Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer (OWBLM)

June 9, 2020 updated by: Second Affiliated Hospital of Nanchang University

Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer

Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) associated with poor prognosis and rapid deterioration of performance status. The incidence of LM is increasing, reaching 3.8% in molecularly unselected NSCLC patients, being more frequent in adenocarcinoma subtype and up to 9% in epidermal growth factor receptor mutation (EGFRm) lung cancer patients, one-third of patients have concomitant brain metastasis . This increased incidence may in part be conducive to the increased survival of patients with EGFRm advanced NSCLC since the introduction of EGFR-tyrosine kinase inhibitions (TKIs).Currently, no standard therapeutic regimen for LM has been established because of its rarity and heterogeneity[11], and no approved therapies exists to specifically target LM in patients with EGFRm NSCLC. TKIs therapy is the first-line treatment of patients with EGFRm of NSCLC. The leptomeningeal space is a sanctuary site for tumour cells and therapeutic agents due to the presence of an active blood-brain barrier (BBB), so CSF concentration is an important factor affecting treatment of LM by TKIs. Standard-dose first- and second-generation EGFR-TKIs have good systemic efficacy but sub-optimal CNS penetration, as evidenced by preclinical studies of brain distribution and clinical reports of CSF penetration[15, 16]. Osimertinib is a third-generation EGFR-TKI, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, which has demonstrated efficacy in NSCLC CNS metastasis[17-22]. Preclinical, I/II clinical studies and AURA program (AURA extension, AURA2, AURA17 and AURA3) have shown that Osimertinib has higher brain permeability than the first- and second-generation.

Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), animal studies and autopsy specimens show that VEGF plays an important role in LM. VEGF and EGFR share many overlapping and parallel downstream pathways. The biological rationale shows that inhibiting of EGFR and VEGR signaling pathways could improve the efficacy of antitumor and remove the resistance of EGFR inhibition. Besides, preclinical researches have shown the similar results. Based on these, numbers of clinical trials have confirmed that VEGF inhibitors in combination with EGFR-TKI significantly prolong patients' survival.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This is a phase II pilot study to evaluate the efficacy and safety of osimertinib with bevacizumab for LM from EGFRm NSCLC patients. ALL patients were treated with Osimertinib 80mg oral daily and bevacizumab 7.5mg/kg intravenous every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent.

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Jiangxi
      • Nanchang, Jiangxi, China, 330006
        • Recruiting
        • The Second Afiliated Hospital of Nanchang University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Osimertinib With Bevacizumab group
Osimertinib 80 mg oral daily; and bevacizumab 7.5 mg/kg intravenous every 3 weeks
Drug: Osimertinib
Treatment of LM With osimertinb
Drug: Bevacizumab
Treatment of LM With Bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
LM progression-free survival
Time Frame: up to 1 year
Time from LM diagnosis to the first documentation of disease progression or death
up to 1 year
Objective Response Rate
Time Frame: up to 1 year
ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)
up to 1 year

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Second Affiliated Hospital of Nanchang University

Collaborators

Nanchang University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2017

Primary Completion (Anticipated)

July 1, 2020

Study Completion (Anticipated)

June 1, 2021

Study Registration Dates

First Submitted

June 8, 2020

First Submitted That Met QC Criteria

June 9, 2020

First Posted (Actual)

June 11, 2020

Study Record Updates

Last Update Posted (Actual)

June 11, 2020

Last Update Submitted That Met QC Criteria

June 9, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20161BBG70210

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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