Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0
NCT ID: NCT05476939
Last Updated: 2024-12-13
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
409 participants
INTERVENTIONAL
2022-09-29
2031-09-30
Brief Summary
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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. Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity or consent withdrawal. A switch between treatment groups is allowed after confirmation of the disease progression (real-time central review blinded to the treatment arm allocation).
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.
Detailed Description
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Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
NONE
Study Groups
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everolimus
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.
Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity, or consent withdrawal.
At the time of centrally confirmed 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 before starting:
* the second treatment,
* or a reirradiation (if applicable). No treatment is allowed during reirradiation. Then, if an additional treatment is needed, the second treatment will be started within one week after the end of the reirradiation.
Everolimus
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.
Radiotherapy
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.
ONC201
Capsules of 125 mg. The prescribed dose is 375 mg/m², once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose.
Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity, or consent withdrawal.
At the time of centrally confirmed 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 before starting:
* the second treatment,
* or a reirradiation (if applicable). No treatment is allowed during reirradiation. Then, if an additional treatment is needed, the second treatment will be started within one week after the end of the reirradiation.
ONC201
Capsules of 125mg. The prescribed dose is 375mg/m², once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose.
Radiotherapy
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.
Interventions
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Everolimus
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.
ONC201
Capsules of 125mg. The prescribed dose is 375mg/m², once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose.
Radiotherapy
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion 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 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
* 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 (biopsy not informative), 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.
* 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 \> 1.5 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).
* ONC201 administration should be avoided for patients with:
* 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).
6 Months
ALL
No
Sponsors
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Jazz Pharmaceuticals
INDUSTRY
Innovative Therapies For Children with Cancer Consortium
OTHER
Ministry of Health, France
OTHER_GOV
Gustave Roussy, Cancer Campus, Grand Paris
OTHER
Responsible Party
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Principal Investigators
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Jacques GRILL, MD, PhD
Role: STUDY_CHAIR
Gustave Roussy, Cancer Campus, Grand Paris
Locations
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Aarhus Universitetshospital Skejby
Aarhus, , Denmark
Rigshospitalet
Copenhagen, , Denmark
H.C. Andersen Children's Hospital, Odense Universitetshospital
Odense, , Denmark
Gustave Roussy
Villejuif, Val De Marne, France
CHU d'Amiens-Picardie Site Sud
Amiens, , France
Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin
Angers, , France
CHU d'Angers - Bâtiment Robert Debré
Angers, , France
CHU Besançon - Hôpital Jean Minjoz
Besançon, , France
CHU de Bordeaux - Groupe hospitalier Saint André - Hôpital Saint André
Bordeaux, , France
CHU de Bordeaux - Groupe hospitalier Pellegrin - Hôpital des enfants
Bordeaux, , France
CHRU de Brest - Hôpital Morvan
Brest, , France
CHU de Caen - Hôpital Côte de Nacre
Caen, , France
CHU Estaing
Clermont-Ferrand, , France
Centre Jean Perrin
Clermont-Ferrand, , France
CHU François Mitterrand
Dijon, , France
CHU Grenoble Alpes - Hôpital Couple-Enfant
Grenoble, , France
Centre Oscar Lambret
Lille, , France
Hôpital de la mère et de l'enfant
Limoges, , France
Centre Léon Bérard
Lyon, , France
Hôpital de La Timone
Marseille, , France
Hôpital Arnaud de Villeneuve
Montpellier, , France
CHRU Nancy - Hôpital central
Nancy, , France
CHRU Nancy Brabois - Hôpital d'enfants
Nancy, , France
CHU de Nice - Hôpital L'Archet 2
Nice, , France
Hôpital Saint Louis
Paris, , France
Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix
Paris, , France
Institut Curie
Paris, , France
CHU Poitiers
Poitiers, , France
CHU de Reims - American Memorial Hospital 2
Reims, , France
Centre Eugène Marquis
Rennes, , France
CHU Rennes - Hôpital Sud
Rennes, , France
CHU Rouen Normandie - Hôpital Charles-Nicolle
Rouen, , France
CHU de Saint-Etienne - Hôpital Nord
Saint-Etienne, , France
Institut de cancérologie Strasbourg Europe (ICANS) - Centre Paul Strauss
Strasbourg, , France
Hôpital de Hautepierre
Strasbourg, , France
Hôpital des enfants
Toulouse, , France
CHRU Tours - Hôpital Clocheville
Tours, , France
CHRU Tours - Hôpital Bretonneau
Tours, , France
Hospital Vall D´Hebron
Barcelona, , Spain
Hospital Universitario Niño Jesus
Madrid, , Spain
Hospital Universitario y Politécnico de La Fe
Valencia, , Spain
Karolinska University Hospital
Stockholm, , Sweden
Countries
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Central Contacts
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Facility Contacts
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Torben Stamm MIKKELSEN, MD
Role: primary
Karsten NYSOM, MD, PhD
Role: primary
Michael CALLESEN, MD, PhD
Role: primary
Jacques GRILL, MD, PhD
Role: primary
Camille KHANFAR, MD
Role: primary
Paule AUGEREAU, MD
Role: primary
Emilie DE CARLI, MD
Role: primary
Véronique LAITHIER, MD
Role: primary
Charlotte BRONNIMANN, MD
Role: primary
Céline ICHER de BOUYN, MD
Role: primary
Liana CARAUSU, MD
Role: primary
Marianna DEPARIS, MD
Role: primary
Justyna KANOLD, MD, PhD
Role: primary
Xavier DURANDO, MD, PhD
Role: primary
Claire BRIANDET, MD
Role: primary
Anne PAGNIER, MD
Role: primary
Sandra RAIMBAULT, MD
Role: primary
Christophe PIGUET, MD
Role: primary
Pierre LEBLOND, MD, PhD
Role: primary
Nicolas ANDRE, MD, PhD
Role: primary
Gilles PALENZUELA, MD
Role: primary
Luc TAILLANDIER, MD, PhD
Role: primary
Pascal CHASTAGNER, MD
Role: primary
Gwenaëlle DUHIL DE BENAZE, MD
Role: primary
Stefania CUZZUBBO, MD
Role: primary
Mehdi TOUAT, MD
Role: primary
Franck BOURDEAUT, MD
Role: primary
Frédéric MILLOT, PhD
Role: primary
Grégory GUIMARD, MD
Role: primary
Elodie VAULEON, MD
Role: primary
Chloé PUISEUX, MD
Role: primary
Pascale SCHNEIDER, PhD
Role: primary
Sandrine THOUVENIN, MD, PhD
Role: primary
Roland SCHOTT, MD
Role: primary
Natacha ENTZ-WERLE, MD, PhD
Role: primary
Anne Isabelle BERTOZZI SALAMON, MD
Role: primary
Marion GILLIBERT-YVERT, MD
Role: primary
Bérangère NARCISO-RAHARIMANANA, MD
Role: primary
Anna LLORT, MD
Role: primary
Álvaro LASSALETTA, MD
Role: primary
Adela CAÑETE NIETO, MD
Role: primary
Klas BLOMGREN, MD, PhD
Role: primary
Other Identifiers
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2014-001929-32
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
2023-506027-29-00
Identifier Type: CTIS
Identifier Source: secondary_id
2014/2126
Identifier Type: -
Identifier Source: org_study_id