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.
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
Drug | Synonyms | Arms |
---|
Infusate with MTX110 and gadolinium | | MTX110 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
Name | Type | Description | Interventions |
---|
MTX110 and CED | Experimental | 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. | - 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
January 26, 2021