A Safety and Feasibility Study of NeuroNavigation-Guided Low Intensity Focused Ultrasound With Microbubbles to Enhance Nivolumab Delivery for the Treatment of Relapsed and Progressive Diffuse Midline Glioma and Other High Grade Brain Tumors
This is an open-label phase 1 safety and feasibility study evaluating a novel combination therapy for progressive and relapsed diffuse midline glioma (DMG) and other progressive and relapsed high-grade brain tumors. This study combines intravenous nivolumab therapy infused following transient blood-brain barrier opening (BBBO) using low-intensity focused ultrasound with microbubble (LIFU-MB) treatment using NeuroNavigation-Guided Focused Ultrasound (NgFUS). There are two groups in this study: * Group A: Patients with relapsed or progressive diffuse midline glioma in the brainstem * Group B: Patients with relapsed or progressive high grade brain tumor that clinically require surgical resection The primary outcome is to evaluate the safety and feasibility of 3 cycles of nivolumab with BBB disruption using NgFUS with microbubbles in pediatric patients with progressive or relapsed brainstem DMG or with high grade brain tumors after surgery. Secondary outcomes include preliminary efficacy and immunological effects.
• Age ≥ 3 and ≤ 25 years.
• Diagnosis of brainstem DMG/DIPG or any high-grade brain tumor.
‣ Group A: Relapsed or progressive brainstem DMG.
⁃ Group B: Relapsed or progressive high-grade intracranial brain tumor requiring surgical resection.
• Lansky/Karnofsky rating ≥ 60.
• Patients must have received at least one line of prior therapy upfront for their disease.
• At least four weeks from radiation therapy, prior immunotherapy, or monoclonal antibody therapy.
• At least 2 weeks from prior myelosuppressive chemotherapy and post nadir meeting organ function criteria.
• At least 1 week or 5 half-lives (whichever is longer) from last targeted therapy.
• If on steroids, stable or decreasing dose for at least 7 days prior to study entry and ≤ 0.4 mg/m2/day of dexamethasone or equivalent.
• Stable or improving neurological status for 7 days prior to study entry.
• Organ function:
‣ Absolute Neutrophil Count (ANC) ≥750/μL.
⁃ Absolute Lymphocyte Count (ALC) \>500/μL.
⁃ Platelets ≥75K, unsupported.
⁃ Coagulation studies: PT and PTT \<1.5 ULN and INR (\<1.5).
⁃ Bilirubin ≤1.5x upper limit of normal (ULN).
⁃ AST/ALT ≤5x ULN.
⁃ Serum creatinine within normal limits for age.
⁃ Pulse oximetry \>93% on room air.
⁃ Ejection Fraction (EF) above institutional lower limit of normal (LLN).
• For females of childbearing potential (FOCBP): negative pregnancy test within 7 days of study entry.
• Patients of childbearing or child-fathering potential must agree to use contraceptive measures for at least 5 months following nivolumab infusion.
• Patient or parent/guardian capable of providing informed consent.