A Randomized Phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 80
- 主要终点
- Intracranial progression-free
研究概览
简要总结
Leptomeningeal metastasis (LM) is a devastating and terminal complication of advanced non-small-cell lung cancer (NSCLC), especially in patients harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib is an oral,third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations .AURA I/II study and other preclinical study suggested that Osimertinib exhibited a better blood-brain barrier(BBB) penetration than the other EGFR-TKIs (gefitinib, erlotinib, or afatinib).The BLOOM 、AURA and FLURA study demonstrated that osimertinib showed encouraging activity and manageable tolerability in pretreated EGFR-mutant NSCLC patients with LM. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). Animal study and autopsy specimens showed that VEGF is an essential factor in LM. Recently study showed EGFR-TKIs plus bevacizumab prolonged PFS and OS in patients with EGFR-mutant NSCLC and multiple brain mteastasis when compared with EGFR-TKIs alone. Howerver osimertinib combined with bevacizumab could benefit patients with LM from EGFR- mutant NSCLC remains undetermined. Therefore, the purpose of the study is to evaluate the safety and efficacy of osimertinib combined with bevacizumab for EGFR- mutant non-small cell lung cancer with leptomeningeal metastasis
详细描述
This is a randomized phase II clinical trial. The objective of the study is to assess the efficacy of osimertinib combined with bevacizumab for LM from EGFR- mutant NSCLC. Patients were randomized with equal allocation to 80 mg of oral Osimertinib daily alone or with 7.5 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent
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
- Single (Outcomes Assessor)
盲法说明
single
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age in 18-80 years
- •Pathologically proven NSCLC
- •EGFR mutation , the EGFR status was identified from primary lung tumors using the amplification refractory mutation system (ARMS) or next-generation sequencing (NGS) analysis.
- •LM diagnosis was based on the detection of malignant cells in the CSF, the focal or diffuse enhancement of leptomeninges, and nerve roots or the ependymal surface on gadolinium-enhanced MRI .
- •No severe abnormal liver and kidney function;
- •No other severe chronic diseases;
- •Signed informed consent form
排除标准
- •Patients with the clinical manifestation of nervous system failure including severe encephalopathy, grade III-IV white matter lesions confirmed by imaging examination, moderate or severe coma, and glasgow coma score less than 9 points;
- •Allergic to osimertinib or bevacizumab
- •Any of the following: Pregnant women ;Nursing women ;Men or women of childbearing potential who are unwilling to employ adequate contraception
- •History of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (New York Heart Association ≥ grade 2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has no evidence of active disease for at least 6 months prior to randomization;
- •History of cerebral vascular accident (CVA) or transient ischemic attack (TIA)≤ 6 months prior to randomization
- •History of bleeding diathesis or coagulopathy
- •History of hemoptysis da≥ grade 2 (defined as bright red blood of at least 2.5 mL) ≤3 months prior to randomization
- •Leukocytes below 2*10^9/L, neutrophils below 1*10^9/L; platelets below 50*10^9/L;
- •Had major surgery within 60 days;
- •History of arteriovenous thrombosis
- •Gastrointestinal perforator in the past 6 months
- •Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or diastolic pressure > 100 mmHg on anti-hypertensive medications); Note: history of hypertensive crisis or hypertensive encephalopathy not allowed
- •Grade 4 proteinuria
研究组 & 干预措施
osimertinb group
Osimertinib 80 mg oral daily
干预措施: Osimertinib (Drug)
osimertinb combined with bevacizumab group
Osimertinib 80 mg oral daily;
.bevacizumab 7.5 mg/kg intravenous every 3 weeks
干预措施: Osimertinib (Drug)
osimertinb combined with bevacizumab group
Osimertinib 80 mg oral daily;
.bevacizumab 7.5 mg/kg intravenous every 3 weeks
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Intracranial progression-free
时间窗: Every 6 weeks, up to 2 years,
iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,)
Objective Response Rate
时间窗: Every 6 weeks, up to 2 years
ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)
次要结局
- LM Overall survival(Every 3 weeks, up to 5 years,)
- progression-free survival(Every 6 weeks, up to 2 years,)
- adverse events(Every 3 weeks, up to 2 years,)