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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

https://clinicaltrials.gov/ct2/show/NCT04264143
Stergios Zacharoulis , MD, Columbia University Medical Center, New York, USA

Convection Enhanced Delivery (CED) Basic Principles

The infusion of drugs under controlled pressure to the brain parenchyma via targeted micro-catheters

  • CED utilizes bulk flow rather than diffusion
  • Diffuse flow :Fick’s law, J=−D∇C,
  • Bulk flow pressure gradient :Darcy’s law: v=−K∇p
  • Few cms vs few mms
  • infusion rates typically range from 0.1 to 10 μl/min
  • Diffuse Intrinsic Pontine Glioma
  • 10-20 new patients per year per million population
  • Median survival : 9 months
  • Radiation therapy is the only standard treatment
  • providing benefit in 2/3 patients
  • for extra 3-6 months..

HDACis and DIPG (Panobinostat,VPA)

Grasso et al Nat Med. 2015 Jun;21(6):555-9. doi

Convection Enhanced Delivery (CED) Current Status DIPG MTX110 preclinical work for CED

  • Gills lab investigated the toxicity, distribution, and clearance of a watersoluble formulation of Panobinostat (MTX110) in Juvenile male Wistar rats (n= 24)
  • Large-animal toxicity was investigated using a clinically relevant MRI-guided
    translational porcine model of CED in which a drug delivery system designed
    for humans was used.
  • Panobinostat was administered at 30 mM to the ventral pons of 2 juvenile
    Large White–Landrace cross pigs.

Open at Columbia University Medical Center

A Phase I study examining the feasibility of intermittent convection-enhanced delivery (CED) of MTX110 via ambulatory pump for the treatment of children with newly diagnosed diffuse midline gliomas (DMGs).

Study Objectives

ObjectivesOutcome measures
Primary
Endpoint
A phase I study to evaluate the safety and Maximum
Tolerated Dose (MTD) of chronic MTX110 CED in children
with diffuse midline gliomas
Common
Terminology Criteria for Adverse
Events (CTCAE) v5.0
Secondary
Endpoints
To determine the Objective Response Rate with MTX110
via CED in this population
Documentation of response
based on Pediatric RANO criteria
To determine Progression Free Survival (PFS) and Overall
Survival (OS)
Documentation of PFS and OS
post treatment with IMP
To determine the steady state volume of drug
distribution
Assessment of volumetric and
metabolic changes with contrast
enhancement intensity on MRI
and MR spectroscopy
To evaluate the quality of life of the family and the
patient that is being treated with CED
QoL assessment tool: PedsQLTM
4.0 Brain Tumor Module

Eligibility- Inclusion Criteria

Diagnostic criteria

  • Age more than 3 years up to the 18th birthday
  • Radiological diagnosis of DIPG with tumor confined to the region of the pons or bilateral thalami without cystic
    changes or hematoma obstructing the planned catheter trajectories
  • Radiological diagnosis of bithalamic glioma tumor 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

Prior and concomitant therapy

  • No prior therapy is allowed other than involved field radiotherapy (54Gy) and 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.

Subject characteristics

  • Subjects must be healthy enough to tolerate surgery and general anesthesia 14 days or fewer from registration, based on the opinion of the principal investigator. This includes, but is not limited to:
  • Performance status:
  • Karnofsky performance status or Lansky play score of ≥70 assessed at diagnosis
  • Hepatic:
  • Total bilirubin: within normal institutional limits
  • AST(SGOT)/ALT(SGPT): ≤ 2.5 × institutional upper limit of normal
  • Renal:
  • Creatinine: within normal institutional limits
  • Creatinine clearance: ≥ 60 mL/min/1.73m2 for patients with creatinine levels above institutional normal
  • Hematopoietic:
  • 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
  • PT and APTT: within normal institutional limits
  • No documented current bleeding disorder

Study Schema

This is a phase I open label non-randomized trial.

Infusion Pulse #1 PINE score monitoring

CONVECTION-ENHANCED DELIVERY of MTX110

  • 3 patients treated so far at 30 microM
  • NO SAEs
  • Toxicity: Grade II diplopia ( 1) Grade I sensation (n=1) , headache Grade II ( n=2 )
  • 1 patient progressed 8 months post treatment

Acknowledgments

Neurosurgery: Chankrit Sethi, Rebecca Zylber, Jeff Bruce, Neil Feldstein

Neuropathology: Peter Cannol

Neuro-Radiology: Alexis Maddocks

Columbia University in the City of New York, Gary Yael Foundation, Hope and Heroes, Dara Steinberg, Meghan Tomb