CED of MTX110 Newly Diagnosed Diffuse Midline Gliomas

  • STATUS
    Recruiting
  • End date
    Feb 28, 2024
  • participants needed
    9
  • sponsor
    Stergios Zacharoulis
Updated on 28 January 2021
anesthesia
platelet count
anticonvulsants
seizures
epilepsy
neutrophil count

Summary

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.

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 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.

Details
Condition Diffuse Intrinsic Pontine Glioma, DIPG, Diffuse Midline Glioma, Diffuse Pontine and Thalamic Gliomas
Treatment Convection-Enhanced Delivery (CED), Infusate with MTX110 and gadolinium
Clinical Study IdentifierNCT04264143
SponsorStergios Zacharoulis
Last Modified on28 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Aged more than 3 years up to the 18th birthday
Radiological diagnosis of DIPG with tumor confined to the region of the pons or
thalami without cystic changes or hematoma obstructing the planned catheter trajectories
Radiological diagnosis of thalamic gliomas confined to bilateral thalami without cystic changes or hematoma obstructing the planned catheter trajectories
Radiological features of DIPG: 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
No prior therapy is allowed other than involved field radiotherapy (54Gy) and cerebrospinal fluid (CSF) diversion for hydrocephalus, including endoscopic third ventriculostomy (ETV) or a ventriculo-peritoneal shunt. No concomitant medicine or therapies for treatment are permitted while the patient is enrolled in this study
Karnofsky performance status or Lansky play score of 70 assessed at diagnosis
Total bilirubin: within normal institutional limits
Aspartate Aminotransferase (AST)(SGOT)/Alanine Aminotransferase (ALT)(SGPT): 2.5 institutional upper limit of normal (ULN)
Creatinine: within normal institutional limits
Creatinine clearance: 60 mL/min/1.73m2 for patients with creatinine levels above institutional normal
Absolute neutrophil count: 1,500/L
Platelet count: 100,000/L - no transfusion within 7 days
Hemoglobin level: 10g/dL - no transfusion within 7 days
Partial Thromboplastin Time (PT) and activated partial thromboplastin time (APTT): within normal institutional limits
No documented current bleeding disorder
No medical condition that would preclude general anesthesia
No severe acute infection or unexplained febrile illness
Not pregnant or nursing - negative serum pregnancy test if appropriate within 7 days of study entry (adequate contraceptive methods for females and males required)
No documented allergy to compounds of similar chemical or biologic composition to MTX110 or gadolinium compounds
Subjects with a history of seizures/epilepsy should be on anticonvulsant medication prior to the first operative procedure on study, with serum levels within a therapeutic range
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

Radiological evidence of distant disease outside the pons or thalami
Radiological evidence of metastatic disease within the central nervous system (CNS) at diagnosis
Subjects with an uncorrectable bleeding disorder
Subjects with multifocal or leptomeningeal disease beyond the pons or the thalami
Subjects with signs of impending herniation or an acute intratumoral hemorrhage
Subjects that have received or are on concurrent chemotherapy or biologic therapy for the treatment of their tumor
Subjects who are pregnant or breastfeeding
Previous experimental or trial-based therapy
Patients who are known human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C positive. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MTX110
Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk
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