A Randomized, Multi-center, Open-label Phase II Trial of Irinotecan and Cetuximab With or Without the Combination of Bevacizumab and Sintilimab in RAS Wild-type, Irinotecan-refractory Metastatic Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 1
- 主要终点
- Objective Response Rate
研究概览
简要总结
Primary endpoint: objective response rate Secondary endpoints: progression-free survival (PFS), overall survival (OS) and adverse events.
详细描述
This randomized, multi-center, open-label phase II trial studies the efficacy and safety of irinotecan and cetuximab with or without bevacizumab plus sintilimab in the treatment for RAS wild-type metastatic colorectal cancer (mCR) in third- or later-line setting.
Patients with refractory mCRC have limited treatment options after failure of standard chemotherapies and anti-angiogenic agents. The BOND-3 trial showed that adding bevacizumab to cetuximab and irinotecan may improve outcomes in this setting. Meanwhile, programmed death-1 (PD-1) inhibitors have demonstrated activity in MSI-high tumors but have limited efficacy in MSS mCRC. Preclinical and clinical evidence suggests that anti-VEGF therapy can modulate the tumor immune microenvironment and may synergize with PD-1 blockade. This study therefore tests whether the quadruple combination (bevacizumab + sintilimab + cetuximab + irinotecan) can improve objective response rate compared with cetuximab and irinotecan alone in this heavily pretreated population.
The primary efficacy analysis will be conducted on the intention-to-treat population. Assuming an ORR of 11% in the control arm and 26% in the experimental arm, with a one-sided alpha of 0.05 and power of 80%, the required sample size is approximately 160 to account for 5% dropout.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Metastatic and unresectable colorectal adenocarcinom;
- •RAS wild-type and MSS tumor;
- •Measurable lesions;
- •Failed to at least two lines of standard treatment containing fluoropyrimidine, irinotecan and bevacizumab;
- •Eastern Cooperative Oncology Group performance status 2 or less;
- •White blood cell≥ 3*10^9/L, neutrophil≥ 1.5*10^9/Lplatelet count≥75*10^9/L, hemoglobin≥60g/L;
- •Total serum bilirubin≤upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5*ULN or ≤5*ULN for subjects with liver metastasis;
- •Creatinine ≤ ULN or creatinine clearance ≥ 80 mL/min;
- •Urinary protein negative or 24-hour urinary protein ≤ 2g;
- •Activated partial thromboplastin time≤ULN and international normalized ratio≤1.5;
- •Any major surgery ≥ 4 weeks and any minor surgery ≥ 1 week and fully recovered from the procedure;
- •Life expectancy > 3 months;
- •Provide fully informed written consent;
排除标准
- •Other aggressive malignancies within 3 years (Exceptions: non-melanoma skin cancer or carcinoma-in-situ of the cervix that has been treated);
- •Allergy or intolerance to any of the study drugs;
- •Human immunodeficiency virus positive;
- •Concurrent anti-cancer therapy including radiation therapy, chemotherapy, targeted agents or biological agents not otherwise specified within two weeks;
- •Malignant bowel obstruction;
- •Prior treatment with PD-1 antibody;
- •Autoimmune diseases;
- •Significant bleeding events or pre-existing bleeding diathesis within 6 months (unless the source of bleeding has been resected);
- •Gastrointestinal perforation within 12 months;
- •Serious or non-healing wound, ulcer, or bone fracture;
- •Blood pressure >= 160/90 mmHg after active anti-hypertensive therapy;
- •Arterial or venous thrombotic or embolic events within 6 months (including but not limited to transient ischemic attack, cerebrovascular accident, unstable angina or myocardial infarction);
- •Uncontrolled illness including active infection, symptomatic congestive heart failure, cardiac arrhythmia, respiratory failure, symptomatic pulmonary fibrosis, interstitial pneumonitis or psychiatric illness that may interfere with the conduct of the study;
- •Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis;
- •Any of the following: pregnant, nursing, childbearing potential but unwilling to employ contraception.
研究组 & 干预措施
CI Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks.
干预措施: Cetuximab (Drug)
CIBS Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks; Bevacizumab: 7.5mg/kg every three weeks ; Sintilimab: 200mg every three weeks.
干预措施: Bevacizumab (Drug)
CIBS Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks; Bevacizumab: 7.5mg/kg every three weeks ; Sintilimab: 200mg every three weeks.
干预措施: Sintilimab (Drug)
CI Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks.
干预措施: Irinotecan (Drug)
CIBS Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks; Bevacizumab: 7.5mg/kg every three weeks ; Sintilimab: 200mg every three weeks.
干预措施: Cetuximab (Drug)
CIBS Arm
Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks; Bevacizumab: 7.5mg/kg every three weeks ; Sintilimab: 200mg every three weeks.
干预措施: Irinotecan (Drug)
结局指标
主要结局
Objective Response Rate
时间窗: 12 months
the proportion of participants who achieved a complete or partial response according to RECIST 1.1
次要结局
- Progression-free Survival(12 months)
- Overall Survival(18 months)
- Adverse Events(18 months)