemcitabine sterile powder. Depending on the solubility of the drug, gemcitabine concentration should not exceed 40mg/ml after redissolution. Oxaliplatin: 100mg/m^2, d3, added to 250 to 500ml 5% glucose solution infusion for 2 to 6 hours. A synchronous regimen was adopted for immunochemotherapy, with one cycle every three weeks and four cycles after radiotherapy. Until the occurrence of disease progression, toxicity intolerance or other reasons specified in the protocol.

纳入标准：

Inclusion criteria

1. Diffuse large B-cell lymphoma (DLBCL-NOS) was histologically confirmed;
2. No gender limit, aged 18-75 years;
3. The physical state score of the Eastern Tumor Cooperative Group (ECOG) was 0-2;
4. Subjects must be subjects who have not achieved CR after first-line R-CHOP 4-6 cycles of chemotherapy (refractory to treatment);
5. Evaluable lesions in PET/CT;
6. Life expectancy >=12 weeks;
7. Agree to perform PET/CT evaluation before and after salvage treatment;
8. All screening period laboratory tests are required by the programme and need to be conducted within 14 days prior to inclusion. The values of laboratory tests performed by screening must meet the following criteria:
(1) All routine blood tests met the following criteria (no blood transfusion, no G-CSF, no drug correction within 14 days before screening) : Hb>=90g/L; ANC>=1.5x10^9/L; PLT>=70x10^9/L;
(2) Biochemical examination all met the following criteria: TBIL < 1.5x upper limit of normal range (ULN); ALT and AST<=2.5 x ULN; Serum Cr<=1.25xULN or endogenous creatinine clearance >=45 mL/min (Cockcroft-Gault formula);
(3) Coagulation function (unless subject is receiving anticoagulant therapy and coagulation parameters (PT/INR and APTT) at screening are within the range expected with anticoagulant therapy) : INR <=1.5xULN; Activated partial thromboplastin time (APTT) <=1.5xULN;
9. Women with a potential for pregnancy must have a negative serum pregnancy test within 7 days before the first dose and be willing to use a highly effective method for the duration of the trial and for 120 days after the last dose of the trial drug. Male subjects with a partner of a woman of reproductive age should be surgically sterilized or consent to a highly effective method of contraception during the trial period and 120 days after the last test drug administration;
10. The subjects voluntarily joined the study, signed the informed consent, had good compliance, and cooperated with follow-up.

排除标准：

1.已知患有中枢神经系统（CNS）侵犯；
2.已知骨髓受侵；
3.病史和合并症：
(1)受试者存在任何活动性、已知或可疑自身免疫疾病。允许入组处于稳定状态，不需要全身免疫抑制剂治疗的受试者；
(2)给予研究药物前 14 天内，要求使用皮质类固醇（> 10 mg/天的泼尼松或等价物）或其他免疫抑制剂进行系统治疗的受试者。在没有活动性自身免疫疾病的情况下，允许吸入或局部使用类固醇和剂量> 10 mg/天泼尼松疗效剂量的肾上腺激素替代；
(3)给予研究药物前的 3 个月内用过抗肿瘤疫苗或其他具有免疫刺激作用的抗肿瘤治疗；
(4)以前用过抗 PD-1 抗体、抗 PD-L1 抗体、抗 PD-L2 抗体或抗 CTLA-4 抗体治疗（或作用于 T 细胞协同刺激或检查点通路的任何其他抗体）；
(5)患者正在参加其他临床研究或距离前一项临床研究结束时间不足 4 周；
(6)已知间质性肺炎病史或高度怀疑有间质性肺炎的患者；或可能会干扰可疑的药物相关肺毒性的检测或处理的患者；
(7)有其他恶性肿瘤病史；但进行了可能的治愈性治疗且自治疗开始后 5 年内无疾病复发的皮肤基底细胞癌、表浅膀胱癌、皮肤鳞状细胞癌或原位宫颈癌的患者除外；
(8)先前接受放疗、免疫治疗等；
(9)做过大手术或有严重创伤的受试者在入组之前，手术或创伤的影响已消除不足14 天；
(10)活动性肺结核的患者需排除；
(11)需要全身治疗的严重急性或慢性感染；
(12)随机前 2 个月内存在明显的咳鲜血、或日咯血量达半茶勺（2.5ml）或以上者；
(13)随机前 3 个月内出现过显著临床意义的出血症状或具有明确的出血倾向，如消化道出血、出血性胃溃疡、基线期大便潜血++及以上，或患有脉管炎等；
(14)随机前 6 个月内发生的动/静脉血栓事件，如脑血管意外（包括暂时性缺血性发作、脑出血、脑梗塞）、深静脉血栓及肺栓塞等；
(15)已知存在的遗传性或.获得性出血及血栓倾向（如血友病人，凝血机能障碍，血小板减少，脾功能亢进等）；
(16)患有高血压，且经降压药物治疗无法获得良好控制（收缩压≥140 mmHg 或者舒张压≥90 mmHg）；
(17)患有心力衰竭（纽约心脏病协会标准 III 级或 IV 级）且尽管接受了适当的药物治疗，冠状动脉病控制不良或心律失常不良、或筛选前 6 个月内有心肌梗死病史的患者；
(18)给予研究药物前 4 周内有过活疫苗接种，允许接受针对季节性流感，注射用药的灭活病毒疫苗，但是不允许接受鼻内用药的减毒活流感疫苗；
4.查体和实验室检查所见：
(1)已知有人类免疫缺陷病毒（HIV）检查阳性病史或已知有获得性免疫缺陷综合征（艾滋病）；
(2)未经治疗的活动性肝炎（乙肝：HBsAg 阳性且 HBV DNA≥ 500 IU/mL；丙肝： HCV RNA 阳性且肝功能异常）；合并乙肝及丙肝共同感染；
(3)尿常规提示尿蛋白≥++，或证实24小时尿蛋白量≥1.0 g；
5.经研究者判断，患者可能有其他可能导致本研究被迫中途终止的因素，如其他的严重疾病或严重的实验室检查异常或伴有其他会影响到受试者的安全，或试验资料及样品收集的家庭或社会等因素。

Exclusion criteria：

1. Known central nervous system (CNS) aggression;
2. Known bone marrow invasion;
3. Medical history and complications:
(1) Subject has any active, known, or suspected autoimmune disease. Subjects who were in stable condition and did not require systemic immunosuppressive therapy were allowed to be enrolled;
(2) Subjects requiring systemic therapy with corticosteroids (> 10 mg/ day of prednisone or equivalent) or other immunosuppressant within 14 days prior to study drug administration. In the absence of active autoimmune disease, inhaled or topical steroid use and adrenal hormone replacement at doses > 10 mg/ day of prednisone efficacy dose are permitted;
(3) Anti-tumor vaccine or other anti-tumor therapy with immune stimulation has been used within 3 months before the study drug is given;
(4) Previous treatment with anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, or anti-ctLA-4 antibodies (or any other antibodies acting on the T-cell co-stimulation or checkpoint pathway);
(5) Subjects are participating in other clinical studies or less than 4 weeks after the end of the previous clinical study;
(6) Subjects with known or highly suspected history of interstitial pneumonia; Or may interfere with the detection or management of suspected drug-related pulmonary toxicity;
(7) History of other malignant tumors; Except in subjects who have had potentially curable therapy and have not had disease recurrence for 5 years since treatment began;
(8) Prior radiotherapy, immunotherapy, etc.;
(9) For subjects with major surgery or severe trauma, the effects of surgery or trauma had been resolved less than 14 days before enrollment;
(10) Subjects with active tuberculosis should be excluded;
(11) Severe acute or chronic infections requiring systemic treatment;
(12) Obvious blood coughing or daily hemoptysis of half a teaspoon (2.5ml) or more in the 2 months before randomization;
(13) Had clinically significant bleeding symptoms or definite bleeding tendency within 3 months before randomization, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ or above, or vasculitis;
(14) Arterial/venous thrombosis events occurred within 6 months before randomization, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, pulmonary embolism, etc.
(15) Hereditary or known existence. Acquired bleeding and thrombotic tendencies (e.g., hemophiliacs, coagulation disorders, thrombocytopenia, hyperplenism, etc.);
(16) Have hypertension that is not well controlled by antihypertensive medication (systolic blood pressure >=140 mmHg or diastolic blood pressure >=90 mmHg);
(17) Subjects with heart failure (New York Heart Association standard Class III or IV), poor coronary artery disease control or arrhythmia, or a history of myocardial infarction in the 6 months prior to screening despite receiving appropriate medication;
(18) Live vaccination within 4 weeks prior to administration of the study drug. Inactivated virus vaccine administered injectable for seasonal influenza is allowed, but live attenuated influenza vaccine administered intranasally is not allowed;
4. Physical examination and laboratory examination revealed:
(1) A known history of testing positive for human immunodeficiency virus (HIV) or a known history of acquired immunodeficiency syndrome (AIDS);
(2) Untreated active hepatitis (hepatitis B: HBsAg positive and HBV DNA>= 500 IU/mL; Hepatitis C: HCV RNA positive and abnormal liver function); Combined with hepatitis B and hepatitis C co-infection;
(3) Urine routine indicated urine protein >=++, or confirmed 24 hours urine protein volume >=1.0 g;
5. As determined by the investigator, the subject may have other factors that may lead to the forced termination of the study, such as other serious diseases or serious abnormalities in laboratory tests or accompanied by other factors that may affect the safety of the subjects, or family or social factors such as the collection of test data and samples.

研究实施时间：

Study execute time：

从 From 2022-05-06 00:00:00至 To 2023-11-06 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2022-05-06 00:00:00 至 To 2023-05-06 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	54
Group：	Experimental group	Sample size：	54
干预措施：	大分割放疗序贯R-GEMOX方案+PD1单抗4周期	干预措施代码：
Intervention：	Hypofractionated radiotherapy followed by 4 cycles R-GEMOX+PD1 monoclonal antibody	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

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)：	福建医科大学附属协和医院	单位级别：	三级甲等
Institution hospital：	Fujian Medical University Union Hospital	Level of the institution：	Teritary A

测量指标：

Outcomes：

指标中文名：	完全缓解率	指标类型：	主要指标
Outcome：	Complete remission rate	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：	血液	组织：	淋巴结
Sample Name：	Blood	Tissue：	lymph node
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	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）：

单臂

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

single-arm

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）：	不共享
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	Not available
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：	CRF
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	CRF
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2022-05-16 18:33:28