A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma

This study consists of two parts:

1. The phase I (Part A), dose-finding component of the trial, to estimate the maximum
tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with
radiation therapy followed by maintenance therapy with PTC596, in children with
newly-diagnosed DIPG and HGG.

2. Once the RP2D has been determined, the investigators will enroll a surgical cohort (Part
B) of patients with either a. newly-diagnosed DIPG who are amenable to undergo biopsy
per recommendation of their treating physician OR b. Newly-diagnosed HGG for whom a
second surgical resection is warranted for further debulking or to achieve a near-total
or gross total resection after initial diagnosis has been made, but prior to start of
therapy.

The primary objectives of the Phase I (Part A) study will be to determine the MTD or RP2D of
PTC596 in combination with radiation therapy and to assess pharmacokinetic (PK) and
pharmacodynamics studies. Dose-modifying toxicities for maintenance therapy will also be
monitored.

PK studies will be collected on days 1 and 4 (doses 1 and 2) of cycle 1 and day 1 of cycle 2.

PTC596 will be given twice weekly on Monday and Thursday or Tuesday and Friday, for 6-7
weeks, during daily radiation therapy. Once radiation therapy with concomitant PTC596 is
completed, all patients will continue with maintenance therapy which will begin immediately
after completion of RT for up to 25 cycles.

The objectives of the Surgical Cohort Stratum are to:

1. Assess the ability of PTC596 to inhibit BMI-1 activity in tumor and peripheral blood
mononuclear cells (PBMNCs) of children with newly-diagnosed DIPG or HGG

2. To characterize the pharmacokinetics of PTC596 in plasma, cerebrospinal fluid (CSF), and
tumor tissue of children with newly-diagnosed DIPG or HGG

Once the RP2D has been established, up to 12 patients will be enrolled on the surgical study.
Patients eligible for the Surgical Stratum include:

1. newly-diagnosed DIPG patients who are amenable to undergo biopsy per the recommendation
of their treating physician OR

2. newly-diagnosed HGG patients for whom a second surgical resection is warranted for
further debulking or to achieve a near-total or gross total resection after initial
diagnosis has been made, but prior to start of therapy.

Patients on the surgical cohort study will commence treatment with the surgical cycle. During
the surgical cycle, patients will be treated with two doses of PTC596, on days 1 and 4 of the
surgical cycle prior to biopsy or re-resection; the second dose of PTC596 should ideally be
administered 3-6 hours before surgery (but may be up to 12 hours prior to surgery). The
concentration of PTC596 will then be measured in the tumor and accompanying blood sample by
mass spectrometry. BMI-1 expression and the effects of BMI-1 inhibition in DIPG and HGG on
gene regulation through gene expression profiling and epigenetic studies will be assessed in
tissue and plasma. The PK and PD studies on the surgical cohort study are mandatory. The
surgical cycle will end when patients begin RT.

Patients must begin RT at least two weeks after the date of surgery and may restart PTC596 on
Mondays and Thursdays or Tuesdays and Fridays (twice weekly) after starting RT. Following
completion of radiotherapy, patients will immediately start maintenance therapy on a Monday
and Thursday or Tuesday and Friday schedule. Patients can continue to receive therapy with
PTC596 for up to 25 cycles.

Inclusion Criteria:

Age: Patients must be ≥36 months and ≤ 21 years of age at the time of study enrollment.

Diagnosis: Patients with newly-diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined
as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are
eligible without histologic confirmation.

Patients with brainstem tumors that do not meet radiographic criteria or are not considered
to be typical diffuse intrinsic pontine gliomas will be eligible if the tumors are biopsied
and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma,
H3K27-mutant diffuse midline glioma) or diffuse astrocytoma.

Patients with newly-diagnosed non-brainstem high-grade glioma (HGG) are eligible.

Patients must have had histologically verified high-grade glioma such as anaplastic
astrocytoma, glioblastoma, H3 K27 mutant diffuse midline glioma etc.

Patients eligible for the surgical stratum include patients with:

1. newly-diagnosed DIPG who are amenable to undergo biopsy at the recommendation of their
treating physician

2. newly-diagnosed HGG for whom a second surgical resection is warranted for further
debulking or to achieve a near-total or gross total resection after initial diagnosis
has been made but prior to start of therapy.

Disease Status: Patients with disseminated DIPG or HGG are not eligible, and MRI of
spine must be performed if disseminated disease is suspected clinically by the
treating physician.

Performance Level: Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for
patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but
who are up in a wheelchair, will be considered ambulatory for the purpose of assessing
the performance score.

Neurologic Status: Patients must be able to swallow oral medications to be eligible
for study enrollment.

Patient must be able to swallow whole capsules.

Prior Therapy: Patients must not have received any prior anticancer therapy. Prior
dexamethasone and/or surgery are permissible.

Organ Function Requirements:

Adequate Bone Marrow Function Defined as:

• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3

• Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

• Hemoglobin >10 g/dL (may be transfused).

Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or

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

- 1 to < 2 years: 0.6 (Male) 0.6 (Female)

- 2 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)

Adequate Liver Function Defined as:

- Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age

- AST(SGOT)/ALT(SGPT) < 3 times institutional upper limit of normal

- Serum albumin ≥ 2g/dL

Adequate Cardiac Function Defined As:

- Shortening fraction of ≥ 27% by echocardiogram, or

- Ejection fraction of ≥ 50% by gated radionuclide study.

- QTc ≤ 480 msec.

Adequate Pulmonary Function Defined as - No evidence of dyspnea at rest, and a pulse
oximetry > 94% in room air if there is clinical indication for determination

Adequate Neurologic Function Defined as:

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

Exclusion Criteria:

Diagnosis: patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not
eligible. Patients with juvenile pilocytic astrocytoma, are not eligible.

Patients with non-brainstem diffuse astrocytoma (grade 2) are not eligible for the HGG
stratum of the study.

Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on
this study due to known or unknown risks of fetal and teratogenic adverse events as
seen in animal/human studies. Pregnancy tests must be obtained in girls who are
post-menarchal. Males or females of reproductive potential may not participate unless
they have agreed to use an effective contraceptive method.

Patients of childbearing or child fathering potential must agree to use adequate
contraceptive methods (hormonal or barrier method of birth control; abstinence) while
being treated on this study and for 3 months after completing therapy. Note: The
definition of effective contraception will be based on the judgment of the principal
investigator or a designated associate.

Concomitant Medications • Corticosteroids: Patients receiving corticosteroids are
eligible. The use of corticosteroids must be reported.

• Investigational Drugs: Patients who are currently receiving another investigational
drug are not eligible.

• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible.

• Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants as
listed in appendix II, are not eligible

• Patients who are receiving rifampin are not eligible.

• Patients who are receiving medications known to prolong QTc interval as listed in
appendix III are not eligible.

- Patients who are receiving duloxetine, alosetron or theophylline (CYP1A2
inhibitors) are not eligible

- Patients on beta-blockers are not eligible

- Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa),
escitalopram (Lexapro), Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine
(Paxil), sertraline (Zoloft) should be used with caution but are not
contraindicated.

- Anticoagulants: patients who are receiving therapeutic anticoagulants including
warfarin, low-molecular weight heparin are not eligible

Nasogastric or G tube administration of PTC596 is not permissible.

Infection: Patients who have an uncontrolled infection are not eligible.

Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible.

Patients with evidence of bowel obstruction, malabsorption, or other contraindication
to oral medication are not eligible.

Patients with GI disease or other condition that could affect absorption or predispose
subject to gastrointestinal ulceration are not eligible.

Patients with an active peptic ulcer disease or inflammatory bowel disease (including
ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis are not eligible.

Patients with serious non-healing wounds, ulcers, or bone fractures are not eligible.

Patients with moderate to severe pulmonary problems generally defined by need for
medical intervention (e.g., oxygen, medications) and/or limiting activities of daily
living (generally CTCAE Grade 2 or higher) or shortness of breath with limited
exertion are not eligible Pulmonary conditions include (but are not limited to) COPD,
asthma, and hemi-pneumectomy.

Patients with malignancy related to HIV or solid organ transplant: known history of
HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral
testing is not required unless clinically indicated in patients without a known
history.

Patient with prior or ongoing clinically significant illness, medical or psychiatric
condition, medical history, physical findings, ECG findings, or laboratory abnormality
that, in the investigator's opinion, could affect the safety of the subject, or alter
the absorption, distribution, metabolism, or excretion of the study drugs, or could
impair the assessment of study results are not eligible.