Clinical trial NCT05580562: ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: H3 K27M
Glioma
Keywords: H3 K27M
H3 K28M
H3 K27-altered
histone
H3F3A
HIST1H3B
HIST1H3C
H3.1
H3.3
DMG
thalamus
thalamic
midline
Lead sponsor: Chimerix
Sponsor class: INDUSTRY
First posted: 2022-10-14
Enrollment: 450
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: From date of randomization until date of death from any cause, assessed up to approximately 44 months
measure: Progression free survival (PFS) as assessed by using RANO-HGG criteria
timeFrame: From date of randomization until the date of first documented progression assessed up to approximately 44 months
Secondary outcomes:
measure: Incidence of adverse events
timeFrame: From date of randomization up to 44 months
measure: Change from baseline in clinical laboratory parameters
timeFrame: From date of randomization up to 44 months
measure: PFS using RANO-HGG criteria
timeFrame: From date of randomization up to 44 months
measure: Corticosteroid response
timeFrame: From date of randomization up to 44 months
measure: Performance status response
timeFrame: From date of randomization up to 44 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Phoenix
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Costa Mesa
country: United States
facility: University of California Irvine
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA University of California Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Santa Monica
country: United States
facility: Providence Saint John's Cancer Institute
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Fairfield
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Tampa
country: United States
facility: St Joseph's Children's Hospital of Tampa
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Honolulu
country: United States
facility: Kapi'olani Medical Center for Women and Children
state: Hawaii
city: Chicago
country: United States
facility: Feinberg School of Medicine Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine - Indianapolis
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center - New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Cancer Center - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Great Falls
country: United States
facility: Benefis Hospital Sletten Cancer Institute
state: Montana
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Neptune
country: United States
facility: Jersey Shore University Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: New York
country: United States
facility: Children's Hospital at Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Montefiore Medical Park
state: New York
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center - NYU ACC
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute/ Atrium Health
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Health and Services St. Vincent Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: Neuro-Oncology Associates
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: UT Health Science Center Houston Department of Neurosurgery
state: Texas
city: San Antonio
country: United States
facility: University of Texas - San Antonio - Health Science Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Huntsman Cancer Institute
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughter
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Madison
country: United States
facility: University Of Wisconsin - Madison
state: Wisconsin
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: FLENI Neurologia
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Heidelberg
country: Australia
facility: Olivia Newton-John Cancer Research Institute (ONJCRI)
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Vienna
country: Austria
facility: Medical University of Vienna - Adults
state: Wien
city: Vienna
country: Austria
facility: Medical University of Vienna - Pediatrics
state: Wien
city: São Paulo
country: Brazil
facility: Hospital do GRAACC
city: São Paulo
country: Brazil
facility: Hcor Research Institute
city: São Paulo
country: Brazil
facility: Instituto Do Cancer Do Estado De São Paulo
city: Calgary
country: Canada
facility: Tom Baker Cancer Cetre
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer - The Vancouver Center
state: British Columbia
city: Vancouver
country: Canada
facility: Children's & Women's Health Care of BC
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Childrens Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montréal
country: Canada
facility: Hopital Notre Dame, Lachapelle
state: Quebec
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital
state: Capital
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
state: Nordjylland
city: Odense
country: Denmark
facility: F345 H.C. Andersen's Children's Hospital
state: South Denmark
city: Odense
country: Denmark
facility: Odense Universitetshospital
state: South Denmark
city: Heidelberg
country: Germany
facility: University Clinic Heidelberg
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
state: Bayern
city: Regensburg
country: Germany
facility: University Clinic Regensburg
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann-Wolfgang Goethe-Universitat
state: Hessen
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Uniklinik Köln
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Manheim
country: Germany
facility: Klinikum Mannheim Universitätsklinikum gGmbH
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
state: Tel-Aviv
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Centre
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem Medical Center
city: Petah Tikvah
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Bologna
country: Italy
facility: Ospedale Bellaria
state: Emilia-Romagna
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
state: Lazio
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.l.
state: Lombardia
city: Milano
country: Italy
facility: Fondazione IRCCS Di Rilievo Nazionale Istituto Nazionale Neurologico Carlo Besta
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Lombardia
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
state: Piemonte
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: Veneto
city: Chuo City
country: Japan
facility: National Cancer Center Hospital
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
city: Bundang-Gu, Seongnam-Si
country: Korea, Republic of
facility: CHA Bundang Medical Center
state: Gyeonggido
city: Bundang-gu, Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggido
city: Ilsandong-Gu, Goyang-Si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggido
city: Gangnam-Gu
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul Teugbyeolsi
city: Gangnam
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Jongno-Gu
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht Cancer Center
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Singapore
country: Singapore
facility: National Neuroscience Institute
city: Esplugues De Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Pamplona
country: Spain
facility: Clinica Universidad Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - H. Clinico
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
state: Vaud
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cambridgeshire
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Lanarkshire
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children (Glasgow)
state: Lanarkshire
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre - Liverpool
state: Lancashire
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: Lancashire
city: Sutton
country: United Kingdom
facility: The Royal Marsden in Sutton, Surrey
state: Surrey
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
state: Tyne And Wear
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne And Wear
city: Leeds
country: United Kingdom
facility: St James University Hospital
state: West Yorkshire
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust, Leeds General Infimary
city: London
country: United Kingdom
facility: Guy's Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
References: