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Trial search Nation, Province(City) Code of disease Primary sponsor(s) Secondary sponsor(s) Funding source Recruiting status Register status Measure Ethical committee Study type

Safety and Efficacy of SHR-1210 (an Anti-PD-1 Antibody) in Combination With Apatinib in PD-L1 Positive and/or dMMR Relapsed or Refractory Uterine/Cervical and Ovarian Carcinoma: a Phase II Trial

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注册号：

Registration number：

ChiCTR2000029752 

最近更新日期：

Date of Last Refreshed on：

2020-02-12 22:21:21 

注册时间：

Date of Registration：

2020-02-12 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

抗PD-1抗体SHR-1210联合甲磺酸阿帕替尼治疗PD－L1阳性和／或dMMR的复发或持续性子宫或卵巢恶性肿瘤的疗效和安全性研究

Public title：

Safety and Efficacy of SHR-1210 (an Anti-PD-1 Antibody) in Combination With Apatinib in PD-L1 Positive and/or dMMR Relapsed or Refractory Uterine/Cervical and Ovarian Carcinoma: a Phase II Trial

注册题目简写：

抗PD-1抗体SHR-1210联合甲磺酸阿帕替尼治疗复发或持续性妇科恶性肿瘤的II期临床研究

English Acronym：

A Phase II Trial of SHR-1210 (an Anti-PD-1 Antibody) in Combination With Apatinib in Relapsed or Refractory Gynecologic Carcinoma

研究课题的正式科学名称：

抗PD-1抗体SHR-1210联合甲磺酸阿帕替尼治疗PD－L1阳性和／或dMMR的复发或持续性子宫或卵巢恶性肿瘤的疗效和安全性研究

Scientific title：

Safety and Efficacy of SHR-1210 (an Anti-PD-1 Antibody) in Combination With Apatinib in PD-L1 Positive and/or dMMR Relapsed or Refractory Uterine/Cervical and Ovarian Carcinoma: a Phase II Trial

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：

李菁 

研究负责人：

冯炜炜 

Applicant：

Jing Li 

Study leader：

Weiwei Feng 

申请注册联系人电话：

Applicant telephone：

+86 13764172126

研究负责人电话：

Study leader's telephone：

+86 18917763870

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：

lj11733@rjh.com.cn

研究负责人电子邮件：

Study leader's E-mail：

fww12066@rjh.com.cn

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：

上海黄浦区瑞金二路197号

研究负责人通讯地址：

上海黄浦区瑞金二路197号瑞金医院

Applicant address：

197 Second Ruiiin Road, Huangpu District, Shanghai, China

Study leader's address：

197 Second Ruiiin Road, Huangpu District, Shanghai, China

申请注册联系人邮政编码：

Applicant postcode：

200025

研究负责人邮政编码：

Study leader's postcode：

200025

申请人所在单位：

上海交通大学医学院附属瑞金医院妇产科

Applicant's institution：

Department of Obstetrics and Gynecology, Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine

研究负责人所在单位：

上海交通大学医学院附属瑞金医院妇产科

Affiliation of the Leader：

Department of Obstetrics and Gynecology, Ruijin Hospital affiliated to Shanghai Jiaotong 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：

N2019-170

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：

上海交通大学医学院附属瑞金医院伦理委员会

Name of the ethic committee：

Ethics Committee of Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine

伦理委员会批准日期：

Date of approved by ethic committee：

2019-09-24 00:00:00

伦理委员会联系人：

杨伟国

Contact Name of the ethic committee：

Weiguo Yang

伦理委员会联系地址：

上海市黄浦区瑞金二路197号

Contact Address of the ethic committee：

197 Second Ruiiin Road, Huangpu District, Shanghai, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 21-64370045

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：

上海交通大学医学院附属瑞金医院

Primary sponsor：

Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine

研究实施负责（组长）单位地址：

上海市黄浦区瑞金二路197号

Primary sponsor's address：

197 Second Ruiiin Road, Huangpu District, Shanghai, 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)：

上海

市(区县)：

Country：

China

Province：

Shanghai

City：

单位(医院)：

上海交通大学医学院附属瑞金医院

具体地址：

黄浦区瑞金二路197号

Institution
hospital：

Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine

Address：

197 Second Ruiiin Road, Huangpu District

经费或物资来源：

江苏恒瑞医药股份有限公司资助

Source(s) of funding：

Sponsors and Collaborators: Jiangsu HengRui Medicine Co., Ltd.

Target disease：

Gynecologic Carcinoma

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：

该试验是一项开放性、单中心、非随机、II期临床研究，评价PD-1抗体SHR-1210联合VEGFR2抑制剂甲磺酸阿帕替尼对复发、持续性宫体及卵巢恶性肿瘤患者的疗效及安全性。疗效评估每8周一次，安全性评估（临床和实验室指标）贯彻整个研究，包括基线、每次治疗前。主要终点：评价16周的客观肿瘤应答率OTRR（CR+PR，iRECIST评价标准）；次要终点：16周的客观肿瘤应答率OTRR（RECIST 1.1评价标准）、16周和24周的疾病控制率DCR（CR+PR+SD）、无进展生存期PFS、总生存OS、客观肿瘤应答OTR、疾病控制持续时间DC、不良事件AE、健康相关生活质量HRQoL；第三终点，检测生物标志物，包括：PD-L1表达、MMR状态、MSI状态、基因组、蛋白组和免疫学特性等，观察与临床指标的相关性，以用于发现潜在预测治疗效果的指标。  

Objectives of Study：

This is an open-label, single-center, nonrandomized, Phase 2 study to evaluate efficacy and safety of SHR-1210 (anti-PD-1 antibody) in combination with apatinib (VEGFR2 inhibitor) in subjects with relapsed or refractory uterine /cervical and ovarian carcinoma. Efficacy will be assessed every 8 weeks. Safety evaluations (both clinical and laboratory) are performed at baseline, before each study treatment, and throughout the study. The primary objective of this study is to assess objective tumor response rate（OTRR=CR+PRiRECIST） at 16 weeks. The secondary objective is to observe objective tumor response rate at 16 weeks（RECIST 1.1） at 16 weeks, disease control rate (DCR=CR+PR+SD）at 16 and 24 weeks, progression free survival (PFS), overall survival (OS)objective tumor response (OTR), disease control (DC) time, safety (adverse event and health-related quality of life). The tertiary objective is to detect PD-L1, MMR, MSI, genomics, proteomics, immunology etc. to observe the correlation between clinical indicators and biomarkers, in order to discover potential predictors of therapeutic effectiveness.

药物成份或治疗方案详述：

药物1：SHR-1210 (又名，卡瑞丽珠单抗) SHR-1210是重组人源化抗PD-1单克隆抗体注射液。静脉给药，固定剂量200mg，静脉滴注，每次输注30 min，2周给药1次。直至疾病进展或无法耐受的药物毒副反应。 药物2:阿帕替尼 (又名，甲磺酸阿帕替尼) 甲磺酸阿帕替尼是小分子酪氨酸激酶抑制剂（TKI），为血管内生长因子受体-2（VEGFR-2）的选择性抑制剂。口服给药（餐后），每日1次，每次1片（250mg/片）连续服药，直至疾病进展或无法耐受的药物毒副反应。 研究观察一线化疗失败的转移性、持续性、复发性宫体/宫颈或卵巢恶性肿瘤患者接受SHR-1210联合阿帕替尼的治疗有效性及安全性。 

Description for medicine or protocol of treatment in detail：

Drug 1: SHR-1210 (Other Name: Camrelizumab) SHR-1210 is a humanized monoclonal antibody against Programmed death 1(PD-1). SHR-1210 will be administered as a 30-minute IV infusion Q2W at a dose of 200mg until disease progression or unacceptable toxicity. Drug 2: Apatinib (Other Name: Apatinib Mesylate) Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) selectively inhibits Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2). Apatinib will be administered 250mg orally, once daily until disease progression or unacceptable toxicity. Patients with metastatic, persistent, or recurrent uterine/cervical or ovarian carcinoma who failed to first-line chemotherapy will received SHR-1210 and apatinib. The efficacy and safety will be observed.  

纳入标准：

受试者必须满足下列所有标准：
1. 受试者自愿加入本研究，签署知情同意书；
2. 18～75岁女性；
3. ECOG评分：0～1；
4. 预期生存期≥3个月；
5. 经病理学确诊的复发或持续性子宫或卵巢恶性肿瘤，原发肿瘤免疫组化提示PD-L1阳性和／或dMMR，病理类型不限
6. 复发/转移后至少接受过一种全身性化疗方案，且符合下列治疗失败的定义：治疗期间进展，或疾病进展距离末次治疗间隔＜6个月（注：复发患者初次的辅助治疗包括化疗、放疗或同步放化疗等均不归于复发后的全身性化疗）；
7. 至少具有1个符合RECIST 1.1标准的可测量病灶；
8. 研究开始前4周内未接受过放疗(脑部放疗除外，见排除标准）；
9. 血液学指标符合下列要求：
中性粒细胞绝对计数≥1.5×10^9/L；
血小板≥75×10^9/L；
血红蛋白≥90g/L；
血清白蛋白≥30g/L；
胆红素≤1.5倍ULN；
ALT 和AST ≤3倍ULN；
血清肌酐≤1.5倍ULN或肌酐清除率≥60mL/min；
10. 非手术绝育或育龄期女性患者，需要在研究治疗期间和研究治疗期结束后3个月内采用一种经医学认可的避孕措施（如宫内节育器，避孕药或避孕套）；非手术绝育的育龄期女性患者在研究入组前的72h内血清或尿HCG检查必须为阴性；而且必须为非哺乳期。

Inclusion criteria

1. Be willing and able to provide written informed consent/ for the trial.
2. Women aged 18-75 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status of <= 1.
4. Have a life expectancy of at least 12 weeks.
5. Histologically confirmed diagnosis of relapsed or refractory uterine /cervical or ovarian carcinoma. PD-L1 positive and / or dMMR were detected by immunohistochemistry in primary tumor, with unlimited pathological types.
6. At least one systemic chemotherapy regimen was performed after recurrence or meatastasis, and it meets the following definition of treatment failure: refractory (progressed on chemotherapy) or resistant (recurred less than 6 months after chemotherapy) to prior standard care systemic regimen. The first adjuvant treatment (chemotherapy, radiotherapy or concurrent radio-chemotherapy) of relapsed patients is not attributed to systemic chemotherapy after recurrence.
7. At least one measurable lesion according to RECIST 1.1.
8. No radiotherapy is performed within 4 weeks before the study.
9. The results of patients' blood tests are as follows:
Neutrophils>=1.5 *10^9/L;
Hb >= 90g/L;
Plt>= 75 * 10^9/L;
Serum albumin >= 30g/L
TBIL <= 1.5 times of normal upper limit;
ALT and AST <= triple of normal upper limit;
Creatinine <= 1.5 times of normal upper limit or creatinine clearance rate >= 60mL/min.
10. Female Subjects of childbearing potential must have a negative serum/urine pregnancy test within 72 hours before the first dose and must be willing to use very efficient barrier methods of contraception (IUD, oral contraceptive or condom) for the course of the study through 3 months after the last dose of study treatment. Not in lactation period.

排除标准：

符合以下任一条标准的对象将排除于本研究
1. 受试者既往5年内或同时患有其它恶性肿瘤（已治愈的皮肤基底细胞癌和宫颈原位癌除外），其他部位原发的女性生殖系统转移性肿瘤（如Krukenberg瘤）；
2. 研究开始前4周内参加过未上市的其它药物临床试验；既往使用过其他针对PD-1/PD-L1的免疫治疗、或接受过抗血管生成类药物治疗；研究用药前4周内接种活疫苗；
3. 有临床症状的中枢神经系统转移，既往接受过脑或脑膜转移治疗，临床稳定已维持至少1个月，并且在研究开始前无需糖皮质激素及甘露醇治疗>2周者可以纳入，接受脑放疗者距末次放疗时间需间隔>4周，可以纳入；若无明显临床症状的中枢神经系统转移，接受脑放疗者距末次放疗时间需间隔>1周者可以纳入。
4. 已发生骨转移的患者，在参加研究前4周内接受过的姑息性放疗区域＞5%骨髓区域；
5. 严重的心肺功能不全，肝肾功能不全；严重或未控制的感染；长期未愈的伤口或骨折；任何活动性自身免疫病或正在使用免疫抑制剂、或激素治疗以达到免疫抑制目的（剂量>10mg/天泼尼松或其他等疗效激素），并在入组前2周内仍在继续使用的；先天或后天免疫功能缺陷（如HIV感染者），或活动性肝炎（乙肝、丙肝感染）；
6. 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）；
7. 凝血功能异常（PT>16s、APTT>43s、TT>21s、Fbg<2g/L），具有出血倾向；正在接受溶栓或抗凝治疗；已知存在的遗传性或获得性出血及血栓倾向；
8. 研究开始前6个月内发生过动/静脉血栓事件，如脑血管意外、深静脉血栓、肺栓塞等；
9. 尿常规提示尿蛋白≥ ++，证实24小时尿蛋白量≥1.0 g ；
10. 先前接受放疗、化疗、激素治疗、手术或分子靶向治疗，在治疗完成后(末次用药)，研究用药前不足4周的受试者；先前治疗引起的不良事件（脱发除外）未恢复至≤CTCAE 1度的患者；
11. 受试者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（含精神疾病）需要合并治疗，有严重的实验室检查异常，伴有家庭或社会等因素，会影响到受试者的安全。

Exclusion criteria：

1. Patients with a prior invasive malignancy who have had any evidence of disease within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Patients with metastatic gynecologic carcinoma, such as Krukenberg tumor.
2. Participated in other clinical trials within 4 weeks. Prior exposure to immune checkpoint inhibitors, including but not limited to other anti-PD-1 and anti-PD-L1 antibodies, or prior exposure to VEGFR inhibitor. Patients who may receive live vaccine within 4 weeks.
3. Patient has known active central nervous system (CNS) metastases: if who previously treated brain metastases and/or carcinomatous meningitis may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 2 weeks prior to trial treatment. The time from the last brain radiotherapy is at least 4 weeks prior to trial treatment. If patient has brain metastasis without obvious CNS symptoms , the time from the last brain radiotherapy is at least 1 week prior to trial treatment.
4. Patients with bone metastases received palliative radiotherapy more than 5% of the bone marrow area within 4 weeks before the study.
5. Clinically significant diseases, including but not limited to heart failure, respiratory failure, hepatorenal insufficiency. Acute or uncontrolled severe infection. Non-union of chronic wound or fracture. Patients with any active autoimmune disease. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 2 weeks before study drug administration. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease. Hepatitis B virus (HBV) > 2000 IU/ml or DNA >= 1 * 10^4/ml; or hepatitis C virus (HCV) RNA >= 1 * 10^3/ml).
6. Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents: systolic blood pressure >= 140 mmHg, diastolic blood pressure >= 90 mmHg.
7. Coagulation abnormalities (PT>16s, APTT>43s, TT>21s, Fbg<2g/L), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy. Known hereditary or acquired bleeding and thrombosis tendency.
8. Previous Arterial/venous thrombosis events within 6 monthssuch as cerebrovascular accident, deep vein thrombosis, pulmonary embolism.
9. Proteinuria >= (++) and 24 hours total urine protein > 1.0 g.
10. Prior chemotherapy, radiotherapy, homone therapy, surgery therapy, or molecular targeted therapy within 4 weeks before the study drug administration, or any unresolved AEs > Common Terminology Criteria for Adverse Events (CTCAE) Grade 1.
11. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's safety and participate in the study or would interfere with the interpretation of the results or lead to the trial being terminated early.

研究实施时间：

Study execute time：

从 From 2020-02-14 00:00:00至 To 2023-02-14 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2020-02-14 00:00:00 至 To 2022-02-14 00:00:00  

干预措施：

Interventions：

组别：

干预组

样本量：

30

Group：

Experimental Group

Sample size：

干预措施：

卡瑞丽珠单抗+甲磺酸阿帕替尼

干预措施代码：

Intervention：

SHR-1210 combined with Apatinib

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)：

  

Country：

China 

Province：

Shanghai 

City：

 

单位(医院)：

上海交通大学医学院附属瑞金医院 

单位级别：

三甲医院 

Institution
hospital：

Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

客观肿瘤应答率

指标类型：

主要指标

Outcome：

objective tumor response rate

Type：

Primary indicator

测量时间点：

16周

测量方法：

iRECIST评价标准

Measure time point of outcome：

at 16 weeks

Measure method：

iRECIST

指标中文名：

客观肿瘤应答率

指标类型：

次要指标

Outcome：

objective tumor response rate

Type：

Secondary indicator

测量时间点：

16周

测量方法：

RECIST 1.1

Measure time point of outcome：

at 16 weeks

Measure method：

RECIST 1.1

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：

16周和24周

测量方法：

iRECIST和RECIST 1.1

Measure time point of outcome：

at 16 and 24 weeks

Measure method：

iRECIST and RECIST 1.1

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：

治疗完成后1年

测量方法：

iRECIST和RECIST 1.1

Measure time point of outcome：

1 year after completion of treatment

Measure method：

iRECIST and RECIST 1.1

指标中文名：

总生存率

指标类型：

次要指标

Outcome：

overall survival

Type：

Secondary indicator

测量时间点：

治疗完成后1年

测量方法：

生存率

Measure time point of outcome：

1 year after completion of treatment

Measure method：

Survival rate

指标中文名：

客观肿瘤应答

指标类型：

次要指标

Outcome：

objective tumor response

Type：

Secondary indicator

测量时间点：

治疗完成后3个月

测量方法：

iRECIST和RECIST 1.1

Measure time point of outcome：

3 months after completion of treatment

Measure method：

iRECIST and RECIST 1.1

指标中文名：

疾病控制持续时间

指标类型：

次要指标

Outcome：

duration of disease control

Type：

Secondary indicator

测量时间点：

疾病控制，复发或转移

测量方法：

iRECIST和RECIST 1.1

Measure time point of outcome：

disease control time, relapse or metastasis time

Measure method：

iRECIST and RECIST 1.1

指标中文名：

不良事件

指标类型：

副作用指标

Outcome：

adverse event

Type：

Adverse events

测量时间点：

治疗期间，随访期间

测量方法：

CTCAE v 5.0

Measure time point of outcome：

during treatment and follow-up

Measure method：

CTCAE version 5.0

指标中文名：

健康相关生活质量

指标类型：

副作用指标

Outcome：

health-related quality of life

Type：

Adverse events

测量时间点：

治疗期间，随访期间

测量方法：

EORTC QLQ-30 (V3.0)

Measure time point of outcome：

during treatment and follow-up

Measure method：

EORTC QLQ-30 (V3.0)

指标中文名：

生物标志物

指标类型：

附加指标

Outcome：

biomarkers

Type：

Additional indicator

测量时间点：

治疗前后，复发或转移时

测量方法：

PD-L1表达、MMR状态、MSI状态、基因组、蛋白组和免疫学特性等

Measure time point of outcome：

before and after treatment, relapse or metastasis

Measure method：

PD-L1, MMR, MSI, genomics, proteomics, immunology etc.

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

肿瘤组织

组织：

Uterine/Cervical or Ovarian Carcinoma

Sample Name：

cancer tissue

Tissue：

宫体、宫颈或卵巢肿瘤组织

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：

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：

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：

女性

Gender：

Female

随机方法（请说明由何人用什么方法产生随机序列）：

该研究为非随机试验。

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

This is a nonrandomized study.

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：

N/A

Blinding：

N/A

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

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，文章公开发表后

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

After the trial complete and article being published

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：

设计CRF，化验检查通过病史系统录入

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

Design CRF and data collection through HIS system of the institution.

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2020-02-12 11:39:27
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