This study will enroll children and young adults (2-39 years of age) with diffuse midline gliomas (DMGs; excluding Grade 2, H3K27M negative tumors) at different stages of their disease.

Cohort 1: Will include participants with newly diagnosed DMGs.

Cohort 2: Will include participants with DMGs who have completed focal radiation therapy and are within 4-14 weeks from completion of radiation therapy without evidence of progression.

Cohort 3: Will include participants with DMGs who have evidence of progression but have not been treated for this progression and have not previously undergone re-irradiation therapy.

Despite years of research and much knowledge gained about the underlying biology of diffuse midline gliomas (DMGs) – especially those with H3K27M mutations – little to no progress has been made to improve outcomes for these patients. The reasons for the ongoing failures are multi-factorial but include (a) limited preclinical data from a variety of model systems and validation in multiple laboratories, (b) limited knowledge about the blood brain barrier (BBB) penetration and (c) lack of multi-agent therapy plans. Within this clinical trial, we aim to address these key issues by working with several laboratories around the world to select the most promising combination therapy strategies, leveraging a target validation design to confirm BBB penetration and by offering each participants combination therapy approach. Given the limited treatment options for participants with DMGs, we also aim to offer trial enrollment at different disease stages – newly-diagnosed, after completion of radiation therapy, and at time of progression.

Cohorts 1 and 2

Maintenance Combinations:

• To assess efficacy of combination therapy with ONC201 and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6)

Cohort 3

To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7).

Cohorts 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, 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; WHO Grade 3 and Grade 4 H3 wildtype gliomas.

Cohorts 2A and 2B (participants with DMG who have completed radiation therapy)

• 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 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 Grade 4 H3 wildtype gliomas.
• Participants must be within 4-14 weeks of completion of radiation.

Cohorts 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 completed 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 Grade 4 H3 wildtype gliomas.
• Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.

All Cohorts

• Age 2 to 39 years.
• Participants must have recovered from all acute side effects of prior therapy.
• 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 pseudoprogression is below) or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
  • For participants who have received radiotherapy, participants in Cohort 2 must be between 4 and 14 weeks from the completion of local up-front radiotherapy and not have received additional therapy beyond completion of radiation therapy.
  • 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/m² /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed.
• Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan.
• The participant must have adequate organ function defined as:
  • Adequate Bone Marrow Function
  • Adequate Renal Function
  • Adequate Liver Function
  • Adequate Pulmonary Function
  • Adequate Gastrointestinal Function
  • Adequate Metabolic Function
  • Adequate Cardiac Function
  • Adequate Neurologic Function
• 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. Participants who do not meet this criterion must be discussed with the 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

Cohorts 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy)

• Prior exposure to radiation therapy
• Thalamic 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 H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).

Cohorts 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.

Cohorts 3A and 3B (participants with DMG at progression)

• Prior exposure to re-irradiation for tumor progression
• Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed.

All Cohorts

• Diagnosis of a histone H3 wildtype Grade II diffuse astrocytoma
•  Investigational Drugs
  • 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.
• Anti-cancer Agents
  • Participants who are currently receiving other anti-cancer agents.
• Participants with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-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.
• 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; see Appendix I), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.

Funding is provided by Chad Tough Defeat DIPG Foundation, Storm the Heavens,  Mithil Prasad Foundation, and PNOC Foundation.