BIOMEDE: This phase II trial is testing three oral drugs (Erlotinib, Everolimus and Dasatinib) as a possible treatment for Diffuse Intrinsic Pontine Glioma (DIPG)Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication

Inclusion

Eligibility criteria for the BIOMEDE study (pre-screening for the randomised subtrials)

• Diagnosis of DIPG (clinical and radiological, or histological in case the biopsy was performed before study entry)
• DIPG at diagnosis: no prior chemotherapy for the present cancer;no prior cerebral radiation therapy
• NB : Metastatic disease allowed. Patient with metastatic disease are eligible for the study (including the randomised trial if diagnosis of DIPG confirmed). In this situation, radiotherapy will have to start within three weeks after the biopsy while targerted treatment will start at the end of the irradiation.
• Age > 6 months and < 25 years. For children below the age of 3 years, inclusion in the study and medical decisions should be discussed with the coordinating investigator.
• Eligible for a biopsy, or biopsy performed for diagnostic purpose and material available for the biomarker assessment
• Eligible for cerebral radiotherapy
• Patient covered by an health insurance if national requirement
• Written informed consent given by patient and/or parents/legal representative for biomarkers assessment and registration in the study.

Common eligibility criteria for the BIOMEDE randomised subtrials

• Eligibility criteria for the study (see above)
• Confirmed histological diagnosis of diffuse intrinsic pontine glioma (grade II, III, IV WHO), confirmed by central pathology review (including the assessment of the loss of H3K27me3 by immunohistochemistry or the presence of a mutation in the histone H3 variant genes).

Patients without classical clinical and radiological diagnostic criteria who fulfil the histological and biological criteria of DIPG are eligible for the trial.

Pilocytic astrocytoma and gangliogliomas are not eligible.

• Life expectancy > 12 weeks after the start of study treatment
• Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take the neurologic deficit per se into account. NB: Children and young adults with a worse performance status due to glioma-related motor paresis can be included.
• Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/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 ULN, creatinine clearance must be > 70 ml/min/1,73 m² (EDTA radioisotope GFR or 24 hours urines collection)
• Normal coagulation tests: prothrombin rate (prothrombin time = PT), TCA (PTT), fibrinogen
• No current organ toxicity > grade 2 according to the NCI-CTCAE version 4.0 especially cardiovascular, pulmonary or renal disease (,including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment, interstitial lung disease, pulmonary arterial hypertension). In case of known or possible cardiac disease, a cardiological advice will be required prior to the inclusion in the randomized trial as a preexisting cardiopathy represents a contra-indication to dasatinib.
• Effective 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) evaluated in the last week in females of reproductive potential
• Written informed consent given by patient and/or parents/legal representative for treatment and randomization

Eligibility criteria for the subtrials Eligibility criteria for the different subtrials will be mainly based on biomarkers assessment as detailed in the table above. In addition, contra-indication and precautions for use to specific drugs will be considered.