ChiCTR2600124867 版本V1.0 版本创建时间2026/05/18 17:37:52 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：

 ChiCTR2600124867 

最近更新日期：

Date of Last Refreshed on：

 2026-05-18 17:37:33 

注册时间：

Date of Registration：

 2026-05-18 00:00:00 

注册号状态：

补注册

Registration Status：

Retrospective registration

注册题目：

一项评价MRG002联合HX008治疗HER2表达的局部晚期或转移性尿路上皮癌患者的耐受性、药代动力学及初步有效性的开放、多中心、剂量递增及扩展临床研究

Public title：

An Open-Label, Multicenter, Dose-Escalation and Expansion Clinical Study to Evaluate the Tolerability, Pharmacokinetics and Preliminary Efficacy of MRG002 Combined with HX008 in Patients with HER2-Expressing Locally Advanced or Metastatic Urothelial Carcinoma

注册题目简写：

English Acronym：

研究课题的正式科学名称：

一项评价MRG002联合HX008治疗HER2表达的局部晚期或转移性尿路上皮癌患者的耐受性、药代动力学及初步有效性的开放、多中心、剂量递增及扩展临床研究

Scientific title：

An Open-Label, Multicenter, Dose-Escalation and Expansion Clinical Study to Evaluate the Tolerability, Pharmacokinetics and Preliminary Efficacy of MRG002 Combined with HX008 in Patients with HER2-Expressing Locally Advanced or Metastatic Urothelial 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：

崔传亮 

研究负责人：

郭军 

Applicant：

Cui Chuanliang 

Study leader：

Guo Jun 

申请注册联系人电话：

Applicant telephone：

 +86 10 8819 6951

研究负责人电话：

Study leader's
telephone：

+86 10 8819 6317

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：

 1008ccl@163.com

研究负责人电子邮件：

Study leader's E-mail：

 guoj307@126.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：

北京市海淀区阜成路52号

研究负责人通讯地址：

北京市海淀区阜成路52号

Applicant address：

52 Fucheng road, Haidian district, Beijing, China

Study leader's address：

52 Fucheng road, Haidian district, Beijing, 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：

北京大学肿瘤医院

Applicant's institution：

Peking University Cancer Hospital and Institute

研究负责人所在单位：

北京大学肿瘤医院

Affiliation of the Leader：

Peking University Cancer Hospital and Institute

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：

 2021YJZ88-重; 2021YJZ88-重-ZY01

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：

The Institutional Review Board, Peking Univesity Cancer Hospital and Institute

伦理委员会批准日期：

Date of approved by ethic committee：

 2021-11-02 00:00:00

伦理委员会联系人：

陆婷

Contact Name of the ethic committee：

Lu Ting

伦理委员会联系地址：

阜成路81号院1号楼5层

Contact Address of the ethic committee：

Building 1, Courtyard No. 81, Fucheng Road, 5th Floor

伦理委员会联系人电话：

Contact phone of the ethic committee：

 +86 10 8819 6861

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：

北京大学肿瘤医院

Primary sponsor：

Peking University Cancer Hospital and Institute

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, 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)：

北京

市(区县)：

Country：

China

Province：

Beijing

City：

单位(医院)：

北京大学肿瘤医院

具体地址：

北京市海淀区阜成路52号

Institution
hospital：

Peking University Cancer Hospital and Institute

Address：

52 Fucheng road, Haidian district, Beijing, China

经费或物资来源：

泰州翰中生物医药有限公司

Source(s) of funding：

Taizhou Hanzhong Biomedical Co., Ltd.

研究疾病：

尿路上皮癌  

Target disease：

urothelium carcinoma

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：

 I期+II期 

Study phase：

1-2

研究设计：

单臂 

Study design：

Single arm 

研究目的：

评估MRG002 联合HX008 在HER2 表达的局部晚期或转移性尿路上皮癌患者中的安全性和耐受性，确定联合用药的最大耐受剂量（MTD）或推荐剂量（RP2D）；评估MRG002 联合HX008 在HER2 表达的局部晚期或转移性尿路上皮癌患者中的安全性和初步评估客观缓解率（ORR）。  

Objectives of Study：

To evaluate the safety and tolerability of MRG002 combined with HX008 in patients with locally advanced or metastatic urothelial carcinoma with HER2 expression, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the combined therapy; to assess the safety and preliminary evaluation of the objective response rate (ORR) of MRG002 combined with HX008 in patients with locally advanced or metastatic urothelial carcinoma with HER2 expression.

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.自愿签署知情同意书，并遵循方案要求； 2.年龄≥18岁，且≤85岁，性别不限； 3.预期生存期≥12周； 4.经组织病理学确诊的无法手术切除或手术治疗后复发的局部晚期或转移性尿路上皮癌（包括膀胱、输尿管、肾盂及尿道来源）； 5.未接受过全身抗肿瘤治疗但无法耐受或不适合接受铂类化疗的受试者；或既往复发/转移阶段接受过至少一线全身化疗后出现疾病进展，这其中患者接受过新辅助或辅助化疗方案治疗后12 个月内出现疾病进展，可以入组该临床研究； 无法耐受铂类化疗的受试者应满足以下标准之一： (1) 根据Cockcroft-Gault 公式法计算肌酐清除率（CrCl）＜60 mL/min； (2) 听力减退≥2 级或外周神经毒性≥2 级； 6.受试者能够提供PD-L1与HER2检测的肿瘤原发或转移灶部位标本；既往检查或者中心实验室确认肿瘤组织中HER2表达（IHC 3+、IHC 2+、IHC 1+）； 7.具有至少一处符合RECIST 1.1定义的可评估病灶（CT扫描长径≥10 mm或肿大淋巴结短径≥15 mm）； 8.美国东部肿瘤协作组（ECOG）体能状态评分为0或1； 9.器官功能水平必须符合下列要求： ?骨髓：中性粒细胞计数绝对值（ANC）≥1.5×10^9/L，血小板计数≥100×10^9/L，血红蛋白≥90 g/L，且首次给药/随机分组前4周内未接受过输血或2周内未接受生物反应调节剂（如促粒细胞、红细胞生长因子等）治疗； ?肝脏：无肝转移患者要求血清总胆红素（TBIL）≤1.5×正常上限（ULN）；丙氨酸氨基转移酶（ALT）和天门冬氨酸氨基转移酶（AST）≤2.5×ULN。有肝转移患者要求：TBIL≤1.5×ULN；ALT和AST≤5×ULN； ?肾脏：肌酐（Cr）≤1.5×ULN，或肌酐清除率（Ccr）≥50 mL/min （根据Cockcroft and Gault公式）； ?凝血功能：国际标准化比值（INR）≤1.5×ULN，或活化部分凝血活酶时间（APTT）≤1.5×ULN（除正在接受治疗性抗凝药物外）； ?心脏：无严重心脏功能异常，左心室射血分数（LVEF）≥50%； ?其他：既往抗肿瘤治疗相关AE恢复至美国国立癌症研究所通用不良事件术语第5.0版（NCI CTCAE v5.0）≤1级（脱发、非临床显著性或无症状性实验室异常除外）； 育龄期女性接受研究药物首次给药前72小时内的血清妊娠试验结果为阴性。妊娠或哺乳期女性不得入组。育龄期患者必须在研究中至最后一次给药后6个月内采取有效的避孕措施；

Inclusion criteria

1. Voluntary signing of the informed consent form and compliance with the protocol requirements; 2. Age >= 18 years and <= 85 years, with no gender restrictions; 3. Expected survival period >= 12 weeks; 4. Histopathologically confirmed locally advanced or metastatic urothelial carcinoma (including bladder, ureter, renal pelvis and urethra origin) that is inoperable or has recurred after surgery; 5. Subjects who have not received systemic anti-tumor treatment but are intolerant or unsuitable for platinum-based chemotherapy; or those who have received at least one line of systemic chemotherapy during the recurrent/metastatic stage and have experienced disease progression, including those who have experienced disease progression within 12 months after neoadjuvant or adjuvant chemotherapy, can be enrolled in this clinical study; Subjects intolerant to platinum-based chemotherapy should meet one of the following criteria: (1) Creatinine clearance rate (CrCl) calculated by the Cockcroft-Gault formula < 60 mL/min; (2) Hearing loss >= grade 2 or peripheral neuropathy >= grade 2; 6. Subjects must be able to provide tumor primary or metastatic site specimens for PD-L1 and HER2 testing; and the tumor tissue HER2 expression (IHC 3+, IHC 2+, IHC 1+) has been confirmed by previous examination or the central laboratory; 7. Have at least one measurable lesion as defined by RECIST 1.1 (CT scan long diameter >= 10 mm or short diameter of enlarged lymph nodes >= 15 mm); 8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; 9. Organ function levels must meet the following requirements: ? Bone marrow: Absolute neutrophil count (ANC) >= 1.5×10^9/L, platelet count >= 100×10^9/L, hemoglobin >= 90 g/L, and no blood transfusion or treatment with biological response modifiers (such as granulocyte or erythropoietin growth factors) within 4 weeks before the first dose/randomization; ? Liver: For patients without liver metastasis, serum total bilirubin (TBIL) <= 1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5×ULN. For patients with liver metastasis, TBIL <= 1.5×ULN; ALT and AST <= 5×ULN; ? Kidney: Creatinine (Cr) <= 1.5×ULN, or creatinine clearance rate (Ccr) >= 50 mL/min (calculated by the Cockcroft and Gault formula); ? Coagulation function: International normalized ratio (INR) <= 1.5×ULN, or activated partial thromboplastin time (APTT) <= 1.5×ULN (except for those receiving therapeutic anticoagulant drugs); ? Heart: No severe cardiac dysfunction, left ventricular ejection fraction (LVEF) >= 50%; ? Others: Previous anti-tumor treatment-related adverse events have recovered to <= grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) (except for alopecia, non-clinically significant or asymptomatic laboratory abnormalities); Fertile women must have a negative serum pregnancy test result within 72 hours before the first dose of the study drug. Pregnant or lactating women are not eligible for enrollment. Fertile patients must use effective contraceptive measures during the study and for 6 months after the last dose.

排除标准：

1.既往接受过HER2靶向抗体偶联药物或其他抗肿瘤免疫治疗药物（包括PD-1或PD-L1抑制剂免疫治疗）; 2.已知对MRG002或者HX008的任何成分或辅料（组氨酸、盐酸组氨酸一水合物、蔗糖和聚山梨酯80）有过敏反应，或已知对其他既往抗HER2药物（包括试验用研究药物）或对其他单克隆抗体（PD-1/PD-L1）有≥3级的过敏反应。 3.接受过以下任一治疗： ?首次给药前4周内接受过其他临床试验的研究药物 ?首次给药前4周内接受任何抗肿瘤药物/生物或研究治疗药物（对于小分子靶向药物，该非参与期为2周或5个半衰期内，以较长者为准；对于细胞毒性药物，该非参与期为3周）； ?首次给药前4周内接受过放疗； ?首次给药前2周内或当前需要使用强效CYP3A4抑制剂或诱导剂 ?首次给药前4周内进行过大型手术且未完全恢复，或计划在接受研究药物后第一个12周进行大型手术 4.已知有活动性CNS转移和/或癌性脑膜炎。经治疗的脑转移受试者可参加研究，前提是病情稳定，无以下情况：进行性或新发神经功能缺损、癫痫发作、颅内压升高证据、视神经乳头水肿、呕吐或头痛；试验药物首次给药前至少4周MRI显示复发/进展证据，且任何神经系统症状未恢复至基线水平；有新发脑转移瘤或脑转移瘤增大的证据，且在研究药物给药前至少3天内使用皮质类固醇。这一排除不包括癌性脑膜炎患者，无论是否稳定都应排除。 5.有活动性或进展期感染证据包括乙型肝炎（需同时满足HBsAg阳性，且HBV DNA大于检测下限，并排除药物或其他原因所致肝炎），丙型肝炎（需同时满足抗-HCV抗体阳性，且HCV RNA结果大于检测下限），人类免疫缺陷病毒（HIV）感染，活动性肺结核等；存在其他严重的肝病，包括慢性自身免疫性肝病、原发性胆汁性肝硬化或硬化性胆管炎、酒精性肝病或NASH等。 6.大于1级的外周神经病变； 7.有未良好控制的心脏临床症状或疾病，如NYHA 2级以上的心力衰竭、不稳定心绞痛、1年内发生过心肌梗塞、有临床意义的室上性或室性心律失常需要治疗或干预、QTc > 450 ms（男性）或QTc > 470 ms（女性）； 8.既往有恶性肿瘤史，但皮肤基底细胞癌、皮肤鳞状细胞癌、原位宫颈癌或甲状腺乳头状癌，或已接受根治性治疗并在治疗5年内未复发的受试者除外； 9.具有活动性自身免疫性疾病或有自身免疫性疾病史，正在使用免疫抑制剂、或全身激素治疗（剂量>10 mg/天的泼尼松或其他等效激素），并在入组前2周内仍在继续使用；。 10.研究药物首次给药前3个月内发生肺栓塞或深静脉血栓形成； 11.未控制的活动性细菌、病毒、真菌、立克次体或寄生虫感染，并在14天内未接受过经静脉使用的抗生素，除非在研究药物给药前获得治疗并消退； 12.未控制的胸腔积液、心包积液或复发性腹水，每月需要≥1次引流； 13.曾接受异体组织/实体器官移植； 14.在首次研究给药前1个月内接种过活疫苗，包括但不限于以下各项：麻疹、流行性腮腺炎、风疹、水痘/带状疱疹、黄热病、狂犬病、卡介苗、伤寒疫苗。但季节性流感疫苗为灭活病毒疫苗，可允许使用；但鼻内用流感疫苗（如FluMist?）为减毒活疫苗，不允许使用，接种新冠疫苗的患者依据相关部门的指导意见； 15.严重肺部疾病（包括但不限于重度慢性阻塞性肺病、重度肺功能不全、有症状的支气管痉挛及间质性肺病等）； 16.研究者认为不适合参加本临床试验的其他情况。

Exclusion criteria：

1. Previous treatment with HER2-targeted antibody-drug conjugates or other anti-tumor immunotherapy drugs (including PD-1 or PD-L1 inhibitor immunotherapy); 2. Known hypersensitivity to any component or excipient of MRG002 or HX008 (histidine, histidine hydrochloride monohydrate, sucrose, and polysorbate 80), or known hypersensitivity to other previous anti-HER2 drugs (including investigational study drugs) or to other monoclonal antibodies (PD-1/PD-L1) of grade >= 3; 3. Received any of the following treatments: - Received investigational study drugs in any other clinical trial within 4 weeks before the first dose; - Received any anti-tumor drugs/biologics or investigational treatment drugs within 4 weeks before the first dose (for small molecule targeted drugs, the non-participation period is 2 weeks or 5 half-lives, whichever is longer; for cytotoxic drugs, the non-participation period is 3 weeks); - Received radiotherapy within 4 weeks before the first dose; - Received strong CYP3A4 inhibitors or inducers within 2 weeks before the first dose or currently need to use them; - Underwent major surgery within 4 weeks before the first dose and has not fully recovered, or plans to undergo major surgery within the first 12 weeks after receiving the study drug; 4. Known active CNS metastases and/or carcinomatous meningitis. Subjects with treated brain metastases may participate in the study if the condition is stable and there is no evidence of progressive or new neurological deficits, seizures, increased intracranial pressure, papilledema, vomiting, or headache; MRI within at least 4 weeks before the first dose of the study drug shows no evidence of recurrence/progression, and any neurological symptoms have not returned to baseline; there is evidence of new brain metastases or enlargement of existing brain metastases, and corticosteroids have been used within at least 3 days before the study drug administration. This exclusion does not include patients with carcinomatous meningitis, who should be excluded regardless of stability. 5. Evidence of active or progressive infection, including hepatitis B (must be HBsAg positive and HBV DNA greater than the lower limit of detection, and exclude drug-induced or other causes of hepatitis), hepatitis C (must be anti-HCV antibody positive and HCV RNA result greater than the lower limit of detection), human immunodeficiency virus (HIV) infection, active tuberculosis, etc.; presence of other severe liver diseases, including chronic autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis, alcoholic liver disease or NASH, etc. 6. Peripheral neuropathy greater than grade 1; 7. Presence of uncontrolled cardiac clinical symptoms or diseases, such as NYHA class 2 or above heart failure, unstable angina, myocardial infarction within 1 year, clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention, QTc > 450 ms (male) or QTc > 470 ms (female); 8. History of malignant tumors, except for skin basal cell carcinoma, skin squamous cell carcinoma, in situ cervical cancer, or papillary thyroid cancer, or subjects who have received radical treatment and have not relapsed within 5 years of treatment; 9. Presence of active autoimmune disease or history of autoimmune disease, currently using immunosuppressants or systemic hormone therapy (dose > 10 mg/day of prednisone or other equivalent hormones), and still using them within 2 weeks before enrollment. . 10. Pulmonary embolism or deep vein thrombosis occurred within 3 months before the first administration of the study drug. 11. Uncontrolled active bacterial, viral, fungal, rickettsial or parasitic infection, and no intravenous antibiotics were administered within 14 days, unless the infection was treated and resolved before the administration of the study drug. 12. Uncontrolled pleural effusion, pericardial effusion or recurrent ascites, requiring drainage >= 1 time per month. 13. History of allogeneic tissue/organ transplantation. 14. Live vaccines were administered within 1 month before the first administration of the study drug, including but not limited to: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, typhoid vaccine. However, seasonal influenza vaccine is an inactivated virus vaccine and is allowed; but intranasal influenza vaccine (such as FluMist?) is a live attenuated vaccine and is not allowed. Patients who have received the COVID-19 vaccine should follow the guidelines of relevant departments. 15. Severe pulmonary disease (including but not limited to severe chronic obstructive pulmonary disease, severe pulmonary insufficiency, symptomatic bronchospasm and interstitial lung disease, etc.). 16. Other conditions that the investigator deems unsuitable for participation in this clinical trial.

研究实施时间：

Study execute time：

从 From 2021-11-30 00:00:00至 To 2027-12-30 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2021-12-31 00:00:00 至 To 2024-10-12 00:00:00

干预措施：

Interventions：

组别：

试验组

样本量：

 42

Group：

Test group

Sample size：

干预措施：

MRG002为注射用冻干制剂。静脉滴注，每三周一次（Q3W）。 HX008为注射液。静脉滴注，每三周一次（Q3W）。 剂量递增阶段：MRG002（1.8 mg/kg,2.2 mg/kg）+ HX008 3 mg/kg(最大剂量200mg) 剂量扩展阶段：MRG002+HX008的RP2D剂量

干预措施代码：

Intervention：

MRG002 is a lyophilized powder for injection. Intravenous infusion, once every three weeks (Q3W). HX008 is an injection. Intravenous infusion, once every three weeks (Q3W). Dose escalation phase: MRG002 (1.8 mg/kg, 2.2 mg/kg) + HX008 3 mg/kg (maximum dose 200 mg) Dose expansion phase: RP2D dose of MRG002 + HX008

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)：

 北京大学肿瘤医院  

单位级别：

 三甲 

Institution
hospital：

Peking University Cancer Hospital and Institute

Level of the institution：

Tertiary A hospital

国家：

 中国

省(直辖市)：

 北京  

市(区县)：

  

Country：

China

Province：

Beijing

City：

单位(医院)：

 中国医学科学院肿瘤医院 

单位级别：

 三甲 

Institution
hospital：

Chinese Academy of Medical Sciences Cancer Hospital

Level of the institution：

Tertiary A hospital

测量指标：

Outcomes：

指标中文名：

II期推荐剂量

指标类型：

主要指标

Outcome：

Recommended Phase 2 Dose, RP2D

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

客观缓解率

指标类型：

主要指标

Outcome：

Objective Response Rate, ORR

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

PK特征和免疫原性

指标类型：

次要指标

Outcome：

PK characteristics and 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：

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：

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：

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：

总生存期

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：

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：

结束

/Completed

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）：

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:

不公开/Private

盲法：

Blinding：

是否共享原始数据：

IPD sharing

是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）：

试验完成后向研究者联系索取

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

After the experiment is completed, contact the researcher to request it.

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，电子采集和管理系统

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

CRF+EDC

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：

  2026-05-18 17:37:33