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

Diffuse Intrinsic Pontine Glioma Clinical Trial

— BIOMEDE 2  

Official title:

Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05476939
• Other study ID #: 2014/2126
• Secondary ID: 2014-001929-32
• Status: Recruiting
• Phase: Phase 3
• Start date: September 29, 2022
• Est. completion date: September 2031

Study information

• Verified date: February 2024
• Source: Gustave Roussy, Cancer Campus, Grand Paris
• Contact: Jacques GRILL, MD, PhD
• Phone: +33 (0)1 42 11 62 09
• Email: jacques.grill[@]gustaveroussy.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 409
• Est. completion date: September 2031
• Est. primary completion date: September 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months and older

Eligibility

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).

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Diffuse Midline Glioma, H3 K27M-Mutant
• Glioma

Intervention

Drug:
• 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 per dose, once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose.

Radiation:
• Radiotherapy
All patients will be treated with 30 conventional single daily fraction 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.

Locations

Country	Name	City	State
France	CHU d'Amiens-Picardie Site Sud	Amiens
France	CHU d'Angers - Bâtiment Robert Debré	Angers
France	Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin	Angers
France	CHU Besançon - Hôpital Jean Minjoz	Besançon
France	CHU de Bordeaux - Groupe hospitalier Pellegrin - Hôpital des enfants	Bordeaux
France	CHU de Bordeaux - Groupe hospitalier Saint André - Hôpital Saint André	Bordeaux
France	CHRU de Brest - Hôpital Morvan	Brest
France	CHU de Caen - Hôpital Côte de Nacre	Caen
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	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-Étienne
France	Hôpital de Hautepierre	Strasbourg
France	Hôpital des enfants	Toulouse
France	CHRU Tours - Hôpital Bretonneau	Tours
France	CHRU Tours - Hôpital Clocheville	Tours
France	Gustave Roussy	Villejuif	Val De Marne

Sponsors (3)

Lead Sponsor	Collaborator
Gustave Roussy, Cancer Campus, Grand Paris	Chimerix, Innovative Therapies For Children with Cancer Consortium

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall survival (for all the comparisons to historical controls)	Defined from the date of radiological diagnosis to the date of death from any cause.	Until 5 years after randomization of the last patient
Secondary	Overall survival (for the internal comparison between randomized groups)	Defined from the date of randomization to the date of death from any cause.	Until 5 years after randomization of the last patient
Secondary	Progression-free survival after first progression	It will also be computed from the date of progression to the date of subsequent progression or death from any cause, in order to describe the outcome after progression.	Until 5 years after randomization of the last patient
Secondary	Complication rate of the diagnostic biopsy-based procedure		Until 5 years after randomization of the last patient
Secondary	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
Secondary	Duration of the complications (including delay for starting treatment) of the diagnostic biopsy-base procedure		Until 5 years after randomization of the last patient
Secondary	Safety profile of the drugs	Using the NCI-CTC v5.0 criteria, during radiotherapy and during the entire duration of the administration of the drug, considering all adverse events except adverse events unequivocally related to the disease (pseudo)-progression.	Until 5 years after randomization of the last patient
Secondary	Relative benefit/risk ratio of ONC201 compared to everolimus	It will be assessed using the Q-TWiST approach (Quality-adjusted time without symptoms of disease or adverse event) evaluated from survival times (overall survival and progression-free survival) and adverse events data (date of occurrence of grade 3+ adverse event).	Until 5 years after randomization of the last patient