ONC201 in Pediatric H3 K27M Gliomas

Inclusion Criteria:

1. 2 to less than 19 years of age.

2. Patient body weight must be above the minimum necessary for the patient to receive the
ONC201 dose indicated for the currently enrolling dose level. The minimum body weight
ranges from 10-27.5kg depending on the dose level.

3. Arm A: Patients with glioma who are positive for the H3 K27M mutation (positive
testing in CLIA laboratory) and have completed at least one line of prior therapy.
Evidence of progression is not required so that ONC201 may be administered to patients
in the maintenance setting or to patients with recurrent disease. No more than two
episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of
bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or
treatment effect will not be considered a recurrence. Post-mortem biopsy is required
if H3 K27M status of tumor is unknown and archival tumor tissue not available.

Arm B: Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined
as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible
with or without histologic confirmation. Post-mortem biopsy is required if H3 K27M
status of tumor is unknown and archival tumor tissue not available.

Arm C: Pediatric patients midline gliomas are eligible with or without histologic
confirmation and must be eligible for tumor biopsy as deemed by the site Investigator.

Arm D: Pediatric patients with recurrent glioma who are positive for the H3 K27M
mutation (positive testing in CLIA laboratory), have completed at least one line of
prior therapy, must be willing to undergo serial lumbar puncture to obtain
cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. Local
anesthesia for spinal tap is also allowed. No more than two prior episodes of
recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab
solely for treatment of radiation necrosis, pseudoprogression, or treatment effect
will not be considered a recurrence. Spinal tap should not be performed if treating
clinician or lumbar puncture proceduralist has concern of signs of elevated
intracranial pressure, including recent worsening in headache or somnolence.

Arm E: Patients with glioma who are positive for the H3 K27M mutation (positive
testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG),
defined as tumors with a pontine epicenter and diffuse involvement of the pons, are
eligible with or without histologic confirmation. Patients must be 2-12 weeks from
completion of first-line radiation.

4. Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years
of age.

5. From the projected start of scheduled study treatment, the following time periods must
have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic
therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from
antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor
therapies. For patients who have received radiotherapy, patients in any arm must be at
least 2 weeks from the completion of local palliative radiotherapy (re-irradiation for
progressive disease or upfront RT at initial diagnosis).

6. Adequate organ function defined as:

Bone Marrow:

- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and

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

Renal Function:

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥
70mL/min/1.73 m2 or normal serum creatinine based on age as shown below or GFR >
70ml/min/1.73m^2: Age < 5 years: 0.8 mg/dL maximum Age 5 to < 10 years: 1.0 mg/dL
maximum Age 10 to < 15 years: 1.2 mg/dL maximum Age > 15 years: 1.5 mg/dL maximum

Liver Function:

- Total Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of
institutional normal and

- SGPT (ALT) ≤ 110 U/L and

- Serum albumin ≥ 2 g/dL.

Neurologic Function:

• Patients with seizure disorder may be enrolled if seizure disorder is well
controlled.

7. Ability to understand a written informed consent document, and the willingness to sign
it. Assent will be obtained when appropriate based on the subjects age.

8. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy,
and/or surgery) must be resolved to grade 1 or baseline, except for alopecia and
sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based
on investigator's judgment, are acceptable.

9. For patients post pubertal: Female patients must agree to use effective contraception
during the period of the trial and for at least 90 days after completion of treatment.
Male patients must be surgically sterile or must agree to use effective contraception
during the period of the trial and for at least 90 days after completion of treatment.
The decision of effective contraception will be based on the judgment of the principal
investigator.

10. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the
baseline MRI scan.

11. MRI brain and entire spine MRI within 14 days prior to start of study drug for Arms A,
B, C, and E. Subjects undergoing screening for Arm D must have an MRI of brain and
entire spine within 3 months prior to start of study drug. Subjects in Arm D will have
a baseline MRI of brain and spine with lumbar puncture after study consent is signed
and other eligibility criteria are fulfilled.

12. For Arms A, B, C, and D: Ability to swallow and retain orally administered capsules.

13. Archival tumor specimen: All subjects in all arms submit at least 5 unstained slides
from a tumor specimen that harbors H3 K27M mutation if archival tissue is available.
For subjects in Arms A, B or E, if no archival tumor tissue is available, or if H3
K27M status of tumor is unknown, then subjects must agree to submit a post-mortem
biopsy specimen. Subjects in Arm C do not require prior tumor biopsy or confirmation
of the presence of the H3 K27M mutation. Subjects in Arm D must have confirmation of
the presence of the H3 K27M mutation in any glioma sample prior to enrollment.

Exclusion Criteria:

1. For Arms A, B, D, and E: Evidence of diffuse leptomeningeal disease or evidence of CSF
dissemination.

2. Current or planned participation in a study of another investigational agent or using
an investigational device.

3. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ONC201 or its excipients.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.

5. Any known clinically significant active infection including bacterial, fungal or viral
including hepatitis B (HBV), hepatitis C (HCV) or any underlying disease or in the
recent past which could compromise enrollment and safety of the patient.

6. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias
or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared
patient to receive ONC201. Receiving therapeutic agents known to prolong QT interval
will be excluded, however the use of Zofran is permitted. History of CHF, or MI or
stroke in the last 3 months will be excluded.

7. Active illicit drug use or diagnosis of alcoholism.

8. Known additional malignancy that is progressing or requires active treatment within 3
years of start of study drug.

9. Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study
and within 72 hours prior to starting study drug administration.

10. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing
antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study
and within 2 weeks prior to starting treatment. Concurrent dexamethasone is allowed.