Summary

This is a multicenter, open-label, seven arm, dose escalation, phase I study of oral ONC201
in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and
recurrent/refractory H3 K27M gliomas. Arm A will define the RP2D for single agent ONC201 in
pediatric 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. This will allow for
recurrent patients and also patients who have not yet recurred, but have completed radiation
and will inevitably recur based on prior clinical experience and the literature. Arm B will
define the RP2D for ONC201 in combination with radiation in pediatric patients with newly
diagnosed DIPG. Arm C will determine intratumoral drug concentrations and biomarker
expression in pediatric patients with midline gliomas. Arm D will determine H3 K27M DNA
levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. Arm E
will determine the RP2D for single agent ONC201 administered as a liquid formulation in
Ora-Sweet to patients with DIPG and/or H3 K27M glioma. Arm F is a dose expansion cohort to
confirm the safety and estimate the efficacy in recurrent H3 K27M-mutant glioma population at
the RP2D. Arm G will define the RP2D for single agent ONC201 given on two consecutive days of
each week in pediatric patients with glioma who are positive for the H3 K27M mutation and
have completed at least one line of prior therapy.

Eligibility

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 and G: 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: Patients with midline gliomas are eligible with or without histologic confirmation and must be eligible for tumor biopsy as deemed by the site Investigator. Arm D: 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. 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 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. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. Arm F: Pediatric patients with histologically confirmed diagnosis of high-grade glioma in any tumor sample with a known histone H3 K27M mutation identified by IHC or DNA sequencing test performed in a CLIA setting. Evidence of progressive disease on contrast-enhanced brain MRI as defined by RANO-HGG criteria is required. Patients must have had previous therapy with at least radiotherapy.
4. Karnofsky = 50 for patients = 16 years of age, and Lansky = 50 for patients < 16 years of age. For Arm F, Karnofsky = 60 for patients = 16 years of age, and Lansky = 60 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 radiation at initial diagnosis). For Arm F, patients must be at least 90 days from prior radiation to the first dose of ONC201unless the progressive lesion is outside of the high-dose radiation target volume or there is unequivocal evidence of progressive tumor on a biopsy specimen.
6. Adequate organ function defined as: Bone Marrow:
7. Peripheral absolute neutrophil count (ANC) = 1000/mm3 and
8. 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:
9. Total Bilirubin (sum of conjugated + unconjugated) = 1.5 x upper limit of institutional normal and
10. SGPT (ALT) = 110 U/L and
11. Serum albumin = 2 g/dL. Neurologic Function: • Patients with seizure disorder may be enrolled if seizure disorder is well controlled.
12. 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.
13. 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.
14. 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.
15. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the baseline CT or MRI scan.
16. MRI brain and entire spine MRI within 14 days prior to start of study drug for Arms A, B, C, E, F and G. 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.
17. For Arms A, B, C, D, F and G: Ability to swallow and retain orally administered capsules.
18. Archival tumor specimen: Subjects in all arms must 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, E or G, 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. Subjects in Arm F must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation. Note that the H3 K27M mutation is often reported as H3 K28M in gene sequencing assays.

Treatment Sites in Georgia