ChiCTR2300068631 版本V1.0 版本创建时间2023/02/26 17:22:30 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：

ChiCTR2300068631 

最近更新日期：

Date of Last Refreshed on：

2023-02-26 17:22:05 

注册时间：

Date of Registration：

2023-02-26 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

口服氨茶碱联合苹果酸舒尼替尼胶囊治疗局部晚期不可切除或伴远处转移的肾透明细胞癌前瞻性、开放、单臂、多中心的探索性研究

Public title：

Oral aminophylline combined with sunitinib malate capsule in the treatment of locally advanced unresectable renal clear cell carcinoma or distant metastasis: a prospective, open, single-arm, multicenter exploratory study

注册题目简写：

English Acronym：

研究课题的正式科学名称：

口服氨茶碱联合苹果酸舒尼替尼胶囊治疗局部晚期不可切除或伴远处转移的肾透明细胞癌前瞻性、开放、单臂、多中心的探索性研究

Scientific title：

Oral aminophylline combined with sunitinib malate capsule in the treatment of locally advanced unresectable renal clear cell carcinoma or distant metastasis: a prospective, open, single-arm, multicenter exploratory 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：

印焓锐 

研究负责人：

刘军力 

Applicant：

Yin Hanrui 

Study leader：

Liu Junli 

申请注册联系人电话：

Applicant telephone：

15651820919

研究负责人电话：

Study leader's telephone：

18321928502

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：

yinhanrui2022@163.com

研究负责人电子邮件：

Study leader's E-mail：

ljunnk307@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：

上海市徐汇区宜山路600号

研究负责人通讯地址：

上海市徐汇区宜山路600号

Applicant address：

600 Yishan Road, Xuhui District, Shanghai

Study leader's address：

600 Yishan Road, Xuhui District, Shanghai

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：

上海市第六人民医院

Applicant's institution：

Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

研究负责人所在单位：

上海市第六人民医院

Affiliation of the Leader：

Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

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：

2022-145-（1）

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：

上海市第六人民医院伦理委员会

Name of the ethic committee：

Ethics Committee of Shanghai Sixth People's Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

2022-12-14 00:00:00

伦理委员会联系人：

庞路阳

Contact Name of the ethic committee：

Pang Luyang

伦理委员会联系地址：

上海市宜山路600号

Contact Address of the ethic committee：

600 Yishan Road, Xuhui District, Shanghai

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 21 64369181

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：

上海市第六人民医院

Primary sponsor：

Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

研究实施负责（组长）单位地址：

上海市徐汇区宜山路600号

Primary sponsor's address：

600 Yishan Road, Xuhui District, Shanghai

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)：

徐汇

Country：

China

Province：

Shanghai

City：

Xuhui

单位(医院)：

上海市第六人民医院

具体地址：

上海市徐汇区宜山路600号

Institution
hospital：

Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Address：

600 Yishan Road, Xuhui District, Shanghai

经费或物资来源：

上海市第六人民医院杰青培育基金

Source(s) of funding：

Shanghai Sixth People's Hospital Jieqing Cultivation Fund

Target disease：

locally advanced unresectable renal clear cell carcinoma or distant metastasis

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

 探索性研究/预试验 

Study phase：

0

研究设计：

单臂 

Study design：

Single arm 

研究目的：

主要目的 观察口服氨茶碱联合苹果酸舒尼替尼胶囊治疗局部晚期不可切除或伴远处转移的肾透明细胞癌无进展生存期（PFS）。 次要目的 观察口服氨茶碱联合苹果酸舒尼替尼胶囊治疗局部晚期不可切除或伴远处转移的肾透明细胞癌的客观缓解率（ORR）、总生存期（OS），疗效预测分子标志物探索。  

Objectives of Study：

The main purpose To observe the progression-free survival (PFS) of patients with locally advanced unresectable renal clear cell carcinoma (RCC) or distant metastasis treated with aminophylline combined with sunitinib malate capsule. The secondary purpose To observe the objective response rate (ORR) and overall survival (OS) of oral aminophylline combined with sunitinib malate capsule in the treatment of locally advanced unresectable renal clear cell carcinoma or distant metastasis, and explore the molecular markers for predicting efficacy.

药物成份或治疗方案详述：

苹果酸舒尼替尼胶囊（50mg，每日1次，口服，与食物同时或不同服用均可，用药两周，停一周，联合或不联合免疫治疗），服用期间若出现不良反应，根据不良反应分级进行剂量调整； 氨茶碱（100mg，每日3次，口服，与食物同时或不同服用均可，连续服用3周），服用期间若出现不良反应，根据不良反应分级进行剂量调整； 联合用药，共3周为一个周期，接受两个周期治疗后评估疗效。 

Description for medicine or protocol of treatment in detail：

Sunitinib malate capsule (50mg, once a day, oral, can be taken simultaneously or differently with food, for two weeks, stop for one week, combined with or without combined immunotherapy), dose adjustment will be made according to the grade of adverse reactions in case of adverse reactions. Aminophylline (100mg, 3 times a day, oral, can be taken simultaneously or differently with food, for 3 weeks), dose adjustment is made according to the grade of adverse reactions, if there are adverse reactions during taking ?; Combining drugs, a total of 3 weeks as a cycle, receiving two cycles of treatment to evaluate the efficacy.  

纳入标准：

受试者筛选必须符合下列所有标准才能准入此项研究。如果筛选期内有多次临床实验室检查结果，必须采用最接近入组日期的检查结果来证明受试者入选本研究的资格。
1. 患者自愿参加本次研究，签署知情同意书，依从性好，配合随访；
注意：受试者必须能够理解且愿意签署书面知情同意书，在该试验相关的任何步骤开始之前必须获得受试者已经签名的书面知情同意书，在签署知情同意书(ICF)时，任何既往治疗的所有急性毒性恢复至≤1级（参考NCI-CTCAE 4.03）或更低。
2. 经病理学确诊的局部晚期不可切除或伴远处转移的肾透明细胞癌；
3. 靶病灶无手术治疗指证（影像学上无法进行手术的患者，肿瘤较大外科手术实施困难的患者，局部淋巴结侵犯或者有远处血管转移的患者）或患者拒绝手术；
4. 18 -70岁；
5. ECOG PS评分：≤2分；
6. 预计生存期超过3月；
7. 主要器官功能在治疗前7天内，符合下列标准：
(1) 血常规检查标准（筛选前14天内未输血状态下）：
①血红蛋白（HB）≥90g/L；
②中性粒细胞绝对值（ANC）≥1.5×109/L；
③血小板（PLT）≥80×109/L。
(2) 生化检查需符合以下标准：
①总胆红素（TBIL）≤1.5倍正常值上限(ULN) ；
②丙氨酸氨基转移酶（ALT）和天门冬氨酸氨基转移酶（AST）≤2.5?ULN，如伴肝转移，则ALT和AST≤5?ULN；
③血清肌酐（Cr）≤1.5?ULN或肌酐清除率(CCr)≥60 ml/min。
8. 育龄女性应同意在研究期间和研究结束后6个月内必须采用避孕措施（如宫内节育器，避孕药或避孕套）；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者。

Inclusion criteria


Subject screening must meet all of the following criteria to be admitted to the study. If there are multiple clinical laboratory results during the screening period, the results closest to the enrollment date must be used to demonstrate eligibility for inclusion in the study.

1. The patients voluntarily participated in this study, signed the informed consent, had good compliance, and cooperated with follow-up visits;

Note: Subject must be able to understand and willing to sign a written informed consent, a signed written informed consent must be obtained prior to the commencement of any steps related to this trial, and all acute toxicity of any prior treatment has returned to ≤ Class 1 (refer to NCI-CTCAE 4.03) or lower at the time of signing of the ICF.

2. Locally advanced unresectable clear cell carcinoma of kidney with distant metastasis confirmed by pathology;

3. The target lesions have no evidence of surgical treatment (patients with imaging problems that cannot be operated on, patients with large tumors that are difficult to perform surgical operations, patients with local lymph node invasion or patients with distant vascular metastasis) or patients refuse surgery;

4. Ages 18-70;

5. ECOG PS score: ≤2 points;

6. Expected survival of more than 3 months;

7. Major organ functions within 7 days prior to treatment shall meet the following criteria:

(1) Standard for blood routine examination (without blood transfusion within 14 days before screening) :

① Hemoglobin (HB) ≥90g/L;

② Neutrophil absolute value (ANC) ≥1.5×109/L;

③ Platelet (PLT) ≥80×109/L.

(2) Biochemical examination shall meet the following standards:

① Total bilirubin (TBIL) ≤1.5 times the upper limit of normal value (ULN);

(2) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of 2.5 or less ? ULN, such as with liver metastasis, ALT and AST 5 or less ? ULN.

(3), serum creatinine (Cr) of 1.5 or less ? ULN or creatinine clearance rate (CCr) or 60 ml/min.

8. Women of reproductive age should agree to use contraceptives (such as intrauterine devices, contraceptives or condoms) during the study period and for six months after the study ends; Have a negative serum or urine pregnancy test within 7 days prior to study enrollment and must be non-lactating; Men should consent to patients who must use contraception during the study period and for six months after the study period ends.

排除标准：

1. 凝血功能异常（INR>1.5×ULN，APTT>1.5×ULN），具有出血倾向者；
2. 对氨茶碱或苹果酸舒尼替尼胶囊任何成份过敏者应禁用；
3. 颅内转移；
4. 怀孕或哺乳期妇女；
5. 过去3年内罹患其他恶性肿瘤；
6. 恶性胸腔积液或腹腔积液，引起NCI CTC AE分级 2级以上呼吸困难者；
7. 研究者认为存在可能损害受试者或者导致受试者无法满足或执行研究要求的任何状况。
8. 既往曾接受抗血管生成靶向治疗的患者，如舒尼替尼、索拉非尼，贝伐珠单抗、法米替尼、阿帕替尼、瑞格非尼等或不限于上述药物。
9. 5年内出现过或当前同时患有其它恶性肿瘤，治愈的子宫颈原位癌、非黑色素瘤的皮肤癌和表浅的膀胱肿瘤除外 [Ta (非浸润性肿瘤)，Tis (原位癌) 和T1 (肿瘤浸润基膜)]；
10. 具有影响口服药物的多种因素（比如无法吞咽、慢性腹泻和肠梗阻等）者；存在任何重度和/或未能控制的疾病的患者，包括：
11. 血压控制不理想的（收缩压≥150 mmHg，舒张压≥100 mmHg）患者，患有I级以上心肌缺血或心肌梗塞、心律失常（包括QTC ≥480ms）及≥2级充血性心功能衰竭（纽约心脏病协会（NYHA）分级）；
12. 活动性或未能控制的严重感染(≥CTC AE 2级感染)；
13. 肝硬化、失代偿性肝病，活动性肝炎或慢性肝炎需接受抗病毒治疗；
14. 肾功能衰竭需要血液透析或腹膜透析；
15. 有免疫缺陷病史，包括HIV阳性或患有其它获得性、先天性免疫缺陷疾病，或有器官移植史者；
16. 糖尿病控制不佳（空腹血糖（FBG）＞10mmol/L）；
17. 尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0 g者；
18. 具有癫痫发作并需要治疗的患者；具有精神类药物滥用史且无法戒除或有精神障碍者；
19. 四周内参加过其他抗肿瘤药物临床试验；
20. 根据研究者的判断，有严重危害患者安全或影响患者完成研究的伴随疾病者。

Exclusion criteria：


1. Patients with abnormal coagulation function (INR>1.5×ULN, APTT>1.5×ULN) and bleeding tendency;

2. People who are allergic to aminophylline or sunitinib malate capsules should be prohibited;

3. Intracranial metastasis;

4. Pregnant or lactating women;

5. Other malignant tumors in the past 3 years;

6. Patients with dyspnea caused by malignant pleural effusion or abdominal effusion, NCI CTC AE grade 2 or above;

7. Any condition that, in the opinion of the Investigator, may impair the subject or prevent the Subject from meeting or performing the study requirements.

8. Patients who had previously received antiangiogenic targeted therapy, such as sunitinib, sorafenib, bevacizumab, famitinib, apatinib, regafenib, or not limited to the above drugs.

9. Present or present with other malignant tumors within 5 years, except cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors (Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading basement membrane));

10. With multiple factors affecting oral medication (e.g., inability to swallow, chronic diarrhoea and intestinal obstruction); Patients with any severe and/or uncontrolled disease, including:

11. Patients with poorly controlled blood pressure (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg) with grade I or higher myocardial ischemia or infarction, arrhythmias (including QTC ≥480ms), and congestive heart failure grade 2 (New York Heart Association (NYHA) classification);

12. Active or uncontrolled severe infection (≥CTC AE grade 2 infection);

13. Liver cirrhosis, decompensated liver disease, active hepatitis or chronic hepatitis need antiviral therapy;

14. Renal failure requiring hemodialysis or peritoneal dialysis;

15. Have a history of immunodeficiency, including being HIV positive or suffering from other acquired or congenital immunodeficiency diseases, or a history of organ transplantation;

16. Poor diabetes control (fasting blood glucose (FBG) > 10mmol/L);

17. Patients whose urine routine indicated urinary protein ≥++ and confirmed 24-hour urinary protein quantity > 1.0 g;

18. Patients with epileptic seizures requiring treatment; Those who have a history of psychotropic drug abuse and are unable to quit or have mental disorders;

19. Participated in clinical trials of other antitumor drugs within four weeks;

20. Concomitant diseases that, in the judgment of the investigator, seriously endanger the patient's safety or interfere with the patient's completion of the study.

以上翻译结果来自有道神经网络翻译（YNMT）

逐句对照

研究实施时间：

Study execute time：

从 From 2022-12-01 00:00:00至 To 2024-12-01 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2023-03-01 00:00:00 至 To 2024-12-01 00:00:00  

干预措施：

Interventions：

组别：

试验组

样本量：

22

Group：

Test group

Sample size：

干预措施：

口服氨茶碱联合苹果酸舒尼替尼胶囊

干预措施代码：

Intervention：

Aminophylline combined with sunitinib malate capsule was taken orally

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)：

 徐汇 

Country：

China 

Province：

Shanghai 

City：

Xuhui 

单位(医院)：

上海市第六人民医院 

单位级别：

三甲 

Institution
hospital：

Shanghai Sixth People's Hospital

Level of the institution：

Tertiary A

测量指标：

Outcomes：

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：

客观缓解率

指标类型：

次要指标

Outcome：

Objective remission 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：

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：

指标中文名：

患者疗效相关生物标记物探索

指标类型：

次要指标

Outcome：

Exploration of biomarkers related to patient efficacy

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：

标本中文名：

肾癌组织样本

组织：

Sample Name：

Kidney cancer tissue sample

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）：

本研究为单臂观察性研究，计划入组病人数22-30例

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

This study is a single-arm observational study with a planned enrollment of 22-30 patients

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）：

如需要，可直接来电索取

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

If necessary, you can call directly to obtain

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：

1.病例报告表的填写与移交 原始病例报告表由研究者填写，每个签署知情同意的患者必须完成病例报告表。完成的病例报告表由临床监查员审查，确保填写完整后，交给数据录入人员录入EDC。 2.数据的录入与修改 数据录入与管理由独立的数据管理单位负责。 数据管理经理负责制定数据管理计划，EDC填写指南，数据质疑管理手册等标准SOP，确保提交给统计分析部门的数据的质量。 数据录入人员采用百奥知提供的EDC电子数据采集系统，根据EDC填写指南或数据录入手册，如实进行数据录入。 数据录入人员录入完成提交后，由临床监查员对已录入EDC的数据与原始病历报告表进行源数据核查（SDV）。临床监查员对EDC中存在疑问的数据，创建数据质疑，敦促CRC及时进行修改。 数据管理员根据数据质疑管理手册，对完成SDV的数据中存在的疑问，创建数据质疑，由数据录入人员或临床监查员核对原始病例，或与研究者核实，再由数据录入员根据核实结果进行数据确认，修改，删除，解答质疑。数据管理员根据质疑解答结果关闭质疑，必要时可以再次质疑。 医学审核员对完成SDV的数据中需要进行医学核查的关键变量进行医学专业审核，存在疑问时，创建数据质疑，由数据录入人员或临床监查员核对原始病例，或与研究者核实，再由数据录入员根据核实结果进行数据确认，修改或删除操作，并填写修改理由。 3.数据表锁定与冻结 以表为单位，数据经理确认数据无误且所有质疑都被关闭后，进行独立表数据的锁定，冻结。 4.数据库锁定 试验结束，所有数据清理干净且所有质疑都被关闭后，由数据管理经理进行数据库锁定，并提交统计分析部门进行数据分析。数据库锁定后不再作改动。 5.试验数据的分析数据集 5.1全分析集（Full Analysis Set，FAS集） 按照意向性分析（ITT）原则，包括所有入组的受试者。 5.2符合方案集（Per-protocol Set，PPS集） 所有符合试验方案、依从性好、并至少服用2个周期药物（入组后因疾病进展且有明确医学证据的除外），试验期间未服禁用药物、完成病例报告表规定填写内容的病例。对缺失数据不进行任何填补（imputation)。 对药物的疗效指标的分析采用FAS集和PPS集。 5.3安全性分析集（Safety Analysis Set，SAS集） 包括所有入组的受试者，至少使用过一次试验用药，并至少有一次用药后安全性评价的患者。该数据集主要用于安全性分析。 5.4统计分析计划 在数据库锁定前确定统计分析计划，统计分析严格按照统计分析计划进行。 所有统计分析将采用SAS 9.3及以上版本统计分析软件编程计算。所有的统计学检验均采用双侧检验，P值≤0.05将被认为所检验的差别有统计意义，可信区间采用95%的可信度。计数、等级指标的统计描述采用例数（%）表达；计量指标的统计描述采用均数（标准差）、中位数、最小值和最大值表达。 对于主要疗效指标3、6个月无进展生存率（6个月PFS率），采用Kaplan-Meier法进行估计，用正态近似法计算该率与目标值差值的可信区间。 对于次要疗效指标，如总生存期（OS），采用kaplan-Meier法估计中位值及其95%CI，并绘制生存曲线图；计算客观缓解率（ORR=CR+PR）及其95%CI。 安全性分析以描述性统计分析为主，必要时可比较用药前后检查结果的均数或发生率。生命体征、体格检查、实验室检查指标主要描述用药前后的变化情况以及发生异常改变时与试验药物的关系；所有不良事件均采用MedDRA编码进行标准化处理，并按照MedDRA编码中的系统器官分类（SOC）和首选语（PT）以及CTCAE分级等汇总统计不良事件发生率、3级及以上不良事件发生率等，并列表描述本研究所发生的不良事件、不良反应及严重不良事件。

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

1.Filling and handing over the case report form The original case report form was completed by the investigator and must be completed by each patient who signed informed consent. The completed case report form was reviewed by the clinical monitor to ensure completion and given to the data entry staff for entry into the EDC. 2. Data entry and modification An independent data management unit is responsible for data entry and management. The Data Management Manager is responsible for developing standard Sops such as data management plan, EDC filling guide, Data Challenge Management manual, etc., to ensure the quality of data submitted to the statistical analysis department. The data entry personnel shall use the EDC electronic data acquisition system provided by BKNOW, and enter the data truthfully according to the EDC filling guide or data entry manual. After data entry is completed and submitted by data entry personnel, the clinical monitor will conduct source data verification (SDV) between the data entered into EDC and the original medical record report form. Clinical monitors create data challenges for questionable data in EDC and urge CRC to make timely modifications. According to the data query management manual, the data manager will create data query for the existing questions in the completed SDV data, and the data entry personnel or clinical monitors will check the original cases or verify with the researchers. Then the data entry personnel will confirm, modify, delete and answer the questions according to the verification results. The data manager closes the challenge based on the result of the challenge solution and can challenge it again if necessary. Medical auditors to complete the SDV need for medical check the key variables in the data of medical professional audit, when in doubt, create data, clinical arbitrator or by data entry personnel check the original case, or in connection with the researchers to verify, by data operator again according to the data to verify the results confirmed that the modify, or delete operation, the reasons and fill in the modification. 3 Lock and freeze data tables In the unit of table, after the data manager confirms that the data is correct and all questions are closed, the independent table data is locked and frozen. 4 Locking the Database At the end of the trial, after all data is cleaned up and all doubts are closed, the data management manager will lock the database and submit it to the statistical analysis department for data analysis. No changes are made after the database is locked. 5 Analysis data set of test data 5.1 Full Analysis Set (FAS set) All enrolled subjects were included according to intentionality analysis (ITT). 5.2 Per-protocol Set (PPS Set) All patients who met the trial protocol, had good compliance, had taken drugs for at least 2 cycles (except those with clear medical evidence due to disease progression after enrollment), had not taken prohibited drugs during the trial, and had completed the contents specified in the case report form. No imputation was performed on missing data. FAS set and PPS set were used to analyze the efficacy indexes of drugs. 5.3 Safety Analysis Set (SAS Set) All enrolled subjects who had used at least one trial drug and had had at least one post-medication safety evaluation were included. This dataset is mainly used for security analysis. 5.4 Statistical analysis plan Determine the statistical analysis plan before database lock, and the statistical analysis is carried out in strict accordance with the statistical analysis plan. All statistical analyses will be calculated by SAS statistical analysis software 9.3 or above. All statistical tests were two-sided. A P value of 0.05 or less was considered statistically significant, and the confidence interval was 95% confidence. The statistical description of count and grade index was expressed by the number of cases (%). The statistical description of measurement indexes was expressed by mean (standard deviation), median, minimum value and maximum value. The primary efficacy measure, progression-free survival at 3 and 6 months (PFS rate at 6 months), was estimated using the Kaplan-Meier method, and the confidence interval of the difference between the rate and the target value was calculated using the normal approximation method. For secondary efficacy measures, such as overall survival (OS), kaplan-Meier method was used to estimate the median and 95% confidence interval (CI), and survival curves were plotted. Objective response rate (ORR=CR+PR) and 95% confidence interval (CI) were calculated. The safety analysis was mainly descriptive statistical analysis. If necessary, the mean or incidence of examination results before and after medication could be compared. Vital signs, physical examination and laboratory examination indexes mainly describe the changes before and after medication and the relationship between abnormal changes and test drugs. All adverse events were standardized by MedDRA coding, and the incidence of adverse events, grade 3 and above, were summarized according to the systematic organ classification (SOC), preferred language (PT) and CTCAE classification in MedDRA coding. The adverse events, adverse reactions and serious adverse events that occurred in this study were listed and described.

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2023-02-26 17:22:05