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

Primary Purpose

Leptomeningeal Metastasis, Non-small Cell Lung Cancer, EGFR Activating Mutation

Status

Unknown status

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Osimertinib

Bevacizumab

About this trial

This is an interventional treatment trial for Leptomeningeal Metastasis focused on measuring leptomeningeal metastasis, non small cell lung cancer, EGFR Activating Mutation, Osimertinib, Bevacizumab

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

osimertinb group

osimertinb combined with bevacizumab group

Arm Description

Osimertinib 80 mg oral daily

Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks

Outcomes

Primary Outcome Measures

Intracranial progression-free

iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,)

Objective Response Rate

ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Secondary Outcome Measures

LM Overall survival

LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up

progression-free survival

Proportion of patients progression-free by investigator assessment per RECIST v1.1

adverse events

Number of patients with adverse events (AEs) as a measure of safety and tolerability

Full Information

NCT ID

NCT04148898

First Posted

October 3, 2019

Last Updated

November 1, 2019

Sponsor

Second Affiliated Hospital of Nanchang University

Collaborators

Nanchang University

1. Study Identification

Unique Protocol Identification Number

NCT04148898

Brief Title

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

Acronym

OWONBNSCLCLM

Official Title

A Randomized Phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

Study Type

Interventional

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Unknown status

Study Start Date

November 1, 2019 (Anticipated)

Primary Completion Date

March 1, 2021 (Anticipated)

Study Completion Date

July 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Second Affiliated Hospital of Nanchang University

Collaborators

Nanchang University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leptomeningeal Metastasis, Non-small Cell Lung Cancer, EGFR Activating Mutation

Keywords

leptomeningeal metastasis, non small cell lung cancer, EGFR Activating Mutation, Osimertinib, Bevacizumab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Crossover Assignment

Masking

Outcomes Assessor

Masking Description

single

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

osimertinb group

Arm Type

Experimental

Arm Description

Osimertinib 80 mg oral daily

Arm Title

osimertinb combined with bevacizumab group

Arm Type

Experimental

Arm Description

Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks

Intervention Type

Drug

Intervention Name(s)

Osimertinib

Other Intervention Name(s)

AZD9291

Intervention Description

Treatment of LM With osimertinb

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Other Intervention Name(s)

Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb

Intervention Description

Treatment of LM With osimertinb combined with bevacizumab

Primary Outcome Measure Information:

Title

Intracranial progression-free

Description

iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,)

Time Frame

Every 6 weeks, up to 2 years,

Title

Objective Response Rate

Description

ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Time Frame

Every 6 weeks, up to 2 years

Secondary Outcome Measure Information:

Title

LM Overall survival

Description

LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up

Time Frame

Every 3 weeks, up to 5 years,

Title

progression-free survival

Description

Proportion of patients progression-free by investigator assessment per RECIST v1.1

Time Frame

Every 6 weeks, up to 2 years,

Title

adverse events

Description

Number of patients with adverse events (AEs) as a measure of safety and tolerability

Time Frame

Every 3 weeks, up to 2 years,

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Liu Anwen, Phd

Phone

+8613767120022

awliu666@163.com

First Name & Middle Initial & Last Name or Official Title & Degree

Cai Jing, Phd

Phone

+8615270905381

cjdl879@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Liu Anwen, Phd

Organizational Affiliation

Second Affiliated Hospital of Nanchang University

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

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

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