Combination Therapy for the Treatment of Diffuse Midline Gliomas

Inclusion Criteria:

CLOSED TO ENROLLMENT: COHORT 1A AND 1B: (participants with newly diagnosed DMG prior to radiation therapy)

• New diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG ismandatory and pathology must be consistent with a DMG including diffuse midlineglioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) gradeIII and IV H3 wildtype gliomas.

• Must be within 6 weeks of diagnosis to begin standard of care radiation therapy onstudy.

CLOSED TO ENROLLMENT: : COHORT 2A AND 2B: (participants with DMG who have completed radiation therapy)

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must beconsistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade IIIand IV H3 wildtype gliomas.

• Participants must be within 4-14 weeks of completion of radiation. Radiation shouldhave started within 6 weeks of diagnosis.

CLOSED TO ENROLLMENT: : COHORT 3A AND 3B: (participants with DMG at progression)

• Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG,including spinal cord tumors, who have complete standard-of-care radiation therapy.In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathologymust be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHOgrade III and IV H3 wildtype gliomas.

• Participants must have evidence of progression and not have received any treatmentfor this progression and have not previously received re-irradiation.

Cohort 4A^1 and 4B^1 (participants with newly diagnosed DMG prior to radiation):

• New diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors. In cohort 4B^1, previous tumor tissue confirmation of DMG ismandatory and pathology must be consistent with a DMG diffuse midline gliomaH3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Must be able to begin standard of care radiation therapy on study within 6 weeks ofdiagnosis.

Cohort 4A^2 and 4B^2 (participants with newly diagnosed DMG who have completed radiation):

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 4B^2, previous tumor tissue confirmation of DMG is mandatory and pathology must beconsistent with a DMG including diffuse midline glioma H3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Participants must be within 4-14 weeks of completion of radiation and not havereceived additional therapy beyond completion of radiation therapy. Radiation shouldhave started within 6 weeks of diagnosis.

Cohort 4A^3 and 4B^3 (participants with DMG at progression):

• Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG,including spinal cord tumors, who have completed standard-of-care radiation therapy.In cohort 4B^3, previous tumor tissue confirmation of DMG is mandatory and pathologymust be consistent with a DMG including diffuse midline glioma H3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Participants must have evidence of progression and not have received any treatmentfor this progression and have not previously received re-irradiation.

Cohort 5^1 (participants pre-radiation):

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors. In cohort 5^1, previous tumor tissue confirmation of DMG ismandatory and pathology must be consistent with a DMG diffuse midline gliomaH3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Must be able to begin standard of care radiation therapy on study within 6 weeks ofdiagnosis.

• Multifocal and leptomeningeal disease will be eligible for Cohort 5.

• Participant's tumor must demonstrate one of the following molecular alterationsconsidered targetable by an approved agent:

• BRAFV600E

• PDGFRA (DNA point mutation or amplification with >=5 copy numbers)

• FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copynumbers)

• NF1

Cohort 5^2 (participants post-radiation):

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, includingspinal cord tumors. In cohort 5^2, previous tumor tissue confirmation of DMG ismandatory and pathology must be consistent with a DMG diffuse midline gliomaH3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Participants must be within 4-14 weeks of completion of radiation and not havereceived additional therapy beyond completion of radiation therapy. Radiation shouldhave started within 6 weeks of diagnosis.

• Multifocal and leptomeningeal disease will be eligible for Cohort 5.

• Participant's tumor must demonstrate one of the following molecular alterationsconsidered targetable by an approved agent:

• BRAFV600E

• PDGFRA (DNA point mutation or amplification with >=5 copy numbers)

• FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copynumbers)

• NF1

Cohort 5^3 (participants with progression):

• Diagnosis recurrent DMG with imaging and/or pathology consistent with a DMG,including spinal cord tumors. In cohort 5^3, previous tumor tissue confirmation ofDMG is mandatory and pathology must be consistent with a DMG including diffusemidline glioma H3K27-altered.

• Not currently eligible for any other clinical trials that include administration ofONC201.

• Participants must have evidence of progression and not have received any treatmentfor this progression and have not previously received re-irradiation.

• Multifocal and leptomeningeal disease will be eligible for Cohort 5.

• Participant's tumor must demonstrate one of the following molecular alterationsconsidered targetable by an approved agent:

• BRAFV600E

• PDGFRA (DNA point mutation or amplification with >=5 copy numbers)

• FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copynumbers)

• NF1

All Cohorts

• Age 2 to 39 years

• Participants must have recovered from all acute side effects of prior therapy and bebeyond the window for expected ongoing acute toxicities. Any number of priortherapies are allowed.

• Participant body weight must be above the minimum necessary for the participant toreceive ONC201 (at least 10 kilograms (kg))

• From the projected start of scheduled study treatment, the following time periodsmust have elapsed: At least 7 days after last dose of a biologic agent or beyondtime during which adverse events are known to occur for a biologic agent, 5half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21days for bevacizumab when used for tumor-directed therapy, guidance on use forpseudo-progression is below), or, or 4 weeks (or 5 half-lives, whichever is shorter)from other anti-tumor therapies.

• The use of bevacizumab to control radiation therapy-induced edema is allowed (if used for tumor-directed therapy, please see required time period above).

• • Dosing limitations are as follows:
• • • Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing perinstitutional standard. There is no required washout period.

• Prior use of temozolomide during radiation at maximum of the standard pediatricdosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42days) or dexamethasone is allowed. Any other agent given throughout radiationtherapy must be discussed with the study chairs prior to beginning the agent.

• Corticosteroids: Participants who are receiving dexamethasone must be on a stable ordecreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan.

The participant must have adequate organ function defined as:

• Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l) AND

• Platelet count >= 75,000/mm^3 (100x10^9/l) (transfusion independent, defined as notreceiving platelet transfusions for at least 7 days prior to enrollment).

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

• A serum creatinine within the normal limits for age

• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN)for age AND

• Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase (ALT)) =< 3 xULN AND

• Serum albumin >= 2 g/dL

• No evidence of dyspnea at rest, no exercise intolerance due to pulmonaryinsufficiency, and a pulse oximetry of > 92% while breathing room air.

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

• No history of congestive heart failure or family history of long QT syndrome.

• ECG must be obtained to verify the Corrected QT Interval (QTc). If an abnormalreading is obtained, the ECG should be repeated in triplicate. QTC < 470 msec.

• Participants with history of congestive heart failure, at risk of having or haveunderlying cardiovascular disease, or with history of exposure to cardiotoxic drugsmust have adequate cardiac function as determined by echocardiogram. Shorteningfraction of >= 27%.

• Participants with seizure disorder may be enrolled if seizure disorder is wellcontrolled

• The effects of the study drugs on the developing human fetus are unknown. For thisreason, females of child-bearing potential and males must agree to use adequatecontraception. Adequate methods include: hormonal or barrier method of birthcontrol; or abstinence prior to study entry and for the duration of studyparticipation. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately. Males treated or enrolled on this protocol must also agree touse adequate contraception prior to the study and for the duration of studyparticipation.

• Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, butwho are up in a wheelchair, will be considered ambulatory for the purpose ofassessing the performance score.

• Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffinembedded unstained slides OR 1 block with tumor content of 40% or greater isrequired. Frozen tissue is also acceptable. Participants who previously enrolled onPNOC023 or on another arm of PNOC022 and provided adequate tissue, may not need tosubmit additional tissue. Participants who do not meet these criteria must bediscussed with Study Chair(s).

• A legal parent/guardian or participant must be able to understand, and willing tosign, a written informed consent and assent document, as appropriate.

(CLOSED TO ENROLLMENT - Cohorts 1-3 only)

• Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents (Cohorts 1-3 only)

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

• Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl - can be on lipidlowering medications as needed to achieve. (Cohorts 1-3 only)

Exclusion Criteria:

CLOSED TO ENROLLMENT: COHORT 1A AND 1B (participants with newly diagnosed DMG prior to radiation therapy)

• Prior exposure to radiation therapy.

• Thalamic and Cerebellar H3K27M DMG.

CLOSED TO ENROLLMENT: COHORT 2A AND 2B

• For tumors that do not have a pontine or spinal cord epicenter the followingspecific exclusion criteria apply:

• Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation withoutconcurrent therapy (other than temozolomide).

CLOSED TO ENROLLMENT: COHORT 1A AND 2A (participants with newly diagnosed DMG prior to radiation therapy and who have not previously undergone tumor tissue collection prior to study entry)

• Deemed not appropriate for tissue resection/biopsy.

CLOSED TO ENROLLMENT: COHORT 3A AND 3B (participants with DMG at progression)

• Prior exposure to re-irradiation for tumor progression.

• Thalamic and cerebellar H3K27M mutant DMG.

Cohort 4A^1and 4B^1

• Prior exposure to radiation therapy

• Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026from alternative source prior to 2024 or US patients enrolled while the acceleratedapproval new drug application for dordaviprone to treat recurrent H3 K27M-mutantdiffuse glioma is under review by US FDA.

Cohort 4A^2 and 4B^2 • Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.

Cohort 4A^3 and 4B^3

• Prior exposure to re-irradiation for tumor progression

• Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026from alternative source prior to 2024 or US patients enrolled while the acceleratedapproval new drug application for dordaviprone to treat recurrent H3 K27M-mutantdiffuse glioma is under review by US FDA.

Cohort 5^1

• Prior exposure to radiation therapy

• Thalamic and cerebellar H3K27M DMG, except those who received ONC201/ONC026 fromalternative source prior to 2024 or US patients enrolled while the acceleratedapproval new drug application for dordaviprone to treat recurrent H3 K27M-mutantdiffuse glioma is under review by US FDA.

Cohort 5^2

• Thalamic and cerebellar H3K27M DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.

Cohort 5^3

• Prior exposure to re-irradiation for tumor progression

• Thalamic and cerebellar H3K27M DMG, except those who received ONC201/ONC026 fromalternative source prior to 2024 or US patients enrolled while the acceleratedapproval new drug application for dordaviprone to treat recurrent H3 K27M-mutantdiffuse glioma is under review by US FDA.

All Cohorts:

• Diagnosis of a histone H3 wildtype grade II diffuse astrocytoma.

• Participants who are currently receiving another investigational drug.Investigational imaging agents or agents used to enhance tumor visibility on imagingor during tumor biopsy/resection should be discussed with the study chairs.

• Participants who are currently receiving other anti-cancer agents.

• Participants with a known disorder that affects their immune system, such as humanimmunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorderrequiring systemic cytotoxic or immunosuppressive therapy. Note: Participants thatare currently using inhaled, intranasal, ocular, topical or other non-oral ornon-intravenous (IV) steroids are not necessarily excluded from the study but needto be discussed with the study chair.

• Participants with uncontrolled infection or other uncontrolled systemic illness.

• Female participants of childbearing potential must not be pregnant orbreast-feeding. Female participants of childbearing potential must have a negativeserum or urine pregnancy test prior to the start of therapy (as clinicallyindicated).

• Active illicit drug use or diagnosis of alcoholism.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition as the agents used in study.

• Evidence of disseminated disease, including diffuse leptomeningeal disease orevidence of CSF dissemination, with the exception of Cohort 5.

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

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

• Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducingantiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2weeks prior to starting treatment. Concurrent corticosteroids is allowed.