Navigated Focused Ultrasound and Pembrolizumab in the Treatment of Recurrent WHO Grade 4 IDH-Wildtype Glioblastoma with Mismatch Repair Deficiency.
Patient previously diagnosed with WHO grade 4 IDH-wildtype GBM, determined through genomic and/or histopathological analysis.
Prior treatment for GBM with surgical resection and standard of care TMZ and radiation therapy.
Patient who has undergone repeat surgery (including biopsy or resection) for rGBM.
MMR deficiencies confirmed per standard of care immunohistochemical analysis or Next Generation Sequencing (NGS) of the patient's surgical sample from the time of initial GBM diagnosis or recurrence.
Multifocal or leptomeningeal disease observed at the time of GBM recurrence.
Patient for whom the repeat surgical cavity is ≤30 mm from the skull surface or otherwise not reasonably accessible for sonification using the NaviFUS platform, assessed on screening MRI.
Patient with a prior or concurrent malignancy that is deemed to be clinically significant in the context of rGBM.
Patient receiving concurrent treatment with an immune checkpoint inhibitor, other investigational agent, or live vaccine administered within 14 days prior to the first dose of trial treatment.
Single group
Pembrolizumab
DrugTreatment dosing will be 200mg of pembrolizumab every three weeks for up to six months or until disease progression, whichever occurs first.
Navifus Focused Ultrasound Sonification
DeviceFocused Ultrasound Sonification- Post Pembro infusion, patients will received NaviFUS sonication to the complete volume of the tumor resection bed (as limited by anatomic constraints relative to the tumor extension) following microbubble (Bracco Imaging, SonoVue® or Lumason®; 0.1 mL/Kg; maximum 4.8 mL) administration on a 2-minute schedule. The NaviFUS procedure will be guided using the compatible navigation system, Medtronic StealthStation®. Microbubble administration and operation of the NaviFUS unit will be completed by qualified delegated study investigators. Treatment sessions will occur every 3 weeks for 6 months or until evidence of disease progression, whichever occurs first. A 6-month treatment duration was determined in order to report a 6-month PFS rate as one of the secondary outcomes for this study population.
Safety of using navigated focused ultrasound (NaviFUS) CTCAE v6.0
To evaluate the safety of using navigated focused ultrasound (NaviFUS) combined with pembrolizumab (PEM) after repeat surgery for patients with recurrent glioblastoma (rGBM) and mismatch repair (MMR) deficiency. Given that NaviFUS and PEM have defined intracranial dosing, no dose-escalation scheme will be employed. A CTCAE v6.0 grade 4 or higher toxicity probably or definitely attributable (see Section 13.2.3) to the administration of NaviFUS or PEM will be used as the definition for unacceptable toxicity
Feasibility of using navigated focused ultrasound (NaviFUS) -CTCAE v6.0 criteria
To evaluate feasibility of using navigated focused ultrasound (NaviFUS) combined with pembrolizumab (PEM) after repeat surgery for patients with recurrent glioblastoma (rGBM) and mismatch repair (MMR) deficiency. Given that NaviFUS and PEM have defined intracranial dosing, no dose-escalation scheme will be employed. A CTCAE v6.0 grade 4 or higher toxicity probably or definitely attributable (see Section 13.2.3) to the administration of NaviFUS or PEM will be used as the definition for unacceptable toxicity
Overall survival- standard Kaplan-Meier method and calculated from the date of GBM diagnosis
To evaluate overall survival (OS) in patients treated with NaviFUS combined with PEM after repeat surgery for patients with rGBM and MMR deficiency.
Progression free survival - standard Kaplan-Meier method and calculated from the date of GBM diagnosis
To evaluate progression free survival (PFS) in patients treated with NaviFUS combined with PEM after repeat surgery for patients with rGBM and MMR deficiency.
Baseline levels of markers of immune function and genetic repair
To evaluate levels of baseline tumor markers related to immune and genetic repair function, including PD-L1, microsatellite instability (MSI), and tumor mutational burden (TMB).
radiographic response to treatment in patients with postsurgical residual disease as determined via mRANO criteria
To evaluate radiographic treatment response according to Modified Response Assessment in Neuro-Oncology (mRANO) criteria prior to treatment with NaviFUS combined with PEM in patients with postsurgical residual tumor.
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Jennifer Leddon
Lead sponsor
University of Cincinnati
Sponsor institution
NaviFUS Corporation
Collaborator
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