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.
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
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:
- 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).
• 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
- 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.
• Patients with seizure disorder may be enrolled if seizure disorder is well
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
10. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the
baseline CT or MRI scan.
11. 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.
12. For Arms A, B, C, D, F and G: Ability to swallow and retain orally administered
13. 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.
1. For Arms A, B, D, E, F and G: 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
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.
11. For Arm F: Exclusively non-contrast-enhancing disease or primary malignant lesion
located in the pons or spinal cord.
12. For Arm F: Atypical non-astrocytic histologies such as ependymoma, ganglioma and
pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or pilocytic astrocytoma and
subependymal giant cell astrocytoma (SEGA).
13. Prior treatment with ONC201