Combination Therapy for the Treatment of Diffuse Midline Gliomas

Inclusion Criteria

• COHORT 1A AND 1B: New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; World Health Organization (WHO) grade 3 and 4 H3 wildtype gliomas.
• COHORT 1A AND 1B: Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
• COHORT 2A AND 2B: Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade 3 and 4 H3 wildtype gliomas.
• COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
• COHORT 3A AND 3B: 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 pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade 3 and 4 H3 wildtype gliomas.
• COHORT 3A AND 3B: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
• COHORT 4A^1 AND 4B^1: New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
• COHORT 4A^1 AND 4B^1: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 4A^1 AND 4B^1: Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
• COHORT 4A^2 AND 4B^2: Diagnosis of 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^2, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
• COHORT 4A^2 AND 4B^2: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 4A^2 AND 4B^2: Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
• COHORT 4A^3 AND 4B^3: 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 pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
• COHORT 4A^3 AND 4B^3: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 4A^3 AND 4B^3: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
• COHORT 5^1: Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
• COHORT 5^1: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 5^1: Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
• COHORT 5^1: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
• COHORT 5^1: Participant’s tumor must demonstrate one of the following molecular alterations considered 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 copy numbers) * NF1.
• COHORT 5^2: Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^2, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
• COHORT 5^2: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 5^2: Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
• COHORT 5^2: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
• COHORT 5^2: Participant’s tumor must demonstrate one of the following molecular alterations considered 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 copy numbers) * NF1.
• COHORT 5^3: Diagnosis recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^3, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
• COHORT 5^3: Not currently eligible for any other clinical trials that include administration of ONC201.
• COHORT 5^3: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
• COHORT 5^3: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
• COHORT 5^3: Participant’s tumor must demonstrate one of the following molecular alterations considered 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 copy numbers) * NF1.
• Age 2 to 39 years.
• Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Any number of prior therapies are allowed.
• Prior participation in a different PNOC022 cohort or PNOC023 arm is allowed if all other eligibility criteria are met. Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201.
• Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201
• Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kg).
• From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 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 (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), 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 per institutional standard. There is no required washout period.
• Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m^2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to beginning the agent.
• Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan. This may not be applicable to newly diagnosed participants.
• Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l).
• Platelet count >= 75,000/mm^3 (100 x 10^9/l) (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 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.
• Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase [ALT]) =< 3 x ULN.
• Serum albumin >= 2 g/dL.
• No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, 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.
• COHORTS 1-3: Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents.
• COHORTS 1-3: If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, participant will meet adequate metabolic function criteria.
• COHORTS 1-3: Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl – can be on lipid lowering medications as needed to achieve.
• No history of congestive heart failure or family history of long QT syndrome.
• Electrocardiogram (ECG) must be obtained to verify the corrected QT interval (QTC). If an abnormal reading is obtained, the ECG should be repeated in triplicate. * QTC < 470 msec.
• For Cohorts 1, 2 and 3: Participants with history of congestive heart failure, at risk of having or have underlying cardiovascular disease, or with history of exposure to cardiotoxic drugs must have adequate cardiac function as determined by echocardiogram. * Shortening fraction of >= 27% by echocardiogram.
• Participants with seizure disorder may be enrolled if seizure disorder is well controlled.
• The effects of the study drugs on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation.
• 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, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffin embedded unstained slides OR 1 block with tumor content of 40% or greater is required. Frozen tissue is also acceptable. Participants who previously enrolled on PNOC023 or on another arm of PNOC022 and provided adequate tissue, may not need to submit additional tissue. Participants who do not meet this criteria must be discussed with study chair(s).
• A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.

Exclusion Criteria

• COHORT 1A AND 1B: Prior exposure to radiation therapy.
• COHORT 1A AND 1B: Thalamic and cerebellar H3K27M DMG.
• COHORT 2A AND 2B: For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: * Thalamic and cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
• COHORT 1A AND 2A: Deemed not appropriate for tissue resection/biopsy.
• COHORT 3A AND 3B: Prior exposure to re-irradiation for tumor progression.
• COHORT 3A AND 3B: Thalamic and cerebellar H3K27M mutant DMG.
• COHORT 4A^1 AND 4B^1: Prior exposure to radiation therapy.
• COHORT 4A^1 AND 4B^1: Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or United States (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 Food and Drug Administration (FDA).
• COHORT 4A^2 AND 4B^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 4A^3 and 4B^3: Prior exposure to re-irradiation for tumor progression.
• COHORT 4A^3 and 4B^3: 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 5^1: Prior exposure to radiation therapy.
• COHORT 5^1: 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 5^2: 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.
• COHORT 5^3: 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.
• Diagnosis of a histone H3 wildtype grade 2 diffuse astrocytoma.
• Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or 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 human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants who are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair.
• Participants with uncontrolled infection or other uncontrolled systemic illness.
• Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).
• Active illicit drug use or diagnosis of alcoholism.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study.
• Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or evidence of CSF dissemination, with 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 the study and within 72 hours prior to starting study drug administration.
• Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent use of corticosteroids is allowed.