ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

Inclusion Criteria:

• ARM A: Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21years of age; Dose expansion: 2 years of age and above) who completed at least oneline of prior therapy. Prior treatment must have included focal radiation therapyand patients must be within 4-14 weeks from completion of radiation therapy toregistration (patients must start treatment within 1 week from registration), havenot started any other therapies post-radiation, and have no evidence of diseaseprogression.

• ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathologymust be consistent with a DMG, H3K27 altered.

• ARM A: Participants must have recovered from all acute side effects of priortherapy.

• ARM A: From the projected start of scheduled study treatment, the following timeperiods must have elapsed: 5 half-lives from any investigational agent, 4 weeks fromcytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4weeks from antibodies and must be at least 7 days since the completion of therapywith a biologic or small molecule agent. For any biologic or small molecule agentwith known adverse events that can occur beyond 7 days after administration, theperiod prior to enrollment must be beyond the time during which adverse events areknown to occur (these should be discussed with the study team)

• ARM B: Newly diagnosed children and young adults (Dose escalation: 2-21 years ofage; Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27altered are eligible, including spinal cord DMGs.

• ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must beconsistent with a DMG, H3K27 altered.

• ARM C: Children and young adults with DMGs (Dose escalation: 2-21 years of age; Doseexpansion: 2 years of age and above) who have evidence of progression but have notbeen treated for this progression and are recommended to get re-irradiation.

• ARM C: Patients must have undergone prior focal radiation therapy as part of theirinitial therapy and should be at least 6 months from prior radiation therapy. Iftiming is less than 6 months from prior focal radiation, these patients need to bediscussed with the study chair(s).

• ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent witha DMG, H3K27 altered.

• ARM C: Participants must have recovered from all acute side effects of prior therapy

• ARM C: From the projected start of scheduled study treatment, the following timeperiods must have elapsed: 5 half-lives from any investigational agent, 4 weeks fromcytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4weeks from antibodies and must be at least 7 days since the completion of therapywith a biologic or small molecule agent. For any biologic or small molecule agentwith known adverse events that can occur beyond 7 days after administration, theperiod prior to enrollment must be beyond the time during which adverse events areknown to occur (these should be discussed with the study team)

• ARM D: Children and young adults with recurrent primary malignant CNS tumors (Doseescalation: 2-21 years of age; Dose expansion: 2 years of age and above ) who haveevidence of progression but have not been treated for this progression .Participants who received a surgical resection for that progression are eligible ifsurgery has no curative intent. These patients need to be discussed with the studyteam.

• ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primarytumor must be consistent with malignant CNS tumor (diagnosis of ependymoma isallowed).Tissue at the time of progression is not required.

• ARM D: Participants must have recovered from all acute side effects of prior therapy

• ARM D: From the projected start of scheduled study treatment, the following timeperiods must have elapsed: 5 half-lives from any investigational agent, 4 weeks fromcytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4weeks from antibodies and must be at least 7 days since the completion of therapywith a biologic or small molecule agent. For any biologic or small molecule agentwith known adverse events that can occur beyond 7 days after administration, theperiod prior to enrollment must be beyond the time during which adverse events areknown to occur (these should be discussed with the study team). Bevacizumab used forpseudoprogression does not require a wash out period.

• TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above)with imaging consistent with a DMG, H3K27 altered are eligible.

• TARGET VALIDATION: Children and young adults with recurrent primary malignant CNStumors, including recurrent DMG, (2 years of age and above) who have evidence ofprogression but have not been treated for this progression.

• TARGET VALIDATION: Participants must undergo tumor tissue collection as part oftheir standard of care

• Participants who are receiving steroids must be on a stable or decreasing dose forat least 3 days prior to baseline MRI scan.

• Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l.

• Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receivingplatelet transfusions for at least 7 days prior to enrollment).

• Serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender.

• Total bilirubin <= 1.5 x upper limit of normal (ULN) for age; in presence ofGilbert's syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN.

• Alanine aminotransferase (ALT) <= 3 x ULN.

• Aspartate aminotransferase (AST) <= 3 x ULN.

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

• The effects of ONC206 on the developing human fetus is unknown. For this reason,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. Fronzen tissue is also acceptable. Participants who previously enrolled onPNOC022 and provided adequate tissue, may not need to submit additional tissue -confirm with Study Chairs. Participants who do not meet this criteria may bediscussed on a case-by-case basis with the Study Chairs.

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

Exclusion Criteria:

• Arm A & B: For tumors that do not have a pontine or spinal cord epicenter thefollowing specific exclusion criteria apply: Thalamic DMG and cerebellar, H3K27altered that has undergone standard radiation without concurrent therapy (other thantemozolomide).

• Arm C & D: Patients who participated in trials investigating ONC201 in the upfrontsetting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expandedaccess programs will be allowed.

• Participants who are currently receiving another investigational drug are noteligible.

• Participants who are currently receiving other anti-cancer agents are not eligible.

• 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 are not eligible. Note:Participants that are currently using inhaled, intranasal, ocular, topical or othernon-oral or non-intravenous (IV) steroids are not necessarily excluded from thestudy but need to be discussed with the study chair.

• Participants with uncontrolled infection.

• 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.

• Active illicit drug use or diagnosis of alcoholism.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ONC206.

• Inability to follow the procedures of the study, e.g. due to language problems,psychological disorders, dementia, etc. of the participant or family.

• Any participants with illnesses that may affect absorption of ONC206.

• Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19at least 14 days prior and throughout the study.