Clinical trial NCT05476939: Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0
Official title: Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diffuse Intrinsic Pontine Glioma
Diffuse Midline Glioma, H3 K27M-Mutant
Keywords: Children
Adolescents
Adults
Newly diagnosed
Lead sponsor: Gustave Roussy, Cancer Campus, Grand Paris
Sponsor class: OTHER
Collaborators: name: Chimerix
name: Innovative Therapies For Children with Cancer Consortium
name: Ministry of Health, France
First posted: 2022-07-27
Enrollment: 409
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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. 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Progression-free survival
timeFrame: Until 2 years after inclusion of the last patient
Secondary outcomes:
measure: Overall survival (for all the comparisons to historical controls)
timeFrame: Until 5 years after randomization of the last patient
measure: Overall survival (for the internal comparison between randomized groups)
timeFrame: Until 5 years after randomization of the last patient
measure: Progression-free survival after first progression
timeFrame: Until 5 years after randomization of the last patient
measure: Complication rate of the diagnostic biopsy-based procedure
timeFrame: Until 5 years after randomization of the last patient
measure: Severity of the complications (including prolongation of the hospital stay) of the diagnostic biopsy-based procedure
timeFrame: Until 5 years after randomization of the last patient
measure: Duration of the complications (including delay for starting treatment) of the diagnostic biopsy-base procedure
timeFrame: Until 5 years after randomization of the last patient
measure: Safety profile of the drugs
timeFrame: Until 5 years after randomization of the last patient
measure: Relative benefit/risk ratio of ONC201 compared to everolimus
timeFrame: Until 5 years after randomization of the last patient
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital Skejby
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: H.C. Andersen Children's Hospital, Odense Universitetshospital
city: Villejuif
country: France
facility: Gustave Roussy
state: Val De Marne
city: Amiens
country: France
facility: CHU d'Amiens-Picardie Site Sud
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin
city: Angers
country: France
facility: CHU d'Angers - Bâtiment Robert Debré
city: Besançon
country: France
facility: CHU Besançon - Hôpital Jean Minjoz
city: Bordeaux
country: France
facility: CHU de Bordeaux - Groupe hospitalier Saint André - Hôpital Saint André
city: Bordeaux
country: France
facility: CHU de Bordeaux - Groupe hospitalier Pellegrin - Hôpital des enfants
city: Brest
country: France
facility: CHRU de Brest - Hôpital Morvan
city: Caen
country: France
facility: CHU de Caen - Hôpital Côte de Nacre
city: Clermont-Ferrand
country: France
facility: CHU Estaing
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: CHU François Mitterrand
city: Grenoble
country: France
facility: CHU Grenoble Alpes - Hôpital Couple-Enfant
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Hôpital de la mère et de l'enfant
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital de La Timone
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve
city: Nancy
country: France
facility: CHRU Nancy - Hôpital central
city: Nancy
country: France
facility: CHRU Nancy Brabois - Hôpital d'enfants
city: Nice
country: France
facility: CHU de Nice - Hôpital L'Archet 2
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix
city: Paris
country: France
facility: Institut Curie
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU de Reims - American Memorial Hospital 2
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rennes
country: France
facility: CHU Rennes - Hôpital Sud
city: Rouen
country: France
facility: CHU Rouen Normandie - Hôpital Charles-Nicolle
city: Saint-Étienne
country: France
facility: CHU de Saint-Etienne - Hôpital Nord
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe (ICANS) - Centre Paul Strauss
city: Strasbourg
country: France
facility: Hôpital de Hautepierre
city: Toulouse
country: France
facility: Hôpital des enfants
city: Tours
country: France
facility: CHRU Tours - Hôpital Clocheville
city: Tours
country: France
facility: CHRU Tours - Hôpital Bretonneau
city: Barcelona
country: Spain
facility: Hospital Vall D´Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Niño Jesus
city: Valence
country: Spain
facility: Hospital Universitario y Politécnico de La Fe
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Jacques GRILL, MD, PhD
role: STUDY_CHAIR
References: