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：	ChiCTR2500113259
最近更新日期： Date of Last Refreshed on：	2025-11-26 14:27:18
注册时间： Date of Registration：	2025-11-26 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	一线含PD-1抑制剂方案失败后再联合帕里骨化醇在不可切除的血清维生素D水平缺乏的肝细胞癌患者中的一项的单中心、单臂、开放标签的II期临床研究
Public title：	A Single-Center, Single-Arm, Open-Label Phase II Clinical Study of Recombination with Paricalcitol After First-Line PD-1 Inhibitor Regimen Failure in Unresectable Hepatocellular Carcinoma Patients with Serum Vitamin D Deficiency
注册题目简写：
English Acronym：
研究课题的正式科学名称：	一线含PD-1抑制剂方案失败后再联合帕里骨化醇在不可切除的血清维生素D水平缺乏的肝细胞癌患者中的一项的单中心、单臂、开放标签的II期临床研究
Scientific title：	A Single-Center, Single-Arm, Open-Label Phase II Clinical Study of Recombination with Paricalcitol After First-Line PD-1 Inhibitor Regimen Failure in Unresectable Hepatocellular Carcinoma Patients with Serum Vitamin D Deficiency
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：	丁冬阳	研究负责人：	袁声贤
Applicant：	Dongyang Ding	Study leader：	Shengxian Yuan
申请注册联系人电话： Applicant telephone：	+86 176 1210 6276	研究负责人电话： Study leader's telephone：	+86 135 6477 4853
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：	d1906172531@163.com	研究负责人电子邮件： Study leader's E-mail：	yuanshengx@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：	上海市杨浦区长海路225号	研究负责人通讯地址：	上海市杨浦区长海路225号
Applicant address：	No. 225, Changhai Road, Yangpu District, Shanghai	Study leader's address：	No. 225, Changhai Road, Yangpu 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：	海军军医大学第三附属医院
Applicant's institution：	The Third Affiliated Hospital of Naval Medical University
研究负责人所在单位：	海军军医大学第三附属医院
Affiliation of the Leader：	The Third Affiliated Hospital of Naval Medical University

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：	EHBHKY2025-H036-P001	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：	海军军医大学第三附属医院伦理委员会
Name of the ethic committee：	The Third Affiliated Hospital of Naval Medical University
伦理委员会批准日期： Date of approved by ethic committee：	2025-09-18 00:00:00
伦理委员会联系人：	邰小云
Contact Name of the ethic committee：	Xiaoyun Tai
伦理委员会联系地址：	上海市杨浦区长海路225号
Contact Address of the ethic committee：	No. 225, Changhai Road, Yangpu District, Shanghai
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 152 2139 0719	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：

海军军医大学第三附属医院

Primary sponsor：

The Third Affiliated Hospital of Naval Medical University

研究实施负责（组长）单位地址：

上海市杨浦区长海路225号

Primary sponsor's address：

No. 225, Changhai Road, Yangpu 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)：	上海
Country：	China	Province：	Shanghai	City：	Shanghai
单位(医院)：	海军军医大学第三附属医院	具体地址：	上海市杨浦区长海路225号
Institution hospital：	The Third Affiliated Hospital of Naval Medical University	Address：	No. 225, Changhai Road, Yangpu District, Shanghai

经费或物资来源：

国家自然科学基基金(82473341)

Source(s) of funding：

National Natural Science Foundation of China (82473341)

研究疾病：

肝癌

Target disease：

hepatocellular 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：

帕里骨化醇是传统药物，具有良好的安全性，我们前期在接受PD-1抑制剂治疗的临床回顾性队列中发现病人血清或肿瘤局部的维生素D水平的缺乏可能导致较差的治疗效果，并且在体外和体内水平均发现PD-1抑制剂联合帕里骨化醇对肝细胞癌能取得显著优于PD-1抑制剂单药的效果，本研究主要观察一线含PD-1抑制剂方案失败后再联合帕里骨化醇在血清维生素D缺乏的肝细胞癌患者中的抗肿瘤效应： 1.观察经含PD-1抑制剂方案一线治疗失败后再联用帕里骨化醇治疗的安全性和耐受性； 2.观察经含PD-1抑制剂方案一线治疗失败后再联用帕里骨化醇治疗的疗效。

Objectives of Study：

Paricalcitol is a conventional drug with a favorable safety profile. Our previous clinical retrospective cohort of patients receiving PD-1 inhibitor therapy revealed that deficiencies in serum or localized tumor vitamin D levels may lead to poorer treatment outcomes. Furthermore, both in vitro and in vivo studies have demonstrated that the combination of PD-1 inhibitors and paricalcitol yields significantly superior efficacy against hepatocellular carcinoma compared to PD-1 inhibitor monotherapy. This study aims to investigate the antitumor effects of combining paricalcitol after first-line PD-1 inhibitor regimen failure in hepatocellular carcinoma patients with serum vitamin D deficiency: 1. To evaluate the safety and tolerability of paricalcitol combination therapy following failure of first-line treatment containing PD-1 inhibitors. 2. To assess the efficacy of paricalcitol combination therapy after failure of first-line treatment containing PD-1 inhibitors.

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.性别不限，年龄18-75岁;
2.血清维生素D水平 < 30ng/mL；
3.临床或病理学、细胞学诊断的肝细胞癌；
4.一线方案含PD-1抑制剂治疗后影像学明确进展；
5.受试者或者监护人理解并自愿签署知情同意书，有意愿和能力完成方案要求的定期访视、治疗计划、实验室检查等；
6.受试者不适合根治性切除、移植或者消融术，包括根治术后复发不适合再次根治性切除或者消融术；
7.预计生存期超过12周；
8.既往未接受过针对肝癌的系统治疗；
9.首次给药前12周内未接受过放射治疗；
10.肝功能Child-Pugh A级或得分为7的B级；
11.ECOG评分为0-1分；
12.具有充分的器官和骨髓功能，入组前7天内实验室检查值符合下列要求(获得实验室检查的前14天内不允许通过给予任何血液成分、细胞生长因子、白蛋白及其他纠正治疗的药物来满足条件)，具体如下：
（1）血常规：绝对中性粒细胞计数（absolute neutrophil count, ANC）≥1.5×10^9/L； 血小板计数（platelet, PLT）≥75×10^9/L； 血红蛋白含量（hemoglobin, HGB）≥9.0 g/dL；
（2）肝功能：血清总胆红素（total bilirubin, TBIL）≤3×正常上限（upper limit of normal value, ULN）；丙氨酸氨基转移酶（alanine aminotransferase, ALT）、天门冬氨酸氨基转移酶（aspartate transferase, AST）和碱性磷酸酶（alkaline phosphatase, ALP）≤5×ULN； 血清白蛋白≥28 g/L； 
（3）肾功能：血清肌酐（creatinine, Cr）≤ 1.5×ULN 或肌酐清除率（clearance of creatinine, CCr）≥ 50mL/min（Cockcroft-Gault 公式）；尿常规结果显示尿蛋白<2+；对基线时尿常规检测显示尿蛋白≥2+的患者，应进行24小时尿液采集且24小时尿蛋白定量<1g；
（4）凝血功能：国际标准化比率（international normalized ratio，INR）和活化部分凝血活酶时间（activated partial thromboplastin time ，APTT）≤ 1.5倍ULN
13.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。并在观察期内和最后一次服用研究药物后8周内自愿使用适当的避孕方法；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；对于男性，应在观察期内和最后一次服用研究药物后的8周内使用适当的避孕方法；
14.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. No restrictions on gender, age 18-75 years;  
2. Serum vitamin D level < 30 ng/mL;  
3. Clinical, pathological, or cytologically diagnosed hepatocellular carcinoma;  
4. Radiographically confirmed disease progression after first-line treatment containing a PD-1 inhibitor;  
5. The subject or their guardian understands and voluntarily signs the informed consent form, and is willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures as required by the protocol;  
6. The subject is unsuitable for curative resection, transplantation, or ablation, including those with recurrent disease after curative resection who are not candidates for repeat curative resection or ablation;  
7. Expected survival of more than 12 weeks;  
8. No prior systemic therapy for hepatocellular carcinoma;  
9. No radiotherapy within 12 weeks prior to the first dose;  
10. Liver function classified as Child-Pugh class A or class B with a score of 7;  
11. ECOG performance status of 0-1;  
12. Adequate organ and bone marrow function, with laboratory test values within 7 days prior to enrollment meeting the following criteria (within 14 days prior to obtaining laboratory tests, correction with blood components, growth factors, albumin, or other supportive medications to meet the criteria is not allowed), as detailed below:  
(1) Hematology: Absolute neutrophil count (ANC) >= 1.5 × 10^9/L; Platelet count (PLT) >= 75 × 10^9/L; Hemoglobin (HGB) >= 9.0 g/dL;  
(2) Liver function: Serum total bilirubin (TBIL) <= 3 × upper limit of normal (ULN); Alanine aminotransferase (ALT), aspartate transferase (AST), and alkaline phosphatase (ALP) <= 5 × ULN; Serum albumin >= 28 g/L;  
(3) Renal function: Serum creatinine (Cr) <= 1.5 × ULN or creatinine clearance (CCr) >= 50 mL/min (calculated by Cockcroft-Gault formula); Urinalysis shows urine protein < 2+; For patients with baseline urinalysis showing urine protein >= 2+, a 24-hour urine collection must demonstrate 24-hour urine protein < 1 g;  
(4) Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) <= 1.5 × ULN;  
13. For female subjects of childbearing potential, a negative urine or serum pregnancy test must be confirmed within 3 days prior to the first dose of the study drug (Cycle 1, Day 1). If the urine pregnancy test result is inconclusive, a blood pregnancy test is required. Additionally, they must voluntarily use appropriate contraception methods during the observation period and for 8 weeks after the last dose of the study drug. Non-childbearing potential is defined as being postmenopausal for at least 1 year, or having undergone surgical sterilization or hysterectomy. For male subjects, appropriate contraception methods must be used during the observation period and for 8 weeks after the last dose of the study drug;  
14. If there is a risk of pregnancy, all subjects (regardless of gender) must use contraception with a failure rate of <1% per year throughout the treatment period and for 120 days after the last dose of the study drug (or 180 days after the last dose of chemotherapy).

排除标准：

1.不可纠正的凝血功能障碍，具有明显出血倾向者； 2.目标疾病例外情况：混合性肝细胞癌和胆管细胞癌；任何共存恶性疾病的证据； 3.首次给药前3年内诊断为其他恶性疾病（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）； 4.需要长期抗凝、抗血小板治疗而无法停药患者； 5.肝性脑病或需要治疗的顽固性胸腹水患者； 6.其他抗肿瘤治疗或者全身治疗：2周之内接受过明确具有抗肿瘤治疗的中成药治疗、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） 7.系统性全身治疗：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、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，允许使用生理剂量的糖皮质激素（≤10 mg/天的泼尼松或等效药物）； 8.肝肾功能严重不全者； 9.存在任何严重或不能控制的全身性疾病，例如：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；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；随机化前6个月内出现心肌梗死；最近6个月内有食道或胃静脉曲张破裂出血；血压控制不理想（收缩压＞140 mmHg，舒张压＞90 mmHg）；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；活动性肺结核；存在需要全身性治疗的活动性或未能控制的感染；存在临床活动性憩室炎、腹腔脓肿、胃肠道梗阻；肝脏疾病如肝硬化、失代偿性肝病、急性或慢性活动性肝炎；存在不稳定或活动性溃疡、消化道出血的患者；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；未控制的高钙血症（大于1.5 mmol/L钙离子或钙大于12 mg/dL或校正后血清钙大于ULN），或需要继续双磷酸盐治疗的症状性高钙血症；长期未治愈的伤口或骨折；存在精神障碍且无法配合治疗的患者； 10.血清维生素D水平 ≥ 30ng/mL； 11.哺乳或妊娠期女性受试者； 12.研究者评估认为患者不能或不愿意依从研究方案的要求； 13.对本研究受试药物过敏者。

Exclusion criteria：

1. Uncorrectable coagulation dysfunction with evident bleeding tendency; 2. Exceptions related to the target disease: mixed hepatocellular carcinoma and cholangiocarcinoma; evidence of any coexisting malignant disease; 3. Diagnosis of other malignant diseases within 3 years prior to the first dose (excluding cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ); 4. Patients requiring long-term anticoagulation or antiplatelet therapy that cannot be discontinued; 5. Patients with hepatic encephalopathy or refractory pleural effusion/ascites requiring treatment; 6. Other antitumor or systemic therapies: treatment with Chinese patent medicines with clear antitumor effects within 2 weeks; use of Chinese patent medicines with antitumor indications or immunomodulatory drugs (including thymosin, interferon, interleukin, excluding local use for controlling pleural effusion) within 2 weeks; 7.Systemic therapy: active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, glucocorticoids, or immunosuppressants) within 2 years prior to administration. Replacement therapy (e.g., thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) is not considered systemic treatment; systemic glucocorticoid therapy (excluding nasal sprays, inhaled, or other forms of local glucocorticoids) or any other form of immunosuppressive therapy within 7 days prior to the first dose. Physiological doses of glucocorticoids (≤10 mg/day of prednisone or equivalent) are permitted; 8. Severe hepatic or renal insufficiency; 9. Presence of any severe or uncontrolled systemic diseases, such as: resting electrocardiogram showing significant and symptomatic abnormalities in rhythm, conduction, or morphology that are difficult to control, including complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation; unstable angina, congestive heart failure, chronic heart failure of New York Heart Association (NYHA) class >= 2; myocardial infarction within 6 months prior to randomization; esophageal or gastric variceal bleeding within the last 6 months; poorly controlled blood pressure (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg); history of non-infectious pneumonia requiring glucocorticoid treatment within 1 year prior to the first dose, or current clinically active interstitial lung disease; active tuberculosis; active or uncontrolled infection requiring systemic treatment; clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction; liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis; patients with unstable or active ulcers or gastrointestinal bleeding; poorly controlled diabetes (fasting blood glucose > 10 mmol/L); urinalysis showing urine protein >= ++ and confirmed 24-hour urine protein > 1.0 g; uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, total calcium > 12 mg/dL, or corrected serum calcium above ULN), or symptomatic hypercalcemia requiring continued bisphosphonate therapy; long-term unhealed wounds or fractures; patients with psychiatric disorders unable to cooperate with treatment; 10. Serum vitamin D level >= 30 ng/mL; 11. Female subjects who are breastfeeding or pregnant; 12. Patients deemed by the investigator as unable or unwilling to comply with the requirements of the study protocol; 13 Patients with known allergies to the investigational drug(s) in this study.

研究实施时间：

Study execute time：

从 From 2025-12-01 00:00:00至 To 2027-12-01 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2025-12-01 00:00:00 至 To 2027-11-01 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	53
Group：	treatment group	Sample size：	53
干预措施：	原有治疗基础上联合应用帕里骨化醇	干预措施代码：
Intervention：	Addition of paricalcitol to the existing treatment regimen	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	市(区县)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	海军军医大学第三附属医院	单位级别：	三甲
Institution hospital：	The Third Affiliated Hospital of Naval Medical University	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：	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：	安全性和耐受性	指标类型：	主要指标
Outcome：	Safety and tolerability	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	总体生存期	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：	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：	中位有效时间	指标类型：	次要指标
Outcome：	Median effective time	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：	肿瘤	组织：
Sample Name：	Tumor	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：	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：

尚未开始

Not yet 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）：

无

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

None

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）：	无
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	None
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：	电子采集和管理系统
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Electronic Data Capture
数据与安全监察委员会： Data and Safety Monitoring Committee：	暂未确定/Not yet
注册人： Name of Registration：	2025-11-26 14:26:59