ChiCTR1900027114 版本V1.1 版本创建时间2020/06/14 23:52:57 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：

ChiCTR1900027114 

最近更新日期：

Date of Last Refreshed on：

2020-06-14 23:51:50 

注册时间：

Date of Registration：

2019-11-01 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

氟唑帕利联合卡瑞利珠单抗和阿帕替尼用于复发铂耐药卵巢癌的II期临床研究

Public title：

A phase II study for fuzuoparib in combination with apatinib and Camrelizumab in the treatment of patients with recurrent platinum-resistant ovarian cancer

注册题目简写：

English Acronym：

研究课题的正式科学名称：

氟唑帕利联合卡瑞利珠单抗（SHR1210）和阿帕替尼用于复发铂耐药卵巢癌的II期临床研究

Scientific title：

A phase II study for fuzuoparib (PARP inhibitor) in combination with apatinib and Camrelizumab (SHR-1210) in the treatment of patients with advanced Ovarian cancer

研究课题代号(代码)：

Study subject ID：

 OBU-OvaC-MUL-IIT-SHR1210-APA-FZPL

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：

叶明侠 

研究负责人：

孟元光 

Applicant：

Mingxia Ye 

Study leader：

Yuanguang Meng 

申请注册联系人电话：

Applicant telephone：

+86 15901229215

研究负责人电话：

Study leader's telephone：

+86 13501093681

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：

ymx298013@126.com

研究负责人电子邮件：

Study leader's E-mail：

meng6512@vip.sina.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：

北京市海淀区复兴路28号

研究负责人通讯地址：

北京市海淀区复兴路28号

Applicant address：

28 Fuxing Road, Haidian District, Beijing, China

Study leader's address：

28 Fuxing 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：

中国人民解放军总医院

Applicant's institution：

The General Hospital of the People's Liberation Army (PLAGH)

研究负责人所在单位：

中国人民解放军总医院

Affiliation of the Leader：

The General Hospital of the People's Liberation Army (PLAGH)

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：

S2018-163-03

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：

中国人民解放军总医院医学伦理委员会

Name of the ethic committee：

Ethics Committee of the PLA General Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

2020-04-30 00:00:00

伦理委员会联系人：

曹江

Contact Name of the ethic committee：

Jiang Cao

伦理委员会联系地址：

北京市海淀区复兴路28号

Contact Address of the ethic committee：

28 Fuxing Road, Haidian District, Beijing, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 010-66937166

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：

中国人民解放军总医院

Primary sponsor：

The General Hospital of the People's Liberation Army (PLAGH)

研究实施负责（组长）单位地址：

北京市海淀区复兴路28号

Primary sponsor's address：

28 Fuxing 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)：

中国人民解放军总医院

具体地址：

海淀区复兴路28号

Institution
hospital：

The General Hospital of the People's Liberation Army (PLAGH)

Address：

28 Fuxing Road, Haidian District

经费或物资来源：

科研项目

Source(s) of funding：

scientific research project

Target disease：

recurrent platinum-resistant ovarian cancer

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：

初步探索氟唑帕利、阿帕替尼和PD-1抗体SHR-1210用于复发铂耐药卵巢癌的有效性和安全性。  

Objectives of Study：

To preliminary explore the efficacy and safety of PARP inhibitor fluzoparal combined with carelizumab and apatinib in the treatment of recurrent platinum-resistant ovarian cancer.

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. 既往病理确诊为上皮性、高级别浆液性卵巢癌；有既往手术蜡块保存；
2. 铂类初次耐药复发（不限定既往铂敏感复发次数），末次含铂治疗复发时间＜6个月，排除原发性铂难治患者（指在初次含铂治疗期间复发或一线含铂治疗结束后28天内复发）；
3. ECOG体力状态评分0-1分；
4. 预期生存期≥4个月；
5. 依据RECIST 1.1 版的标准，经 CT 或MRI 证实，要求病人至少具有一个可测量病灶作为靶病灶。如果靶病灶是淋巴结要求短径大于1.5cm，且目标病灶不适合手术治疗；目标病灶未接受过放疗或在放疗野内复发者；
6. 能正常吞咽药片。
7. 既往抗肿瘤治疗或外科手术所致的所有急性毒性反应缓解至0-1级（根据NCI CTCAE 5.0版）或者至入组/排除标准所规定的水平。脱发等研究者认为对患者不产生安全性风险的其他毒性除外。
8. 有充足的器官和骨髓功能，定义如下：
1) 嗜中性粒细胞计数（ANC）≥ 1,500/mm3 (1.5 × 10^9/L)；
2) 血小板计数（PLT）≥ 100,000/mm3（100 × 10^9/L）；
3) 血红蛋白（Hb）≥ 9 g/dL（90 g/L）；
4) 血清肌酐≤ 1.5倍正常值上限（ULN）；
5) 总胆红素（BIL）≤ 1.5倍正常值上限（ULN）；
6) 谷草转氨酶（AST/SGOT）或谷丙转氨酶（ALT/SGPT）水平≤ 1.5倍正常值上限（ULN）；
7) 国际标准化比值（INR）≤ 1.5，凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）≤ 1.5倍ULN；
8) 尿蛋白<2+；如果尿蛋白≥2+，则24小时尿蛋白定量显示蛋白质必须≤1 g；
9) 促甲状腺激素（TSH）≤ 正常值上限（ULN）；如果异常应考察FT3和FT4水平，FT3和FT4水平正常则可以入选。
9. 育龄期女性受试者必须在开始研究用药前3天内进行血清妊娠试验，且结果为阴性，并且愿意在研究期间和末次给予研究药物后3个月内采用一种经医学认可的高效避孕措（如：宫内节育器、避孕药或避孕套）；
10. 经本人同意并已签署知情同意书，愿意并有能力遵从计划的访视、研究治疗、实验室检查及其他试验程序。

Inclusion criteria

1. Previous pathological diagnosis of epithelial and high-grade serous ovarian cancer; Preserving previous surgical wax blocks
2. Primary relapse of platinum resistance (not limited to the number of previous platinum-sensitive relapses), the relapse time of the last platinum-containing treatment is less than 6 months, excluding patients with primary platinum-refractory treatment (refers to relapse during the initial platinum-containing treatment or the end of first-line platinum-containing treatment Relapse within 28 days);
3. An Eastern Cooperative Oncology Group performance status of 0-1;
4. Expected survival >= 4 months;
5. According to the solid tumor efficacy evaluation standard (RECIST1.1), patients with at least one measurable lesion as a target lesion were confirmed by CT or MRI. If the target lesion is a lymph node, the short diameter is required to be greater than 1.5 cm, and the target lesion is not suitable for surgical treatment; The target lesion has not received radiotherapy or recurred in the field of radiotherapy.
6. Can swallow pills normally;
7. All acute toxic reactions resulting from prior anti-tumor therapy or surgery are alleviated to grade 0-1 (according to NCI CTCAE 4.03) or to the level specified in the inclusion/exclusion criteria.Hair loss and other toxins that researchers say do not pose a safety risk to patients are excluded.
8. There are sufficient organ and bone marrow functions, defined as follows:
a) Absolute neutrophil count (ANC) >= 1,500/mm3 (1.5 x 10^9/L);
b) Platelet count (PLT) >= 100,000/mm3 (100 x 10^9/L);
c) Hemoglobin (Hb) > 9 g/dL (90 g/L);
d) Serum creatinine (SCr) <= 1.5 times normal upper limit (ULN) ;
e) Total bilirubin (TBIL) <= 1.5 times the upper limit of normal value (ULN);
f) The level of Glutamate transaminase (AST /SGOT) or glutamate transaminase (ALT/SGPT) <= 1.5 times the upper limit of normal value (ULN);
g) The international standardization ratio INR <= 1.5 ULN; Prothrombin time(PT) < 1.5 ULN; Partial thromboplastin time (APTT)< 1.5 ULN;
h) Urinary protein < 2+; if urinary protein (> 2+), 24-hour urinary protein quantitative display must be (< 1 g);
i) Thyrotropin (TSH) <= ULN; if abnormal ,FT3 (T3) and FT4 (T4) levels should be examined, FT3 (T3) and FT4 (T4) levels can be selected if normal.
9. Female subjects of childbearing age must have a serum pregnancy test within 3 days before starting the study medication and the result is negative, and they are willing to use a medically approved highly effective contraception during the study period and within 3 months after the last study medication administration ( (Eg: IUD, contraceptives or condoms);
10. Obtaining the patient's consent and having signed an informed consent form, willing and able to comply with planned visits, research treatments, laboratory tests and other testing procedures.

排除标准：

1.既往接受过骨盆或下腹部的局部放射治疗；
2.既往接受过小分子TKI类抗血管生成药物（允许先前接受过贝伐单抗治疗，但不允许如帕唑帕尼、索拉菲尼，瑞戈非尼，西地尼布等）、PARP抑制剂药物（如奥拉帕利、尼拉帕利等）以及曾经使用过抗PD-1抗体、抗CTLA-4 抗体、TCR-T、CAR-T等免疫治疗；
3.有明确过敏史，可能对阿帕替尼、氟唑帕利以及卡瑞利珠单抗等生物制剂潜在过敏或不耐受；
4.首次给药前4周内参加过其他抗肿瘤药物临床试验；或首次给药前4周内或计划在研究期间接受减毒活疫苗；
5.5年内发生过其他恶性肿瘤（经过充分治疗的宫颈原位癌或皮肤鳞癌、或已控制的皮肤基底细胞癌除外）；
6.首次使用卡瑞利珠单抗前14天之内使用过免疫抑制药物，不包括喷鼻和吸入性皮质类固醇或生理剂量的系统性类固醇激素（即不超过10 mg/天强的松龙或同等药物生理学剂量的其他皮质类固醇）
7.具有症状的、已播散到内脏的、短期内有出现危及生命的并发症风险的晚期患者（包括有无法控制的大量渗出液[胸腔、心包、腹腔]、肺淋巴管炎及30%以上肝脏受累的患者）
8.存在任何活动性自身免疫病或有自身免疫病病史（包括但不局限于：自身免疫性肝炎、间质性肺炎，葡萄膜炎、肠炎、肝炎、垂体炎、血管炎、肾炎、甲状腺功能亢进、甲状腺功能降低；受试者患有白癜风或在童年期哮喘已完全缓解，成人后无需任何干预的可纳入；受试者需要支气管扩张剂进行医学干预的哮喘则不能纳入）
9.无法控制的高血压（收缩压≥140 mmHg 或者舒张压≥90 mmHg，尽管进行了最佳药物治疗）
10.患有Ⅱ级以上心肌缺血或心肌梗塞、控制不良的心律失常（包括 QTc间期男性≥450ms、女性≥470ms）。按NYHA标准，Ⅲ～Ⅳ级心功能不全，或心脏彩超检查提示左室射血分数（LVEF）＜50%者；入组前6个月内发生过心肌梗死，纽约心脏学会II级或以上心力衰竭，未得到控制的心绞痛，未得到控制的严重室性心律失常，有临床意义的心包疾病，或者心电图提示急性缺血或活动性传导系统异常
11.凝血功能异常（INR＞1.5或凝血酶原时间（PT）＞ULN+4 秒或 APTT>1.5ULN），具有出血倾向或正在接受溶栓或抗凝治疗；
12.进入研究前2个月内存在明显的咳鲜血、或日咯血量达半茶勺（2.5 ml）或以上者；或进入研究前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；或进入研究前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；
13.首次用药前4周内并发重度感染（如：需要静脉滴注抗生素、抗真菌或抗病毒药物），或在筛选期间/首次给药前出现不明原因的发热>38.5°C；
14.具有精神类药物滥用史且无法戒除者或有精神障碍的；
15.首次给药前4周内接受过重大外科手术。或具有开放性伤口或者骨折；
16.具有明显影响口服药物吸收的因素，如无法吞咽、慢性腹泻和肠梗阻等；或6个月内出现过空腔脏器窦道或穿孔。
17.尿常规提示尿蛋白≥++，或证实24h小时尿蛋白量≥1.0g。
18.人类免疫缺陷病毒（HIV）感染或已知有获得性免疫缺陷综合征（艾滋病），活动性乙型肝炎（HBV DNA ≥ 500 IU/ml）， 丙型肝炎（丙肝抗体阳性，且 HCV-RNA 高于分析方法的检测下限）或合并乙肝和丙肝共同感染。
19.受试者有未经治疗的中枢神经系统转移，既往接受过系统性、根治性脑或脑膜转移治疗（放疗或手术），如影像学证实稳定已维持至少1个月，且已停止全身性激素治疗（剂量>10mg/天泼尼松或其他等疗效激素）大于2周、无临床证状的患者可以纳入；
20.研究者判定不适合参与本研究的其他情况。

Exclusion criteria：

1. Previous local radiotherapy for pelvis or lower abdomen;
2. Previously exposed to other anti-angiogenic small-molecule TKI drugs (permitted to bevacizumab treatment before, but not allowed such as pazopanib, sorafenib, regofenib, sildenib, etc.), PARP inhibition Drugs (such as olaparib, niraparib, etc.) or had used an anti-PD-1 antibody, an anti-CTLA-4 antibody, TCR-T, CAR-T and other immune therapy;
3. Patients with a clear history of allergies may be potentially allergic or intolerant to the biologics of apatinib, fluzoparil, and Camrelizumab;
4. 4 weeks before the first administration participated in any other clinical trials of anticancer drugs; or before the first dose Live attenuated vaccines are accepted within 4 weeks or during the study period
5. Other malignant tumors have occurred within 5 years (except for fully treated cervical carcinoma in situ or squamous cell carcinoma of the skin, or controlled basal cell carcinoma of the skin);
6. Immunosuppressive drugs used within 14 days prior to the first use of Camrelizumab, excluding nasal and inhaled corticosteroids or physiological doses of systemic steroid hormones (ie, no more than 10 mg/day of turmeric or equivalent drug physiological dose) Other corticosteroids).
7. Late-stage patients with symptomatic, disseminated to visceral, short-term risk of life-threatening complications (including uncontrolled large amounts of exudate [thoracic, pericardium, abdominal cavity], pulmonary lymphangitis, and more than 30% liver involvement patients).
8. Any active autoimmune diseases or a history of autoimmune diseases (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, decreased thyroid function; subjects with vitiligo or complete remission asthma in childhood and without any intervention, all above can be included; asthma requiring medical intervention for bronchodilators should be excluded).
9. Uncontrollable hypertension (systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg, despite with the optimal medical treatment.
10. Grade II or higher myocardial ischemia, myocardial infarction or poor control arrhythmia (including male with QTc interval >= 450ms, or female with QTc interval >= 470ms). According to NYHA criteria, grade III to IV cardiac insufficiency, or cardiac color Doppler ultrasound examination showed left ventricular ejection fraction (LVEF) < 50%; myocardial infarction occurred within 6 months before enrollment, New York Heart Association Level II or above failure, uncontrolled angina, uncontrolled severe ventricular arrhythmia, pericardial disease with clinically significant, or electrocardiogram suggesting acute ischemia or abnormal active conduction system.
11. Abnormal coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5ULN), with bleeding tendency or undergoing thrombolysis or anticoagulant therapy.
12. Half of a teaspoons (2.5 ml) or more hemoptysis was found within the first 2 months or there were significant clinical bleeding symptoms or clearly propensity bleeding within 3 months before participant in the study, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood ++ or above in baseline or vasculitis; artery or venous thrombosis events within 6 months prior to the study, such as cerebrovascular accidents (Including transient ischemic attacks, cerebral hemorrhage, cerebral infarction, deep vein thrombosis and pulmonary embolism.
13. Severe infections within 4 weeks prior to accept medication (eg, intravenous infusion of antibiotics, antifungal or antiviral drugs), or unexplained fever during screening/first administration >38.5 °C
14. Those who have a history of psychotropic drug abuse and are unable to quit or have mental disorders.
15. Major surgical procedures were performed within 4 weeks before the first administration. Or open wounds or fractures.
16. There are obvious factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction. Or sinus or perforation of empty organs within 6 months.
17. Routine urine test indicated that urinary protein (++) or more, confirmed urinary protein (>1.0 g) within 24 hours.
18. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), active hepatitis B (HBV DNA (> 500 IU/ml), hepatitis C (hepatitis C antibody positive, and HCV-RNA higher than the lower limit of the analysis method) or co-infection with hepatitis B and hepatitis C.
19. The subject has untreated central nervous system metastasis and has previously received systemic, radical brain or meningeal metastasis therapy (radiotherapy or surgery), if imaging confirmed that the stability has been maintained for at least 1 month, and systemic hormone therapy has been discontinued (Dose>10mg/day prednisone or other curative hormones) Patients who are more than 2 weeks and have no clinical symptoms can be included;
20. There is any situation that may damage the subject or cause the subject to fail to meet or implement the research requirements.

研究实施时间：

Study execute time：

从 From 2020-06-12 00:00:00至 To 2021-12-31 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2020-06-12 00:00:00 至 To 2022-06-12 00:00:00  

干预措施：

Interventions：

组别：

干预组

样本量：

30

Group：

Case series

Sample size：

干预措施：

氟唑帕利 (PARP抑制剂)、阿帕替尼、卡瑞利珠单抗（PD-1单抗）

干预措施代码：

Intervention：

fuzuoparib (PARP inhibitor) in combination with apatinib and Camrelizumab (PD-1 inhibitor)

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)：

中国人民解放军总医院 

单位级别：

三级医院 

Institution
hospital：

The General Hospital of the People's Liberation Army (PLAGH)

Level of the institution：

Tertiary A Hospital

测量指标：

Outcomes：

指标中文名：

客观缓解率

指标类型：

主要指标

Outcome：

Objective Response Rate

Type：

Primary 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：

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：

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：

安全性

指标类型：

次要指标

Outcome：

safety

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：

正在进行

Recruiting

年龄范围：

Participant age：
最小 Min age 岁 years
最大 Max age 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）：

未使用

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

Not used

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）：

暂无

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：

暂无

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

Not available

数据与安全监察委员会：

Data and Safety Monitoring Committee：

无/No

注册人：

Name of Registration：

  2019-11-01 14:39:55