Convection-Enhanced Delivery of MTX110 and Gadolinium for the Treatment of Diffuse Midline Glioma

Inclusion Criteria

• Age more than 3 years up to the 18th birthday
• Radiological diagnosis of diffuse intrinsic pontine glioma (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
• No prior therapy is allowed other than involved field radiotherapy (54 Gy) and cerebral spinal 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
• 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:
• Karnofsky performance status or Lansky play score of >= 70 assessed at diagnosis
• Total bilirubin: within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): =< 2.5 x institutional upper limit of normal
• Creatinine: within normal institutional limits
• Creatinine clearance: >= 60 mL/min/1.73m^2 for patients with creatinine levels above institutional normal
• Absolute neutrophil count: >= 1,500/uL
• Platelet count: >= 100,000/uL - no transfusion within 7 days
• Hemoglobin level: >= 10 g/dL - no transfusion within 7 days
• Prothrombin 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
• The effects of MTX110 on the developing human fetus are unknown. For this reason and because category D agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception. Fertile female subjects must use effective contraception during and for 2 months after study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men must practice birth control for at least 4 months following termination of chemotherapy infusion
• 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 anti-convulsant medication prior to the first operative procedure on study, with serum levels within a therapeutic range
• Subjects must be able to undergo magnetic resonance (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. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. HIV, hepatitis B and hepatitis C testing is not required for patients not known to have those infections
• Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk