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.
Symptoms and signs of increased intracranial pressure.
Patients with metallic ventricular peritoneal shunts. Subjects with nonmetallic VP shunts or similar will have a technical evaluation of the screening non-contrast CT scan of the head. During the mapping of the target area, if the technical NaviFUS specialist determines that the patient cannot be treated within the safety limits of the system, the patient will not be eligible and will be considered a screen failure.
Evidence of uncal herniation.
Edema and/or mass effect that causes hydrocephalus.
Parallel
NeuroNavigation-Guided Focused Ultrasound (NgFUS)
DeviceNeuroNavigation-Guided Focused Ultrasound, every 2 or 4 weeks for 3 cycles of 28 days
Lumason
DrugLumason is a sulfur hexafluoride microsphere ultrasound contrast agent which will be used as a mechanical resonator. Lumason will be given in combination with NgFUS every 2 or 4 weeks for 3 cycles of 28 days.
Nivolumab
DrugNivolumab is a monoclonal antibody targeting the immune checkpoint axis PD-1/PD-L1. Nivolumab will be given prior to NgFUS with microbubbles (Lumason) every 2 or 4 weeks for 3 cycles of 28 days.
Incidence of dose limiting toxicities (DLT) as assessed by CTCAE v6.0.
Safety will be evaluated by the incidence of DLTs. DLT is defined as toxicities which are at least possibly related to treatment and meeting protocol-specified criteria for grade, duration, severity, and/or delay of subsequent treatment cycles. If the overall toxicity rate exceeds protocol-specified criteria, enrollment will be halted and the study will be amended to modify the treatment plan.
Percentage of patients completing at least two cycles of planned therapy
Treatment will be determined feasible if at least 80% of enrolled patients complete at least 2 cycles of planned therapy. Feasibility will be assessed separately for each cohort.
Overall response assessment per RAPNO.
Overall response assessment: complete response (CR), partial response (PR), minor response (MR), stable disease (SD), or progressive disease (PD) following treatment, will be assessed based on the Response Assessment in Pediatric Neuro-Oncology (RAPNO) scale.
Progression-free survival (PFS)
PFS is defined as the interval of time between the date of protocol treatment initiation and the earliest date of documentation of progressive disease, or second malignancy or death (for any reason) for patients who fail, or to date of last contact or initiation of other therapy for patients who remain at risk of failure.
Overall survival (OS)
OS post nivolumab infusion will be analyzed by the Kaplan-Meier method.
Tissue expression of PD-1 and PD-L1
Lymphocyte counts according to FUS area treated
Immunologic correlates
Immunohistochemistry for PD1/PDL1
Click on the lead sponsor to view all of their trials.
