Combination Therapy for the Treatment of Diffuse Midline Gliomas

Recruiting now · Phase 2

Conditions studied: Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Diffuse Midline Glioma, H3 K27M-Mutant, Recurrent WHO Grade III Glioma, WHO Grade III Glioma

In brief

This phase II trial determines if the combination of ONC201 with different drugs 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. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial. Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).

Key facts

Study ID: NCT05009992
Run by: University of California, San Francisco
People needed: 360
Starts: 2021-10-20
Expected to finish: 2029-06-30
Last updated by the study team: 2026-06-26

Who can join

Age: 2 and older, up to 39. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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.

You may not qualify 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.

Where it is running

The University Children's Hospital in Zurich — Zurich, Switzerland (enrolling)
Children's Hospital Los Angeles — Los Angeles, California, United States (enrolling)
University of California, San Diego / Rady Children's Hospital, San Diego — San Diego, California, United States (enrolling)
University of California, San Francisco — San Francisco, California, United States (enrolling)
Children's National Hospital — Washington D.C., District of Columbia, United States (enrolling)
Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago, Illinois, United States (enrolling)
Indiana University Riley Children's Hospital — Indianapolis, Indiana, United States (enrolling)
Johns Hopkins University — Baltimore, Maryland, United States (enrolling)
Dana-Farber Cancer Institute Harvard University — Boston, Massachusetts, United States (enrolling)
University of Michigan — Ann Arbor, Michigan, United States (enrolling)
Children's Hospital Minnesota — Minneapolis, Minnesota, United States (enrolling)
Washington University in St. Louis — St Louis, Missouri, United States (enrolling)
Hackensack Meridian Health — Hackensack, New Jersey, United States (enrolling)
New York University — New York, New York, United States (enrolling)
Duke University — Durham, North Carolina, United States (enrolling)
Nationwide Children's Hospital — Columbus, Ohio, United States (enrolling)
Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (enrolling)
University of Utah — Salt Lake City, Utah, United States (enrolling)
Seattle Children's Hospital — Seattle, Washington, United States (enrolling)
John Hunter Children's Hospital — New Lambton Heights, New South Wales, Australia (enrolling)
Women and Children's Hospital — Adelaide, Australia (enrolling)
Sheba Medical Center — Tel Litwinsky, Ramat Gan, Israel (enrolling)
Shaare Zedek Medical Center — Jerusalem, Israel (enrolling)
Starship Children's Hospital — Auckland, New Zealand (enrolling)
University of Alabama at Birmingham — Birmingham, Alabama, United States (enrolling)

Full record on ClinicalTrials.gov

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