NgFUS NIVO: NeuroNavigation-Guided Focused Ultrasound With Nivolumab in Relapsed and Progressive DMG and Other High Grade Brain Tumors

Official title

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

Overview

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.

Interventions

• Device NeuroNavigation-Guided Focused Ultrasound (NgFUS)
  NeuroNavigation-Guided Focused Ultrasound, every 2 or 4 weeks for 3 cycles of 28 days
• Drug Lumason
  Lumason 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.
• Drug Nivolumab
  Nivolumab 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.

Primary outcome measures

• Incidence of dose limiting toxicities (DLT) as assessed by CTCAE v6.0. [Time frame: First treatment through 28 days post-first treatment.]
• Percentage of patients completing at least two cycles of planned therapy [Time frame: Enrollment through end of Cycle 2 (each cycle is 28 days).]

Secondary outcome measures (3)

• Overall response assessment per RAPNO. [Time frame: From screening through 1 year post-final treatment.]
• Progression-free survival (PFS) [Time frame: From enrollment through up to 2 years post-final treatment.]
• Overall survival (OS) [Time frame: From enrollment through up to 2 years post-final treatment.]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• Tumor presenting with the following imaging characteristics:

• Evidence of uncal herniation.
• Edema and/or mass effect that causes hydrocephalus.
• Significant areas of necrosis within the tumor that the neurosurgeon feels cannot be avoided during the ultrasound sonication.
• Evidence of a significant new hemorrhage. Area of microhemorrhage (defined as less than 5 mm in diameter) in the treatment area can be acceptable but requires the review of the neurosurgeon.
• Containing calcifications in the focused ultrasound sonication beam path and system tools cannot tailor the treatment around these calcification spots.
• Patients who are deemed to have overly bulky tumor by the PI of the study.
• The sonication pathway to the tumor involves:

• More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp.
• Clips, or other non-MRI compatible metallic implanted objects in the skull or the brain, except for shunts.
• Patients receiving anti-coagulant therapy, or medications known to increase risk of hemorrhage, (e.g., ASA, non-steroidal anti-inflammatory drugs \[NSAIDs\], statins). There is no required washout for eligibility assessment, but patients should be off agents for at least 3 days at the time of procedure or until 5 half-lives of the agent, whichever is longer.
• History of a bleeding disorder, coagulopathy or with a history of clinically significant spontaneous tumor hemorrhage.
• Cerebral or systemic vasculopathy, including intracranial thrombosis, vascular malformation, cerebral aneurysm, or vasculitis.
• Immunosuppression (corticosteroids to prevent/treat brain edema are permitted).
• Patients with uncontrolled HIV.
• Active seizure disorder or epilepsy (clinically significant seizures despite medical treatment) within four weeks prior to first cycle/NaviFUS BBBO procedure captured by history.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to Lumason® ultrasound contrast agent or known hypersensitivity to sulphur hexafluoride microsphere or its components, e.g., polyethylene glycol.
• Patients unable to fit comfortably into the MRI scanner (generally >250 lbs.).
• Evidence of cranial or systemic infection.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07664176 · STUDY00001735

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗