This study will include participants with diffuse midline gliomas at all stages of the disease and recurrent primary malignant CNS tumors.

Participants will receive ONC206 as single agent or in combination with radiation therapy in three cohorts of patients: 1) newly diagnosed, 2) at completion of radiation therapy, or 3) at time of first progression.  Participants with recurrent primary malignant CNS tumors can enter the trial anytime when progressive disease has been determined.

The study will include participants age ≥2 years but ≤21 years of age in dose escalation phase and ≥2 years of age in dose expansion and target validation cohorts.

Despite years of research and significant gains in knowledge of the underlying biology of diffuse midline gliomas (DMGs) and recurrent primary malignant CNS tumors such as medulloblastoma or atypical teratoid rhabdoid tumor (ATRT), little to no progress has been made to improve clinical outcomes for patients with these tumors. ONC206 is a small molecule imipridone that antagonizes the G protein-coupled receptors (GPCRs), dopamine receptor D2 (DRD2) and D3 (DRD3). Downstream of target engagement in tumor cells, ONC206 causes activation of the integrated stress response (ISR), inactivation of pro- survival Akt and ERK signaling, and induction of the DR5/TRAIL pathway. More recent data indicates that imipridones target mitochondrial metabolism by directly binding to, and potently activating the mitochondrial caseinolytic protease P (ClpP). ClpP is a mitochondrial protease responsible for degrading excess or misfolded proteins in the mitochondrial matrix, and under basal conditions its activity is tightly regulated. ONC201-induced ClpP hyperactivation has been shown to induce tumor cell death in leukemia and lymphoma cells by inducing selective proteolysis of subsets of the mitochondrial proteome that are involved in mitochondrial respiration and oxidative phosphorylation. We have shown that ClpP is commonly overexpressed in a variety of pediatric brain tumors including, but potentially not limited to, DMGs, medulloblastoma, and ATRT. As such, a potential biomarker of response to ONC206 is the degree of expression of ClpP. Preclinical studies in models of DMG, ATRT and medulloblastoma show very promising anti-tumor efficacy and therefore, we aim to test the tumor penetration and preliminary efficacy of ONC206 within a target validation study in children and young adults with DMGs, as well as recurrent primary malignant CNS tumors.

Phase 1:

Arm A: To determine the MTD of ONC206 as single agent in children and young adults with DMG who completed at least one line of prior therapy that included focal radiation therapy.

Arm B: To determine the MTD of ONC206 in combination with focal radiation therapy in newly diagnosed children and young adults with DMG.

Arm C: To determine the MTD of ONC206 in combination with re- irradiation in children and young adults with first progression of DMG.

Arm D: To determine the MTD of ONC206 in children and young adults with recurrent primary malignant CNS tumors including participants with recurrent DMGs if they are not eligible for the other arms.

Target Validation:

• To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG predominantly localized to the thalamus and compare to serum drug levels pre-surgery.
• To assess the concentration of ONC206 in tumor tissue in children and young adults with DMG predominantly localized to the pons and compare to serum drug levels pre-surgery.
• To assess the concentration of ONC206 in tumor tissue in children and young adults with DMG in non-thalamic and non-pontine locations and compare to serum drug levels pre-surgery.
• To assess the concentration of ONC206 in tumor tissue in children and young adults with recurrent primary malignant CNS tumors and compare to serum drug levels pre-surgery.

INCLUSION CRITERIA:

Inclusion criteria for Dose Escalation/Dose Expansion: Arms A-C

Arm A

• Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who completed at least one line of prior therapy. Prior treatment must have included focal radiation therapy and patients must be within 4-14 weeks from completion of radiation therapy to registration (patients must start treament within 1 week from registration ), have not started any other therapies post-radiation, and have no evidence of disease progression.
• Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered.
• Participants must have recovered from all acute side effects of prior therapy.
• 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to nrolment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team).

Arm B

• Newly diagnosed children and young adults (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27 altered are eligible, including spinal cord DMGs.
• Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG, H3K27 altered.

Arm C

• Children and young adults with DMGs (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression and are recommended to get re-irradiation.
• Patients must have undergone prior focal radiation therapy as part of their initial therapy and should be at least 6 months from prior radiation therapy. If timing is less than 6 months from prior focal radiation, these patients need to be discussed with the study chair(s).
• Tumor tissue confirmation is mandatory and pathology must be consistent with a DMG, H3K27 altered
• Participants must have recovered from all acute side effects of prior therapy.
• 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team).

Inclusion criteria for Dose Escalation/Dose Expansion: Arm D (recurrent primary malignant CNS tumors)

• Children and young adults with recurrent primary malignant CNS tumors (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above ) who have evidence of progression but have not been treated for this progression . Participants who received a surgical resection for that progression are eligible if surgery has no curative intent. These patients need to be discussed with the study team.
• Prior tumor tissue confirmation is mandatory and pathology from the primary tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is allowed).Tissue at the time of progression is not required.
• Participants must have recovered from all acute side effects of prior therapy.
• 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team). Bevacizumab used for pseudoprogression does not require a wash out period.

Inclusion criteria for Target Validation Phase

• Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG, H3K27 altered are eligible.
• Children and young adults with recurrent primary malignant CNS tumors, including recurrent DMG, (2 years of age and above) who have evidence of progression but have not been treated for this progression.
• Participants must undergo tumor tissue collection as part of their standard of care.

General Inclusion Criteria for Dose Escalation/Dose Expansion Phases: Arms A – D and Target Validation Phase

• Corticosteroids: Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan.
• The patient must have adequate organ function defined as:
  • Adequate Bone Marrow Function
  • Adequate Renal Function
  • Adequate Liver Function
  • Adequate Neurologic Function
• The effects of ONC206 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 criteria may be discussed on a case-by-case basis with the Study Chairs.
• 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

• Arm A & B: For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply:
  • Thalamic DMG and cerebellar, H3K27 altered that has undergone standard radiation without concurrent therapy (other than temozolomide)
• Arm C & D: 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.
• Investigational Drugs
  • Participants who are currently receiving another investigational drug are not eligible.
• Anti-cancer Agents
  • Participants who are currently receiving other anti-cancer agents are not eligible.
• 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 are not eligible. 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.
• Active illicit drug use or diagnosis of alcoholism.
• History of allergic reactions attributed to compounds of similar chemical or biologic 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, 2C8, 2C9 and 2B6 at least 14 days prior and throughout the study.

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