Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0
- Conditions
- Diffuse Intrinsic Pontine GliomaDiffuse Midline Glioma, H3 K27M-Mutant
- Registration Number
- NCT05476939
- Lead Sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 409
Eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study:<br><br> - Diagnosis Criteria:<br><br> - Diagnosis of DIPG (clinical and radiological). As biopsy is not standard for<br> these tumors, an informed consent is required for the necessary histological<br> verification. [Biopsy-part of BIOMEDE 2.0 trial]. OR<br><br> - Histological diagnosis of DIPG (i.e. H3K28M or EZHIP positive Diffuse Midline<br> Glioma located in the pons) in case the biopsy was performed before study<br> entry. The diagnosis will be defined by 1/ diffuse glioma, 2/ H3K28M mutation<br> or loss of H3K28 trimethylation together with EZHIP overexpression. In this<br> situation, patient will sign the consent after the diagnosis to allow central<br> review and biomarkers assessment thereafter. OR<br><br> - Non-DIPG diffuse midline gliomas (ND-DMG), H3K28M mutant or with H3K28<br> trimethylation loss together with EZHIP overexpression, will be eligible for<br> the trial after biopsy or surgery. As biopsy and surgery is considered as<br> standard practice for these locations, informed consent for the biopsy will not<br> be necessary. Patient will sign the consent after the diagnosis to allow<br> central review and biomarkers assessment thereafter. OR<br><br> - Non-DIPG diffuse midline gliomas (ND-DMG) will be eligible for the trial before<br> the biopsy in case the diagnosis is clinically or radiologically suspected.<br> Informed consent for the biopsy and molecular analysis will be necessary. Then,<br> if the central pathology review concludes to a ND-DMG with H3K28M mutant or<br> H3K28 trimethylation loss together with EZHIP overexpression, these patients<br> will be eligible for the treatment part of the trial.<br><br> - Eligible for a biopsy, or biopsy material available for the biomarker assessment.<br><br> - Age > 6 months, with no upper age limit. Children between 6 months and 3 years will<br> be discussed on a case by case basis for inclusion in the study for the feasibility<br> of the stereotactic biopsy.<br><br> - Eligible for cerebral or craniospinal radiotherapy.<br><br> - Tumor at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral<br> radiation therapy even for another neoplasm. Surgery is allowed when performed for<br> diagnostic or therapeutic purpose.<br><br> - Metastatic diseases or spinal tumors allowed; in this case, patients would receive<br> craniospinal or spinal radiotherapy and medical treatment (everolimus or ONC201)<br> will be postponed and only started after the end of radiotherapy.<br><br> - Patients must be affiliated to a social security system or beneficiary of the same<br> according to local requirements.<br><br> - Written informed consent from parents/legal representative, patient, and<br> age-appropriate assent before any study-specific procedures are conducted according<br> to local, regional or national guidelines.<br><br>Non eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study:<br><br> - Uncontrolled spontaneous massive intratumor bleeding. Patients with post-operative<br> bleeding will be allowed to enter the study provided the hemorrhage is controled.<br> Same rule applies for the other post-operative complications (infection, CSF<br> leakage, absence of wound closure, subdural collection...).<br><br> - Any other concomitant anti-cancer treatment not foreseen by this protocol is not<br> allowed, except corticosteroids and Bevacizumab which are allowed during the<br> protocol. Bevacizumab is not allowed before and until 15 days after the surgery. The<br> use of bevacizumab and corticosteroids will be taken into account when judging the<br> possibility of progression/pseudoprogression.<br><br> - Any other cancer diagnosed during the last 5 years.<br><br> - Uncontrolled intercurrent illness or active infection.<br><br> - Any other co-morbid condition that in the investigator's opinion would impair study<br> participation.<br><br> - Unable for medical follow-up (geographic, social or mental reasons).<br><br> - Patient previously treated with irradiation on the brainstem for another neoplasm.<br><br> - Participation in another clinical study with an investigational product while on<br> study treatment.<br><br> - Patient under guardianship or deprived of his/her liberty by a judicial or<br> administrative decision or incapable of giving his/her consent.<br><br>Eligibility criteria for the randomization in BIOMEDE 2.0 study:<br><br> - Patient enrolled in the BIOMEDE 2.0 study.<br><br> - Life expectancy > 12 weeks after the start of study treatment.<br><br> - Histological diagnosis of DIPG (as per the WHO criteria) confirmed by central<br> pathology review, OR Typical radiology of a DIPG (mandatory central radiological<br> review) as well as the short clinical history (less than three months of<br> pre-existing symptoms) in case of suspected DIPG but no histological confirmation<br> (biopsy not informative), OR Histological diagnosis of ND-DMG confirmed by central<br> pathology review, with mutation in the histone H3.1, H3.2, H3.3 genes, or loss of<br> H3K28me3 and EZHIP overexpression by immunohistochemistry.<br><br> - Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not<br> take the neurologic deficit per se into account. NB: Children and adults with a<br> worse performance status due to glioma-related motor paresis can be included.<br><br> - Effective and appropriate contraception for patients (male and female) of<br> reproductive potential during their entire participation in the study and during 6<br> months after the end of treatment.<br><br> - Negative pregnancy test (serum beta-HCG or urinary test) evaluated within one week<br> prior randomization in sexually active females of reproductive potential.<br><br> - Absolute neutrophil count > 1.5 x 10^9/l, Platelets > 100 x 10^9/l.<br><br> - Total bilirubin < 1.5 x ULN, AST and ALT< 2.5 x ULN.<br><br> - Serum creatinine < 1.5 X ULN for age. If serum creatinine > 1.5 x ULN, creatinine<br> clearance must be > 70 ml/min/1.73 m² (as per local practice).<br><br> - Normal coagulation tests within the local reference ranges.<br><br> - Written informed consent from parents/legal representative, patient, and<br> age-appropriate assent before randomization according to local, regional or national<br> guidelines.<br><br>Non Eligibility criteria for the randomization in BIOMEDE 2.0 study:<br><br> - Current organ toxicity > grade 2 according to the NCI-CTCAE version 5.0 especially<br> cardiovascular or renal disease (including but not limited to: congenital long QT<br> syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure<br> despite adequate treatment).<br><br> - ONC201 administration should be avoided for patients with:<br><br> - Prolongation of QT/QTcF interval (QTc interval > 480 milliseconds) preferably<br> using Frederica's QT correction formula on two ECGs separated by at least 48<br> hours.<br><br> - A history of Torsades de pointes or heart failure, hypokalemia, or family<br> history of prolonged QT Syndrome.<br><br> - Required concomitant use of medication(s) known to prolong the QT/QTc interval.<br><br>In this case, patients will be treated in the Everolimus arm without randomization<br>(except if contra-indication to Everolimus).<br><br> - Pregnant or breastfeeding women.<br><br> - Patients with chronic HBV disease
Not provided
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Progression-free survival
- Secondary Outcome Measures
Name Time Method Overall survival (for all the comparisons to historical controls);Overall survival (for the internal comparison between randomized groups);Progression-free survival after first progression;Complication rate of the diagnostic biopsy-based procedure;Severity of the complications (including prolongation of the hospital stay) of the diagnostic biopsy-based procedure;Duration of the complications (including delay for starting treatment) of the diagnostic biopsy-base procedure;Safety profile of the drugs;Relative benefit/risk ratio of ONC201 compared to everolimus