Combination Therapy for the Treatment of Diffuse Midline Gliomas

The film gives the main points. The full list below is copied from the registry; the study team makes the final decision.

• Age2 Years to 39 Years
• SexAll
• Healthy volunteersNo

You may be able to join if

• -COHORTS 1, 2, AND 3 CLOSED---
• 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 Histone 3 lysine 27 - mutant (H3K27M); 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:
• 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. 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 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 AND 4B:
• 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.
• Not currently eligible for any other clinical trials that include administration of ONC201.
• Cohort 4A^1 and 4B^1 (participants with newly diagnosed DMG prior to radiation): 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): 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): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
• COHORT 5
• 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.
• Not currently eligible for any other clinical trials that include administration of ONC201.
• 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 5^1 (participants pre-radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
• Cohort 5^2 (participants post-radiation): 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 5^3 (participants with progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
• All Cohorts (except Cohort 6):
• 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 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 kilograms (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, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
• o 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. 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 magnetic resonance imaging (MRI) scan.
• The participant must have adequate organ function defined as:
• Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l) AND
• Platelet count >= 75,000/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)) =< 3 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
• No history of congestive heart failure or family history of long QT syndrome.
• 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.
• 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
• Females of child-bearing potential and males must agree to use adequate contraception.
• 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.
• COHORT 6 Inclusion Criteria:
• Diagnosis of newly diagnosed thalamic or pontine located DMG with imaging and/or pathology consistent with a DMG, excluding spinal cord tumors, who have completed standard-of-care radiation therapy. If archival tissue is available prior to first biopsy, 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 must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
• Age 2-39 years.
• 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) is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to enrollment.
• Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Washout requirements from prior therapy include:
• 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 30 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (28 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.
• At least 4 weeks prior to study enrollment from last immune therapy
• Corticosteroids: Participants treated with corticosteroids must be on stable or decreasing dose for at least 1 week prior to enrollment, with maximum dexamethasone dose 0.1 mg/kg/day dexamethasone equivalent at time of enrollment.
• The participant must have adequate organ function defined as:
• Peripheral absolute neutrophil count (ANC) >= 750/mm3 (1.0g/l) and
• Platelet count >= 75,000/mm3 (100x109/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment.
• Creatinine clearance or radioisotope GFR >= 70mL/min/1.73 m2 or
• A serum creatinine within the normal limits for age.
• Total bilirubin <= 3 x upper limit of normal (ULN); in presence of Gilbert's syndrome, total bilirubin </= 6 x ULN or direct bilirubin <= 3 x ULN
• ALT <= 5 x ULN
• AST <= 5 x ULN.
• Serum albumin >= 2 g/dL
• Diarrhea < grade 2 by CTCAE v5.0.
• No history of congestive heart failure or family history of long QT syndrome.
• 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.
• Karnofsky >/= 70 for Participants > 16 years of age and Lansky >/= 70 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

You cannot join if

• COHORT 1A AND 1B:
• 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:
• Deemed not appropriate for tissue resection/biopsy.
• COHORT 3A AND 3B:
• Prior exposure to re-irradiation for tumor progression.
• Thalamic and cerebellar H3K27M mutant DMG.
• COHORT 4A AND 4B:
• Cohort 4A^1and 4B^1: Prior exposure to radiation therapy 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 4A^1and 4B^1: Prior exposure to radiation therapy
• Cohort 4A^3 and 4B^3: Prior exposure to re-irradiation for tumor progression
• COHORT 5:
• 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 5^3: Prior exposure to re-irradiation for tumor progression
• All Cohorts (except Cohort 6):
• 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.
• COHORT 6 Exclusion Criteria:
• • DMGs located outside the thalamus and pons including bilateral thalamic tumors.
• Unacceptable anesthesia or surgery risk, as determined by the anesthesiologist or the neurosurgeon.
• Evidence of significant mass effect
• Evidence of herniation on imaging.
• Participants with a known history coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
• Participants must not require systemic anti-coagulation that cannot be halted for each intraoperative and perioperative biopsy time-period.
• Participants with active viral infection or who are currently receiving antiviral treatment.
• Participants with active, known, or suspected immunosuppressive disorders, such as acquired or congenital immune deficiency syndromes and autoimmune diseases.
• This virus infects cells with a deficit in the RB gene. Therefore, participants with Li-Fraumeni Syndrome or a known germ line deficit in the retinoblastoma gene or its related pathway are excluded.
• Participants must not have live or live-attenuated vaccinations within 30 days prior to DNX-2401 administration and while participating in the study. Killed vaccines are permitted.
• 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 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 who 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(s).
• 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 the study.
• Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or CSF dissemination.

This is how the treatment is meant to work. Whether it helps, and how safe it is, is what this trial is testing.

oncolytic adenovirus Ad5-DNX-2401. An adenovirus serotype 5 strain, selectively replication competent in cells defective in the Rb/p16 tumor suppressor pathway, with potential oncolytic activity. Oncolytic adenovirus Ad5-Delta 24RGD contains an integrin binding RGD-4C motif, allowing Coxsackie adenovirus receptor-independent infection of tumor cells, which are often deficient for Coxsackie and adenovirus receptors (CARs). Selectively replication competent in cells that are defective in retinoblastoma gene (Rb) or cyclin-dependent kinase inhibitor-2A (p16), active replication of oncolytic adenovirus Ad5-Delta 24RGD in tumor cells may induce oncolysis or cell lysis. As integral components of the late G1 restriction point, the Rb gene product and p16 are negative regulators of the cell cycle; ovarian cancer cells and non-small cell lung cancer cells may be defective in the Rb/p16 pathway. NCI Drug Dictionary

Treatments listed in the registry

• ONC201 (Drug): Given orally (PO)
• Radiation Therapy (Radiation): Undergo radiation therapy
• Paxalisib (Drug): Given PO
• DNX-2401 (Drug): DNX-2401 is an oncolytic adenovirus that will be administered through direct intratumoral infusion of DNX-2401 via a specialized Neuro Ventricular Cannula.

Randomized · Parallel · masking: None

As the registry describes them. Requirements to join, such as a tissue sample, are in the eligibility list above even when on-study procedures are optional. Ask the study team which steps apply to you.

• biopsy: Part of the study plan
• questionnaires: Part of the study plan
• radiation: Part of the study plan

Main goals

• Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only (6 months after diagnosis)
• Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only (6 months after diagnosis)
• Overall survival at 7 months (OS7) - Cohort 3A & 3B Only (7 months after administration of ONC201 in the maintenance phase)
• Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4) (Up through the first cycle of maintenance therapy, approximately 8 months)
• Number of participants requiring dose modification through first cycle of maintenance (Cohort 5) (Up through the first cycle of maintenance therapy, approximately 8 months)
• Maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who have completed radiotherapy (Cohort 6) (A maximum of 6 infusions will be administered every 30 days - approximately 8 months)

Planned enrollment: 360 (estimated).

• University of Alabama at Birmingham, Birmingham, Alabama
• Children's Hospital Los Angeles, Los Angeles, California
• University of California, San Diego / Rady Children's Hospital, San Diego, San Diego, California
• University of California, San Francisco, San Francisco, California
• Children's National Hospital, Washington D.C., District of Columbia
• Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
• Indiana University Riley Children's Hospital, Indianapolis, Indiana
• Johns Hopkins University, Baltimore, Maryland
• Dana-Farber Cancer Institute Harvard University, Boston, Massachusetts
• University of Michigan, Ann Arbor, Michigan
• Children's Hospital Minnesota, Minneapolis, Minnesota
• Washington University in St. Louis, St Louis, Missouri
• Hackensack Meridian Health, Hackensack, New Jersey
• New York University, New York, New York
• Duke University, Durham, North Carolina
• Nationwide Children's Hospital, Columbus, Ohio
• Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
• University of Utah, Salt Lake City, Utah
• Seattle Children's Hospital, Seattle, Washington

8 recruiting sites outside the US. Site status as of Oct 30, 2026. Check the live record before contacting a site.

These papers are listed in the registry record. Unless a paper is marked as about this trial, it is background research on the treatment or disease, not results from this study.

• Publication about this trial (to be verified before citing)Jackson ER, Duchatel RJ, Staudt DE, Persson ML, Mannan A, Yadavilli S, Parackal S, Game S, Chong WC, Jayasekara WSN, Grand ML, Kearney PS, Douglas AM, Findlay IJ, Germon ZP, McEwen HP, Beitaki TS, Patabendige A, Skerrett-Byrne DA, Nixon B, Smith ND, Day B, Manoharan N, Nagabushan S, Hansford JR, Govender D, McCowage GB, Firestein R, Howlett M, Endersby R, Gottardo NG, Alvaro F, Waszak SM, Larsen MR, Colino-Sanguino Y, Valdes-Mora F, Rakotomalala A, Meignan S, Pasquier E, Andre N, Hulleman E, Eisenstat DD, Vitanza NA, Nazarian J, Koschmann C, Mueller S, Cain JE, Dun MD. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. Cancer Res. 2023 May 17:OF1-OF17. doi: 10.1158/0008-5472.CAN-23-0186. Online ahead of print.
• Publication about this trial (to be verified before citing)Przystal JM, Cianciolo Cosentino C, Yadavilli S, Zhang J, Laternser S, Bonner ER, Prasad R, Dawood AA, Lobeto N, Chin Chong W, Biery MC, Myers C, Olson JM, Panditharatna E, Kritzer B, Mourabit S, Vitanza NA, Filbin MG, de Iuliis GN, Dun MD, Koschmann C, Cain JE, Grotzer MA, Waszak SM, Mueller S, Nazarian J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 2022 Sep 1;24(9):1438-1451. doi: 10.1093/neuonc/noac041.

• ClinicalTrials.gov NCT05009992
• NCI Drug Dictionary: C74067

Registry record reviewed as fetched Oct 30, 2026, last updated by the sponsor Jun 25, 2026. Public record; not medical advice.