ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)

Recruitment Status
RECRUITING
(See Contacts and Locations)Verified March 2026 by Jazz Pharmaceuticals
Sponsor
Jazz Pharmaceuticals
Information Provided by (Responsible Party)
Jazz Pharmaceuticals
Clinicaltrials.gov Identifier
NCT05580562
Other Study ID Numbers:
ONC201-108
First Submitted
September 26, 2022
First Posted
October 13, 2022
Last Update Posted
April 15, 2026
Last Verified
March 2026

ClinicalTrials.gov processed this data on April 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

Condition or DiseaseIntervention/Treatment
H3 K27MGlioma
Drug: Dordaviprone (ONC201)Drug: Dordaviprone (ONC201) + PlaceboOther: Placebo

Study Design

Study TypeInterventional
Actual Enrollment510 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingTriple
Primary PurposeTreatment
Official TitleONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study
Study Start DateJanuary 22, 2023
Actual Primary Completion Date1yr 9mos from now
Actual Study Completion Date1yr 9mos from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Dordaviprone Twice Weekly Group
Drug: Dordaviprone (ONC201)
Participants ≥ 52.5 kg will receive 625 mg of dordaviprone (5 × 125-mg capsules) dosing days; participants \< 52.5 kg will receive a dose (and corresponding number of capsules) scaled by body weight and rounded to 125-mg increments.
Dordaviprone Once Weekly Group
Drug: Dordaviprone (ONC201) + Placebo
Participants ≥ 52.5 kg will receive 625 mg of dordaviprone (5 × 125-mg capsules) or matching placebo on dosing days; participants \< 52.5 kg will receive a dose (and corresponding number of capsules) scaled by body weight and rounded to 125-mg increments
Placebo Group
Other: Placebo
Participants will receive placebo (same number of capsules as the dordaviprone dose) on dosing days

Outcome Measures

Primary Outcome Measures
  1. Overall survival (OS)
    Overall Survival is defined as the time from randomization to death due to any cause.
Secondary Outcome Measures
  1. Progression Free Survival (PFS) using RANO 2.0 Criteria for All Participants
    PFS is defined as time from randomization to disease progression (PD) or death.
  2. PFS Using RANO 2.0 Criteria for Participants with Measurable Contrast-Enhancing Disease
    PFS is defined as time from randomization to disease progression (PD) or death.
  3. Incidence of adverse events
    Incidence of overall, treatment-related, Grade 3 or higher in severity, serious, fatal, those resulting in treatment discontinuation, and events of special interest
  4. Change from baseline in clinical laboratory parameters
    Percentage of participants with clinically significant laboratory results
  5. Distribution of Graded Clinical Laboratory Parameter
    Breakdown of how many participants fall into each severity grade. Grade 1 for mild up to Grade 4 for severe or life threatening.
  6. Corticosteroid response
    Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent
  7. Time to First Corticosteroid Response
    Time from the first dose to the nominal analysis timepoint when the response criteria are first met.
  8. Duration of First Corticosteroid Response
    Time from first response to end of first response.
  9. Cumulative Duration of Corticosteroid Responses
    Total durations of response, irrespective of censoring, to account for participants with multiple responses during the study.
  10. Corticosteroid Dose and Change from Baseline Over Time
  11. Time to Corticosteroid Use Deterioration
    Time from first dose of study intervention to time when corticosteroid daily dose ≥ baseline daily dose + 2 mg at 2 consecutive analysis time points or death.
  12. Performance status response
    Performance status response will be measured by confirmed increase in Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS).
  13. Time to first performance status response
    time from the first dose of study intervention to the nominal analysis timepoint when the response criteria are first met.
  14. Duration of first performance status response
    Time from response to end of response.
  15. Cumulative duration of performance status responses
    Total durations of response, irrespective of censoring, to account for patients with multiple responses during the study
  16. Performance status and change from baseline over time
  17. Time to performance status deterioration
    As time from the first dose of study intervention to time when KPS/LPS score \< baseline or death.
  18. Change from Baseline in European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life-Core Questionnaire (QLQ-C30)
    The EORTC QLQ-C30 will be administered to participants ≥ 18 years. It evaluates the following scales: functional, symptom, global health, quality of life, and financial impact.
  19. Change from Baseline in Quality of Life-Core Questionnaire Brain Module (QLQ-BN20)
    The QLQ-bN20 will be administered to participants ≥ 18 years of age and will measure health related quality of life.
  20. Change from Baseline in MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT)
    The MDASI-BT will be administered to participants ≥ 18 years of age. It is a 22-item assessment that measures brain tumor related symptoms and impact on daily function. It will assess six areas on a scale of 0-10 (10 indicating worse or more severe symptoms): affective, cognitive, focal neurologic deficit, constitutional, generalized symptom, and gastrointestinal.
  21. Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module
    The PedsQL will be administered to participants 2 to \< 18 years of age. It measures 4 scales: physical, emotional, social, and school functioning.
  22. Change from Baseline in Neurologic Assessment in Neuro-Oncology (NANO) Score
    The NANO score evaluates gait, strength, ataxia in the upper extremity, sensation, visual field, facial strength, language, level of consciousness, and behavior.

Eligibility Criteria

Ages Eligible for Study(Child, Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
1. Able to understand the study procedures and agree to participate in the study by providing written informed consent (by participant or legally authorized representative), and assent when applicable. 2. Body weight ≥ 10 kg at time of randomization. 3. Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a missense K27M mutation in any histone H3-encoding gene detected by testing of tumor tissue (immunohistochemistry \[IHC\] or next-generation sequencing \[NGS\] in a Clinical Laboratory Improvement Amendments \[CLIA\]-certified or equivalent laboratory). \[Site to provide (as available): ≥ 11 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.\] 4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to starting radiotherapy for submission to sponsor's imaging vendor for central read. For participants who had a surgical resection, this scan must be post-resection; for participants who did not have a resection, this scan may be pre- or post-biopsy. 5. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. If unable to obtain contrast-enhanced imaging due to lack of venous access after multiple attempts, a patient may still be eligible after collection of a nonenhanced MRI of the brain. \[Site to also provide all available MRIs completed prior to initiating treatment with study intervention.\] 6. Received frontline radiotherapy 1. Initiated radiotherapy within 12 weeks from the initial diagnosis of H3 K27M-mutant diffuse glioma. 2. Completed radiotherapy within 2 to 6 weeks prior to randomization 3. Completed standard fractionated radiotherapy (eg. 54 to 60 Gy in 28 to 33 fractions given over approximately 6 weeks or hypofractionated radiotherapy (eg. 40 Gy in 15 fractions given over approximately 3 weeks). 7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization. 8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day increase (based on dexamethasone dose or equivalent dose of an alternative steroid).
Exclusion Criteria
1. Primary spinal tumor. 2. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons. 3. Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination. 4. Any known concurrent malignancy. 5. New lesion(s) outside of the radiation field. 6. Received whole-brain radiotherapy. 7. Received proton therapy for glioma. 8. Use of any of the following treatments within the specified time periods prior to randomization: 1. Dordaviprone (ONC201) or ONC206 at any time. 2. Systemic bevacizumab (includes biosimilars) at any time since the initial diagnosis of H3 K27M-mutant diffuse glioma. 3. Temozolomide within past 3 weeks. 4. Tumor treating fields at any time. 5. DRD2 antagonist within past 2 weeks. 6. Any investigational therapy within past 4 weeks. 7. Strong CYP3A4 inhibitors within 3 days. 8. Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks. 9. Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization: 1. Absolute neutrophil count \< 1.0 × 109/L or platelets \< 75 × 109/L. 2. Total bilirubin \> 1.5 × upper limit of normal (ULN) (participants with Gilbert's syndrome may be included with total bilirubin \> 1.5 × ULN if direct bilirubin is ≤ 1.5 × ULN). 3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × ULN. 4. Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate \< 60 mL/min/1.73 m2). 10. QTc \> 480 msec (based on mean from triplicate electrocardiograms) during screening. 11. Known hypersensitivity to any excipients used in the study intervention formulation. 12. Pregnant, breastfeeding, or planning to become pregnant while receiving study intervention or within 3 months after the last dose. Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study intervention. 13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy or psychiatric illness/social situations that would limit compliance with study requirements. 14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, may interfere with participant safety or the ability to complete the study according to the protocol.

Contacts and Locations

Sponsors and CollaboratorsJazz Pharmaceuticals
Locations
Banner MD Anderson Cancer Center | Phoenix Arizona, United States, 85006Barrow Neurological Institute | Phoenix Arizona, United States, 85013Phoenix Childrens Hospital | Phoenix Arizona, United States, 85016Mayo Clinic Arizona | Phoenix Arizona, United States, 85054UC San Diego Moores Cancer Center | La Jolla California, United States, 92093Kaiser Permanente Los Angeles Medical Center | Los Angeles California, United States, 90027UCLA University of California Los Angeles | Los Angeles California, United States, 90095Children's Hospital of Orange County | Orange California, United States, 92868University of California Irvine | Orange California, United States, 92868UCSF Benioff Children's Hospital | San Francisco California, United States, 94143University of California San Francisco | San Francisco California, United States, 94143Providence Saint John's Cancer Institute | Santa Monica California, United States, 90404Stanford Cancer Center | Stanford California, United States, 94350Yale University | New Haven Connecticut, United States, 06511MedStar Georgetown University Hospital | Washington D.C. District of Columbia, United States, 20007Mayo Clinic Jacksonville | Jacksonville Florida, United States, 32224Miami Cancer Institute | Miami Florida, United States, 33176St Joseph's Children's Hospital of Tampa | Tampa Florida, United States, 33607Moffitt Cancer Center | Tampa Florida, United States, 33612Cleveland Clinic Florida | Weston Florida, United States, 33331Children's Healthcare of Atlanta | Atlanta Georgia, United States, 30342Kapi'olani Medical Center for Women and Children | Honolulu Hawaii, United States, 96826Feinberg School of Medicine Northwestern University | Chicago Illinois, United States, 60611Indiana University School of Medicine - Indianapolis | Indianapolis Indiana, United States, 46202University of Iowa Hospitals & Clinics | Iowa City Iowa, United States, 52242Norton Healthcare | Louisville Kentucky, United States, 40241Ochsner Medical Center - New Orleans | New Orleans Louisiana, United States, 70121University of Maryland School of Medicine | Baltimore Maryland, United States, 21201Massachusetts General Hospital Cancer Center | Boston Massachusetts, United States, 02114Dana Farber Cancer Institute | Boston Massachusetts, United States, 02215University of Michigan Hospital | Ann Arbor Michigan, United States, 48109University of Minnesota | Minneapolis Minnesota, United States, 55455Mayo Clinic - Cancer Center - Rochester | Rochester Minnesota, United States, 55905Washington University School of Medicine/St. Louis Children's Hospital | St Louis Missouri, United States, 63110Benefis Hospital Sletten Cancer Institute | Great Falls Montana, United States, 59405University of Nebraska Medical Center | Omaha Nebraska, United States, 68114Jersey Shore University Medical Center | Neptune City New Jersey, United States, 07753Overlook Medical Center | Summit New Jersey, United States, 07901Albany Medical Center | Albany New York, United States, 12208Children's Hospital at Montefiore Medical Center | New York New York, United States, 10029Montefiore Medical Park | New York New York, United States, 10029Laura & Isaac Perlmutter Cancer Center - NYU ACC | New York New York, United States, 10032-3726Columbia University Medical Center | New York New York, United States, 10032Lenox Hill Hospital | New York New York, United States, 10075University of Rochester Medical Center | Rochester New York, United States, 14642Levine Cancer Institute/ Atrium Health | Charlotte North Carolina, United States, 28204Duke Cancer Institute | Durham North Carolina, United States, 27710Cincinnati Children's Hospital Medical Center | Cincinnati Ohio, United States, 45229Cleveland Clinic | Cleveland Ohio, United States, 44195Ohio State University | Columbus Ohio, United States, 43210University of Oklahoma Peggy and Charles Stephenson Cancer Center | Oklahoma City Oklahoma, United States, 73104Providence Health and Services St. Vincent Medical Center | Portland Oregon, United States, 97239University of Pennsylvania | Philadelphia Pennsylvania, United States, 19104Thomas Jefferson University | Philadelphia Pennsylvania, United States, 19107UPMC Children's Hospital of Pittsburgh | Pittsburgh Pennsylvania, United States, 15232UPMC Hillman Cancer Center | Pittsburgh Pennsylvania, United States, 15232Dell Children's Medical Center of Central Texas | Austin Texas, United States, 78723Neuro-Oncology Associates | Dallas Texas, United States, 75246University of Texas Southwestern Medical Center | Dallas Texas, United States, 75390University of Texas MD Anderson Cancer Center | Houston Texas, United States, 77030UT Health Houston Neurosciences - Texas Medical Center | Houston Texas, United States, 77030University of Texas - San Antonio - Health Science Center | San Antonio Texas, United States, 78229University of Utah - Huntsman Cancer Institute | Salt Lake City Utah, United States, 84112Inova Schar Cancer Institute | Fairfax Virginia, United States, 22031Children's Hospital of The King's Daughter | Norfolk Virginia, United States, 23507University of Washington | Seattle Washington, United States, 98195University Of Wisconsin - Madison | Madison Wisconsin, United States, 53792FLENI Neurologia | Buenos Aires , Argentina, C1426ABPSydney Children's Hospital | Randwick New South Wales, Australia, 2031Royal North Shore Hospital | Sydney New South Wales, Australia, 2065Royal Brisbane and Women's Hospital | Herston Queensland, Australia, Royal Hobart Hospital | Hobart Tasmania, Australia, 7000Olivia Newton-John Cancer Research Institute (ONJCRI) | Heidelberg Victoria, Australia, 3084Perth Children's Hospital | Nedlands Western Australia, Australia, 6009Medical University of Vienna - Adults | Vienna State of Vienna, Austria, 01090Medical University of Vienna - Pediatrics | Vienna State of Vienna, Austria, Hospital do GRAACC | São Paulo , Brazil, 04023-062Hcor Research Institute | São Paulo , Brazil, Instituto Do Cancer Do Estado De São Paulo | São Paulo , Brazil, Tom Baker Cancer Cetre | Calgary Alberta, Canada, T2N 2T9BC Cancer - The Vancouver Center | Vancouver British Columbia, Canada, V5Z 4E6Children's & Women's Health Care of BC | Vancouver British Columbia, Canada, V6H 0B3London Health Sciences Centre | London Ontario, Canada, N6A 5W9Childrens Hospital of Eastern Ontario | Ottawa Ontario, Canada, K1H 8L1Sunnybrook Health Sciences Centre | Toronto Ontario, Canada, M4N 3M5Princess Margaret Hospital | Toronto Ontario, Canada, M5G 1X8Hopital Notre Dame, Lachapelle | Montreal Quebec, Canada, H2X 3E4Copenhagen University Hospital | Copenhagen Capital, Denmark, 2100Aalborg Universitetshospital | Aalborg North Denmark, Denmark, 9000F345 H.C. Andersen's Children's Hospital | Odense Region Syddanmark, Denmark, 5000Odense Universitetshospital | Odense Region Syddanmark, Denmark, 5000University Clinic Heidelberg | Heidelberg Baden-Wurttemberg, Germany, 69120Universitätsklinikum Heidelberg | Heidelberg Baden-Wurttemberg, Germany, 69120Universitätsklinikum Augsburg | Augsburg Bavaria, Germany, 86156University Clinic Regensburg | Regensburg Bavaria, Germany, 93053Klinikum der Johann-Wolfgang Goethe-Universitat | Frankfurt am Main Hesse, Germany, 60528Universitätsklinikum Bonn | Bonn North Rhine-Westphalia, Germany, 53127Uniklinik Köln | Cologne North Rhine-Westphalia, Germany, 50937Universitätsklinikum Essen | Essen North Rhine-Westphalia, Germany, 45147Vivantes Klinikum Neukölln | Berlin , Germany, 12351Klinikum Mannheim Universitätsklinikum gGmbH | Manheim , Germany, 68167Universitätsklinikum Tübingen | Tübingen , Germany, 72076Queen Mary Hospital | Hong Kong , Hong Kong, 999077Sheba Medical Center | Ramat Gan Tel Aviv, Israel, 5262100Soroka University Medical Centre | Beersheba , Israel, 50937Rambam Medical Center | Haifa , Israel, 31096Hadassah Ein Kerem Medical Center | Jerusalem , Israel, 91120Rabin Medical Center | Petah Tikva , Israel, 49372Schneider Children's Medical Center of Israel | Petah Tikvah , Israel, 4920235Tel Aviv Sourasky Medical Center | Tel Aviv , Israel, 64239Ospedale Bellaria | Bologna Emilia-Romagna, Italy, 40139Istituto Nazionale Tumori Regina Elena | Rome Lazio, Italy, 00144Ospedale San Raffaele S.r.l. | Milan Lombardy, Italy, 20132Fondazione IRCCS Di Rilievo Nazionale Istituto Nazionale Neurologico Carlo Besta | Milan Lombardy, Italy, 20133Istituto Clinico Humanitas | Rozzano Lombardy, Italy, 20089Azienda Ospedaliera Città della Salute e della Scienza di Torino | Turin Piedmont, Italy, 10126Istituto Oncologico Veneto | Padova Veneto, Italy, 35128National Cancer Center Hospital | Chūō , Japan, 104-0045National Hospital Organization Kyushu Cancer Center | Fukuoka , Japan, 812-8582Kyoto University Hospital | Kyoto , Japan, 606-8507Osaka City General Hospital | Osaka , Japan, 534-0021Hokkaido University Hospital | Sapporo , Japan, 060-8648The University of Tokyo Hospital | Tokyo , Japan, Erasmus MC | Rotterdam South Holland, Netherlands, 3015 GDUniversitair Medisch Centrum Utrecht Cancer Center | Utrecht , Netherlands, 3584 CXKK Women's and Children's Hospital | Singapore , Singapore, 229899National Cancer Centre | Singapore , Singapore, 308433National Neuroscience Institute | Singapore , Singapore, 308433CHA Bundang Medical Center | Bundang-Gu, Seongnam-Si Gyeonggido, South Korea, 13496Seoul National University Bundang Hospital | Bundang-gu, Seongnam-si Gyeonggido, South Korea, 13620Seoul National University Hospital | Bundang-gu, Seongnam-si Gyeonggido, South Korea, 13620National Cancer Center | Ilsandong-Gu, Goyang-Si Gyeonggido, South Korea, 10408Gangnam Severance Hospital, Yonsei University Health System | Gangnam Seoul Teugbyeolsi, South Korea, 06273Samsung Medical Center | Gangnam-Gu Seoul Teugbyeolsi, South Korea, 06351Seoul National University Hospital | Jongno-Gu Seoul Teugbyeolsi, South Korea, 03080Asan Medical Center | Seoul Seoul Teugbyeolsi, South Korea, 5505Severance Hospital Yonsei University Health System | Seoul , South Korea, 03722The Catholic University of Korea, Seoul St. Mary's Hospital | Seoul , South Korea, 6591Hospital Sant Joan de Deu | Esplugues de Llobregat Barcelona, Spain, 8950Clinica Universidad Navarra | Pamplona Navarre, Spain, 31008Hospital Clinic de Barcelona | Barcelona , Spain, 08036Hospital Universitario Vall d'Hebron | Barcelona , Spain, 8035Hospital Infantil Universitario Niño Jesus | Madrid , Spain, 28009Hospital Universitario 12 de Octubre | Madrid , Spain, 28041Hospital Universitario HM Sanchinarro | Madrid , Spain, 28050Complejo Asistencial Universitario de Salamanca - H. Clinico | Salamanca , Spain, 37007Hospital Universitari i Politecnic La Fe de Valencia - Adults | Valencia , Spain, 46026Hospital Universitari i Politecnic La Fe de Valencia - Pediatrics | Valencia , Spain, 46026Centre Hospitalier Universitaire Vaudois | Lausanne Canton of Vaud, Switzerland, 1011Universitätsspital Zürich | Zurich , Switzerland, 8091Addenbrooke's Hospital | Cambridge Cambridgeshire, United Kingdom, CB2 0QQBeatson West of Scotland Cancer Centre | Glasgow Lanarkshire, United Kingdom, G12 0YNRoyal Hospital for Children (Glasgow) | Glasgow Lanarkshire, United Kingdom, G51 4TFClatterbridge Cancer Centre - Liverpool | Liverpool Lancashire, United Kingdom, L7 8YAThe Christie NHS Foundation Trust | Manchester Lancashire, United Kingdom, M20 4BXThe Royal Marsden in Sutton, Surrey | Sutton Surrey, United Kingdom, SM2 5PTRoyal Victoria Infirmary | Newcastle upon Tyne Tyne and Wear, United Kingdom, NE1 4LPFreeman Hospital | Newcastle upon Tyne Tyne and Wear, United Kingdom, NE7 7DNSt James University Hospital | Leeds West Yorkshire, United Kingdom, LS9 7TFThe Leeds Teaching Hospitals NHS Trust, Leeds General Infimary | Leeds , United Kingdom, LS1 3EXGuy's Hospital | London , United Kingdom, SE19RTChurchill Hospital | Oxford , United Kingdom, Ox3 7LE