MTX110 by Convection-Enhanced Delivery in Treating Participants With Newly-Diagnosed Diffuse Intrinsic Pontine Glioma

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of repeated administration of MTX110 co-infused
with gadoteridol given by intratumoral convection enhanced delivery in children with newly
diagnosed diffuse intrinsic pontine glioma (DIPG).

SECONDARY OBJECTIVES:

I. To determine the clinical efficacy of repeated administration of MTX110 given by
intratumoral convection-enhanced delivery (CED) in children with newly diagnosed DIPG in the
confines of a phase I and early efficacy study.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Participants receive panobinostat nanoparticle formulation MTX110 intratumorally (IT) by CED
infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks
for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment participants are followed up at 30 days and then every 2
months.

Inclusion Criteria:

- Patients with newly diagnosed DIPG by magnetic resonance imaging (MRI); defined as
patients with a pontine location and diffuse involvement of at least 2/3 of the pons
are eligible without histologic diagnosis. For lesions with typical imaging features,
biopsy is neither encouraged nor required for eligibility. Tumors that are biopsied
will be eligible if proven to be supportive of the diagnosis of a DIPG. Consensus of
diagnosis by the study team must be met.

- Patients who have completed focal radiotherapy within 14 weeks from time of enrollment
are eligible.

- Treatment must begin at a minimum of 4 weeks after, but no later than 14 weeks after,
the date of completion of radiotherapy.

- Prior chemotherapy: Patients should be at least 30 days from last chemotherapy dose
prior to start of CED infusion, with exception of antibody half-lives. For antibody
therapies, at least 3 half-lives of the antibody after last dose of monoclonal
antibody should have passed prior to CED infusion

- Prior radiation: Patients must have received prior treatment with focal radiotherapy
as part of initial treatment for DIPG and had their last dose at least 4 weeks prior
to and no later than 14 weeks from the first CED treatment. Standard focal radiation
therapy will include 54 to 60 Gy by external beam radiotherapy to the brainstem.

- Karnofsky Performance Score >= 50 for patients > 16 years of age and Lansky
Performance Score >= 50 for patients =< 16 years of age. Patients who are unable to
walk because of paralysis, but who are able to mobilize using a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score.

- Life expectancy of greater than 12 weeks measured from the date of completion of
radiotherapy.

- Corticosteroids: Patients who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to registration.

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3.

- Hemoglobin >= 8g/dl.

- Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment).

- Normal coagulation defined as normal International Normalized Ratio (INR) or per
institutional guidelines.

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73
m^2.

- A serum creatinine (mg/dL) based on age/gender as follows:

- Age: 3 to < 6 years; Male: 0.8; Female: 0.8

- Age: 6 to < 10 years; Male: 1; Female: 1

- Age: 10 to < 13 years; Male: 1.2; Female: 1.2

- Age: 13 to < 16 years; Male:1.5; Female: 1.4

- Age >= 16 years; Male: 1.7; Female: 1.4

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age.

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L.

- Serum albumin >= 2 g/dL.

- Patients with seizure disorder may be enrolled if on non-enzyme inducing
anticonvulsants and well controlled.

- The effects of MTX110 on the developing human fetus are unknown. For this reason women
of child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry, for the duration
of study participation and 4 months after completion of MTX110 injection
administration. 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.

- Able to understand, and willing to sign, a written informed consent document.

- Patients who are unable to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy.

Exclusion Criteria:

- Patients who had clinical and/or radiographic (MRI) progression of tumor following
external beam radiation therapy.

- Patients with metastatic disease, including leptomeningeal or subarachnoid
disseminated disease.

- Patients with tumor morphology that predicts poor coverage of the majority of the
tumor including bilateral thalamic involvement, or cysts that represent > 50% of
cross-sectional areas of the pons. These subjects should be discussed with the study
chairs.

- Patients who are receiving any other investigational agents or other tumor-directed
therapy.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MTX110 or gadolinium.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Female patients of childbearing potential must not be pregnant or breast-feeding.
Female patients of childbearing potential must have a negative serum or urine
pregnancy test within 14 days of registration.

- Patients with MRI or clinical evidence of uncontrolled tumor mass effect are excluded;
the assessment of mass effect should be made by the study chairs and study
neurosurgeons prior to any planned CED treatment.

- Untreated symptomatic hydrocephalus determined by treating physician.

- Patients with evidence of intra-tumoral hemorrhage > 5 mm maximal diameter. These
subjects should be discussed with the study chair.

- Subjects with prolonged corrected QT (QTc) (> 450 msec) will be excluded from the
study.