HIT HGG 2013

high grade glioma, diffuse intrinsic pontine glioma, and gliomatosis cerebri

First-line treatment of high grade glioma, diffuse intrinsic pontine glioma, and gliomatosis cerebri in children

The present trial is aimed to investigate if the addition of VPA or CQ to radiochemo- and maintenance therapy with temozolomide provides a survival advantage in comparison to each other and also in comparison to radiochemo- and maintenance therapy with temozolomide alone.
Differences in therapeutic efficiencies between comparison with a historical patient control from the previous trial HIT-HGG-2007 with temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities will also be analysed.

As soon as diagnosis is confirmed the patients will be included into the trial. After the start of induction therapy with VPA , follows the combined radiation therapy (fractioned local radiation with a total dose of 54-60 Gy and administration of Temozolomide) and daily oraladminstration of Valproine acid. Four weeks after the end of the combined radio-chemotherapy the temozolomide
After the start of induction therapy with VPA, combined radiochemotherapy (fractionated local irradiation with a total dose of 54-60 Gy and daily oral temozolomide for a maximum of 49 days) and additional daily oral valproic acid are administered.
Four weeks after completion of simultaneous radiochemotherapy, treatment with oral temozolomide [150-200 mg/m2/d] is started for 5 days at a time and repeated a total of 12 times at 28-day intervals. VPA is administered until the 28th day of the 12th Temodal cycle.

• Newly diagnosed, previously untreated high-grade diffuse glioma (WHO grade IV), anaplastic astrocytoma (WHO grade III) confirmed by reference histology.
• Newly diagnosed, previously untreated diffuse intrinsic pons glioma confirmed by reference radiologic assessment.
• Newly diagnosed, previously untreated gliomatosis cerebri of all WHO grades confirmed by reference radiology assessment
• Patient age at diagnosis from 3 years and under 18 years
• Written consent to participate in the study by the patient or their legal representative

• Previous treatment of pediatric high-grade glioma (WHO grade IV), anaplastic astrocytoma (WHO grade III), (radiologically confirmed) diffuse intrinsic pons glioma and (radiologically confirmed) gliomatosis cerebri deviating from the study protocol.
• Known allergies/hypersensitivity to the study medication and/or dacarbazine and/or 4-aminoquinoline-related substances (hydroxychloroquine, amodiaquine)
• Previous chemotherapy within the last 30 days before the start of treatment according to HIT-HGG-2013, or radiotherapy that no longer allows radiotherapy to be carried out according to the protocol.
• Other (simultaneous) malignancies
• Pregnancy / breastfeeding
• Sexually active patients who refuse reliable contraception (e.g. oral contraception; intrauterine devices, condoms in combination with spermicides)
• Current or recent (within the last 30 days before the start of treatment according to HIT-HGG-2013) treatment with another study medication or participation in another treatment study.
• Clinical evidence (e.g. a constitutional mismatch repair deficiency score ≥ 3; Wimmer et al. 2014) and/or other evidence (e.g. lack of intratumoral immunohistochemical expression of at least one of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2, and/or high microsatellite instability) indicates the presence of a biallelic (constitutional) mismatch repair defect (bMMRD/CMMRD) or a heterozygous mismatch repair defect (hereditary non-polyposis co-loncinoma syndrome/HNPCC syndrome/Lynch syndrome).
• Very poor general clinical condition requiring mechanical ventilation and/or intravenous catecholamines and/or severe neurological damage
• Severe concomitant disease (e.g. severe congenital immunodeficiency)
• Known HIV positivity
• Serious manifest liver disease such as porphyria or a family history of severe hepatic dysfunction, particularly drug-associated
• Serious disease of the pancreas
• Fatal liver dysfunction in siblings who were treated with valproic acid
• Known defect of the uric acid cycle
• Serious coagulation disorders (in the case of thrombocytopenia, please observe the basic blood count requirements before starting treatment)
• Retinopathy and restricted visual field (exception: impairment of the visual field due to a brain tumor)
• Glucose-6-phosphate dehydrogenase deficiency (favism)
• Myasthenia gravis
• Known porphyria
• The use of valproic acid as part of the treatment of pre-existing epilepsy
• The use of chloroquine or hydroxychloroquine in the context of a pre-existing medical indication (malaria, lupus erythematosus or other diseases).