Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0

NCT05476939 | Recruiting Phase 3 DMC

• 3 other identifiers: 2014/21262014-001929-322023-506027-29-00
• Study Type: interventional
• Target: 433
• Locations: 4 countries
• Sites: 50

Brief Summary

The BIOMEDE 2.0 study is the second stage of the BIOMEDE multi-arm, multistage rolling programme (adaptive platform protocol). It is a multicenter, randomized, open-label, controlled phase-3 trial evaluating efficacy of ONC201 in comparison with everolimus (primary objective based on internal comparison) and subsequently to historical controls. Two treatment groups will be compared. A switch between treatment groups is allowed after confirmation of the disease progression (real-time central review blinded to the treatment arm allocation). Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity or consent withdrawal. The final conclusion of the trial will be successful for ONC201, if ONC201 is found significantly superior to everolimus in terms of centrally-reviewed PFS (Progression-free survival) from randomization (internal comparison) either overall, considering ND-DMG and DIPG-patients together, or in the subgroup of ND-DMG patients alone. In other cases, Everolimus will remain the standard arm unless it appears associated with an excess of toxicity compared to ONC201 which could then be discussed as a new standard.

Conditions

Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Diffuse Midline Glioma, H3K27-altered

Keywords

Children; Adolescents; Adults; Newly diagnosed

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

  Defined as the time between date of randomization and unequivocal clinical, cytological or radiological progression confirmed by central review, or death whatever the cause.

  Until 2 years after inclusion of the last patient

Secondary Outcomes (8)

• Overall survival (for all the comparisons to historical controls)

  Until 5 years after randomization of the last patient

• Overall survival (for the internal comparison between randomized groups)

  Until 5 years after randomization of the last patient

• Progression-free survival after first progression

  Until 5 years after randomization of the last patient

• Complication rate of the diagnostic biopsy-based procedure

  Until 5 years after randomization of the last patient

• Severity of the complications (including prolongation of the hospital stay) of the diagnostic biopsy-based procedure

  Until 5 years after randomization of the last patient

Study Arms (2)

everolimus

ACTIVE COMPARATOR

Tablets of 2.5 mg or 10 mg. The prescribed dose is 5 mg/m²/day, orally, once daily. Dose will be capped at 10 mg once daily. Treatment will be continued until unacceptable toxicity, centrally confirmed tumor progression (either radiologically or histologically) and/or withdrawal of patient, parents or legal representative consent. At the time of centrally confirmed relapse or progression, patients will stop treatment and will be allowed to switch to the other arm in case no better option is available after considering the results of the molecular profiling. In case of switch (everolimus to ONC201 or vice-versa), the patient will observe a wash-out period of 7 days before starting: * the second treatment, * or a reirradiation (if applicable). No treatment is allowed during reirradiation, except setroids and bevacizumab. Then, if an additional treatment is needed, the second treatment will be started within one week after the end of the reirradiation.

Drug: Everolimus; Radiation: Radiotherapy

Dordaviprone (ONC201)

EXPERIMENTAL

Capsules of 125 mg. The prescribed dose is 375 mg/m², orally, once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose. Treatment will be continued until unacceptable toxicity, centrally confirmed tumor progression (either radiologically or histologically), and/or withdrawal of patient, parents or legal representative consent. At the time of centrally confirmed relapse or progression, patients will stop treatment and will be allowed to switch to the other arm in case no better option is available after considering the results of the molecular profiling. In case of switch (everolimus to ONC201 or vice-versa), the patient will observe a wash-out period of 7 days before starting: * the second treatment, * or a reirradiation (if applicable). No treatment is allowed during reirradiation, except setroids and bevacizumab. Then, if an additional treatment is needed, the second treatment will be started within one week after the end of the reirradiation.

Drug: ONC201; Radiation: Radiotherapy

Interventions

Everolimus DRUG

Tablets of 2.5 mg or 10 mg. The prescribed dose is 5 mg/m²/day, orally, once daily. Dose will be capped at 10 mg once daily.

Also known as: VOTUBIA, AFINITOR

everolimus

ONC201 DRUG

Capsules of 125mg. The prescribed dose is 375mg/m², orally, once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose.

Dordaviprone (ONC201)

Radiotherapy RADIATION

All patients will be treated with 30 conventional single daily fractions of 1.8 Gy to a total of 54 Gy over a planned period of 6 weeks. Dose may be increased up to 60 Gy for adult patients with supratentorial ND-DMG. The clinical target volume will include all the areas of abnormality on T2/FLAIR sequences with a 1-cm margin. Radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery. The study medication will be started at Day 1 (+3 days max) of radiotherapy. Reirradiation is permitted only at disease progression according to local practice. In case of metastatic disease or intramedullary tumors, patients can be included in the study. In this situation, radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery while targeted treatment will start at the end of the irradiation.

Dordaviprone (ONC201); everolimus

Eligibility Criteria

• Age: 6 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

Eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study: * Diagnosis Criteria: * Diagnosis of DIPG (clinical and radiological). As biopsy is not standard for these tumors, an informed consent is required for the necessary histological verification. \[Biopsy-part of BIOMEDE 2.0 trial\]. OR * Histological diagnosis of DIPG (i.e. H3K28M or EZHIP positive Diffuse Midline Glioma located in the pons) in case the tumor biopsy was performed before study entry. The diagnosis will be defined by 1/ diffuse glioma, 2/ H3K28M mutation or loss of H3K28 trimethylation together with EZHIP overexpression. In this situation, patient will sign the consent after the diagnosis to allow central review and biomarkers assessment thereafter. OR * Molecular diagnosis of DIPG (i.e. H3K28M) in case a liquid biopsy (CSF or blood) was performed before study entry, in a patient who could not undergo a tumor biopsy because it was too dangerous according to the patient's clinical condition. The diagnosis will be defined by 1/ DIPG, 2/ H3K28M mutation. In this situation, patient will sign the consent after the diagnosis to allow collection of the molecular report. OR * Non-DIPG diffuse midline gliomas (ND-DMG), H3K28M mutant or with H3K28 trimethylation loss together with EZHIP overexpression, will be eligible for the trial after biopsy or surgery. As biopsy and surgery is considered as standard practice for these locations, informed consent for the biopsy will not be necessary. Patient will sign the consent after the diagnosis to allow central review and biomarkers assessment thereafter. OR * Non-DIPG diffuse midline gliomas (ND-DMG) will be eligible for the trial before the biopsy in case the diagnosis is clinically or radiologically suspected. Informed consent for the biopsy and molecular analysis will be necessary. Then, if the central pathology review concludes to a ND-DMG with H3K28M mutant or H3K28 trimethylation loss together with EZHIP overexpression, these patients will be eligible for the treatment part of the trial. * Eligible for a biopsy, or biopsy material available for the biomarker assessment. * Age \> 6 months, with no upper age limit. Children between 6 months and 3 years will be discussed on a case by case basis for inclusion in the study for the feasibility of the stereotactic biopsy. * Eligible for cerebral or craniospinal radiotherapy. * Tumor at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy even for another neoplasm. Surgery is allowed when performed for diagnostic or therapeutic purpose. * Metastatic diseases or spinal tumors allowed; in this case, patients would receive craniospinal or spinal radiotherapy and medical treatment (everolimus or ONC201) will be postponed and only started after the end of radiotherapy. * Patients must be affiliated to a social security system or beneficiary of the same according to local requirements. * Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific procedures are conducted according to local, regional or national guidelines. Non eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study: * Uncontrolled spontaneous massive intratumor bleeding. Patients with post-operative bleeding will be allowed to enter the study provided the hemorrhage is controled. Same rule applies for the other post-operative complications (infection, CSF leakage, absence of wound closure, subdural collection…). * Any other concomitant anti-cancer treatment not foreseen by this protocol is not allowed, except corticosteroids and Bevacizumab which are allowed during the protocol. Bevacizumab is not allowed before and until 15 days after the surgery. The use of bevacizumab and corticosteroids will be taken into account when judging the possibility of progression/pseudoprogression. * Any other cancer diagnosed during the last 5 years. * Uncontrolled intercurrent illness or active infection. * Any other co-morbid condition that in the investigator's opinion would impair study participation. * Unable for medical follow-up (geographic, social or mental reasons). * Patient previously treated with irradiation on the brainstem for another neoplasm. * Participation in another clinical study with an investigational product while on study treatment. * Patient under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent. Eligibility criteria for the randomization in BIOMEDE 2.0 study: * Patient enrolled in the BIOMEDE 2.0 study. * Life expectancy \> 12 weeks after the start of study treatment. * Histological diagnosis of DIPG (as per the WHO criteria) confirmed by central pathology review, OR Typical radiology of a DIPG (mandatory central radiological review) as well as the short clinical history (less than three months of pre-existing symptoms) in case of suspected DIPG but no histological confirmation (tumor biopsy performed but not informative), or suspected DIPG with detection of H3K28M mutation in the CSF or blood (ctDNA analysis in the CSF or blood), OR Histological diagnosis of ND-DMG confirmed by central pathology review, with mutation in the histone H3.1, H3.2, H3.3 genes, or loss of H3K28me3 and EZHIP overexpression by immunohistochemistry. * Karnofsky performance status scale or Lansky Play Scale \> 50%. The PS should not take the neurologic deficit per se into account. NB: Children and adults with a worse performance status due to glioma-related motor paresis can be included. * Highly effective and appropriate contraception for patients (male and female) of reproductive potential during their entire participation in the study and during 6 months after the end of treatment. * Negative pregnancy test (serum beta-HCG or urinary test) evaluated within one week prior randomization in sexually active females of reproductive potential. * Absolute neutrophil count \> 1.0 x 10\^9/l, Platelets \> 100 x 10\^9/l. * Total bilirubin \< 1.5 x ULN, AST and ALT\< 2.5 x ULN. * Serum creatinine \< 1.5 X ULN for age. If serum creatinine \> 1.5 x ULN, creatinine clearance must be \> 70 ml/min/1.73 m² (as per local practice). * Normal coagulation tests within the local reference ranges. * Written informed consent from parents/legal representative, patient, and age-appropriate assent before randomization according to local, regional or national guidelines. Non Eligibility criteria for the randomization in BIOMEDE 2.0 study: * Current organ toxicity \> grade 2 according to the NCI-CTCAE version 5.0, especially cardiovascular or renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment). * Patients with the following cardiac history cannot take ONC201: * Prolongation of QT/QTcF interval (QTc interval \> 480 milliseconds) preferably using Frederica's QT correction formula on two ECGs separated by at least 48 hours. * A history of Torsades de pointes or heart failure, hypokalemia, or family history of prolonged QT Syndrome. * Required concomitant use of medication(s) known to prolong the QT/QTc interval. In this case, patients will be treated in the Everolimus arm without randomization (except if contra-indication to Everolimus). * Pregnant or breastfeeding women. * Patients with chronic HBV disease compatible with the trial are not excluded from the study. These patients randomized to everolimus treatment will have regular viral load monitoring throughout the study. * Patients taking strong P450 inhibitors or inducers or PgP inhibitors are not excluded from the study but drug concentration of everolimus should be monitored carefully to avoid toxicity. Preferably alternative medications should be considered. * Patient with known congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption will not be randomized and will be treated in the ONC201 arm (except if contra-indication to ONC201). * Patients with known hypersensitivity to any component of Everolimus (active substance, other rapamycin derivatives or excipients) will not be randomized and will be treated in the ONC201 arm (except if contra-indication to ONC201). * Patients with known hypersensitivity to any component of ONC201 (drug product or excipients) will not be randomized and will be treated in the Everolimus arm (except if contra-indication to Everolimus).

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Innovative Therapies For Children with Cancer Consortium: collaborator
• Gustave Roussy, Cancer Campus, Grand Paris: lead
• Ministry of Health, France: collaborator
• Jazz Pharmaceuticals: collaborator

Study Sites (50)

Aarhus Universitetshospital Skejby

Aarhus, 8200, Denmark

RECRUITING

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

H.C. Andersen Children's Hospital, Odense Universitetshospital

Odense, 5000, Denmark

RECRUITING

Gustave Roussy

Villejuif, Val de Marne, 94805, France

RECRUITING

CHU d'Amiens-Picardie Site Sud

Amiens, 80054, France

RECRUITING

Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin

Angers, 49055, France

RECRUITING

CHU d'Angers - Bâtiment Robert Debré

Angers, 49933, France

RECRUITING

CHU Besançon - Hôpital Jean Minjoz

Besançon, 25030, France

RECRUITING

CHU de Bordeaux - Groupe hospitalier Saint André - Hôpital Saint André

Bordeaux, 33000, France

RECRUITING

CHU de Bordeaux - Groupe hospitalier Pellegrin - Hôpital des enfants

Bordeaux, 33076, France

RECRUITING

CHRU de Brest - Hôpital Morvan

Brest, 29609, France

RECRUITING

CHU de Caen - Hôpital Côte de Nacre

Caen, 14033, France

RECRUITING

CHU Estaing

Clermont-Ferrand, 63003, France

RECRUITING

Centre Jean Perrin

Clermont-Ferrand, 63011, France

RECRUITING

CHU François Mitterrand

Dijon, 21079, France

RECRUITING

CHU Grenoble Alpes - Hôpital Albert Michallon

Grenoble, 38700, France

NOT YET RECRUITING

CHU Grenoble Alpes - Hôpital Couple-Enfant

Grenoble, 38700, France

RECRUITING

Centre Oscar Lambret

Lille, 59020, France

RECRUITING

Hôpital Roger Salengro

Lille, 59037, France

NOT YET RECRUITING

Hôpital de la mère et de l'enfant

Limoges, 87042, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Hôpital Pierre Wertheimer

Lyon, 69500, France

RECRUITING

Hôpital de La Timone

Marseille, 13005, France

RECRUITING

Hôpital Arnaud de Villeneuve

Montpellier, 34090, France

RECRUITING

CHRU Nancy - Hôpital central

Nancy, 54035, France

RECRUITING

CHRU Nancy Brabois - Hôpital d'enfants

Nancy, 54500, France

RECRUITING

CHU de Nice - Hôpital Pasteur 2

Nice, 06000, France

RECRUITING

CHU de Nice - Hôpital L'Archet 2

Nice, 06202, France

RECRUITING

Hôpital Saint Louis

Paris, 75010, France

RECRUITING

Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix

Paris, 75013, France

RECRUITING

Institut Curie

Paris, 75248, France

RECRUITING

CHU Poitiers

Poitiers, 86021, France

RECRUITING

CHU de Reims - American Memorial Hospital 2

Reims, 51092, France

RECRUITING

Centre Eugène Marquis

Rennes, 35042, France

RECRUITING

CHU Rennes - Hôpital Sud

Rennes, 35203, France

RECRUITING

CHU Rouen Normandie - Hôpital Charles-Nicolle

Rouen, 76000, France

RECRUITING

CHU de Saint-Denis de La Réunion

Saint-Denis, 97400, France

RECRUITING

CHU de Saint-Etienne - Hôpital Nord

Saint-Etienne, 42270, France

RECRUITING

CHU de Saint-Pierre de La Réunion Sud

Saint-Pierre, 97488, France

NOT YET RECRUITING

Centre Régional Lutte Contre le Cancer Paul STRAUSS

Strasbourg, 67065, France

RECRUITING

Hôpital de Hautepierre

Strasbourg, 67200, France

RECRUITING

Hôpital Foch

Suresnes, 92150, France

NOT YET RECRUITING

Hôpital des enfants

Toulouse, 31059, France

RECRUITING

Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O) - Institut Claudius Regaud

Toulouse, 31059, France

RECRUITING

CHRU Tours - Hôpital Clocheville

Tours, 37000, France

RECRUITING

CHRU Tours - Hôpital Bretonneau

Tours, 37044, France

RECRUITING

Hospital Vall D´Hebron

Barcelona, 8035, Spain

RECRUITING

Hospital Universitario Niño Jesus

Madrid, 28009, Spain

RECRUITING

Hospital Universitario y Politécnico de La Fe

Valencia, 46026, Spain

RECRUITING

Karolinska University Hospital

Stockholm, 17176, Sweden

RECRUITING

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma

Interventions

Everolimus; TIC10 compound; Radiotherapy

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Therapeutics

Study Officials

• Jacques GRILL, MD, PhD

  Gustave Roussy, Cancer Campus, Grand Paris

  STUDY CHAIR

Central Study Contacts

Jacques GRILL, MD, PhD

CONTACT

+33 (0)1 42 11 62 09; jacques.grill@gustaveroussy.fr

Anne-Sophie BLANC, PharmD

CONTACT

+33 (0)1 42 11 57 02; annesophie.blanc@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2022
• First Posted: July 27, 2022
• Study Start: September 29, 2022
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2031
• Last Updated: February 5, 2026

Record last verified: 2026-02

Locations

DK (3); FR (43); SE (1); ES (3)