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BRAINFUL (BRAIN Tumor Focused Ultrasound-enabled Liquid Biopsy) Trial (BRAINFUL)

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ClinicalTrials.gov Identifier: NCT04940507
Recruitment Status : Recruiting
First Posted : June 25, 2021
Last Update Posted : July 9, 2021
Sponsor:
Collaborators:
Canadian Cancer Society (CCS)
Brain Canada
Information provided by (Responsible Party):
Andres M. Lozano, University Health Network, Toronto

Brief Summary:

Background:

Accessing brain tumor material for pathological diagnosis requires invasive procedures that carry risk to patients including brain hemorrhages and death. Liquid biopsies are emerging non-invasive alternatives to direct tumour biopsies but the abundance of circulating tumor DNA (ctDNA) is relatively low and this limits our ability to accurately make the molecular diagnosis of brain tumors. We have recently shown promising results that suggest that the analysis of blood samples can distinguish brain tumor types. We now want to couple liquid biopsies with high intensity focused ultrasound (HIFU) to enhance the release of tumor DNA into the circulation and increase the sensitivity/and specificity of liquid biopsies for brain tumors. The aim of this project is to build on our preliminary findings and investigate the the time dependent changes associated with HIFU of a tumor to see if it improves accuracy of diagnosis and specifically molecular subtyping of tumors based on peripheral blood and cerebrospinal fluid (CSF) circulating tumor derived markers following HIFU.


Condition or disease Intervention/treatment Phase
Brain Neoplasms Liquid Biopsy Procedure: Magnetic Resonance Guided Focused Ultrasound Tumor Ablation and Liquid Biopsy Acquisition Procedure: Magnetic Resonance Guided Focused Ultrasound Thalamotomy Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: Safety and Feasibility of Focused Ultrasound-enabled Liquid Biopsy in Patients With Brain Tumours
Actual Study Start Date : June 10, 2021
Estimated Primary Completion Date : June 10, 2022
Estimated Study Completion Date : June 10, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tumor cohort

Intervention 1:

Participants will undergo a partial tumor ablation with MRgFUS using ExAblate Neuro 4000 device (InSightec Ltd, Tirat Carmel, Israel). Blood and CSF samples will be drawn on several timepoints before and after the procedure.

Intervention 2:

Participants will undergo a standard of care tumor biopsy/excision one day after the "Intervention 1". Blood samples will be drawn on several timepoints before and after the procedure.

Procedure: Magnetic Resonance Guided Focused Ultrasound Tumor Ablation and Liquid Biopsy Acquisition
Partial ablation of tumor using ExAblate Neuro 4000 device (InSightec Ltd, Tirat Carmel, Israel) and blood and CSF draws for liquid biopsy
Other Name: Neurosurgical Tumor Biopsy/Excision

Essential tremor cohort
To identify the levels of circulating free DNA release after MRgFUS procedure in non-tumoral patients and to check whether the MRgFUS procedure induce tumoral mutations itself, we will draw blood samples from essential tremor patients before and after standard of care MRgFUS thalamotomy procedure.
Procedure: Magnetic Resonance Guided Focused Ultrasound Thalamotomy
Ablation of VIM nucleus of thalamus with MRgFUS using ExAblate Neuro 4000 Device (InSightec Ltd, Tirat Carmel, Israel) and blood draws.




Primary Outcome Measures :
  1. Blood and CSF levels of the circulating free DNA [ Time Frame: Pre-MRgFUS: Within 1 hour; Post-MRgFUS: Within 1 hour, between 3-4 hours; Pre-surgery: Within 1 hour; Post-surgery:Within 1 hour, between 16-24 hours ]
    Difference in concentration of cfDNA between the blood and CSF samples acquired before and after MRgFUS


Secondary Outcome Measures :
  1. The optimal time-point of liquid biopsy acquisition [ Time Frame: Pre-MRgFUS: Within 1 hour; Post-MRgFUS: Within 1 hour, between 3-4 hours; Pre-surgery: Within 1 hour; Post-surgery:Within 1 hour, between 16-24 hours ]
    by understanding the time of highest plasma cfDNA concentration by the comparison of the cfDNA concentrations across all time-points after the MRgFUS procedure

  2. Safety (procedure-related complications) [ Time Frame: Post-MRgFUS: Within 1 hour, between 3-4 hours; Pre-surgery: Within 1 hour; Post-surgery: Within 1 hour, between 16-24 hours and 1 month ]
    incidence of adverse events as assessed by clinical examination during surgery and at 1-month follow-up

  3. Epigenomic analysis [ Time Frame: Pre-MRgFUS: Within 1 hour; Post-MRgFUS: Within 1 hour, between 3-4 hours; Pre-surgery: Within 1 hour; Post-surgery:Within 1 hour, between 16-24 hours ]
    Involves detection of DNA methylation signatures of tumours and application of set of models to discriminate them. Impact of MRgFUS will assessed by the change in AUC values of brain tumor classification models in MRgFUS treated patients, comparing plasma and CSF samples obtained prior to and after the procedure

  4. Genomic analysis [ Time Frame: Pre-MRgFUS: Within 1 hour; Post-MRgFUS: Within 1 hour, between 3-4 hours; Pre-surgery: Within 1 hour; Post-surgery:Within 1 hour, between 16-24 hours ]
    Involves detection of relevant tumoral gene mutations. For tumour group, we will compute the concordance of plasma and CSF based genomic alteration targeted sequencing results with tissue-based results. For control group, we will compare the baseline and post-procedure tumoral gene mutations to understand FUS cause de novo tumoral mutations.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • New MRI-diagnosed intracranial lesions that are suitable to biopsy surgically
  • The lesion to be treated is clearly defined and can be well distinguished from surrounding brain tissue.
  • Male or female aged 18 years or older
  • Capable of providing informed consent and complying with study procedures, including tolerability in the supine position and MRI examination without significant claustrophobia, and acceptance of surgery (open or stereotactic) after HIFU treatment.
  • Able to communicate during the ExAblate® MRgFUS procedure.
  • Karnofsky rating 70-100

Exclusion Criteria:

  • If region of treatment locates in < 1.0 cm from the inner table of the skull, on skull base or in the posterior fossa
  • Presence of hydrocephalus, severe vomiting, intractable headache or decreased level of consciousness due to increased intracranial pressure
  • Unable to complete high-density CT and MRI studies of the head at the any other MRI contraindication, such as:

    • Large body habitus and not fitting comfortably into the scanner
    • Difficulty lying supine and still for up to 2 in the MRI unit or significant claustrophobia
  • MRI findings:

    • Active infection/inflammation
    • Acute or chronic brain haemorrhages
    • Moderate/severe brain edema or midline shift >15 mm
  • Clips or other metallic implanted objects in the skull or the brain, except shunts
  • Significant cardiac disease or unstable hemodynamic status.
  • On medications that increase the bleeding risk, specifically: a) aspirin or another antiplatelet medication (clopidogrel, prasugrel, ticlopidine, abciximab) for the last 7 days prior to treatment; b) oral, subcutaneous or intravenous anticoagulant medications, such as oral vitamin K inhibitors for the last 7 days, non-vitamin K inhibitor oral anticoagulant (dabigatran, apixaban, rivaroxaban) for the last 72 hours, and intravenous or subcutaneous heparin-derived compounds for the last 48 hours
  • Abnormal coagulation profile, specifically: platelet <100,000/μl, Prothrombin Time >14 seconds, activated partial thromboplastin time (aPTT) >36 seconds, and INR > 1.3
  • Unqualified fit for the anaesthesia by an anesthesiologist assessment, ASA IV-V.
  • Currently in a clinical trial involving an investigational product or non-approved use of a drug or device.
  • Pregnant and lactating women

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): NCT04940507


Contacts
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Contact: Martha Lenis, BHA +14166035800 ext 2797 martha.lenis@uhnresearch.ca
Contact: Can Sarica, MD +14377772269 can.sarica@mail.utoronto.ca

Locations
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Canada, Ontario
Toronto Western Hospital, University Health Network Recruiting
Toronto, Ontario, Canada, M5T 2S8
Contact: Martha Lenis, BHA    +14166035800 ext 2797    martha.lenis@uhnresearch.ca   
Sponsors and Collaborators
University Health Network, Toronto
Canadian Cancer Society (CCS)
Brain Canada
Investigators
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Principal Investigator: Andres M. Lozano, MD, PhD University of Toronto
Principal Investigator: Gelareh Zadeh, MD, PhD University of Toronto
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Responsible Party: Andres M. Lozano, University Professor, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT04940507    
Other Study ID Numbers: 20-6243
707126 ( Other Grant/Funding Number: Canadian Cancer Society and Brain Canada Foundation )
First Posted: June 25, 2021    Key Record Dates
Last Update Posted: July 9, 2021
Last Verified: July 2021
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 Andres M. Lozano, University Health Network, Toronto:
High-Intensity Focused Ultrasound Ablation
Additional relevant MeSH terms:
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Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases