Informations générales (source: ClinicalTrials.gov)
Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication (BIOMEDE 2)
Interventional
Phase 3
Gustave Roussy, Cancer Campus, Grand Paris (Voir sur ClinicalTrials)
septembre 2022
septembre 2031
14 décembre 2024
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. 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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT CURIE | 04/12/2024 12:44:15 | Contacter | |||
| CLCC INSTITUT GUSTAVE ROUSSY | Nadia YOUNAN | 23/12/2024 08:04:34 | Contacter | ||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Eugène Marquis - 35042 - Rennes - France | Elodie VAULEON, MD | Contact (sur clinicalTrials) | |||
| Centre Jean Perrin - 63011 - Clermont-Ferrand - France | Xavier DURANDO, MD, PhD | Contact (sur clinicalTrials) | |||
| Centre Léon Bérard - 69373 - Lyon - France | Pierre LEBLOND, MD, PhD | Contact (sur clinicalTrials) | |||
| Centre Oscar Lambret - 59020 - Lille - France | Sandra RAIMBAULT, MD | Contact (sur clinicalTrials) | |||
| CHRU de Brest - Hôpital Morvan - 29609 - Brest - France | Liana CARAUSU, MD | Contact (sur clinicalTrials) | |||
| CHRU Nancy - Hôpital central - 54035 - Nancy - France | Luc TAILLANDIER, MD, PhD | Contact (sur clinicalTrials) | |||
| CHRU Nancy Brabois - Hôpital d'enfants - 54500 - Nancy - France | Pascal CHASTAGNER, MD | Contact (sur clinicalTrials) | |||
| CHRU Tours - Hôpital Bretonneau - 37044 - Tours - France | Bérangère NARCISO-RAHARIMANANA, MD | Contact (sur clinicalTrials) | |||
| CHRU Tours - Hôpital Clocheville - 37000 - Tours - France | Marion GILLIBERT-YVERT, MD | Contact (sur clinicalTrials) | |||
| CHU Besançon - Hôpital Jean Minjoz - 25030 - Besançon - France | Véronique LAITHIER, MD | Contact (sur clinicalTrials) | |||
| CHU d'Amiens-Picardie Site Sud - 80054 - Amiens - France | Camille KHANFAR, MD | Contact (sur clinicalTrials) | |||
| CHU d'Angers - Bâtiment Robert Debré - 49933 - Angers - France | Emilie DE CARLI, MD | Contact (sur clinicalTrials) | |||
| CHU de Bordeaux - Groupe hospitalier Pellegrin - Hôpital des enfants - 33076 - Bordeaux - France | Céline ICHER de BOUYN, MD | Contact (sur clinicalTrials) | |||
| CHU de Bordeaux - Groupe hospitalier Saint André - Hôpital Saint André - 33000 - Bordeaux - France | Charlotte BRONNIMANN, MD | Contact (sur clinicalTrials) | |||
| CHU de Caen - Hôpital Côte de Nacre - 14033 - Caen - France | Marianna DEPARIS, MD | Contact (sur clinicalTrials) | |||
| CHU de Nice - Hôpital L'Archet 2 - 06202 - Nice - France | Gwenaëlle DUHIL DE BENAZE, MD | Contact (sur clinicalTrials) | |||
| CHU de Reims - American Memorial Hospital 2 - 51092 - Reims - France | Grégory GUIMARD, MD | Contact (sur clinicalTrials) | |||
| CHU de Saint-Etienne - Hôpital Nord - 42270 - Saint-Étienne - France | Sandrine THOUVENIN, MD, PhD | Contact (sur clinicalTrials) | |||
| CHU Estaing - 63003 - Clermont-Ferrand - France | Justyna KANOLD, MD, PhD | Contact (sur clinicalTrials) | |||
| CHU François Mitterrand - 21079 - Dijon - France | Claire BRIANDET, MD | Contact (sur clinicalTrials) | |||
| CHU Grenoble Alpes - Hôpital Couple-Enfant - 38700 - Grenoble - France | Anne PAGNIER, MD | Contact (sur clinicalTrials) | |||
| CHU Poitiers - 86021 - Poitiers - France | Frédéric MILLOT, PhD | Contact (sur clinicalTrials) | |||
| CHU Rennes - Hôpital Sud - 35203 - Rennes - France | Chloé PUISEUX, MD | Contact (sur clinicalTrials) | |||
| CHU Rouen Normandie - Hôpital Charles-Nicolle - 76000 - Rouen - France | Pascale SCHNEIDER, PhD | Contact (sur clinicalTrials) | |||
| Hôpital Arnaud de Villeneuve - 34090 - Montpellier - France | Gilles PALENZUELA, MD | Contact (sur clinicalTrials) | |||
| Hôpital de Hautepierre - 67200 - Strasbourg - France | Natacha ENTZ-WERLE, MD, PhD | Contact (sur clinicalTrials) | |||
| Hôpital de la mère et de l'enfant - 87042 - Limoges - France | Christophe PIGUET, MD | Contact (sur clinicalTrials) | |||
| Hôpital de La Timone - 13005 - Marseille - France | Nicolas ANDRE, MD, PhD | Contact (sur clinicalTrials) | |||
| Hôpital des enfants - 31059 - Toulouse - France | Anne Isabelle BERTOZZI SALAMON, MD | Contact (sur clinicalTrials) | |||
| Hôpital Saint Louis - 75010 - Paris - France | Stefania CUZZUBBO, MD | Contact (sur clinicalTrials) | |||
| Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix - 75013 - Paris - France | Mehdi TOUAT, MD | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin - 49055 - Angers - France | Paule AUGEREAU, MD | Contact (sur clinicalTrials) | |||
| Institut de cancérologie Strasbourg Europe (ICANS) - Centre Paul Strauss - 67065 - Strasbourg - France | Roland SCHOTT, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
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 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).
- 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 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).