International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)

Inclusion Criteria:

* Newly diagnosed, previously untreated diffuse paediatric high grade glioma with central neuropathological review including paedHGG (WHO grade IV) and anaplastic astrocytoma (WHO grade III).
* Newly diagnosed, previously untreated diffuse intrinsic pontine glioma with central neuroradiological review
* Newly diagnosed, previously untreated gliomatosis cerebri of all tumour grades with central neuroradiological review
* Patient ≥ 3 years and \< 18 years of age at time of diagnosis
* Written informed consent of the patient and/or the patient's parents or legal guardian according to national laws

Exclusion Criteria:

* Pre-treatment of paedHGG (WHO grade IV), anaplastic astrocytoma (WHO grade III), diffuse intrinsic pontine glioma (as confirmed by neuroradiological review), and gliomatosis cerebri (as confirmed by neuroradiological review).
* Known hypersensitivity or contraindication to study drugs and/or dacarbazine
* Prior chemotherapy within the last 30 days before HIT-HGG-2013 treatment or radiotherapy which prevents adequate Performance of radiotherapy as outlined by the present protocol. This may mainly apply to patients with secondary high grade glioma after previous malignant brain tumour, e.g. medulloblastoma, ependymoma, craniopharyngeoma. If previous treatment does not prevent the adequate performance of the outlined Treatment protocol patients with secondary high grade glioma will be eligible for the present trial.
* Other (simultaneous) malignancies
* Pregnancy and / or lactation
* Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly)
* Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial.
* Clinical (e.g. a constitutional mismatch repair deficiency score ≥ 3; Wimmer et al. 2014) and/or other hints (e.g. absent intratumoral immunohistochemical expression of at least one of the MLH1, MSH2, MSH6, or PMS2 mismatch repair proteins and/or high microsatellite instability) for an underlying biallelic (constitutional) mismatch repair deficiency (bMMRD/CMMRD) or a heterozygous mismatch repair deficiency (hereditary non-polyposis colon cancer syndrome/HNPCC syndrome/Lynch syndrome): These patients and their relatives should be offered human genetic counseling and rapid genetic diagnostics to confirm or rule out These conditions. These patients might not benefit from the present study treatment but maybe from other therapeutic strategies (Bouffet et al. 2016). Since patients with clinically suspected neurofibromatosis type 1 may display similar symptoms as in CMMRD, patients with clinically suspected neurofibromatosis type 1 should be also checked for CMMRD as suggested above.
* Very poor clinical condition as defined by demand of mechanical ventilation and/or demand for intravenous catecholamines and/or very severe neurological damage equivalent to a coma and/or tetraplegia with complete incapability for communication (deafness, blindness, mutism)
* Severe concomitant diseases (e.g. immune deficiency syndrome; known tumour predisposition syndromes which do not affect adequate performance of the trial represent no exclusion criterion a priori
* Known HIV positivity
* Known severe manifest hepatic disease including hepatic porphyria as well as personal or family history of severe hepatic dysfunction, especially drug-related
* Known severe pancreatic disease
* Known lethal hepatic dysfunction in a sibling during valproic acid treatment
* Known urea cycle defect
* Known mitochondrial diseases caused by genetic mutations within the gene coding for the enzyme polymerase gamma (POLG), e.g. Alpers-Huttenlocher syndrome, as well as suspected POLGrelated disorders in children under the age of two years
* Known severe coagulation disorders (in regards to thrombopenia see prerequisite for blood cell count before starting treatment)
* Valproic acid as antiepileptc drug for any pre-existing epilepsy (Exception: Valproic acid treatment due to tumour-related epilepsy will be tolerated, if the time interval between start of valproic acid treatment and trial enrolment is ≤ 8 weeks.