Don't get left behind! The modernized is coming. Check it out now.
Say goodbye to!
The new site is coming soon - go to the modernized
Working… Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04804709
Recruitment Status : Active, not recruiting
First Posted : March 18, 2021
Last Update Posted : February 14, 2022
Focused Ultrasound Foundation
Information provided by (Responsible Party):
Cheng-Chia (Fred) Wu, Columbia University

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Diffuse Intrinsic Pontine Glioma Diffuse Pontine and Thalamic Gliomas Diffuse Midline Glioma, H3 K27M-Mutant Drug: Panobinostat 15 MG Device: Focused Ultrasound with neuro-navigator-controlled sonication Phase 1

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).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Study Examining the Use of Non-Invasive Focused Ultrasound (FUS) With Oral Panobinostat Administration in Children With Progressive Diffuse Midline Glioma (DMG)
Actual Study Start Date : July 28, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2025

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).

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.

Primary Outcome Measures :
  1. Number of adverse events [ Time Frame: Up to 90 days after the end of the last FUS treatment ]
    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).

Secondary Outcome Measures :
  1. 6-month Progression Free Survival (PFS6) [ Time Frame: Up to 6 months after last FUS treatment. ]
    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,

  2. 6-month Overall Survival (OS6) [ Time Frame: Up to 6 months after last FUS treatment. ]
    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.

  3. Blood brain barrier/Tumor imaging changes [ Time Frame: Up to 90 days after the end of the last FUS treatment ]
    MRI and other radiological evidence to show successful BBB opening and closing

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   4 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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


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


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


  • 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


  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04804709

Layout table for location information
United States, New York
Columbia University Irving Medical Center / NewYork-Presbyterian Hospital
New York, New York, United States, 10032
Sponsors and Collaborators
Cheng-Chia (Fred) Wu
Focused Ultrasound Foundation
Layout table for investigator information
Principal Investigator: Cheng-Chia Wu, MD, PhD Columbia University
Layout table for additonal information
Responsible Party: Cheng-Chia (Fred) Wu, Assistant Professor of Radiation Oncology, Columbia University Identifier: NCT04804709    
Other Study ID Numbers: AAAS5953
First Posted: March 18, 2021    Key Record Dates
Last Update Posted: February 14, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by Cheng-Chia (Fred) Wu, Columbia University:
Blood brain barrier
Diffuse Midline Gliomas
Focused Ultrasound
Pontine Gliomas
Thalamic Gliomas
Additional relevant MeSH terms:
Layout table for MeSH terms
Diffuse Intrinsic Pontine Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Infratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action