中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2300071203
最近更新日期： Date of Last Refreshed on：	2023-06-04 15:57:21
注册时间： Date of Registration：	2023-05-08 00:00:00
注册号状态：	补注册
Registration Status：	Retrospective registration
注册题目：	信迪利单抗联合化疗序贯放疗一线治疗食管癌寡转移的Ⅱ期探索性临床研究
Public title：	A phase Ⅱ clinical trial of sintilimab combined with chemotherapy followed by radiotherapy as first-line treatment for oligometastatic esophageal cancer
注册题目简写：
English Acronym：
研究课题的正式科学名称：	信迪利单抗联合化疗序贯放疗一线治疗食管癌寡转移的Ⅱ期探索性临床研究
Scientific title：	A phase Ⅱ clinical trial of sintilimab combined with chemotherapy followed by radiotherapy as first-line treatment for oligometastatic esophageal cancer
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：	王琳琳	研究负责人：	王琳琳
Applicant：	Wang Linlin	Study leader：	Wang Linlin
申请注册联系人电话： Applicant telephone：	+86 13793187739	研究负责人电话： Study leader's telephone：	+86 13793187739
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：	wanglinlinatjn@163.com	研究负责人电子邮件： Study leader's E-mail：	wanglinlinatjn@163.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：	山东省济南市槐荫区济兖公路440号	研究负责人通讯地址：	山东省济南市槐荫区济兖公路440号
Applicant address：	440 Jiyan Road, Huaiyin District, Ji'nan, Shandong	Study leader's address：	440 Jiyan Road, Huaiyin District, Ji'nan, Shandong
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：	山东第一医科大学附属省肿瘤医院
Applicant's institution：	Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
研究负责人所在单位：	山东第一医科大学附属省肿瘤医院
Affiliation of the Leader：	Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences

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：	SDZLEC2020-115-01	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：	山东第一医科大学附属省肿瘤医院伦理委员会
Name of the ethic committee：	Ethics Committee of Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
伦理委员会批准日期： Date of approved by ethic committee：	2020-10-07 00:00:00
伦理委员会联系人：	李朝伟
Contact Name of the ethic committee：	Li Chaowei
伦理委员会联系地址：	山东省济南市槐荫区济兖公路440号
Contact Address of the ethic committee：	440 Jiyan Road, Huaiyin District, Ji'nan, Shandong
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 15553119258	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：

山东第一医科大学附属省肿瘤医院

Primary sponsor：

Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences

研究实施负责（组长）单位地址：

山东省济南市槐荫区济兖公路440号

Primary sponsor's address：

440 Jiyan Road, Huaiyin District, Ji'nan, Shandong

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	山东	市(区县)：	济南
Country：	China	Province：	Shandong	City：	Ji'nan
单位(医院)：	山东第一医科大学附属省肿瘤医院	具体地址：	槐荫区济兖公路440号
Institution hospital：	Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences	Address：	440 Jiyan Road, Huaiyin District

经费或物资来源：

无

Source(s) of funding：

NA

研究疾病：

食管癌

Target disease：

Esophageal carcinoma, EC

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.主要目的：评价信迪利单抗联合化疗序贯放疗一线治疗食管癌寡转移患者的疗效； 2.次要目的：探究信迪利单抗联合化疗序贯放疗一线治疗食管癌寡转移患者的疗效与安全性； 3.探索性目的：探索潜在预测疗效的生物标志物，包括但不限于肿瘤组织标本或血液中的PD-L1表达、肿瘤突变负荷（Tumor Mutational Burden，TMB）水平和T细胞亚群等对疗效及预后的提示作用。

Objectives of Study：

1. Main objective: To evaluate the efficacy of sindillimab combined with chemotherapy and radiotherapy in the first-line treatment of patients with oligometastatic esophageal cancer; 2. Secondary objective: To explore the efficacy and safety of sindillimab combined with chemotherapy and radiotherapy in the first-line treatment of patients with oligometastatic esophageal cancer; 3. Exploratory objective: To explore potential biomarkers for predicting the efficacy, including but not limited to the expression of PD-L1 in tumor tissue specimens or blood, the level of tumor mutational burden (TMB) and T cell subsets, which may suggest 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：

1.	在实施任何试验相关流程之前，签署书面知情同意；
2.	年龄：≥18 周岁且≤75 周岁，性别不限；
3.	初诊患者，组织病理学及影像学检查确诊的IVB期或复发转移食管癌，具有可测量寡转移灶≤5个/3个器官，且至少1处可行放疗；
4.	根据实体肿瘤疗效评价标准（RECIST1.1版），至少有一处影像学可测量病灶；
5.	既往未接受过针对晚期/转移性疾病的任何系统性抗肿瘤治疗。对于既往曾接受过辅助/新辅助化疗，或针对进展期疾病接受过根治性放化疗的患者，如疾病进展或复发与末次药物治疗结束间隔至少6个月以上，允许入组本研究；
6.	允许无症状或经局部治疗后症状稳定的脑转移患者入组，患者需满足以下条件：
(1)	中枢神经系统之外有可测量病灶；
(2)	无中枢神经系统症状或至少2月内症状无加重；
(3)	无需糖皮质激素治疗或首次研究药物给药前3天内停用糖皮质激素治疗者；
7.	ECOG评分0-1分；
8.	预期生存时间>3个月；
9.	足够器官功能，受试者需满足如下实验室指标：
(1)	近14天未使用粒细胞集落刺激因子的情况下，中性粒细胞绝对值（ANC）≥1.5x10^9/L；
(2)	近14天未输血的情况下，血小板≥100×10^9/L；
(3)	近14天内无输血或使用促红细胞生成素的情况下，血红蛋白>9g/dL；
(4)	总胆红素≤1.5×正常值上限（ULN）；
(5)	天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）在≤2.5×ULN（有肝转移的患者允许ALT或AST≤5×ULN）；
(6)	血肌酐≤1.5×ULN并且肌酐清除率（采用Cockcroft-Gault公式计算）≥60ml/min；
(7)	凝血功能良好，定义为国际标准化比值（INR）或凝血酶原时间（PT）≤1.5倍ULN；
(8)	甲状腺功能正常，定义为促甲状腺激素（TSH）在正常范围内。如基线TSH超出正常范围，如果总T3（或FT3）及FT4在正常范围内的受试者亦可入组；
(9)	心肌酶谱在正常范围内（如研究者综合判断为不具有临床意义的单纯实验室异常也允许入组）；
10.	对于育龄期女性受试者，应在接受首次研究药物给药（第1周期第1天）之前的3天内接受尿液或血清妊娠试验且结果为阴性。如果尿液妊娠试验结果无法确认为阴性，则要求进行血液妊娠试验。非育龄期女性定义为绝经后至少１年，或进行过手术绝育或子宫切除术；
11.	如存在受孕风险，所有受试者（不论男性或女性）均需在整个治疗期间直至治疗末次研究药物给药后120天（或末次化疗药物给药后180天）内采用年失败率低于1%的避孕措施。

Inclusion criteria

1. Sign a written informed consent prior to the implementation of any test related procedures;
2. Aged 18-75 years, gender is not limited;
3. Newly diagnosed subjects with stage IVB or recurrent metastatic esophageal cancer confirmed by histopathology and imaging examination, with measurable oligometastases <=5 /3 organs, and at least 1 place feasible for radiotherapy;
4. According to the solid tumor efficacy evaluation criteria (Recist version 1.1), there was at least one radiologically measurable lesion;
5. No previous systematic antitumor therapy for advanced/metastatic disease. Subjects who had previously received adjuvant/neoadjuvant chemotherapy, or had received radical chemoradiotherapy for advanced disease, if the interval between disease progression or recurrence and the end of the last drug therapy was at least 6 months, were allowed to be enrolled in this study.
6. Subjects with asymptomatic brain metastases or stable symptoms after local treatment are allowed to be enrolled, and subjects must meet the following conditions:
(1) Measurable lesions outside the central nervous system;
(2) There are no central nervous system symptoms or symptoms have not worsened for at least 2 months;
(3) Subjects who did not need glucocorticoid treatment or stopped glucocorticoid treatment within 3 days before the first study drug administration;
7. ECOG score 0-1;
8. Expected survival time >3 months;
9. Adequate organ function, subjects shall meet the following laboratory criteria:
(1) The absolute value of neutrophil granulocyte (ANC) >=1.5x10^9/L in the last 14 days without the use of granulocyte colony stimulating factor;
(2) Platelets >=100x10^9/L without blood transfusion in the last 14 days;
(3) Hemoglobin >9g/dL in the last 14 days without blood transfusion or erythropoietin use;
(4) Total bilirubin <=1.5x upper limit of normal value (ULN);
(5) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) <=2.5xULN (ALT or AST<=5xULN in subjects with liver metastasis);
(6) Serum creatinine <=1.5xULN and creatinine clearance (calculated by Cockcroft-Gault formula) >=60ml/min;
(7) Good coagulation function, defined as International Standardized ratio (INR) or prothrombin time (PT) <=1.5 times ULN;
(8) Normal thyroid function, defined as thyroid stimulating hormone (TSH) within the normal range. Subjects whose baseline TSH is outside the normal range can be enrolled if total T3 (or FT3) and FT4 are within the normal range;
(9) The myocardial enzyme profile was within the normal range (if the researchers comprehensively judged that the simple laboratory abnormality was not clinically significant, it was also allowed to be included);
10. For female subjects of childbearing age, a urine or serum pregnancy test should be tested negative within 3 days prior to initial study drug administration (day 1 of cycle 1). If the urine pregnancy test results cannot be confirmed negative, a blood pregnancy test is requested. Women of non-reproductive age were defined as at least one year after menopause or having undergone surgical sterilization or hysterectomy;
11. If there is a risk of conception, all subjects (male or female) are required to use contraception with an annual failure rate of less than 1% for the entire duration of treatment up to 120 days after the last study drug administration (or 180 days after the last chemotherapy drug administration).

排除标准：

1. 已知内镜下趋于完全梗阻需要介入治疗解除梗阻的； 2. 食管或气管腔内支架植入术后； 3. 既往接受过针对晚期或者转移性食管癌的系统性治疗； 4. 由于肿瘤明显入侵食管病灶相邻器官（大动脉或气管）导致具有较高的出血或穿孔危险的患者，或已形成瘘管的患者； 5. 首次给药前3年内诊断为食管癌之外的其他恶性疾病（不包括经过根治的皮肤基底细胞癌、皮肤鳞状上皮癌、和/或经过根治性切除的原位癌）； 6. 当前正在参与干预性临床研究治疗，或在首次给药前4周内接受过其他研究药物或使用过研究器械治疗； 7. 既往接受过下列疗法：抗PD-1、抗PD-L1或抗PD-L2药物或者针对另一种刺激或协同抑制T细胞受体（例如，CTLA-4、OX-40、CD137）的药物； 8. 首次给药前2周内接受过具有抗肿瘤适应症的中成药或免疫调节作用的药物（包括胸腺肽、干扰素、白介素，除外为控制胸水局部使用）系统性全身治疗； 9. 首次给药前2年内发生过需要全身性治疗（例如使用缓解疾病药物、糖皮质激素或免疫抑制剂）的活动性自身性免疫疾病。替代疗法（例如甲状腺素、胰岛素或者用于肾上腺或垂体机能不全的生理性糖皮质激素等）不视为全身性治疗； 10. 研究首次给药前7天内正在接受全身性糖皮质激素治疗（不包括喷鼻、吸入性或其他途径的局部糖皮质激素）或任何其他形式的免疫抑制疗法；注：允许使用生理剂量的糖皮质激素（≤10mg/天的泼尼松或等效药物）； 11. 已知异体器官移植（角膜移植除外）或异体造血干细胞移植； 12. 已知对本研究药物信迪利单抗、顺铂、白蛋白紫杉醇活性成分或辅料过敏者； 13. 在开始治疗前，尚未从任何干预措施引起的毒性和/或并发症中充分恢复（即，≤1级或达到基线，不包括乏力或脱发）； 14. 已知人类免疫缺陷病毒（HIV）感染史（即HIV1/2抗体阳性）； 15. 未经治疗的活动性乙肝（定义为HBsAg阳性同时检测到HBV-DNA拷贝数大于所在研究中心检验科正常值上限）；注：符合下列标准的乙肝受试者亦可入组： (1) 首次给药前HBV病毒载量<1000拷贝/ml（200IU/ml），受试者应在整个研究化疗药物治疗期间接受抗HBV治疗避免病毒再激活； (2) 对于抗HBc（+）、HBsAg（-）、抗HBs（-）和HBV病毒载量（-）的受试者，不需要接受预防性抗HBV治疗，但是需要密切监测病毒再激活； 16. 活动性的HCV感染受试者（HCV抗体阳性且HCV-RNA水平高于检测下限）； 17. 首次给药之前（第1周期，第1天）30天内接种过活疫苗；注：允许首次给药前30天内接受针对季节性流感的注射用灭活病毒疫苗；但是不允许接受鼻内用药的减毒活流感疫苗； 18. 妊娠或哺乳期妇女； 19. 存在任何严重或不能控制的全身性疾病，例如： (1) 静息心电图在节律、传导或形态上出现有重大且症状严重难以控制的异常，如完全性左束支传导阻滞，Ⅱ度以上心脏传导阻滞，室性心律失常或心房颤动； (2) 不稳定型心绞痛，充血性心力衰竭，纽约心脏病协会（NYHA）分级≥2级的慢性心衰； (3) 在入选治疗前6个月内发生过任何动脉血栓、栓塞或缺血，如心肌梗死、不稳定型心绞痛、脑血管意外或一过性脑缺血发作等； (4) 血压控制不理想（收缩压＞140mmHg，舒张压＞90mmHg）； (5) 首次给药前1年内存在需要糖皮质激素治疗的非感染性肺炎病史，或当前存在临床活动性间质性肺病； (6) 活动性肺结核； (7) 存在需要全身性治疗的活动性或未能控制的感染； (8) 存在临床活动性憩室炎、腹腔脓肿、胃肠道梗阻； (9) 肝脏疾病如肝硬化、失代偿性肝病、急性或慢性活动性肝炎； (10) 糖尿病控制不佳（空腹血糖（FBG）＞10mmol/L）； (11) 尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0g者； (12) 存在精神障碍且无法配合治疗的患者； 20. 有可能干扰试验结果、妨碍受试者全程参与研究的病史或疾病证据、治疗或实验室检查值异常，或研究者认为其他不适合入组的情况研究者认为存在其他潜在风险不适合参加本研究。

Exclusion criteria：

1. It is known that endoscopic obstruction tends to be complete and requires interventional treatment to remove the obstruction; 2. After stent implantation in esophagus or trachea; 3. Previous systematic treatment for advanced or metastatic esophageal cancer; 4. Patients with high risk of bleeding or perforation due to tumor obvious invasion of the organs adjacent to the esophageal lesion (major artery or trachea), or patients with fistula; 5. Malignant diseases other than esophageal carcinoma diagnosed within 3 years prior to initial administration (excluding basal cell carcinoma of the skin after radical treatment, squamous epithelial carcinoma of the skin, and/or carcinoma in situ after radical resection); 6. Currently participating in an interventional clinical study, or receiving other investigational drugs or using investigational devices within 4 weeks prior to initial dosing; 7. Previous treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs or drugs that target another stimulus or synergistic inhibition of T cell receptors (e.g., CTLA-4, OX-40, CD137); 8. Systemic treatment with Chinese patent drugs with anti-tumor indications or immunomodulatory drugs (including thymosin, interferon and interleukin, except for local use to control pleural effusion) was received within 2 weeks before the first administration; 9. An active autoimmune disease requiring systemic treatment (e.g. with disease-modifying drugs, glucocorticoids, or immunosuppressants) has occurred within 2 years prior to initial administration. Alternative therapies (such as thyroxine, insulin, or physiologic glucocorticoids for adrenal or pituitary insufficiency) are not considered systemic therapy; 10. Being treated with systemic corticosteroids (excluding intranasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days before the first dose of the study; Note: Physiological doses of glucocorticoids (<=10mg/ day of prednisone or equivalent) are permitted; 11. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation; 12. Those who are known to be allergic to the active ingredients or excipients of sindillimab, cisplatin and albumin-paclitaxel of the drug in this study; 13. Have not fully recovered from toxicity and/or complications caused by any intervention before starting treatment (i.e., <= grade 1 or baseline, excluding weakness or hair loss); 14. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV1/2 antibody positive); 15. Untreated active hepatitis B (defined as HBsAg positive coupled with a detected HBV-DNA copy number greater than the upper limit of normal in the laboratory of the study center); Note: Hepatitis B patients who meet the following criteria can also be enrolled: (1) HBV viral load <1000 copies /ml (200IU/ml) prior to initial dosing, patients should receive anti-HBV therapy to avoid viral reactivation throughout the study chemotherapeutic regimen; (2) For patients with anti-HBC (+), HBsAg (-), anti-HBS (-) and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring of viral reactivation is required; 16. Active HCV infected patients (HCV antibody positive and HCV-RNA level above the lower limit of detection); 17. The live vaccine was administered within 30 days prior to initial administration (cycle 1, day 1); Note: Inactivated injectable virus vaccine against seasonal influenza is permitted for 30 days prior to initial administration; Intranasal live attenuated influenza vaccines are not allowed; 18. Pregnant or lactating patients; 19. There is any serious or uncontrolled systemic disease, such as: (1) The resting electrocardiogram (ECG) has major and difficult to control abnormalities in rhythm, conduction or morphology, such as complete left bundle branch block, heart block above Ⅱ degree, ventricular arrhythmia or atrial fibrillation; (2) Unstable angina pectoris, congestive heart failure, and NYHA grade >=2 chronic heart failure; (3) Any arterial thrombosis, embolism, or ischemia, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, occurred within 6 months prior to treatment; (4) Poor blood pressure control (systolic > 140mmHg, diastolic > 90mmHg); (5) There was a history of non-infectious pneumonia requiring glucocorticoid therapy or clinically active interstitial lung disease within 1 year prior to initial administration; (6) Active pulmonary tuberculosis; (7) There is an active or uncontrolled infection that requires systemic treatment; (8) Clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction; (9) Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis; (10) Poor diabetes control (fasting blood glucose (FBG) > 10mmol/L); (11) Urine routine indicated urine protein >=++, and confirmed 24 hours urine protein quantity > 1.0g; (12) Patients with mental disorders and unable to cooperate with treatment; 20. Medical history or evidence of disease that may interfere with test results, prevent participants from participating fully in the study, abnormal values of treatment or laboratory tests, or other conditions that the investigator considers unsuitable for enrollment. The Investigator considers other potential risks unsuitable for participation in the study.

研究实施时间：

Study execute time：

从 From 2021-03-10 00:00:00至 To 2024-12-31 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2021-03-10 00:00:00 至 To 2023-12-31 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	50
Group：	Experimental group	Sample size：	50
干预措施：	化疗+信迪利单抗+放疗	干预措施代码：
Intervention：	chemotherapy+sintilimab+radiotherapy	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	山东	市(区县)：	济南
Country：	China	Province：	Shandong	City：	Ji'nan
单位(医院)：	山东第一医科大学附属省肿瘤医院	单位级别：	三甲
Institution hospital：	Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences	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：	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：	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：	安全性指标	指标类型：	次要指标
Outcome：	safety index	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	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）：

不适用

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

NA

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	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）：	Resman临床试验公共管理平台 www.medresman.org
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	RESMAN www.medresman.org
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
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Case Record Form
数据与安全监察委员会： Data and Safety Monitoring Committee：	无/No
注册人： Name of Registration：	2023-05-08 10:52:45