Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioma

Diffuse Intrinsic Pontine Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

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

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

All patients enrolled in the study will receive infusion of MTX110 and Gadolinium delivered by the CED delivery system directly into the tumor over 9-11 days.

Pulses 1 and 2 will be prepared with 30, 60 or 90 uM concentration of MTX110. The infusate consists of gadolinium and MTX110 (30, 60, or 90 uM) at approximately 1:100 ratio.

Infusate with MTX110 and gadolinium

CED is the method by which the drug are delivered to the brain under controlled pressure to the brain by targeted micro-catheters.

Convection-Enhanced Delivery (CED)

Luca Szalontay, MD

The blood brain barrier (BBB) prevents some drugs from successfully reaching the target source. Convection-Enhanced Delivery (CED) is a method of direct infusion of drugs under controlled pressure to the tumor that may reduce systemic side effects of drugs in the patient.

The purpose of this Phase I study is to find the maximum tolerated dose of MTX110 (a water-soluble Panobinostat nanoparticle formulation) and Gadolinium that can be given safely in children with newly diagnosed diffuse midline gliomas. All patients enrolled in the study will receive infusion of MTX110 and Gadolinium delivered with a pump directly into the tumor over 9-11 days.

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 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 form 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 form the site of injection tends to be limited. The convection-enhanced delivery (CED) of drugs describes the infusion of drugs under controlled pressure to the brain parenchyma via targeted microcatheter. This technique facilitates and deliver higher drug concentrations in brain tissue or tumor. The BBB can now operate to retain drug and to significantly reduce systemic side effects. In addition, the fact that panobinostat seems to be most efficacious clinically available drug against DIPG cells.

CED of MTX110 Newly Diagnosed Diffuse Midline Gliomas

A Phase I Study Examining the Feasibility of Intermittent Convection-Enhanced Delivery (CED) of MTX110 for the Treatment of Children With Newly Diagnosed Diffuse Midline Gliomas

Safety of repeated convection-enhanced delivery (CED) of MTX110 will be reported by summarizing the incidence rate of adverse events observed or reported. Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The MTD will be determined based on the number of dose limiting toxicities (DLT) observed in each of the titrated doses.

Measured by volumetric contrast enhancement intensity on MRI and magnetic resonance (MR) spectroscopy

PFS is defined as the duration of time from start of MTX110 treatment to time of progression or death from any cause, whichever occurs first.

Overall survival is defined as the duration of time from the start of MTX110 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.

The 24-item PedsQL 4.0 Brain Tumor Module encompasses six scales: (1) cognitive problems (seven items), (2) pain and hurt (three items), (3) movement and balance (three items), (4) procedural anxiety (three items), (5) nausea (five items), and (6) worry (three items). Each item is measured with a 5-point Likert scale from 0 (never a problem) to 4 (almost always a problem), which is then transformed on a scale from 0-100. Higher scores indicate lower problems and therefore a better outcome.

Midatech Pharma US Inc.

Luca Szalontay

Herbert and Florence Irving Associate Professor of Pediatric Neuro-Oncology

Antineoplastic Agents

All Drugs and Chemicals

Panobinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

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.

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).

Panobinostat 15 MG

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.

Focused Ultrasound with neuro-navigator-controlled sonication

Cheng-Chia Wu, MD, PhD

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.

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).

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)

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).

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,

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.

MRI and other radiological evidence to show successful BBB opening and closing

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
CED of MTX110 Newly Diagnosed Diffuse Midline Gliomas	NCT04264143	Diffuse Intrins... Diffuse Pontine... Diffuse Midline...	Infusate with M... Convection-Enha...	3 Years - 18 Years	Columbia University
Non-Invasive Focused Ultrasound (FUS) With Oral Panobinostat in Children With Progressive Diffuse Midline Glioma (DMG)	NCT04804709	Diffuse Intrins... Diffuse Pontine... Diffuse Midline...	Panobinostat 15... Focused Ultraso...	4 Years - 21 Years	Columbia University

Spots Global Cancer Trial Database for diffuse midline gliomas