RECRUITING

Combination Therapy for the Treatment of Diffuse Midline Gliomas

Conditions

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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).

Official Title

A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

Quick Facts

Study Start:2021-10-20

Study Completion:2029-06-30

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05009992

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:2 Years to 39 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT

Inclusion Criteria	Exclusion Criteria
* 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.	* Prior exposure to radiation therapy. * Thalamic and Cerebellar H3K27M DMG. * 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). * 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.

Inclusion Criteria

Exclusion Criteria

* 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.

* Prior exposure to radiation therapy.
* Thalamic and Cerebellar H3K27M DMG.
* 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).
* 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.

Contacts and Locations

Study Contact

Kelly Hitchner

CONTACT

(415) 502-1600

PNOC022@ucsf.edu

Principal Investigator

Sabine Mueller, MD, PhD

PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Study Locations (Sites)

University of Alabama at Birmingham

Birmingham, Alabama, 35233

United States

Children's Hospital Los Angeles

Los Angeles, California, 90027

United States

University of California, San Diego / Rady Children's Hospital, San Diego

San Diego, California, 92123

United States

University of California, San Francisco

San Francisco, California, 94143

United States

Children's National Hospital

Washington D.C., District of Columbia, 20010

United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611

United States

Indiana University Riley Children's Hospital

Indianapolis, Indiana, 46202

United States

Johns Hopkins University

Baltimore, Maryland, 21287

United States

Dana-Farber Cancer Institute Harvard University

Boston, Massachusetts, 02215-6024

United States

University of Michigan

Ann Arbor, Michigan, 48109

United States

Children's Hospital Minnesota

Minneapolis, Minnesota, 55404

United States

Washington University in St. Louis

St Louis, Missouri, 63110

United States

Hackensack Meridian Health

Hackensack, New Jersey, 07601

United States

New York University

New York, New York, 10016

United States

Duke University

Durham, North Carolina, 27708

United States

Nationwide Children's Hospital

Columbus, Ohio, 43205

United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

United States

University of Utah

Salt Lake City, Utah, 84101

United States

Seattle Children's Hospital

Seattle, Washington, 98101

United States

Collaborators and Investigators

Sponsor: University of California, San Francisco

Sabine Mueller, MD, PhD, PRINCIPAL_INVESTIGATOR, University of California, San Francisco

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-10-20

Study Completion Date2029-06-30

Study Record Updates

Study Start Date2021-10-20

Study Completion Date2029-06-30

Terms related to this study

Additional Relevant MeSH Terms

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