ChiCTR2100044229 版本V2.1 版本创建时间2021/08/30 14:54:00 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：

 ChiCTR2100044229 

最近更新日期：

Date of Last Refreshed on：

 2021-08-30 14:42:03 

注册时间：

Date of Registration：

 2021-03-12 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

请填写伦理委员会联系人。 评价信迪利单抗联合安罗替尼用于铂类药物治疗失败的复发性和或转移性头颈部鳞状细胞癌患者有效性和安全性的前瞻性临床研究

Public title：

A prospective clinical study to evaluate the efficacy and safety of Sintilimab combined with Anlotinib in patients with recurrent and or metastatic head and neck squamous cell carcinoma who failed platinum-based drug therapy

注册题目简写：

English Acronym：

研究课题的正式科学名称：

评价信迪利单抗联合安罗替尼用于铂类药物治疗失败的复发性和或转移性头颈部鳞状细胞癌患者有效性和安全性的前瞻性临床研究

Scientific title：

A prospective clinical study to evaluate the efficacy and safety of Sintilimab combined with Anlotinib in patients with recurrent and or metastatic head and neck squamous cell carcinoma who failed platinum-based drug therapy

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：

桂琳 

研究负责人：

桂琳 

Applicant：

Gui Lin 

Study leader：

Gui Lin 

申请注册联系人电话：

Applicant telephone：

 +86 13520372817

研究负责人电话：

Study leader's
telephone：

+86 13520372817

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：

 guilindoctor@126.com

研究负责人电子邮件：

Study leader's E-mail：

 guilindoctor@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：

北京市朝阳区潘家园南里17号

研究负责人通讯地址：

北京市朝阳区潘家园南里17号

Applicant address：

17 South Panjiayuan Lane, Chaoyang District, Beijing, China

Study leader's address：

17 South Panjiayuan Lane, Chaoyang District, Beijing, China

申请注册联系人邮政编码：

Applicant postcode：

 100021

研究负责人邮政编码：

Study leader's postcode：

 100021

申请人所在单位：

中国医学科学院肿瘤医院

Applicant's institution：

Chinese Academy of Medical Sciences Cancer Hospital

研究负责人所在单位：

中国医学科学院北京协和医学院国家癌症中心/国家肿瘤临床研究中心/癌症医院

Affiliation of the Leader：

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital，Chinese Academy of Medical Sciences and Peking Union Medical College

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：

 21/001-2672

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：

国家癌症中心/中国医学科学院北京协和医学院肿瘤医院国家抗肿瘤药GCP中心伦理委员会

Name of the ethic committee：

National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College National GCP Center for Anticancer Drugs, The independent Ethics Committee

伦理委员会批准日期：

Date of approved by ethic committee：

 2021-01-14 00:00:00

伦理委员会联系人：

未说明

Contact Name of the ethic committee：

Not stated

伦理委员会联系地址：

北京市朝阳区潘家园南里17号东院病房内科三病区伦理委员会办公室

Contact Address of the ethic committee：

17 South Panjiayuan Lane, Chaoyang District, Beijing, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

 +86 010-87788495

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：

中国医学科学院肿瘤医院

Primary sponsor：

Chinese Academy of Medical Sciences Cancer Hospital

研究实施负责（组长）单位地址：

北京市朝阳区潘家园南里17号

Primary sponsor's address：

17 South Panjiayuan Lane, Chaoyang 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)：

中国医学科学院肿瘤医院

具体地址：

朝阳区潘家园南里17号

Institution
hospital：

Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Address：

17 South Panjiayuan Lane, Chaoyang District

经费或物资来源：

吴阶平基金

Source(s) of funding：

Wu Jie-Ping Foundation

研究疾病：

复发性和或转移性头颈部鳞状细胞癌  

Target disease：

Recurrent and or metastatic head and neck squamous cell 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：

 II期临床试验 

Study phase：

2

研究设计：

单臂 

Study design：

Single arm 

研究目的：

1、主要研究目标 评价信迪利单抗联合盐酸安罗替尼胶囊用于铂类药物治疗失败的复发性和/或转移性头颈部鳞状细胞癌患者的客观缓解率（ORR）； 2、次要研究目标 评估中国晚期晚期头颈鳞癌患者信迪利单抗联合安罗替尼方案治疗的其他有效性指标，包括疾病控制率（DCR）、缓解持续时间（DOR）、无进展生存期（PFS）、生存期（OS） 评估中国晚期晚期头颈鳞癌患者信迪利单抗联合安罗替尼方案治疗的安全性及患者生活质量（QoL） 肿瘤组织PDL1 的表达与疗效的相关性 3、探索性研究目标 基线患者肿瘤组织TMB、炎性T细胞基因表达谱分析结果与疗效、预后的相关性。  

Objectives of Study：

1. Main research objectives To evaluate the objective response rate (ORR) of Sintilimab combined with Anlotinib Hydrochloride Capsules in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who failed platinum-based drug therapy; 2. Secondary research objectives To evaluate other efficacy indicators of sintilimab combined with anlotinib regimen in patients with advanced head and neck squamous cell carcinoma in China, including disease control rate (DCR), duration of remission (DOR), progression-free survival (PFS), and survival Period (OS) To assess the safety and quality of life (QoL) of sintilimab combined with anlotinib regimen in patients with advanced head and neck squamous cell carcinoma in China Correlation between the expression of PDL1 in tumor tissues and curative effect 3. Exploratory research goals Correlation between the results of TMB and inflammatory T cell gene expression profiles in tumor tissues of baseline patients and the efficacy and prognosis.

药物成份或治疗方案详述：

 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

⑴ 病理学确诊的HNSCC（鼻咽癌除外）；
⑵ 不适合接受局部治疗的复发性和/或转移性HNSCC。仅患有复发性疾病（无转移）的患者既往必须接受放疗（作为手术后辅助治疗或者作为局部晚期HNSCC的治疗）作为“局部区域治疗”，并且放疗必须在筛选影像检查前至少 6 个月完成；
⑶ 男性或女性，年龄≥18周岁；
⑷ ECOG体能状态评分0-1级；
⑸ 根据实体瘤疗效评价标准（RECIST版本1.1），至少有一个可测量的病灶；
⑹ 患者既往接受过以铂类药物（顺铂/卡铂/奈达铂）为基础的治疗并于治疗过程中（至少2个周期）或治疗结束后出现明确的疾病进展（参照RECIST版本1.1），且铂类药物最小剂量需满足：
顺铂最小剂量：每个周期剂量≥60mg/m2，或8周内总剂量≥120mg/m2；
卡铂最小剂量：AUC≥4/周期，或者8周内总AUC≥8。
如果顺铂卡铂转换，可用以下公式计算铂剂量：卡铂1 AUC=顺铂15mg/m2；
奈达铂最小剂量：每个周期剂量≥80mg/m2，或8周内总剂量≥160mg/m2；
⑺ 可提供肿瘤组织样本进行PD-L1表达检测；
⑻ 主要器官功能正常，即符合下列标准：
血常规（筛选检查前14天内未输血）：中性粒细胞≥1.5×l0^9/L，血小板≥100×10^9/L，血红蛋白≥90g/L；
肝功能：谷丙转氨酶（ALT）和谷草转氨酶（AST），无肝转移者ALT和AST≤3×ULN，有肝转移者ALT和AST≤5×ULN；总胆红素（TBIL）≤1.5×ULN（Gilbert综合征患者，≤3 ×ULN）；
⑼ 预期生存期超过3个月；
⑽ 筛选前自愿签署书面知情同意书；

Inclusion criteria

1. HNSCC confirmed pathologically (except nasopharyngeal carcinoma);
2. Recurrent and/or metastatic HNSCC not suitable for local treatment.
Patients with only recurrent disease (no metastasis) must receive radiotherapy (as a postoperative adjuvant treatment or as a treatment for locally advanced HNSCC) as "local area treatment", and radiotherapy must be completed at least 6 months before screening imaging
3. Male or female, age >= 18 years;
4. ECOG performance status score 0-1;
5. According to the curative effect evaluation standard of solid tumors (RECIST version 1.1);
6. The patient has previously received platinum-based drug (cisplatin/carboplatin/nedaplatin)-based treatment and has a clear disease progression during the treatment (at least 2 cycles) or after the end of the treatment (refer to RECIST version 1.1), And the minimum dose of platinum drugs must meet:
The minimum dose of cisplatin: the dose per cycle >= 60mg/m2, or the total dose within 8 weeks >= 120mg/m2;
Minimum carboplatin dose: AUC>=4/cycle, or total AUC8 in 8 weeks.
If the cisplatin is converted to carboplatin, the platinum dose can be calculated by the following formula: carboplatin 1 AUC = cisplatin 15mg/m2;
The minimum dose of nedaplatin: the dose per cycle >= 80mg/m2, or the total dose within 8 weeks >= 160mg/m2;
7. Can provide tumor tissue samples for PD-L1 expression detection there is at least one measurable lesion;
8. The main organs function normally, that is, they meet the following standards:
Routine blood test (no blood transfusion within 14 days before the screening test): neutrophils >=1.5 x 10^9/L, platelets >= 100 x 10^9/L, hemoglobin >= 90g/L;
Liver function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ALT and AST <= 3 ULN for those without liver metastasis, ALT and AST <= 5 ULN for those with liver metastasis; total bilirubin (TBIL) <= 1.5 ULN (Patients with Gilbert syndrome, <= 3 ULN);
9. The expected survival period exceeds 3 months;
10. Sign written informed consent voluntarily before screening.

排除标准：

⑴ 患者有坏死病灶，经研究者判断有大出血风险；
⑵ 可能对安罗替尼、信迪利单抗或任何辅料发生超敏反应；
⑶ 既往使用过PD1、PDL1、CTLA4单抗等免疫调节药物 或 抗血管生成类药物（如安罗替尼，阿帕替尼、贝伐单抗、恩度等）；
⑷ 患者正在使用（或者在研究治疗首次给药前1周内无法停用）以抗肿瘤为适应症的中草药；
⑸ 控制不良的胸腔积液、心包积液或需要经常性引流的腹水；允许留置导管的患者（如 PleurX?导管）参加；
⑹ 研究治疗开始时，既往治疗仍有未愈毒性反应，并且《不良事件通用术语标准（CTCAE 5.0）级别超过1级（脱发除外）；
⑺ 脊髓压迫或有症状且未经治疗的脑、脊髓转移（无症状、病情稳定、研究治疗开始前不需要使用类固醇药物治疗满4周者除外）；
⑻ 控制不良的肿瘤相关疼痛。对于需要镇痛药治疗的患者，在参加研究前必须接受稳定剂量的治疗。入组前应对适合姑息性放疗（例如，骨转移或导致神经损伤的转移）的有症状病灶进行治疗。入组前，如适当，应考虑对进一步生长可能导致功能缺陷或顽固性疼痛（例如，目前与脊髓压迫无关的硬膜外转移）的无症状转移病灶进行局部-区域性治疗。
⑼ 乙型肝炎、丙型肝炎或人免疫缺陷病毒（HIV 抗体阳性）。乙型肝炎抗体阳性的患者只有在HBV DNA ?2000cps/ml时有资格参加本研究。丙型肝炎抗体阳性的患者只有聚合酶链反应显示HCV RNA 阴性时才有资格参加本研究；
⑽ 随机化前 5 年内患有除晚期头颈鳞癌之外的其它恶性肿瘤，转移或死亡风险可忽略且治疗后预期可获得根治性结果的恶性肿瘤（例如，充分治疗的宫颈原位癌、基底或鳞状细胞皮肤癌、根治性目的治疗的局限性前列腺癌、根治性目的手术治疗的原位导管癌）除外；
⑾ 随机化前 28 天内除诊断晚期头颈鳞癌之外有其它大手术或预计在研究期间需要进行大手术；
⑿ 既往进行骨髓移植或既往进行实体器官移植的患者；
⒀ 随机化前 4 周（28 天）内接种任何活疫苗（例如，针对传染性疾病的疫苗，如流感疫苗、水痘疫苗等）；
⒁ 任何影响患者口服药物的因素，比如无法吞咽、胃肠道切除术后、慢性腹泻和肠梗阻等；
⒂ 符合下列任一心脏标准：在静息状态下，心电图（ECG）检查得出的平均校正QT间期（QTc）>470 msec（第1次异常时，在48 h内复测1次，以2次平均结果计算）。各种有临床意义的心律、传导、静息ECG形态异常，例如完全性左束支传导阻滞，III度传导阻滞，II度传导阻滞，PR间期>250 msec。可能增加QTc延长风险或心律失常事件风险的各种因素，例如冠心病，心力衰竭，低钾血症，先天性长QT综合症，家族史中一级亲属有长QT综合征或不到40岁就不明原因猝死，正在使用任何已知QT间期延长的药物；
⒃ 存在任何重度和/或未能控制的疾病的患者，包括但不局限于以下情况：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 ≥440ms）及≥2级充血性心功能衰竭（纽约心脏病协会（NYHA）分级）；活动性或未能控制的严重感染(≥CTC AE 2级感染)；肝硬化、失代偿性肝病；肾功能衰竭需要血液透析或腹膜透析；糖尿病控制不佳（空腹血糖（FBG）＞10mmol/L）；尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0 g者；
⒄ 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；
⒅ 有下列既往史：间质性肺病，药物性间质性肺病，需要类固醇治疗的放射性肺炎，具临床证据的活动性间质性肺病；
⒆ 入组前6个月内出现血栓性或栓塞性静脉或动脉事件，如脑血管意外，包括一过性脑缺血发作、动脉血栓形成、深静脉血栓形成和肺栓塞等；曾患有出血性疾病或凝血功能异常。
⒇ 哺乳期女性患者。

Exclusion criteria：

1. The patient has necrotic lesions, and the investigator judges that there is a risk of hemorrhage;
2. May have hypersensitivity to Anlotinib, Sintilimab or any excipients;
3. Have used PD1, PDL1, CTLA4 monoclonal antibodies and other immunomodulatory drugs or anti-angiogenesis drugs (such as Anlotinib, Apatinib, Bevacizumab, Endo, etc.);
4. The patient is using (or cannot be stopped within 1 week before the first administration of the study treatment) Chinese herbal medicine with anti-tumor indications;
5. Poorly controlled pleural effusion, pericardial effusion, or ascites requiring frequent drainage; patients with indwelling catheters (such as PleurX? catheters) are allowed to participate;
6. At the beginning of the study treatment, there are still unhealed toxic reactions from the previous treatment, and the "Common Terminology Standards for Adverse Events (CTCAE 5.0) level exceeds level 1 (except for hair loss);
7. Spinal cord compression or symptomatic and untreated brain and spinal cord metastases (except those who are asymptomatic, stable, and do not need to use steroids for 4 weeks before the start of research treatment);
8. Poorly controlled tumor-related pain.
For patients who need analgesics, they must receive a stable dose of treatment before participating in the study.
Symptomatic lesions suitable for palliative radiotherapy (for example, bone metastases or metastases that cause nerve damage) should be treated before admission.
Before enrollment, if appropriate, local-regional treatment should be considered for asymptomatic metastases that may cause functional defects or intractable pain (for example, epidural metastases that are not currently associated with spinal cord compression);
9. Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV antibody positive).
Patients with positive hepatitis B antibodies are only eligible to participate in this study when HBV DNA>2000cps/ml.
Patients with positive hepatitis C antibodies are only eligible to participate in this study if the polymerase chain reaction shows negative HCV RNA;
10. Patients suffering from other malignant tumors other than advanced head and neck squamous cell carcinoma within 5 years before randomization, with negligible risk of metastasis or death, and malignant tumors with curative results expected after treatment (for example, fully treated cervical carcinoma in situ, basal carcinoma)
Except for squamous cell skin cancer, localized prostate cancer for radical treatment, and ductal carcinoma in situ for radical surgery;
11. In the 28 days before randomization, there are other major operations besides the diagnosis of advanced head and neck squamous cell carcinoma or major surgery is expected to be performed during the study period;
12. Patients who have undergone bone marrow transplantation or solid organ transplantation in the past;
13. Inoculate any live vaccines (for example, vaccines against infectious diseases, such as influenza vaccine, chickenpox vaccine, etc.) within 4 weeks (28 days) before randomization;
14. Any factors that affect the patient's oral medication, such as inability to swallow, gastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.;
15. Meet any of the following cardiac standards: In the resting state, the average corrected QT interval (QTc) obtained from the ECG examination > 470 msec (when the first abnormality occurs, repeat the measurement within 48 hours, and then 2 average results calculation).
Various clinically significant heart rhythm, conduction, and resting ECG morphological abnormalities, such as complete left bundle branch block, third-degree block, second-degree block, and PR interval> 250 msec.
Various factors that may increase the risk of QTc prolongation or the risk of arrhythmia events, such as coronary heart disease, heart failure, hypokalemia, congenital long QT syndrome, family history of first-degree relatives with long QT syndrome or less than 40 years old;
15. Sudden death of unknown cause, using any drugs known to prolong the QT interval;
16. Patients with any severe and/or uncontrolled diseases, including but not limited to the following conditions: patients with poor blood pressure control (systolic blood pressure> 150 mmHg, diastolic blood pressure > 100 mmHg); patients with myocardial deficiency or myocardial infarction above grade I, arrhythmia (including QTC >= 440ms) and congestive heart failure >= 2 grade (New York Heart Association (NYHA) classification); active or uncontrolled serious infection (>= CTC AE grade 2 infection); Liver cirrhosis, decompensated liver disease; renal failure requires hemodialysis or peritoneal dialysis; poor control of diabetes (fasting blood glucose (FBG) > 10mmol/L); urine routines suggest urine protein >= ++, and 24-hour urine is confirmed; Protein quantitative > 1.0 g;
17. Patients who have epileptic seizures and need treatment, have a history of psychotropic drug abuse and cannot be quit or have mental disorders;
18. Past history of the following: interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy, active interstitial lung disease with clinical evidence;
19. Thrombotic or embolic venous or arterial events occurred within 6 months before enrollment, such as cerebrovascular accidents, including transient ischemic attack, arterial thrombosis, deep vein thrombosis, pulmonary embolism, etc.; had hemorrhage; Sexual disease or abnormal blood coagulation function.
20. Female patients during lactation.

研究实施时间：

Study execute time：

从 From 2021-01-31 00:00:00至 To 2023-12-31 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2021-03-15 00:00:00 至 To 2022-12-31 00:00:00

干预措施：

Interventions：

组别：

Case series

样本量：

 23

Group：

Case series

Sample size：

干预措施：

anlotinib 12mg once daily for 2 weeks ,then was stopped for 1 week,combined with sintilimab injection 200 mg the first day,every 21 days for a cycle, until disese progression or intolerable toxicity

干预措施代码：

Intervention：

anlotinib 12mg once daily for 2 weeks ,then was stopped for 1 week,combined with sintilimab injection 200 mg the first day,every 21 days for a cycle, until disese progression or intolerable toxicity

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)：

 中国医学科学院肿瘤医院 

单位级别：

 三甲 

Institution
hospital：

Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

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：

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：

DOR

指标类型：

次要指标

Outcome：

DOR

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

DCR

指标类型：

主要指标

Outcome：

DCR

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：

肿瘤组织切片

组织：

Sample Name：

Tumour 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 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)：

N/A

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：

N/A

Blinding：

N/A

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 请阅读网页注册指南中关于 原始数据共享 的内容。

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

Do not share

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表

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

Case Report Form (CRF)

数据与安全监察委员会：

Data and Safety Monitoring Committee：

无/No

注册人：

Name of Registration：

  2021-03-12 09:42:41