Randomized Double-blind, Placebo-controlled, Multicenter Clinical Study of Nimotuzumab Combined With Trifluridine/Tipiracil in Third-line and Beyond for the Treatment of Metastatic Colorectal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 420
- 主要终点
- overall survival (OS)
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled, multicenter study. The main purpose of the study is to evaluate the clinical efficacy and safety of nimotuzumab combined with trifluridine/tipiracil in third-line and beyond for the treatment of metastatic colorectal cancer (mCRC). This study planned to be divided into two parts: Part A and Part B. Part A (safety run-in) with a 3 + 3 study design, which primary endpoint is safety; Part B (main study) with a prospective, randomized, double-blind, placebo-controlled design, which primary endpoint is overall survival (OS).
详细描述
This is a randomized, double-blind, placebo-controlled, multicenter study. The main purpose of the study is to evaluate the clinical efficacy and safety of nimotuzumab combined with trifluridine/tipiracil in third-line and beyond for the treatment of metastatic colorectal cancer (mCRC). This study planned to be divided into two parts: Part A and Part B. Part A is a dose escalation study, and two dose levels are set up in terms of the dose of nimotuzumab (dose level 1: nimotuzumab 400 mg weekly; dose level 2: nimotuzumab 600 mg weekly), while the dose of trifluridine/tipiracil remains unchanged. The aim of this part is to investigate the safety of combination therapy and ensure the dose of nimotuzumab in Part B. After completed the safety-run-in of Part A, Part B can be started. In Part B (main study), a prospective, randomized, double-blind, placebo-controlled design is proposed. Patients of this part will be stratified by tumor site (left half of colorectal vs right half of colon), age (less than 65 years old vs 65 years old or older) and number of metastases (<3 vs ≥3) and randomly divided into experimental group (nimotuzumab plus trifluridine/tipiracil) and control group (placebo plus trifluridine/tipiracil) at a ratio of 2:1. Treatment will continue until disease progression or intolerable toxicity or withdrawal of consent. In part B, the primary endpoint is overall survival (OS); the secondary endpoint included: Progression free survival (PFS), time to progress (TTP), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), quality of life (QoL), etc.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Age 18-75 years old, gender unlimited;
- •Histologically or cytologically confirmed diagnosis of colorectal cancer (CRC);
- •Metastatic colorectal cancer, disease progression after previous second-line or above standard therapy;
- •Efficacy of previous line therapy containing an anti-EGFR agent (panitumumab or cetuximab) with complete or partial response, or disease stable; and more than 4 months from last dose of anti-EGFR agent administered before randomization;
- •MSS/pMMR status detected by IHC or PCR;
- •RAS and BRAF wild-type status;
- •ECOG Performance Status 0-1;
- •Measurable disease according to RECIST criteria v1.1;
- •Life expectancy of at least 3 months;
- •Adequate organ and bone marrow function, defined as follows: hemoglobin≥9.0 g/dL; absolute neutrophil count (ANC)≥1.5×10^9/L; white Blood Cell Count≥4×10^9/L;platelets≥100×10^9/L; serum total bilirubin (TBIL)≤1.5×ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal (ULN), patients with liver metastases should be ≤ 5 times the ULN; serum creatinine≤1.5×ULN or estimated creatinine clearance > 60 mL/min;
- •Women of childbearing age should have a negative result of serum HCG or urine pregnancy tests within 72 hours prior to randomization (Postmenopausal women who have had amenorrhea for at least 12 months are considered sterile and women known to have had tubal ligation are not required to undergo pregnancy tests) ;
- •Good compliance and signed informed consent.
排除标准
- •Had other malignancies within the past 5 years or at the same time (exceptions include: cured thyroid cancer, non-melanoma skin cancer, carcinoma in situ of the cervix, stage I ductal carcinoma in situ, stage I endometrial cancer or other solid tumors, and effectively treated lymphoma with no evidence of disease for more than 5 years);
- •Has a serious underlying medical condition that makes it impossible to safely administer the trial treatment. Including but not limited to active infections requiring systemic medication: compensatory heart failure (NYHA grade III and IV), unstable angina, and acute myocardial infarction within 3 months prior to enrollment;
- •Patients who received trifluridine/tipiracil or treated with EGFR monoclonal antibody or EGFR tyrosine kinase inhibitor within four months;
- •Known allergy to prescription or any component of the prescription used in this study;
- •Women who are pregnant or are breastfeeding;
- •Has brain metastases or any symptoms of brain metastases
- •Factors that significantly affect oral drug absorption, such as dysphagia, chronic diarrhea, gastrointestinal obstruction, etc; Uncontrolled Crohn's disease or ulcerative colitis;
- •Participated in other clinical trials within 4 weeks;
- •With HIV, HPV, or syphilis infection, or active hepatitis (hepatitis B, hepatitis C)
- •Other reasons that are not suitable to participate in this study according to the researcher's judgment.
研究组 & 干预措施
experimental group
Nimotuzumab will be administered weekly (dose of nimotuzumab depends on part A). Trifluridine/tipiracil will be administered (35 mg/m2) twice daily, 5 days a week, with 2 days of rest, for 2 weeks, followed by a 14-day rest. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent or death due to any cause.
干预措施: Nimotuzumab injection (Drug)
experimental group
Nimotuzumab will be administered weekly (dose of nimotuzumab depends on part A). Trifluridine/tipiracil will be administered (35 mg/m2) twice daily, 5 days a week, with 2 days of rest, for 2 weeks, followed by a 14-day rest. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent or death due to any cause.
干预措施: Trifluridine/tipiracil (Drug)
control group
Placebo will be administered weekly (dose of placebo depends on part A). Trifluridine/tipiracil will be administered (35 mg/m2) twice daily, 5 days a week, with 2 days of rest, for 2 weeks, followed by a 14-day rest. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent or death due to any cause.
干预措施: Placebo (Drug)
control group
Placebo will be administered weekly (dose of placebo depends on part A). Trifluridine/tipiracil will be administered (35 mg/m2) twice daily, 5 days a week, with 2 days of rest, for 2 weeks, followed by a 14-day rest. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent or death due to any cause.
干预措施: Trifluridine/tipiracil (Drug)
结局指标
主要结局
overall survival (OS)
时间窗: Up to 18 months
The primary endpoint is overall survival (OS, defined as from randomization to death due to any cause).
dose-limiting toxicity (DLT)
时间窗: Up to 4 weeks for each participant in part A
DLTs at the end of the 4 weeks' treatment in part A (safety run-in).
次要结局
- disease control rate (DCR)(Up to 18 months)
- European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)(Up to 18 months)
- European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Colorectal Cancer 29 (EORTC-QLQ-CR29)(Up to 18 months)
- Adverse Events(Up to 18 months)
- Progression free survival (PFS)(Up to 18 months)
- overall response rate (ORR)(Up to 18 months)
- duration of response (DoR)(Up to 18 months)
- time to progress (TTP)(Up to 18 months)