Osimertinib With or Without Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

Phase 2

• Conditions: Leptomeningeal Metastasis; Non-small Cell Lung Cancer; EGFR Activating Mutation
• Interventions: Drug: Osimertinib; Drug: Bevacizumab

• Registration Number: NCT04148898
• Lead Sponsor: Second Affiliated Hospital of Nanchang University

Brief Summary

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

Detailed Description

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

Study Timeline

• Status Verified: 2019-10
• Study First Submitted: 2019-10-03
• Study Start: 2019-11-01
• Study First Submitted QC: 2019-11-01
• Last Update Submitted: 2019-11-01
• Study First Posted: 2019-11-04
• Last Update Posted: 2019-11-04
• Primary Completion: 2021-03-01
• Study Completion: 2021-07-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

• 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

Exclusion Criteria

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
osimertinb group	Osimertinib	Osimertinib 80 mg oral daily
osimertinb combined with bevacizumab group	Osimertinib	Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks
osimertinb combined with bevacizumab group	Bevacizumab	Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks

Primary Outcome Measures

Name	Time	Method
Intracranial progression-free	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	Every 6 weeks, up to 2 years	ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Secondary Outcome Measures

Name	Time	Method
LM Overall survival	Every 3 weeks, up to 5 years,	LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up
progression-free survival	Every 6 weeks, up to 2 years,	Proportion of patients progression-free by investigator assessment per RECIST v1.1
adverse events	Every 3 weeks, up to 2 years,	Number of patients with adverse events (AEs) as a measure of safety and tolerability