Clinical Trials /

CED of MTX110 Newly Diagnosed Diffuse Midline Gliomas

NCT04264143

Description:

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.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CED of MTX110 Newly Diagnosed Diffuse Midline Gliomas
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: AAAS2936
  • NCT ID: NCT04264143

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Pontine and Thalamic Gliomas
  • Diffuse Midline Glioma

Interventions

DrugSynonymsArms
Infusate with MTX110 and gadoliniumMTX110 and CED

Purpose

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.

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
MTX110 and CEDExperimentalAll 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.
  • Infusate with MTX110 and gadolinium

Eligibility Criteria

        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/μL

          -  Platelet count: ≥ 100,000/μL - 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
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Adverse Events
Time Frame:Up to six weeks after second infusion
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Steady state volume of drug distribution
Time Frame:14 days
Safety Issue:
Description:Measured by volumetric contrast enhancement intensity on MRI and magnetic resonance (MR) spectroscopy
Measure:Time to tumor progression/recurrence (PFS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Overall survival (OS) or time to death
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Score on PedsQL 4.0 Brain Tumor Module
Time Frame:2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stergios Zacharoulis

Trial Keywords

  • Blood brain barrier
  • Diffuse Midline Gliomas
  • Convection-Enhanced Delivery (CED)
  • Diffuse Intrinsic Pontine Glioma
  • Thalamic Gliomas

Last Updated

February 7, 2020