ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
- Conditions
- H3 K27MGlioma
- Interventions
- Registration Number
- NCT05580562
- Lead Sponsor
- Chimerix
- Brief Summary
This is a randomized, double-blind, placebo-controlled, parallel-group, international, Phase 3 study in patients with newly diagnosed H3 K27M-mutant diffuse glioma to assess whether treatment with ONC201 following frontline radiotherapy will extend overall survival and progression-free survival in this population. Eligible participants will have histologically diagnosed H3 K27M-mutant diffuse glioma and have completed standard frontline radiotherapy.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 450
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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.
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Body weight ≥ 10 kg at time of randomization.
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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): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.]
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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.
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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.]
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Received frontline radiotherapy
- Initiated radiotherapy within 12 weeks from the initial diagnosis of H3 K27M-mutant diffuse glioma.
- Completed radiotherapy within 2 to 6 weeks prior to randomization
- 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).
-
Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization.
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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).
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Primary spinal tumor.
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Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons.
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Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination.
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Any known concurrent malignancy.
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New lesion(s) outside of the radiation field.
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Received whole-brain radiotherapy.
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Received proton therapy for glioma.
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Use of any of the following treatments within the specified time periods prior to randomization:
- ONC201 or ONC206 at any time.
- Systemic bevacizumab (includes biosimilars) at any time since the initial diagnosis of H3 K27M-mutant diffuse glioma.
- Temozolomide within past 3 weeks.
- Tumor treating fields at any time.
- DRD2 antagonist within past 2 weeks.
- Any investigational therapy within past 4 weeks.
- Strong CYP3A4 inhibitors within 3 days.
- Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks.
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Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization:
- Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.
- 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).
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN.
- Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate < 60 mL/min/1.73 m2).
-
QTc > 480 msec (based on mean from triplicate electrocardiograms) during screening.
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Known hypersensitivity to any excipients used in the study intervention formulation.
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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.
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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.
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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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ONC201 Twice Weekly Group Dordaviprone (ONC201) - ONC201 Once Weekly Group Dordaviprone (ONC201) + Placebo - Placebo Group Placebo -
- Primary Outcome Measures
Name Time Method Overall survival (OS) From date of randomization until date of death from any cause, assessed up to approximately 44 months Overall Survival is defined as the time from randomization to death due to any cause.
Progression free survival (PFS) as assessed by using RANO-HGG criteria From date of randomization until the date of first documented progression assessed up to approximately 44 months PFS is defined as time from randomization to disease progression (PD) or death.
- Secondary Outcome Measures
Name Time Method Incidence of adverse events From date of randomization up to 44 months Incidence of overall, treatment-related, Grade 3 or higher in severity, serious, fatal, those resulting in treatment discontinuation, and events of special interest
Change from baseline in clinical laboratory parameters From date of randomization up to 44 months Percentage of participants with clinically significant laboratory results
PFS using RANO-HGG criteria From date of randomization up to 44 months PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease
Corticosteroid response From date of randomization up to 44 months Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent
Performance status response From date of randomization up to 44 months Performance status response will be measured by confirmed increase in Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS)
Trial Locations
- Locations (156)
Churchill Hospital
🇬🇧Oxford, United Kingdom
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Banner MD Anderson Cancer Center
🇺🇸Phoenix, Arizona, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
University of California Irvine
🇺🇸Costa Mesa, California, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸Los Angeles, California, United States
UCLA University of California Los Angeles
🇺🇸Los Angeles, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
UCSF Benioff Children's Hospital
🇺🇸San Francisco, California, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Providence Saint John's Cancer Institute
🇺🇸Santa Monica, California, United States
Stanford Cancer Center
🇺🇸Stanford, California, United States
Yale University
🇺🇸Fairfield, Connecticut, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
St Joseph's Children's Hospital of Tampa
🇺🇸Tampa, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Kapi'olani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Feinberg School of Medicine Northwestern University
🇺🇸Chicago, Illinois, United States
Indiana University School of Medicine - Indianapolis
🇺🇸Indianapolis, Indiana, United States
University of Iowa Hospitals & Clinics
🇺🇸Iowa City, Iowa, United States
Norton Healthcare
🇺🇸Louisville, Kentucky, United States
Ochsner Medical Center - New Orleans
🇺🇸New Orleans, Louisiana, United States
University of Maryland School of Medicine
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Michigan Hospital
🇺🇸Ann Arbor, Michigan, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic - Cancer Center - Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Benefis Hospital Sletten Cancer Institute
🇺🇸Great Falls, Montana, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Jersey Shore University Medical Center
🇺🇸Neptune, New Jersey, United States
Overlook Medical Center
🇺🇸Summit, New Jersey, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Children's Hospital at Montefiore Medical Center
🇺🇸New York, New York, United States
Montefiore Medical Park
🇺🇸New York, New York, United States
Laura & Isaac Perlmutter Cancer Center - NYU ACC
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Lenox Hill Hospital
🇺🇸New York, New York, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Levine Cancer Institute/ Atrium Health
🇺🇸Charlotte, North Carolina, United States
Duke Cancer Institute
🇺🇸Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
University of Oklahoma Peggy and Charles Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Providence Health and Services St. Vincent Medical Center
🇺🇸Portland, Oregon, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Neuro-Oncology Associates
🇺🇸Dallas, Texas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
UT Health Science Center Houston Department of Neurosurgery
🇺🇸Houston, Texas, United States
University of Texas - San Antonio - Health Science Center
🇺🇸San Antonio, Texas, United States
University of Utah - Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Inova Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
Children's Hospital of The King's Daughter
🇺🇸Norfolk, Virginia, United States
University of Washington
🇺🇸Seattle, Washington, United States
University Of Wisconsin - Madison
🇺🇸Madison, Wisconsin, United States
FLENI Neurologia
🇦🇷Ciudad Autónoma de Buenos Aires, Argentina
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Royal North Shore Hospital
🇦🇺Sydney, New South Wales, Australia
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
Olivia Newton-John Cancer Research Institute (ONJCRI)
🇦🇺Heidelberg, Victoria, Australia
Perth Children's Hospital
🇦🇺Nedlands, Western Australia, Australia
Medical University of Vienna - Adults
🇦🇹Vienna, Wien, Austria
Medical University of Vienna - Pediatrics
🇦🇹Vienna, Wien, Austria
Hospital do GRAACC
🇧🇷São Paulo, Brazil
Tom Baker Cancer Cetre
🇨🇦Calgary, Alberta, Canada
BC Cancer - The Vancouver Center
🇨🇦Vancouver, British Columbia, Canada
Children's & Women's Health Care of BC
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Childrens Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Hopital Notre Dame, Lachapelle
🇨🇦Montréal, Quebec, Canada
Copenhagen University Hospital
🇩🇰Copenhagen, Capital, Denmark
Aalborg Universitetshospital
🇩🇰Aalborg, Nordjylland, Denmark
F345 H.C. Andersen's Children's Hospital
🇩🇰Odense, South Denmark, Denmark
Odense Universitetshospital
🇩🇰Odense, South Denmark, Denmark
University Clinic Heidelberg
🇩🇪Heidelberg, Baden-Württemberg, Germany
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Baden-Württemberg, Germany
Universitätsklinikum Augsburg
🇩🇪Augsburg, Bayern, Germany
University Clinic Regensburg
🇩🇪Regensburg, Bayern, Germany
Klinikum der Johann-Wolfgang Goethe-Universitat
🇩🇪Frankfurt am Main, Hessen, Germany
Universitätsklinikum Bonn
🇩🇪Bonn, Nordrhein-Westfalen, Germany
Universitätsklinikum Essen
🇩🇪Essen, Nordrhein-Westfalen, Germany
Uniklinik Köln
🇩🇪Köln, Nordrhein-Westfalen, Germany
Vivantes Klinikum Neukölln
🇩🇪Berlin, Germany
Klinikum Mannheim Universitätsklinikum gGmbH
🇩🇪Manheim, Germany
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany
Queen Mary Hospital
🇭🇰Hong Kong, Hong Kong
Sheba Medical Center
🇮🇱Ramat Gan, Tel-Aviv, Israel
Soroka University Medical Centre
🇮🇱Be'er Sheva, Israel
Rambam Medical Center
🇮🇱Haifa, Israel
Hadassah Ein Kerem Medical Center
🇮🇱Jerusalem, Israel
Schneider Children's Medical Center of Israel
🇮🇱Petah Tikvah, Israel
Rabin Medical Center
🇮🇱Petah Tikva, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Ospedale Bellaria
🇮🇹Bologna, Emilia-Romagna, Italy
Istituto Nazionale Tumori Regina Elena
🇮🇹Roma, Lazio, Italy
Ospedale San Raffaele S.r.l.
🇮🇹Milano, Lombardia, Italy
Fondazione IRCCS Di Rilievo Nazionale Istituto Nazionale Neurologico Carlo Besta
🇮🇹Milano, Lombardia, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano, Lombardia, Italy
Azienda Ospedaliera Città della Salute e della Scienza di Torino
🇮🇹Torino, Piemonte, Italy
Istituto Oncologico Veneto
🇮🇹Padova, Veneto, Italy
National Cancer Center Hospital
🇯🇵Chuo City, Japan
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka, Japan
Kyoto University Hospital
🇯🇵Kyoto, Japan
Osaka City General Hospital
🇯🇵Osaka, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Japan
CHA Bundang Medical Center
🇰🇷Bundang-Gu, Seongnam-Si, Gyeonggido, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷Bundang-gu, Seongnam-si, Gyeonggido, Korea, Republic of
National Cancer Center
🇰🇷Ilsandong-Gu, Goyang-Si, Gyeonggido, Korea, Republic of
Samsung Medical Center
🇰🇷Gangnam-Gu, Seoul Teugbyeolsi, Korea, Republic of
Gangnam Severance Hospital, Yonsei University Health System
🇰🇷Gangnam, Seoul Teugbyeolsi, Korea, Republic of
Seoul National University Hospital
🇰🇷Jongno-Gu, Seoul Teugbyeolsi, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea, Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Erasmus MC
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Universitair Medisch Centrum Utrecht Cancer Center
🇳🇱Utrecht, Netherlands
KK Women's and Children's Hospital
🇸🇬Singapore, Singapore
National Cancer Centre
🇸🇬Singapore, Singapore
National Neuroscience Institute
🇸🇬Singapore, Singapore
Hospital Sant Joan de Deu
🇪🇸Esplugues De Llobregat, Barcelona, Spain
Clinica Universidad Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Infantil Universitario Niño Jesus
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, Spain
Complejo Asistencial Universitario de Salamanca - H. Clinico
🇪🇸Salamanca, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Centre Hospitalier Universitaire Vaudois
🇨🇭Lausanne, Vaud, Switzerland
Universitätsspital Zürich
🇨🇭Zürich, Switzerland
Addenbrooke's Hospital
🇬🇧Cambridge, Cambridgeshire, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, Lanarkshire, United Kingdom
Royal Hospital for Children (Glasgow)
🇬🇧Glasgow, Lanarkshire, United Kingdom
Clatterbridge Cancer Centre - Liverpool
🇬🇧Liverpool, Lancashire, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, Lancashire, United Kingdom
The Royal Marsden in Sutton, Surrey
🇬🇧Sutton, Surrey, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle Upon Tyne, Tyne And Wear, United Kingdom
Freeman Hospital
🇬🇧Newcastle Upon Tyne, Tyne And Wear, United Kingdom
St James University Hospital
🇬🇧Leeds, West Yorkshire, United Kingdom
The Leeds Teaching Hospitals NHS Trust, Leeds General Infimary
🇬🇧Leeds, United Kingdom
Guy's Hospital
🇬🇧London, United Kingdom