Fimepinostat in Treating Brain Tumors in Children and Young Adults

PRIMARY OBJECTIVES:

I. To confirm penetration of fimepinostat across the blood brain barrier (BBB) in children
and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG), recurrent
medulloblastoma, or recurrent high-grade glioma (HGG) by measuring concentration of
fimepinostat in primary tumor tissue.

EXPLORATORY OBJECTIVES:

I. To assess pharmacokinetics (PK) of fimepinostat in plasma and tumor tissue of children and
young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

II. To assess pharmacodynamics (PD) of fimepinostat in children and young adults with newly
diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG as measured by phosphorylation
and acetylation in tumor tissue.

III. To correlate acetylation and phosphorylation in tumor tissue with tissue and plasma PK
levels.

IV. To assess the safety and tolerability of fimepinostat in children and young adults with
newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

V. To assess preliminary efficacy of fimepinostat given as monotherapy after surgery in
children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent
HGG, as based on progression-free survival (PFS) and objective response rate (ORR) as
appropriate.

OUTLINE:

Patients receive fimepinostat orally (PO) once daily (QD) on days -2 to 0. Within 2 hours of
receiving fimepinostat on day 0, patients undergo tumor resection.

MAINTENANCE PHASE: Patients receive fimepinostat by mouth, once daily for days 1-5 each week.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity
for up to 12 months from the time treatment begins. Should patients continue to derive
clinical benefit, and not experience excess toxicity or progression, patients can continue to
receive drug for up to 24 months or longer pending discussion with study chairs and study
sponsor.

After completion of study treatment, patients are followed up at 30 days, then every 3 months
for up to 5 years.

Inclusion Criteria:

- Patients must have one of the following histologically confirmed diagnoses (histologic
confirmation from initial diagnosis acceptable, as appropriate):

- Stratum A: Newly diagnosed diffuse intrinsic pontine glioma (DIPG) (World Health
Organization [WHO] grade II-IV)- this stratum does not require tissue
confirmation at time of enrollment, but diagnostic confirmation will be required
to continue on study after biopsy

- Stratum B: Recurrent medulloblastoma (WHO grade IV), any molecular subtype

- Stratum C: Recurrent high-grade glioma (HGG), including anaplastic astrocytoma
(WHO grade III) and glioblastoma (WHO grade IV)

- Stratum B & C: Patients in the recurrent medulloblastoma or recurrent HGG
arm can have locally recurrent or disseminated disease, provided
resection/biopsy would still be clinically indicated. Disseminated disease
can be diagnosed by imaging or cerebrospinal fluid (CSF) cytology

- Patients must be able to swallow intact fimepinostat capsules or mini-tabs without
chewing or crushing

- Patients must have body surface area (BSA) >= 0.5 m^2

- Patients must undergo tumor tissue collection as part of their standard of care

- Minimum possible tissue collected must be equivalent to about 4-6 stereotactic
core biopsies

- Strata B & C: Patients in the medulloblastoma and HGG strata will be allowed to have
undergone prior therapy including surgery, chemotherapy, and radiation therapy.
Patients in the DIPG stratum are not allowed to have prior therapy before the
initiation of fimepinostat. Patients must have fully recovered from acute side effects
related to previous anti-cancer therapies. Patients undergoing radiation during
protocol therapy will not be permitted to receive other concomitant agents with
radiation and pending initiation of maintenance with fimepinostat

- Myelosuppressive chemotherapy: At least 21 days after last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- Hematopoietic growth factors: At least 14 days after last dose of a long-acting
growth factor or 7 days after short-acting growth factor or beyond time during
which adverse events are known to occur

- Biologic (anti-neoplastic agent): At least 7 days after last dose of a biologic
agent or beyond time during which adverse events are known to occur

- Monoclonal antibodies: At least 21 days after last dose of monoclonal antibody

- Radiotherapy:

- At least 2 weeks after local palliative radiotherapy (XRT)

- At least 3 months from craniospinal XRT, or XRT to > 50% pelvis

- Surgery:

- At least 21 days from major surgery (biopsy and central line
placement/removal are not considered major)

- Corticosteroids: Subjects who are receiving dexamethasone must be on a stable or
decreasing dose for at least 7 days prior to enrollment

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

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

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

- A serum creatinine based on age/gender as follows:

- Age: Maximum Serum Creatinine (mg/dL)

- 3 to < 6 years: 0.8 (male), 0.8 (female)

- 6 to < 10 years: 1 (male), 1 (female)

- 10 to < 13 years: 1.2 (male), 1.2 (female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- 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

- Neurologic function:

- Subjects with seizure disorder may be enrolled if well controlled

- Gastrointestinal function:

- Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE)
version (v)5.0

- Metabolic function:

- Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents

- If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If
fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents,
patient will meet adequate metabolic function criteria

- Cardiac function: corrected QT (QTc) < 480 msec

- The effects of fimepinostat 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 30 days after completion of
fimepinostat 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

- A legal parent/guardian or patient must be able to understand, and willing to sign, a
written informed consent and assent document, as appropriate

Exclusion Criteria:

- Subjects who have not recovered from acute adverse events due to therapeutic agents
administered more than 4 weeks earlier

- Patients must not have received prior therapy with single-agent or combination histone
deacetylase (HDAC) and Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)
inhibitors

- Subjects who are receiving any other investigational agent

- History of allergic reaction to compounds of similar chemical or biological
composition to fimepinostat

- 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 situation that would limit compliance with
study requirements

- Patients with active human immunodeficiency virus (HIV) infection and with potential
life-threatening consequences associated with immune-suppressive therapy

- Patients with history of type 1 or 2 diabetes mellitus

- Patients with gastrointestinal condition that could interfere with absorption or
metabolism of fimepinostat