Pilot Study of Navigated Focused Ultrasound and Pembrolizumab in the Treatment of Recurrent WHO Grade 4 IDH-Wildtype Glioblastoma With Mismatch Repair Deficiency

Prior treatment

• 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.
• Prior treatment with an immune checkpoint inhibitor agent.
• Treatment with systemic corticosteroids at an increased dose or dose of ≥10 mg of prednisone (or equivalent) daily within the 5 days prior to starting trial treatment, or treatment with systemic corticosteroids for other indications.
• Patient with an active concurrent comorbidity that, in the opinion of the Investigator, would pose a safety concern for the patient's participation in this clinical trial.

Other illness

• Multifocal or leptomeningeal disease observed at the time of GBM recurrence.
• Period of less than 28 days from the time of the patient's receipt of other systemic anti-cancer therapies to the proposed date of first trial treatment.
• Patient with a history of organ transplant or autoimmune disorder requiring active immunosuppression.
• Patient with current recreational drug use or a history of substance use disorder.

• 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.
• Area of sonication using the NaviFUS platform is \>30 mm from the skull surface, assessed on the Investigator's review of the screening MRI.
• Age ≥18 years.
• Karnofsky Performance Scale (KPS) \>70.
• Adequate organ and marrow function:
  • Leukocytes ≥2,500/mm3 Absolute Neutrophil Count ≥1,500/mm3 Absolute Lymphocyte Count ≥800/mm3 Platelets ≥100,000/mm3 Hemoglobin ≥8 g/dL
• Negative serum or urine pregnancy test in a female patient of childbearing potential.
• Patient or a legally-authorized representative must provide study-specific informed consent.