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

Glioma Clinical Trial

— ACTION  

Official title:

ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05580562
• Other study ID #: ONC201-108
• Status: Recruiting
• Phase: Phase 3
• Start date: January 23, 2023
• Est. completion date: August 2026

Study information

• Verified date: June 2024
• Source: Chimerix
• Contact: Tarapore, PhD
• Phone: 1-919-806-1074
• Email: clinicaltrials[@]chimerix.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 450
• Est. completion date: August 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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): = 10 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. 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.

Related Conditions & MeSH terms

• Glioma
• H3 K27M

Intervention

Drug:
• ONC201
Participants = 52.5 kg will receive 625 mg of ONC201 (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.
• ONC201 + Placebo
Participants = 52.5 kg will receive 625 mg of ONC201 (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

Other:
• Placebo
Participants will receive placebo (same number of capsules as the ONC201 dose) on dosing days

Locations

Country	Name	City	State
Australia	Olivia Newton-John Cancer Research Institute (ONJCRI)	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Perth Children's Hospital	Nedlands	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Royal North Shore Hospital	Sydney	New South Wales
Austria	Medical University of Vienna - Adults	Vienna	Wien
Austria	Medical University of Vienna - Pediatrics	Vienna	Wien
Canada	Tom Baker Cancer Cetre	Calgary	Alberta
Canada	London Health Sciences Centre	London	Ontario
Canada	Hopital Notre Dame, Lachapelle	Montréal	Quebec
Canada	Childrens Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	BC Cancer - The Vancouver Center	Vancouver	British Columbia
Canada	Children's & Women's Health Care of BC	Vancouver	British Columbia
Denmark	Aalborg Universitetshospital	Aalborg	Nordjylland
Denmark	Copenhagen University Hospital	Copenhagen	Capital
Denmark	F345 H.C. Andersen's Children's Hospital	Odense	South Denmark
Denmark	Odense Universitetshospital	Odense	South Denmark
Germany	Universitätsklinikum Augsburg	Augsburg	Bayern
Germany	Vivantes Klinikum Neukölln	Berlin
Germany	Universitätsklinikum Bonn	Bonn	Nordrhein-Westfalen
Germany	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Klinikum der Johann-Wolfgang Goethe-Universitat	Frankfurt am Main	Hessen
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Germany	University Clinic Heidelberg	Heidelberg	Baden-Württemberg
Germany	Uniklinik Köln	Köln	Nordrhein-Westfalen
Germany	Klinikum Mannheim Universitätsklinikum gGmbH	Manheim
Germany	University Clinic Regensburg	Regensburg	Bayern
Germany	Universitätsklinikum Tübingen	Tübingen
Israel	Soroka University Medical Centre	Be'er Sheva
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Ein Kerem Medical Center	Jerusalem
Israel	Rabin Medical Center	Petah Tikva
Israel	Schneider Children's Medical Center of Israel	Petah Tikvah
Israel	Sheba Medical Center	Ramat Gan	Tel-Aviv
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Ospedale Bellaria	Bologna	Emilia-Romagna
Italy	Fondazione IRCCS Di Rilievo Nazionale Istituto Nazionale Neurologico Carlo Besta	Milano	Lombardia
Italy	Ospedale San Raffaele S.r.l.	Milano	Lombardia
Italy	Istituto Oncologico Veneto	Padova	Veneto
Italy	Istituto Nazionale Tumori Regina Elena	Roma	Lazio
Italy	Istituto Clinico Humanitas	Rozzano	Lombardia
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino	Piemonte
Korea, Republic of	CHA Bundang Medical Center	Bundang-Gu, Seongnam-Si	Gyeonggido
Korea, Republic of	Gangnam Severance Hospital, Yonsei University Health System	Gangnam	Seoul Teugbyeolsi
Korea, Republic of	Samsung Medical Center	Gangnam-Gu	Seoul Teugbyeolsi
Korea, Republic of	National Cancer Center	Ilsandong-Gu, Goyang-Si	Gyeonggido
Korea, Republic of	Seoul National University Hospital	Jongno-Gu	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
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	Universitair Medisch Centrum Utrecht Cancer Center	Utrecht
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Sant Joan de Deu	Esplugues De Llobregat	Barcelona
Spain	Hospital Infantil Universitario Niño Jesus	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Spain	Clinica Universidad Navarra	Pamplona	Navarra
Spain	Complejo Asistencial Universitario de Salamanca - H. Clinico	Salamanca
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne	Vaud
Switzerland	Universitätsspital Zürich	Zürich
United Kingdom	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	St James University Hospital	Leeds	West Yorkshire
United Kingdom	The Leeds Teaching Hospitals NHS Trust, Leeds General Infimary	Leeds
United Kingdom	Clatterbridge Cancer Centre - Liverpool	Liverpool	Lancashire
United Kingdom	Guy's Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Manchester	Lancashire
United Kingdom	Freeman Hospital	Newcastle Upon Tyne	Tyne And Wear
United Kingdom	Royal Victoria Infirmary	Newcastle Upon Tyne	Tyne And Wear
United Kingdom	Churchill Hospital	Oxford
United Kingdom	The Royal Marsden in Sutton, Surrey	Sutton	Surrey
United States	Albany Medical Center	Albany	New York
United States	University of Michigan Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Levine Cancer Institute/ Atrium Health	Charlotte	North Carolina
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ohio Statue University	Columbus	Ohio
United States	University of California Irvine	Costa Mesa	California
United States	Neuro-Oncology Associates	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke Cancer Institute	Durham	North Carolina
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Yale University	Fairfield	Connecticut
United States	Benefis Hospital Sletten Cancer Institute	Great Falls	Montana
United States	Kapi'olani Medical Center for Women and Children	Honolulu	Hawaii
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	Indiana University School of Medicine - Indianapolis	Indianapolis	Indiana
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
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	Norton Healthcare	Louisville	Kentucky
United States	University Of Wisconsin - Madison	Madison	Wisconsin
United States	Miami Cancer Institute	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Jersey Shore University Medical Center	Neptune	New Jersey
United States	Ochsner Medical Center - New Orleans	New Orleans	Louisiana
United States	Children's Hospital at Montefiore Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Montefiore Medical Park	New York	New York
United States	Children's Hospital of The King's Daughter	Norfolk	Virginia
United States	University of Oklahoma Peggy and Charles Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Banner MD Anderson Cancer Center	Phoenix	Arizona
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Providence Health and Services St. Vincent Medical Center	Portland	Oregon
United States	Mayo Clinic - Cancer Center - Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah - Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of Texas - San Antonio - Health Science Center	San Antonio	Texas
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	University of Washington	Seattle	Washington
United States	Stanford Cancer Center	Stanford	California
United States	Overlook Medical Center	Summit	New Jersey
United States	Moffitt Cancer Center	Tampa	Florida
United States	St Joseph's Children's Hospital of Tampa	Tampa	Florida
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Chimerix

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Denmark,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)	Overall Survival is defined as the time from randomization to death due to any cause.	From date of randomization until date of death from any cause, assessed up to approximately 44 months
Primary	Progression free survival (PFS) as assessed by using RANO-HGG criteria	PFS is defined as time from randomization to disease progression (PD) or death.	From date of randomization until the date of first documented progression assessed up to approximately 44 months
Secondary	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	From date of randomization up to 44 months
Secondary	Change from baseline in clinical laboratory parameters	Percentage of participants with clinically significant laboratory results	From date of randomization up to 44 months
Secondary	PFS using RANO-HGG criteria	PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease	From date of randomization up to 44 months
Secondary	Corticosteroid response	Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent	From date of randomization up to 44 months
Secondary	Performance status response	Performance status response will be measured by confirmed increase in Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS)	From date of randomization up to 44 months