Combination Therapy for the Treatment of Diffuse Midline Gliomas

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

-NOT CURRENTLY ENROLLING COHORTS 1, 2, or 3-

OUTLINE:

Participants will be randomized at study entry to one of the three study arms and subsequently will be included in one to three phases, and one of 3 cohorts depending on their stage of disease and prior treatment.

PRIMARY OBJECTIVES:

I. To assess efficacy of combination therapy with ONC201 (ONC201) and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6) (Cohorts 1 and 2).

II. To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7) (Cohort 3).

III. To assess the safety and toxicity of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).

IV. To assess the safety and toxicity of a revised ONC201 dosing schedule in combination with radiation or re-irradiation in participants with DMG. (Cohort 4).

V. To evaluate the pharmacokinetic profile of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).

VI. To assess the safety and toxicity of ONC201 with agent(s) that will be determined by a specialized tumor board recommendation that is based on molecular assessments of tumor tissue or cerebrospinal fluid (CSF). (Cohort 5).

EXPLORATORY OBJECTIVES:

I. To confirm blood brain barrier (BBB) penetration of ONC201 in DMGs by measuring the concentration of ONC201 in tumor tissue (All cohorts; target validation phase).

II. To confirm BBB penetration of novel agents in DMGs by measuring the concentration of drug (or metabolite) in tumor tissue (All cohorts; target validation phase).

III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts; target validation phase).

IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts; target validation phase).

V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts; target validation phase).

VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase).

VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase).

VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts; target validation phase).

IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts; maintenance combinations).

X. To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts; maintenance combinations).

XI. To assess the toxicity of weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XII. To assess the toxicity of twice weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XIII. To assess the toxicity of novel agents in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XIV. To assess the toxicity of weekly ONC201 in combination with re-irradiation after progression. (Cohort 3).

XV. To assess the toxicity of twice weekly ONC201 in combination with re-irradiation therapy after progression. (Cohort 3).

XVI. To assess the toxicity of novel agents in combination with re-irradiation after progression. (Cohort 3).

XVII. To assess the toxicity of ONC201 in combination with novel agents in participants after re-irradiation after progression. (Cohort 3).

XVIII. To assess efficacy of a revised ONC201 dose and dosing schedule board based on median progression free survival (PFS) and overall survival (OS). (Cohort 4).

XIX. To assess efficacy of ONC201 in combination with targeted agent(s) that will be determined by a specialized tumor board based on median OS. (Cohort 5).

XX. To assess cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XXI. To assess levels of circulating tumor deoxyribonucleic acid (ctDNA) in the context of imaging response criteria and clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XXII. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XXIII. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. (All cohorts/phases) XXIV. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases).

XXV. To assess participants and/or proxy satisfaction with study participation via participant-reported outcome (PRO) measures. (All cohorts/phases).

XXVI. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. (All cohorts/phases).

XXVII. To assess volumetric measurements of tumor in correlation with median OS. (All cohorts/phases).

XXVIII. To assess MR spectroscopy of tumor in correlation with radiographic response, ONC201 exposure and median PFS and OS. (All cohorts/phases).

COHORT DESCRIPTIONS:

-NOT CURRENTLY ENROLLING- COHORTS 1A \& 2A (Target Validation cohorts); Includes newly diagnosed participants that have not yet undergone tumor tissue collection. Cohort 1A will include participants with DMG who have not yet completed radiation therapy and Cohort 2A will include participants with DMG who have completed radiation therapy.

-NOT CURRENTLY ENROLLING - COHORTS 1B \& 2B: Includes newly-diagnosed participants who have already undergone tumor tissue collection. Cohort 1B will include participants with DMG who have not yet completed radiation therapy and Cohort 2B will include participants with DMG who have completed radiation therapy.

-NOT CURRENTLY ENROLLING- COHORTS 3A \& 3B: Includes participants with progressive DMG. Cohort 3A will include participants planned for standard of care (SOC) tumor tissue collection. Cohort 3B will include participants not planned for SOC tumor tissue collection. The nomenclature will delineate participants previously enrolled in Cohorts 1 or 2.

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Participants who are currently not eligible for defined combination arms are assigned to Cohort 4 and participants whose tumor demonstrates specific molecular alterations considered targetable by an approved/available agent are assigned to Cohort 5.

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COHORTS 4A \& 4B: Includes participants with DMGs who are not otherwise eligible for any alternative clinical trial containing ONC201 such as ONC201-108 ACTION trial, participants who will receive radiation therapy as part of their standard-of-care treatment are also allowed to receive ONC201 with radiation or re-irradiation therapy.

COHORT 5: Includes participants whose tumor demonstrates specific molecular alterations considered targetable by an approved/available agent(s) and recommended by the PNOC022 tumor board.

-NOT CURRENTLY ENROLLING - COMBINATION COHORTS 1, 2 and 3: Participants are randomized to 1 of 3 arms.

ARM 2: During the trial validation phase, participants without prior biopsy receive ONC201 on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib daily. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity.

ARM 4: During the trial validation phase, participants without prior biopsy receive ONC201 on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity.

ARM 6: During trial validation phase, participants without prior biopsy receive paxalisib on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive paxalisib during radiation therapy. During the maintenance phase, participants receive ONC201 and paxalisib during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity.

After completion of study treatment, participants are followed at 30 days and then every 3 months for up to 5 years, until withdrawal of consent, or until death, whichever occurs first.

Eligibility Criteria:
Inclusion Criteria:

* 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, 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 III and IV H3 wildtype gliomas.
  * Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
* COHORT 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 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 III and IV H3 wildtype gliomas.
  * Participants must be within 4-14 weeks of completion of radiation.
* 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 pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV 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.

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, including spinal cord tumors. In cohort 4B1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.

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, including spinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 4B2, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* 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 (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 4B3, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* 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 (participants pre-radiation):

* Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 51, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* Must be able to begin standard of care radiation therapy on study 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 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 (participants post-radiation):

* Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 52, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* 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.
* Multifocal and leptomeningeal disease will be eligible for Cohort 5.
* 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 (participants with progression):

* Diagnosis recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 53, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
* Not currently eligible for any other clinical trials that include administration of ONC201.
* Participants must have evidence of progression and not have received any treatment for 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 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

All Cohorts

* 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.
* 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, 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/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 magnetic resonance imaging (MRI) scan.

The participant must have adequate organ function defined as:

* Peripheral absolute neutrophil count (ANC) \>= 1000/mm\^3 (1.0g/l) AND
* Platelet count \>= 100,000/mm\^3 (100x10\^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) \>= 70 mL/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)) =\< 2 x ULN AND
* 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
* 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 fasting glucose =\< 160 mg/dL without the use of antihyperglycemic agents, participants will meet adequate metabolic function criteria (Cohorts 1-3 only)
* Triglycerides of \< 300 mg/dl and total cholesterol of \< 300 mg/dl - can be on lipid lowering medications as needed to achieve. (Cohorts 1-3 only)
* No history of congestive heart failure or family history of long QT syndrome.
* ECG must be obtained to verify the QTC. If an abnormal reading is obtained, the ECG should be repeated in triplicate. QTC \< 470 msec.
* 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%.
* 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. 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 (participants with newly diagnosed DMG prior to radiation therapy)

  * Prior exposure to radiation therapy.
  * 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 (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.
* 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/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\^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/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
* 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.
* See Appendix N for exclusion criteria specific to targeted drugs

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.
* See Appendix N for exclusion criteria specific to targeted drugs

Cohort 5\^3

* Prior exposure to re-irradiation for tumor progression
* 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.
* See Appendix N for exclusion criteria specific to targeted drugs

All Cohorts:

* Participants 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.
* 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 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 that 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 diffuse leptomeningeal disease or evidence 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 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 corticosteroids is allowed.