Nimotuzumab Combined With Paclitaxel as Second-line Treatment for Recurrent Metastatic Gastric or Esophagogastric Junction Adenocarcinoma With EGFR Over-expression: A Randomized, Double-blind, Placebo-controlled Phase III Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 354
- 试验地点
- 1
- 主要终点
- Overall survival
研究概览
简要总结
In order to evaluate the efficacy and safety of nimotuzumab combined with paclitaxel as second-line treatment for recurrent metastatic gastric or esophagogastric junction adenocarcinoma with EGFR over-expression, investigators performed a randomized, double-blind, placebo-controlled phase III clinical trial. Patients will be randomized (1:1) to receive nimotuzumab plus paclitaxel in the experimental group and placebo plus paclitaxel in the control group. The primary endpoint of this study was OS, and according to the results of the RAINBOW-Asia gastric cancer phase III clinical study, the mOS of paclitaxel single-agent second-line treatment for gastric cancer was 7.92 months, assuming that the mOS increased to 10.92 months after the addition of nimotuzumab, Using the survival module in the PASS15 software, the two-sided test level was set α=0.05, β=0.20, enrolled for 2 years, followed up for 1.5 years, the dropout rate was 5%, the sample size including interim analysis was 354 cases. The secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), patient reported outcome (PRO), and safety.
详细描述
Study design:
This study is a prospective, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of nimotuzumab combined with paclitaxel as second-line treatment for recurrent metastatic gastric or esophagogastric junction adenocarcinoma with EGFR over-expression.A total of 354 patients with recurrent metastatic gastric or esophagogastric junction adenocarcinoma with EGFR over-expression are expected to be enrolled. Patients will be randomized (1:1) to receive nimotuzumab (600 mg for the first dose, then 400 mg, weekly) plus paclitaxel (80 mg/m2, on day 1, 8 and 15, every 4 weeks as a cycle) in the experimental group and placebo plus paclitaxel (same as experimental group) in the control group. The study will be randomized by stratified block randomization, stratification factors included ECOG PS (0 vs. 1), first-line immunotherapy (yes vs. no), and EGFR expression status (IHC 2+ vs. 3+). Treatment will continue until disease progression, intolerance, or patient withdrawal from the trial, and each patient will be followed up until death, loss to follow-up, or the end of study.
Quality Assurance plan： According to the GCP's guidelines, sponsors are responsible for using and maintaining quality assurance and quality control systems in accordance with the corresponding standard operating procedures (SOPs). The sponsor or sponsor's representative shall conduct quality control at every stage of data processing to ensure the accuracy, consistency, completeness and reliability of the data. In addition, the sponsor or its representative, the appropriate regulatory body, may conduct audits and/or inspections of the research process. During audits and/or regulatory inspections, authorized sponsor representatives and relevant regulatory authorities have access to all research-related documents.
Data checks:
Investigators should collect complete participant data as required by the protocol, recorded in the original record. This study will use an electronic data acquisition (EDC) system, and the library builder will build an electronic database according to the plan, set up the corresponding logic verification, and data management personnel will conduct data verification according to the corresponding verification plan.
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 (including boundary value), male or female;
- •The physical status score ECOG is 0-1;
- •Histopathologically or cytologically confirmed gastric or esophagogastric junction adenocarcinoma;
- •Recurrent metastatic disease, previous treatment with first-line standard chemotherapy regimens (including platinum-containing and/or fluorouracil regimens) (recurrence or metastasis during adjuvant therapy or within 6 months after completion is considered first-line therapy), or received anti-HER2 therapy, or received immunotherapy, and has been confirmed by the investigator or has a clear disease progression in the medical history;
- •At least one evaluable tumor lesion according to the RECIST version 1.1 evaluation criteria;
- •Detection of primary or metastatic lesions during the screening period (when multiple specimens exist at the same time, the bulk specimen is preferred over the biopsy specimen, and the metastasis is preferred over the primary lesion) tissue is determined to be EGFR high expression (IHC2+ or IHC3+);
- •Estimated survival≥ 12 weeks;
- •Have proper organ function, defined as:Total bilirubin ≤ 1.5 times the upper normal limit (ULN); glutamyltransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times ULN in the absence of liver metastases; ALT or AST ≤ 5 times ULN in the presence of liver metastases;Serum creatinine level≤ 1.5 times ULN; neutrophil count ≥1.5×109/L; WBC count≥ 3.0×109/L; platelets≥ 100×109/L; Hemoglobin≥ 90g/L;
- •Patients of childbearing age and their spouses are willing to use contraception;
- •Women of potential fertility have negative serum hCG within 72 hours prior to randomization (postmenopausal women with amenorrhea for at least 12 months are considered infertile, and women who are known to have undergone tubal ligation are not required to undergo a pregnancy test);
- •The subject understands and complies with the study process, voluntarily participates, and signs the informed consent form.
排除标准
- •Received the following treatments before this study:
- •The disease has progressed after previous paclitaxel chemotherapy or molecular targeted drug (anti-EGFR antibody) treatment, or received paclitaxel chemotherapy or molecular targeted drug (anti-EGFR antibody) treatment within 4 weeks before randomization;
- •Within 4 weeks before randomization or participating in other therapeutic/intervention clinical trials or receiving combined treatment prohibited by the protocol;
- •Received major surgical treatment, incision biopsy (such as laparotomy) or obvious traumatic injury within 4 weeks before randomization;
- •Brain metastases or meningeal metastases;
- •Has a history of malignant tumors other than gastric adenocarcinoma or esophagogastric junction adenocarcinoma (except for cured cervical carcinoma in situ or skin basal cell carcinoma and other malignant tumors that have been cured for 5 years);
- •Known to have suffered from severe bleeding disorders (such as severe gastrointestinal bleeding) and vasculitis within 3 months before randomization;
- •Known to be accompanied by other serious diseases, including but not limited to:
- •Refractory congestive heart failure (NYHA classification III or IV, see Appendix 2), unstable angina, poorly controlled arrhythmia, uncontrolled moderate or high blood pressure (SBP>160mmHg or DBP>100mmHg );
- •Uncontrolled diabetes;
- •Mental illness that affects informed consent and/or protocol compliance;
- •There are serious diseases that other researchers believe are not suitable for participating in this study;
- •Known allergies or contraindications to anti-EGFR antibody preparations, paclitaxel and other components;
- •Patients who have previously used immune checkpoint inhibitors (such as anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), such as the following adverse events related to immune checkpoint inhibitors and have not recovered to grade 1 And below, not suitable for inclusion: Grade ≥3 ocular adverse events, abnormal liver function in line with Hy's Law standard adverse events, ≥3 neurological toxicity, ≥3 grade colitis, ≥3 grade renal toxicity;
- •Those who are known to have third space effusion (including a large amount of pleural effusion or ascites) that cannot be controlled by drainage or other methods;
- •Known NCI CTC grade 2-4 peripheral neuropathy;
- •Known history of primary or secondary immunodeficiency or current active primary or secondary immunodeficiency;
- •Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) DNA ≥ 1000 IU/ml or hepatitis C virus (HCV) RNA positive (inactive hepatitis B surface antigen carriers, treated And stable hepatitis B patients [HBV DNA <1000 IU/ml and cured hepatitis C patients can be selected]); Treponema pallidum antibody positive or human immunodeficiency virus antibody positive or any uncontrolled infection By;
- •Women of childbearing age who are pregnant, breast-feeding, planning to become pregnant, or who have not taken reliable birth control measures and men in the sexually active period who are unwilling to take birth control measures during the study period and within 3 months after the last medication, and during the above-mentioned specified time Sperm donors;
- •Any medical, psychiatric or other condition or situation that the investigator believes that the subject's participation in this clinical research may have a negative impact on the safety of the subject or the reliability of the research data.
研究组 & 干预措施
nimotuzumab
Participants received nimotuzumab injection 600 mg for the first time, followed by 400 mg once a week until disease progression or inability to tolerate or withdrawal from the trial; At the same time, in combination with paclitaxel 80 mg/m2, it was administered on days 1, 8 and 15 of each treatment cycle (4 weeks) until the disease progressed or could not be tolerated or withdrew from the trial.
干预措施: nimotuzumab plus paclitaxel (Drug)
placebo
Participants received placebo 600 mg for the first time, followed by 400 mg once a week until disease progression or inability to tolerate or withdrawal from the trial; At the same time, in combination with paclitaxel 80 mg/m2, it was administered on days 1, 8 and 15 of each treatment cycle (4 weeks) until the disease progressed or could not be tolerated or withdrew from the trial.
干预措施: placebo plus paclitaxel (Drug)
结局指标
主要结局
Overall survival
时间窗: through study completion, an average of 18 months
The time between the date of randomization and death from any cause .
次要结局
- progression-free survival(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months)
- DCR(Assessment is performed every 4 weeks for the first 3 months, every 8 weeks to 12 months thereafter, and every 3 months thereafter until disease progression,assessed up to 12 months)
- objective response rate(Assessment is performed every 4 weeks for the first 3 months, every 8 weeks to 12 months thereafter, and every 3 months thereafter until disease progression ,assessed up to 12 months)