CSF Analysis in EGFR Mutant Non-Small Cell Lung Cancer With Leptomeningeal Disease

Study Overview
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Brief Summary
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Leptomeningeal disease is malignant seeding of the leptomeninges and presents with a variety of symptoms frequently impacting quality of life. With improvement in treatment options, rates of leptomeningeal disease are increasing and currently found in up to 9% of EGFR mutant NSCLC. Systemic therapy may be more effective if it can target the correct molecular aberration. The molecular characterization of central nervous system disease may differ from disease outside of the central nervous system. The aim of this pilot trial is to evaluate for molecular differences between cerebral spinal fluid (CSF) and blood circulating tumor DNA (ctDNA) through the use of ddPCR and BC Cancer NGS panel molecular testing.

Detailed Description
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The aim of this pilot trial is to evaluate the concordance/discordance of molecular profiling of CSF and plasma ctDNA after the development of leptomeningeal disease in EGFR mutant NSCLC. Patients with EGFR mutant NSCLC who develop leptomeningeal disease on a first, second or third generation tyrosine kinase inhibitor are potentially eligible for this clinical trial. This is a prospective pilot study designed to accrue 10 patients. Baseline MRI brain and spine must be completed prior to enrolment to insure that a lumbar puncture can be completed safely. All eligible subjects will be consented for ddPCR and Canexia Follow It plasma and CSF based molecular testing. Patients will have baseline information collected and will complete baseline quality of life (QoL) questionnaires. QoL questionnaires will be obtained every 12 weeks +/- 2 weeks and survival will be measured through chart review. There will be no treatment intervention; however we will collect information on treatment received after enrolment in trial. Volume of leptomeningeal disease will be scored by number of gadolinium enhancing sites in 8 predetermined locations.

Official Title
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CSF Liquid Biopsy Based Characterization of Leptomeningeal Disease in EGFR Mutant Non-Small Cell Lung Cancer

Conditions
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EGFR Activating Mutation, Leptomeningeal Metastasis, Non Small Cell Lung Cancer

Intervention / Treatment
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* Diagnostic Test: Lumbar puncture and Phlebotomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject age is greater than or equal to 18 years at the time of signature of informed consent. Histologically or cytologically confirmed metastatic EGFR mutant NSCLC. Leptomeningeal disease based on brain MRI or CSF cytology. ECOG 0-3. Life expectancy of at least 8 weeks. Adequate hematologic and end organ function for testing. Ability to give informed consent for the study procedures defined in this protocol. Exclusion Criteria: Inability to undergo a lumbar puncture due to thrombocytopenia, bleeding disorders, as well as inability to cooperate or consent to procedure. Subjects who are otherwise felt by the treating clinician to be unfit to proceed with this protocol. MRI spine demonstrating spinal leptomeningeal disease preventing a safe lumbar puncture.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>ddPCR and BC Cancer NGS panel completed on cerebral spinal fluid and blood circulating tumor DNA | Diagnostic Test: Lumbar puncture and Phlebotomy<br>* Sampling of cerebral spinal fluid and plasma.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance of molecular profiling of CSF and plasma in EGFR mutation positive NSCLC patients with leptomeningeal disease | To determine the concordance rate of molecular alterations detected in the CSF and plasma of EGFR mutation positive NSCLC patients with leptomeningeal disease | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance of treatment recommendations based on ctDNA and CSF | To determine the concordance and discordance between physician treatment recommendations based on ctDNA versus CSF molecular profiling. | 36 months | 
| Molecular profiling comparison | To assess concordance/discordance rates between ddPCR and Canexia Follow It completed on CSF and plasma based testing. | 36 months | 
| Molecular profiling descriptive comparison of patients treated with first/second generation versus 3rd generation EGFR TKIs | To identify molecular aberrations in the ctDNA and CSF of patients who progress on first/second EGFR TKIs and third generation EGFR TKIs to perform a descriptive comparison of shared and unique mutations identified based on prior exposure to first/second versus third generation EGFR TKI | 36 months | 
| Correlation between MRI and CSF | To correlate burden of leptomeningeal disease found on MRI and CSF positivity for tumor DNA. | 36 months | 
| Overall survival | To determine overall survival from time of developing leptomeningeal disease. | 36 months | 
| Quality of life with leptomeningeal disease | To assess the quality of life using the validated instrument, EuroQol 5 Dimension (EQ5D) (Scale of 0-100 where 0 is worst health and 100 is best health) | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-small cell lung cancer, EGFR, leptomeningeal disease