Combination Therapy for Diffuse Midline Gliomas
This study is testing different combinations of treatments for diffuse midline gliomas (DMGs), a type of brain tumor. Researchers are looking at how effective ONC201, Radiation Therapy, Paxalisib, and DNX-2401 (a virus that fights cancer) are when used together. The goal is to see if these combinations can help people with DMGs live longer without their disease getting worse. You might be able to join if you are between 2 and 39 years old and have a DMG. The study is currently enrolling for Cohorts 5 and 6, which include people with specific tumor changes or those who have recently completed radiation therapy.
- Study design
- This is an open-label, multi-arm study with an adaptive design, meaning treatment arms can change based on new information. It is a Phase II trial and plans to enroll 360 participants.
- What's involved
- Not specified in the trial record.
- Compensation
- Not stated in the trial record.
- Follow-up
- The study measures progression-free survival at 6 months and overall survival at 7 months after certain treatments.
AI-generated from the public study record. Only the study team can confirm whether you're eligible — confirm details with them before making decisions.
NCT05009992
Combination Therapy for the Treatment of Diffuse Midline Gliomas
Recruiting
PHASE2Ages 2–39InterventionalTreatmentUniversity of California, San FranciscoInvestigator-initiated
~360 participants
Updated 2026-06-26 on ClinicalTrials.gov
What's tested:ONC201Radiation TherapyPaxalisibDNX-2401
At a glance
Recruiting sites
27 of 32 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
Measured over 6 months after diagnosis
+5 more outcomes measured
Conditions
Where it's being run
32 sites across 26 statesCalifornia3
Washington2
New South Wales2
Victoria2
Australia2
Alabama1
District of Columbia1
Illinois1
Study leadership
- Sabine Mueller, MD, PhD · PRINCIPAL_INVESTIGATOR · University of California, San Francisco
Who to contact
Opens a ready-to-send draft in your own email app — review before sending.
Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
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.
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.
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.
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.
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
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.
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.
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
Exclusion
Prior exposure to radiation therapy.
Thalamic and Cerebellar H3K27M DMG.
Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
Prior exposure to re-irradiation for tumor progression.
Thalamic and cerebellar H3K27M mutant DMG.
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
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
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.
• 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.
What this trial measures
- Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
- Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only6 months after diagnosis
Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
- Overall survival at 7 months (OS7) - Cohort 3A & 3B Only7 months after administration of ONC201 in the maintenance phase
OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.
- Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment.
- Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)Up through the first cycle of maintenance therapy, approximately 8 months
The safety and tolerability of ONC201 in combination with targeted therapies will be measured by the number of participants reporting dose modification during first cycle.
- 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
The safety and tolerability of DNX-2401 at Dose Level 1 (5 × 10\^10 viral particles) will be measured by the proportion of participants reporting a DLT.