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中国临床试验注册中心

花匠小妙招
2025-07-28 14:53

研究实施负责（组长）单位：

菏泽市立医院

Primary sponsor：

Heze Municipal Hospital

研究实施负责（组长）单位地址：

山东省菏泽市曹州路2888号

Primary sponsor's address：

No. 2888, Caozhou Road, Mudan District, Heze City, Shandong Province

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)：

Country：

China

Province：

Shandong

City：

单位(医院)：

菏泽市立医院

具体地址：

山东省菏泽市曹州路2888号

Institution
hospital：

Heze Municipal Hospital

Address：

No. 2888, Caozhou Road, Mudan District, Heze City, Shandong Province

经费或物资来源：

自筹

Source(s) of funding：

Self-financing

研究疾病：

结直肠癌

Target disease：

Colorectal cancer

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：

研究设计：

单臂

Study design：

Single arm

研究目的：

评价伊立替康脂质体（II）联合卡培他滨和贝伐珠单抗二线治疗晚期结直肠癌患者的有效性和安全性。

Objectives of Study：

To evaluate the efficacy and safety of irinotecan liposome (II) combined with capecitabine and bevacizumab as second-line treatment for patients with advanced colorectal 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. 年龄＞＝18 岁且＜＝75 岁，性别不限； 2. 经病理组织学和/或细胞学诊断结肠或直肠癌，临床记录显示为不可手术切除的晚期转移性结肠癌或直肠癌（即，根据 UICC/AJCC TNM 分期系统[2017 年第 8 版]分为 IV 期）； 3. 根据 RECIST v1.1 标准，至少具有 1 个可测量靶病灶（即，非淋巴结病灶 CT 扫描长径 >=10 mm，淋巴结病灶 CT 扫描短径>=15 mm）； 4. 既往接受过针对转移性疾病的奥沙利铂±VEGF/EGFR 一线标准治疗且治疗失败； 5. ECOG 体力状态评分 0-1； 6. 预期生存时间＞＝3 个月； 7.免疫组化 pMMR 或 MSI-L，MSS 8. 重要脏器功能良好，即开始研究治疗前 14 天内受试者的器官功能水平及相关实验室指标必须符合下列要求： (1) 血常规（开始研究治疗前 14 天内未进行过输血、输血小板、生长因子等支持治疗）：白细胞（WBC）＞＝3.0×10^9/L；中性粒细胞绝对计数（ANC）＞＝1.5×10^9/L；血小板计数（PLT）＞＝100×10^9/L；血红蛋白（Hb）＞＝90 g/L (2) 血生化：血清白蛋白（ ALB ）＞＝30 g/L ；谷丙转氨酶（ALT ） / 谷草转氨酶（AST）＜＝2.5 倍正常值上限（ULN），如有肝转移则 ALT/AST＜＝5×ULN；总胆红素（TBIL）＜＝1.5×ULN；血清肌酐（Cr）＜＝1.5×ULN，或根据 Cockcroft-Gault 公式计算的内生肌酐清除率＞＝60 mL/min (3) 尿常规：尿常规提示尿蛋白<++；若基线时尿蛋白＞＝++ ，需证实 24 小时尿蛋白定量＜＝1.0g。 (4) 凝血功能（开始研究治疗前 14 天内）：凝血酶原时间（PT）或活化部分凝血活酶时间（aPTT）＜＝1.5×ULN、国际标准化比值（INR）＜＝1.5 ×ULN（未接受过抗凝治疗）；若受试者应用使用稳定剂量的抗凝剂或维生素 K 拮抗剂（如华法林、肝素或其类似物治疗），在凝血酶原时间国际标准化比值（INR）＜＝1.5 的前提下，允许以预防目的使用小剂量华法林（1mg 口服，每日一次）或小剂量阿司匹林（每日用量不超过 100 mg）； (5) 心脏功能：12-导联心电图正常或经研究者判断无临床意义的 12-导联心电图异常（即，男性 QTcF＜450 ms，女性 QTcF＜470 ms）；左室射血分数（LVEF）＞＝正常值低限（即，LVEF＞＝50%）； 9. 既往接受的其他抗肿瘤治疗需结束治疗 4 周及以上，且一般的身体状况或相关的不良反应已恢复（毒性反应＜=1 级）或达到稳定状态； 10. 开始研究治疗前 7 天内育龄妇女血清妊娠试验必须为阴性，且必须为非哺乳期；育龄期女性受试者或伴侣为育龄期女性的男性受试者必须同意在试验期间和研究治疗期结束后 6 个月内采取医学许可的避孕措施（例如，宫内节育器、男性手术绝育、避孕药或避孕套）； 11. 自愿参加并签署知情同意书，并能依从研究访视计划和其它方案要求

Inclusion criteria

1. Age > = 18 years old and < = 75 years old, gender is not limited; 2. Colon or rectal cancer diagnosed by histopathology and/or cytology, with clinical records showing as inoperable advanced metastatic colon or rectal cancer (i.e., classified as stage IV according to the UICC/AJCC TNM staging system [8th Edition 2017]); 3. According to the RECIST v1.1 standard, there should be at least one measurable target lesion (i.e., the CT scan long diameter of non-lymph node lesions) >=10 mm, short diameter of lymph node lesion on CT scan >=15 mm; 4. Previously received first-line standard treatment of oxaliplatin ±VEGF/EGFR for metastatic diseases and failed the treatment; 5. ECOG Physical Condition score: 0-1; 6. Expected survival time > = 3 months; 7. Immunohistochemistry: pMMR or MSI-L, MSS 8. Good function of vital organs means that the organ function levels and related laboratory indicators of the subjects within 14 days before the start of the study and treatment must meet the following requirements: (1) Blood routine (no blood transfusion, platelet transfusion, growth factor or other supportive treatments have been received within 14 days before the start of the study and treatment), White blood cell (WBC) > = 3.0×10^9/L; Absolute neutrophil count (ANC) > = 1.5×10^9/L; Platelet count (PLT) > = 100×10^9/L; Hemoglobin (Hb) > = 90 g/L (2) Blood biochemistry: Serum albumin (ALB) > = 30 g/L; Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < = 2.5 times the upper limit of normal value (ULN). If there is liver metastasis, ALT/AST < = 5×ULN. Total bilirubin (TBIL) < = 1.5×ULN; Serum creatinine (Cr) < = 1.5×ULN, or endogenous creatinine clearance rate calculated by the Cockcroft-Gault formula > = 60 mL/min. (3) Routine urine test: Routine urine test indicates urine protein <++; If the urine protein at baseline is > = ++, it needs to be confirmed that the 24-hour urine protein quantification is < = 1.0g. (4) Coagulation function (within 14 days before the start of the study treatment). Prothrombin time (PT) or activated partial thromboplastin time (aPTT) < = 1.5×ULN, International normalized ratio (INR) < = 1.5×ULN (no anticoagulant therapy has been received); If the subjects are treated with a stable dose of anticoagulants or vitamin K antagonists (such as warfarin, heparin or their analogues), on the premise that the international normalized ratio of prothrombin time (INR) is < = 1.5, the use of a small dose of warfarin for preventive purposes (1mg orally) is allowed. (once a day) or low-dose aspirin (with a daily dosage not exceeding 100 mg); (5) Cardiac function: Normal 12-lead electrocardiogram or as studied It was judged that there was no clinically significant abnormality in 12-lead electrocardiogram (i.e., QTcF < 450 ms in men and QTcF < 470 ms in women); Left ventricular ejection fraction (LVEF) > = the lower limit of the normal value (that is, LVEF > = 50%); 9. Other anti-tumor treatments received previously should have been completed for 4 weeks or more, and the general physical condition or related adverse reactions have recovered (toxic reactions < = grade 1) or reached a stable state. 10. The serum pregnancy test of women of childbearing age must be negative within 7 days before the start of the study treatment, and they must be in the non-lactation period. Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age must agree to take medically permitted contraceptive measures (such as intrauterine devices, male surgical sterilization, contraceptives or condoms) during the trial and within 6 months after the end of the study treatment period; 11. Voluntarily participate and sign the informed consent form, and be able to comply with the requirements of the research visit plan and other programs

排除标准：

1.在筛选前 5 年内曾患有结直肠癌以外的恶性肿瘤（已治愈的皮肤基底细胞或鳞状上皮细胞癌、宫颈原位癌、研究者评估具有低风险转移和死亡风险的恶性肿瘤除外）； 2. 已知有中枢神经系统转移者，对于临床疑似中枢神经系统转移的患者，开始研究治疗前 28天内必须进行增强电子计算机断层扫描（CT）或增强核磁共振（MRI）检查，排除中枢神经系统转移； 3.既往接受过伊立替康/伊立替康脂质体或卡培他滨为基础的化疗； 4. 开始研究治疗前 14 天内使用 CYP3A4、CYP2C8 和 UGT1A1 强抑制剂/诱导剂； 5. 开始研究治疗前 4 周内参加过其他药物临床试验； 6. 临床记录显示有严重的胃肠功能紊乱（包括出血、梗阻；NCI-CTCAE v5.0＞2 级的炎症；NCI-CTCAE v5.0＞1 级的腹泻），或经研究者判断可能会影响药物的摄入、转运或吸收的其他情况（包括无法吞咽；小肠切除术后或全胃切除等）； 7. 需要临床干预的胸腔积液或腹水（NCI-CTCAE v5.0＞=2 级）； 8. 存在妨碍试验药物治疗的严重合并症、活动性感染或未控制的糖尿病： (1) 研究者认为会影响受试者接受研究方案治疗能力的未受控制的严重医学疾病，例如合并严重的内科疾病，包括严重心脏病、脑血管病、未控制的糖尿病、未控制的高血压、不受控制的感染、活动性消化性溃疡等； (2) 筛选前一年内发生过动/静脉血栓事件，如脑血管意外（包括暂时性缺血性发作）、深静脉血栓（因前期化疗行静脉置管引发静脉血栓经研究者判断已痊愈者除外）及肺栓塞等； (3) 影像学显示肿瘤已侵犯重要血管周围或经研究者判断患者肿瘤在治疗期间有极高可能侵袭重要血管而引起致命大出血的情况； (4) 既往有间质性肺病，或有（非感染性）肺炎且需口服或静脉类固醇激素； (5) 有未能良好控制的心脏临床症状或疾病，如：纽约心脏病协会（NYHA） 2 级以上心力衰竭；不稳定型心绞痛；6 个月内发生过心肌梗死；有临床意义、需要治疗或干预的室上性或室性心律失常； (6) 丙型肝炎病毒（HCV）抗体阳性或人免疫缺陷病毒（HIV）抗体阳性； 9. 筛选前 4 周内发生过严重感染（NCI-CTCAE v5.0＞2 级），如需要住院治疗的严重肺炎、菌血症、感染并发症等；开始研究治疗前 2 周内存在感染的症状和体征需要静脉使用抗生素治疗（预防性使用抗生素的情况除外）; 10. 已知对任意试验药物（盐酸伊立替康脂质体注射液（Ⅱ）、卡培他滨、贝伐珠单抗）或其辅料过敏或不能耐受，或存在任一试验药物禁忌症； 11. 研究者认为应排除在本研究之外，例如经研究者判断，受试者有其他可能导致本研究被迫中途终止的因素，如存在其他的严重疾病（含精神疾病）需要合并治疗等。

Exclusion criteria：

1. Have had malignant tumors other than colorectal cancer within 5 years before screening (excluding cured basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and malignant tumors assessed by the investigator as having a low risk of metastasis and death); 2. For those with known central nervous system metastases, for patients clinically suspected of having central nervous system metastases, enhanced computed tomography (CT) or enhanced magnetic resonance imaging (MRI) examinations must be conducted within 28 days before the start of the study and treatment to rule out central nervous system metastases. 3. Have previously received chemotherapy based on irinotecan/irinotecan liposomes or capecitabine; 4. Use of strong suppressor/inducer CYP3A4, CYP2C8 and UGT1A1 within 14 days before the start of the study treatment; 5. Participated in clinical trials of other drugs within 4 weeks before starting the research treatment; 6. Clinical records show severe gastrointestinal dysfunction (including bleeding and obstruction); Inflammation with NCI-CTCAE v5.0 > grade 2; Diarrhea with NCI-CTCAE v5.0 > 1 grade, or other conditions that the researcher determines may affect the intake, transport or absorption of the drug (including inability to swallow; After small intestinal resection or total gastrectomy, etc. 7. Pleural effusion or ascites requiring clinical intervention (NCI-CTCAE v5.0>= grade 2); 8. There are severe comorbidities, active infections or uncontrolled diabetes that hinder the treatment of the investigational drug: (1) Uncontrolled serious medical diseases that the researchers believe will affect the subjects' ability to receive treatment under the study protocol, such as combined severe internal diseases, including severe heart disease, cerebrovascular disease, uncontrolled diabetes, uncontrolled hypertension, uncontrolled infection, active peptic ulcer, etc. (2) Hyperarterial/venous thrombosis events that occurred within one year before screening, such as cerebrovascular accidents (including temporary ischemic attacks), deep vein thrombosis (except for venous thrombosis caused by intravenous catheterization due to previous chemotherapy and determined to have been cured by the researcher), and pulmonary embolism, etc. (3) Situations where imaging shows that the tumor has invaded the area around important blood vessels or where the researcher determines that the patient's tumor has a very high possibility of invading important blood vessels during treatment and causing fatal massive hemorrhage; (4) A previous history of interstitial lung disease, or (non-infectious) pneumonia requiring oral or intravenous steroid hormones; (5) There are poorly controlled clinical symptoms or diseases of the heart, such as: New York Heart Association (NYHA) grade 2 or above heart failure; Unstable angina pectoris Myocardial infarction occurred within 6 months; Supraventricular or ventricular arrhythmias with clinical significance that require treatment or intervention; (6) Positive for hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) antibodies; 9. Severe infections (NCI-CTCAE v5.0 > 2 grade) occurred within 4 weeks before screening, such as severe pneumonia, bacteremia, infectious complications, etc. that require hospitalization; If there are symptoms and signs of infection within 2 weeks before the start of the study treatment, intravenous antibiotic treatment is required (except for the case of prophylactic antibiotic use). 10. It is known that there is allergy or intolerance to any test drug (iritecan hydrochloride liposome Injection (II), capecitabine, bevacizumab) or its excipients, or there are contraindications to any test drug; 11. The researchers believe that the subjects should be excluded from this study. For example, if the researchers determine that the subjects have other factors that may lead to the forced termination of this study halfway, such as having other serious diseases (including mental disorders) that require combined treatment, etc.