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

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ClinicalTrials.gov Identifier: NCT03243461
Recruitment Status : Recruiting
First Posted : August 9, 2017
Last Update Posted : January 15, 2021
Sponsor:
Collaborators:
Deutsche Kinderkrebsstiftung
Hannover Medical School
Information provided by (Responsible Party):
Prof. Dr. Christof Kramm, University of Göttingen

Brief Summary:

The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for children and adolescents >3 years, suffering from one of the following types of high grade gliomas:

  1. glioblastoma WHO grade IV (GBM)
  2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG)
  3. anaplastic astrocytoma WHO grade III (AA)
  4. diffuse intrinsic pontine glioma (DIPG)
  5. gliomatosis cerebri (GC) For 1.-3. diagnosis has to be confirmed by neuropathological survey, for 4. and 5. diagnosis has to be confirmed by neuroradiological survey.

In addition to standard treatment (radiotherapy and temozolomide chemotherapy) the effect of valproic acid which is traditionally used for treatment of seizure disorder, will be investigated. The aim of the trial will be to investigate whether this drug may increase the effects of radio- and chemotherapy, resulting in a better survival of the treated patients. Scientific studies provided evidence for anti-tumoral effects of valproic acid: the drug seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important genetic processes of tumor growth.

Studies in cell culture, animals and first clinical trials in adults as well provided evidence for efficacy of valproic acid in the treatment of glioblastoma. Due to this we hope children and adolescents suffering from GBM, DMG, AA, DIPG und GC will benefit from the treatment, too.

The aim of the HIT-HGG-2013 trial will be to compare the effects of Valproic acid with data of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with simultaneous temozolomide radiochemotherapy).


Condition or disease Intervention/treatment Phase
Glioblastoma WHO Grade IV Diffuse Midline Glioma Histone 3 K27M WHO Grade IV Anaplastic Astrocytoma WHO Grade III Diffuse Intrinsic Pontine Glioma Gliomatosis Cerebri Drug: Temozolomide + Valproic Acid Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 167 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: International Cooperative Phase III Trial of the HIT-HGG Study Group for the Treatment of High Grade Glioma, Diffuse Intrinsic Pontine Glioma, and Gliomatosis Cerebri in Children and Adolescents < 18 Years.(HIT-HGG-2013)
Actual Study Start Date : July 17, 2018
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Temozolomide + Valproic acid
E.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung oder Orfiril® Saft (Valproic acid), [10 mg/kg/d] tablet oder juice, p.o., every day in parallel to simultaneous radiochemotherapy with cytostatic drug Temodal (Temozolomid): [75 mg/m2/d] during simultaneous radiochemotherapy (7 days a week, max. 49 days); [150-200 mg/m2/d] during consolidation therapy (for 5 days every 28 days, 12 cycles), tablets, p.o. (or powder for preparation of an intravenously applicable solution).
Drug: Temozolomide + Valproic Acid
Valproic acid additionally to simultaneous radiochemotherapy with temozolomide




Primary Outcome Measures :
  1. Comparison of effects of valproine acid with respect to historical control group. [ Time Frame: 5.4 years ]
    To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III (AAIII), DIPG, and gliomatosis cerebri differs for children treated with additional VPA compared to children in the historical HIT-HGG-2007 study sample.



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Ages Eligible for Study:   3 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03243461


Contacts
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Contact: Christof Kramm, Prof., MD 49(0)551 39 63081 christof.kramm@med.uni-goettingen.de

Locations
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Sponsors and Collaborators
University of Göttingen
Deutsche Kinderkrebsstiftung
Hannover Medical School
Investigators
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Study Chair: Christof Kramm, Prof., MD University of Göttingen
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Responsible Party: Prof. Dr. Christof Kramm, Coordinating investigator, University of Göttingen
ClinicalTrials.gov Identifier: NCT03243461    
Other Study ID Numbers: 01153
2013-004187-56 ( EudraCT Number )
First Posted: August 9, 2017    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Prof. Dr. Christof Kramm, University of Göttingen:
Glioblastoma
high grade glioma
brain tumor
Anaplastic astrocytoma
DIPG
Gliomatosis cerebri
Diffuse midline glioma
Valproic acid
Temozolomide
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Valproic Acid
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anticonvulsants
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs