Non-Invasive Focused Ultrasound (FUS) With Oral Panobinostat in Children With Progressive Diffuse Midline Glioma (DMG)

A Feasibility Study Examining the Use of Non-Invasive Focused Ultrasound (FUS) With Oral Panobinostat Administration in Children With Progressive Diffuse Midline Glioma (DMG)

The blood brain barrier (BBB) prevents some drugs from successfully reaching the target tumor. Focused Ultrasound (FUS) using microbubbles and neuro-navigator-controlled sonication is a non-invasive method of temporarily opening up the blood brain barrier to allow a greater concentration of the drug to reach into the brain tumor. This may improve response and may also reduce system side effects in the patient.

The primary purpose of this study is to evaluate the feasibility of safely opening the BBB in children with progressive diffuse midline gliomas (DMG) treated with oral Panobinostat using FUS with microbubbles and neuro-navigator-controlled sonication.

For the purpose of the study, the investigators will be opening up the BBB temporarily in one, two, or three locations around the tumor using the non-invasive FUS technology, and administrating oral Panobinostat in children with progressive DMG.

Study Overview

• Status: Terminated
• Conditions: Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Diffuse Pontine and Thalamic Gliomas
• Intervention / Treatment: Drug: Panobinostat 15 MG; Device: Focused Ultrasound with neuro-navigator-controlled sonication

Detailed Description

Diffuse midline gliomas (DMGs), constitute 10% of all pediatric central nervous system (CNS) tumors. Subjects with Diffuse Intrinsic Pontine Gliomas (DIPG) have a poor prognosis with a median survival that is usually reported to be 9 months, and nearly 90% of children die within 18 months from diagnosis. The mainstay of treatment is radiation to the primary tumor site. Surgical resection does not influence the outcome and is often not feasible in this part of the central nervous system.

Many promising drugs for central nervous system (CNS) disorders have failed to attain clinical success due to an intact blood brain barrier (BBB), limiting their access from the systemic circulation into the brain. Systemic administration of high doses may increase delivery to the brain, but this approach risks significant side effects and systemic toxicities. Direct delivery of the drugs to the brain by injection into the parenchyma bypasses the BBB, however, drug distribution from the site of injection tends to be limited.

The technique of using focused ultrasound (FUS) with microbubbles and neuro-navigator-controlled sonication can temporarily open up the blood brain barrier and allow for a greater concentration of drug to reach the tumor, thus potentially improving response in patients.

With the current study, the investigators are planning to evaluate the safety and feasibility of using FUS and open-space neuronavigator-controlled sonication to open one, two, or three tumor sites. For the purpose of the study, investigators will be administrating oral Panobinostat in children with progressive DMG. This drug has a known toxicity profile, dose, and well-documented efficacy against many metastatic cancers. Successful opening and closing of the BBB will be confirmed with periodic magnetic resonance imaging (MRIs).

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center / NewYork-Presbyterian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ages 4-21 years.
• Subjects with evidence of clinical and/or radiographic progression of Diffuse Midline Glioma
• Radiological diagnosis of DMG with tumor involving the pons (intrinsic, pontine based infiltrative lesion; hypointense in T1 weighted images (T1WIs) and hyperintense in T2 sequences, with mass effect on the adjacent structures and occupying at least 50% of the pons), thalami and/or histological confirmation of H3K27M mutation confirmation of pontine or thalamic glioma.
• Subjects must be healthy enough to tolerate FUS and MRI and any anesthesia necessary based on the opinion of the principal investigator. Subjects must also be able to swallow capsules (for Panobinostat dosing). Other criteria include, but is not limited to:

Prior therapy:

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment.

• Cytotoxic chemotherapy or anti-cancer agents known to be myelosuppressive: At least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy.
• Anti-cancer agents not known to be myelosuppressive: At least 7 days must have elapsed from last dose of agent.
• Antibodies: At least 21 days must have elapsed from infusion of last dose of antibody.
• Interleukins, Interferons, and Cytokines: At least 21 days must have elapsed since the completion of interleukins, interferon, or cytokines.
• Stem cell infusions: At least 42 days must have elapsed after completion of an autologous stem cell infusion, and at least 84 days must have elapsed after completion of an allogeneic stem cell infusion.
• Cellular therapy: At least 42 days must have elapsed since the completion of any type of cellular therapy
• Radiotherapy (XRT): At least 1 month must have elapsed after local XRT.
• Subjects must be on a stable or decreasing dose of steroids, as well as stable dose of anti-seizure medication for 1 week.

Performance status:

• Karnofsky performance status or Lansky play score of ≥70

Hepatic:

• Total bilirubin: within normal institutional limits
• Aspartate Aminotransferase (AST, SGOT)/Alanine aminotransferase (ALT, SGPT): ≤ 2.5 × institutional upper limit of normal

Renal:

• Creatinine: within normal institutional limits
• Creatinine clearance: ≥ 60 mL/min/1.73m2 for subjects with creatinine levels above institutional normal

Hematopoietic:

• Absolute neutrophil count: ≥ 1,500/μL
• Platelet count: ≥ 100,000/μL
• Hemoglobin level: ≥ 10g/dL
• Partial thromboplastin time (PTT) and activated partial thromboplastin time (aPTT): within normal institutional limits
• No documented current bleeding disorder

Other:

• Not pregnant or nursing - negative serum pregnancy test, if of childbearing potential, within 7 days of study entry
• Subjects with a history of seizures/epilepsy should be on anti-convulsant medication prior to the first operative procedure on the study.
• Subjects must undergo a baseline EKG within 7 days of study enrollment.
• Subjects must be able to undergo MR imaging with gadolinium-based contrast administration (e.g. no ferrous-containing implants, no pacemakers, etc.)
• All subjects or their legal guardians must sign a document of informed consent indicating their understanding of the investigational nature and the potential risks associated with this study. When appropriate, pediatric subjects will be included in all discussions in order to obtain verbal and written assent

Exclusion Criteria:

• Subjects with spinal DMGs.
• Subjects with a medical condition that would preclude general anesthesia
• Subjects with evidence of any active infection
• Subjects with documented allergy to compounds of similar chemical or biologic composition to Panobinostat or gadolinium compounds
• Subjects with evidence of tumor hemorrhage
• Subjects with an uncorrectable bleeding disorder
• Subjects with signs of impending herniation or an acute intratumoral hemorrhage
• Subjects with systemic diseases which may be associated with unacceptable anesthetic/operative risk
• Subjects with implanted electrical devices, metallic implants
• Subjects with uncontrollable hypertension
• Subjects with a history of stroke or cardiovascular disease
• Subjects with cerebrovascular diseases
• Subjects with coagulopathy or under anticoagulant therapy.
• Pregnant or breast-feeding women will not be entered on this study, since there is yet no available information regarding human fetal or teratogenic toxicities. A pregnancy test must be obtained in girls who are post-menarchal. Males with female partners of reproductive potential or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control- including a medically accepted barrier method of contraception (e.g., a male or female condom) for the entire period in which they are receiving protocol therapy and for at least 1 week following their last study treatment requirement. Abstinence is an acceptable method of birth control.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FUS using Oral Panobinostat; All patients enrolled in the study will be treated with oral Panobinostat after receiving Focused Ultrasound treatment (FUS) with microbubbles and neuro-navigator-controlled sonication.

Drug: Panobinostat 15 MG; After each instance of opening the BBB using specific parameters of focused ultrasound in the specific number of tumor sites (one, two, or three), the subjects will receive oral Panobinostat (15 mg/m^2).; Other Names: FARYDAK; Device: Focused Ultrasound with neuro-navigator-controlled sonication; The purpose of this study is to evaluate the feasibility of opening the BBB safely using specific parameters of focused ultrasound in progressive/recurrent diffuse midline gliomas in one, two, or three tumor sites. The trial will follow a 3+3 Number of Tumor Sites (NOTS) escalation scheme. The "number of tumor sites" in reference to here is the number of openings in the blood-brain barrier using Focused Ultrasound (FUS). Subjects will start the first cycle of the treatment arm with 1 tumor site and move on to incrementing NOTS levels if no dose-limiting toxicities (DLTs) are observed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events	Safety will be assessed by evaluation of physical and neurologic examinations, laboratory studies, radiographic studies, and by adverse events as per the CTCAE version 5.0. An adverse event is any new or worsening symptom or clinical finding which occurs during the study period. Adverse events are to be recorded irrespective of causality on the adverse event form. Each event will be described by its severity (mild, moderate, severe, life-threatening), duration, and relation to the study medication (unrelated, unlikely, possible, probable, and definite).	Up to 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival at 6 Months (PFS6)	PFS is defined as the duration of the time from the start of FUS treatment to time of progression or death from any cause, whichever occurs first. Response and progression will be evaluated in this study using the international criteria proposed by the updated Pediatric Response Assessment in Neuro-oncology (RANO) guidelines.	Up to 6 months
Overall Survival at 6 Months (OS6)	Overall survival is defined as the duration of time from the start of FUS treatment to death from any cause. OS will be measured by follow-up with a study participant every 3-6 months until death for any reason.	Up to 7 months
Number of Subjects With Blood Brain Barrier/Tumor Imaging Changes	MRI and other radiological evidence to show successful blood brain barrier (BBB) opening and closing will be reviewed and tallied.	Up to 8 months

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Focused Ultrasound Foundation
• Investigators: Principal Investigator: Cheng-Chia Wu, MD, PhD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2021
• Primary Completion (Actual): March 1, 2022
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: March 15, 2021
• First Submitted That Met QC Criteria: March 16, 2021
• First Posted (Actual): March 18, 2021

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 6, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Focused Ultrasound; Blood brain barrier; Diffuse Midline Gliomas; Pontine Gliomas; Thalamic Gliomas
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioma; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Panobinostat
• Other Study ID Numbers: AAAS5953

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes