Detection of Resistance Mechanisms in Cerebrospinal Fluid for EGFR-mutant, ALK- and ROS1-rearranged

Detection of Resistance Mechanisms in Cerebrospinal Fluid for EGFR-mutant, ALK- and ROS1-rearranged Non-small Cell Lung Cancer Patients With Central Nervous System (CNS) Progression After Evidence of Prior CNS Benefit on Relevant Tyrosine Kinase Inhibitors

To determine the detection rate of driver oncogenes and resistance mechanisms in cerebrospinal fluid (CSF) for patients with CNS progression (with or without extra-CNS (eCNS) progression) and concordance with plasma/tissue

Study Overview

• Status: Withdrawn
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Diagnostic test: InVisionFirst-Lung ctDNA assay

Detailed Description

To determine the detection rate of driver oncogenes and resistance mechanisms in cerebrospinal fluid (CSF) for patients with CNS progression (with or without extra-CNS (eCNS) progression) and concordance with plasma/tissue

• For each individual patient with CNS progression (with or without eCNS progression), compare the molecular status (primary oncogene detection and any mechanisms of identifiable resistance including EGFR-, ALK- and ROS1-mutations, ALK-amplification and bypass-tracks activating mutations) of CSF, plasma and CNS tissue (if data from pathology report is available)
• Molecular status will also be compared with previously obtained and stored plasma/tissue prior to the initiation of current next-generation tyrosine-kinase inhibitor (TKI)

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Colorado Research Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Georgetown University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with stage IV EGFR, ALK, or ROS1-mutant NSCLC who had CNS progression after at least 6 months of stable CNS disease on a relevant TKI are screened. Patients must meet all Inclusion/Exclusion Criteria to participate in the study.

Description

Inclusion Criteria:

1. Provision to sign and date the consent form
2. Stated willingness to comply with all study procedures and be available for the duration of the study.
3. Be aged 18 or older.
4. Pathologically confirmed NSCLC with EGFR-mutation, or ALK- or ROS1-rearrangement and currently on an EGFR, or ALK or ROS1 tyrosine-kinase inhibitor (TKI) as applicable
5. Stage IV NSCLC disease according to AJCC 8th edition

6. Known CNS metastasis prior to current line of therapy with CR/PR/SD for at least 6 months (not purely attributable to prior local therapy such as radiation) on current EGFR, or ALK or ROS1 TKI, confirmed by at least one of the following modalities:

   • CT/MRI for brain metastases
   • characteristic signs and/or symptoms indicating progression,
   • cytology,
   • imaging findings for leptomeningeal disease

7. Confirmed current CNS progression, with or without eCNS progression, on the same TKI based on at least one of the following modalities:

   • CT/MRI for brain metastases
   • characteristic signs and/or symptoms indicating progression,
   • cytology,
   • imaging findings for leptomeningeal disease
8. Prior CNS radiation therapy is allowed

Exclusion Criteria:

1. Has contraindications to receive a lumbar puncture which may include, but are not limited to the following, at the discretion of the patient's oncologist or physician performing the LP:

   • Clinical and/or radiographic evidence of mass effect of raised intracranial pressure (ICP) with risk for cerebral herniation
   • Thrombocytopenia (defined as platelet count ≤ 50 or per local guidelines) or other bleeding diathesis
   • Currently on antiplatelet or anticoagulant therapy at time of consent, for which the thrombosis risk of holding for LP is deemed unacceptable
   • Suspected spinal epidural abscess
   • Any other condition determined by the clinician to be a contraindication

2. History of a second primary malignancy (including a second primary lung cancer) with the exceptions for:

   • Malignancy treated with curative intent and with no known active disease ≥5 years, and of low potential risk for recurrence
   • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   • Adequately treated carcinoma in situ without evidence of disease
3. Women who are documented as pregnant or breastfeeding

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort 1; 10 evaluable enrollments to Cohort 1 with EGFR-mutant NSCLC	Diagnostic test: InVisionFirst-Lung ctDNA assay; An enhanced tagged/targeted-amplicon sequencing technology for detection of genomic alterations in 36 commonly mutated genes in plasma ctDNA with a sensitivity of 73.9% and specificity of 99.8%.
Cohort 2; 10 evaluable enrollments to Cohort 2 with ALK-rearranged NSCLC	Diagnostic test: InVisionFirst-Lung ctDNA assay; An enhanced tagged/targeted-amplicon sequencing technology for detection of genomic alterations in 36 commonly mutated genes in plasma ctDNA with a sensitivity of 73.9% and specificity of 99.8%.
Cohort 3; 10 evaluable enrollments to Cohort 3 with ROS1-rearranged NSCLC	Diagnostic test: InVisionFirst-Lung ctDNA assay; An enhanced tagged/targeted-amplicon sequencing technology for detection of genomic alterations in 36 commonly mutated genes in plasma ctDNA with a sensitivity of 73.9% and specificity of 99.8%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the detection rate of driver oncogenes and resistance mechanisms in cerebrospinal fluid (CSF) for patients with CNS progression (with or without extra-CNS (eCNS) progression) and concordance with plasma/tissue	For each individual patient with CNS progression (with or without eCNS progression), compare the molecular status (primary oncogene detection and any mechanisms of identifiable resistance including EGFR-, ALK- and ROS1-mutations, ALK-amplification and bypass-tracks activating mutations) of CSF, plasma and CNS tissue (if data from pathology report is available); Molecular status will also be compared with previously obtained and stored plasma/tissue prior to the initiation of current next-generation tyrosine-kinase inhibitor (TKI)	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare and contrast mechanisms of resistance in CNS progression versus eCNS progression	For patients with both CNS and eCNS progression, compare distribution of resistance mechanisms between CSF, plasma, CNS tissue (if data from pathology report is available) and tissue from site of eCNS progression (if data from pathology report is available); Compare distribution of resistance mechanisms in CSF for all patients with CNS progression (with or without eCNS progression) to historical data of distribution of resistance mechanisms to next-generation TKI from ctDNA/tumor tissue samples	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the clinical outcomes of subsequent lines of therapy base on CNS data from this study	ORR in CNS	3 years
Determine the clinical outcomes of subsequent lines of therapy base on CNS data from this study	PFS in CNS	3 years
Determine the clinical outcomes of subsequent lines of therapy base on eCNS data from this study	ORR in eCNS	3 years
Determine the clinical outcomes of subsequent lines of therapy base on eCNS data from this study	PFS in eCNS	3 years
Determine the safety of CSF sampling for detection of resistance mechanisms in the context of CNS progression	AEs associated with procedure	3 years

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Inivata
• Investigators: Principal Investigator: Ross Camidge, Colorado Research Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 6, 2022
• Primary Completion (ACTUAL): September 15, 2022
• Study Completion (ACTUAL): September 15, 2022

Study Registration Dates

• First Submitted: November 1, 2021
• First Submitted That Met QC Criteria: November 1, 2021
• First Posted (ACTUAL): November 11, 2021

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Progression; Central Nervous System
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 20-1193.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: whole study will be presented

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No