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

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ClinicalTrials.gov Identifier: NCT04425681
Recruitment Status : Recruiting
First Posted : June 11, 2020
Last Update Posted : June 11, 2020
Sponsor:
Collaborator:
Nanchang University
Information provided by (Responsible Party):
Second Affiliated Hospital of Nanchang University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Leptomeningeal Metastasis Non-small Cell Lung Cancer EGFR Activating Mutation Drug: Osimertinib Drug: Bevacizumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer
Actual Study Start Date : October 1, 2017
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : June 1, 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. LM progression-free survival [ Time Frame: up to 1 year ]
    Time from LM diagnosis to the first documentation of disease progression or death

  2. 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)


Secondary Outcome Measures :
  1. 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

  2. progression-free survival [ Time Frame: Every 6 weeks, up to 2 years ]
    Proportion of patients progression-free by investigator assessment per RECIST v1.1

  3. 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



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04425681


Contacts
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Contact: Liu Anwen, Phd +8613767120022 awliu666@163.com
Contact: Huang s Shu, MD,PhD +8607918626884 xiaoshumenfan@126.com

Locations
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China, Jiangxi
The Second Afiliated Hospital of Nanchang University Recruiting
Nanchang, Jiangxi, China, 330006
Contact: Anwen Liu, MD    +8613767120022    awliu666@163.com   
Sponsors and Collaborators
Second Affiliated Hospital of Nanchang University
Nanchang University
Investigators
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Study Director: Liu Anwen, Phd Second Affiliated Hospital of Nanchang University
Publications of Results:

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Responsible Party: Second Affiliated Hospital of Nanchang University
ClinicalTrials.gov Identifier: NCT04425681    
Other Study ID Numbers: 20161BBG70210
First Posted: June 11, 2020    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Second Affiliated Hospital of Nanchang University:
leptomeningeal metastasis
non small cell lung cancer
EGFR Activating Mutation
Osimertinib
Bevacizumab
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Neoplasms, Second Primary
Meningeal Carcinomatosis
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplastic Processes
Pathologic Processes
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Bevacizumab
Osimertinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors