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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 : August 8, 2018
Sponsor:
Collaborators:
Deutsche Kinderkrebsstiftung
Hannover Clinical Trial Center GmbH
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 effects of two further drugs, which have been applied to millions of children and adolescents in other indications, will be compared to each other. The aim of the trial will be to investigate whether these drugs may increase the effects of radio- and chemotherapy, resulting in a better survival of the treated patients. One of these additional drugs will be valproic acid, traditionally used for treatment of seizure disorder. The other drug will be Chloroquin, a well-established drug for Malaria treatment. Recently, scientific studies provided evidence for anti-tumoral effects of both drugs: Valproat seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important genetic processes of tumor growth. Chloroquin is an autophagy inhibitor. It prevents the shutting-down of tumor cell metabolism, a strategy to ensure survival of the whole tumor by developing a resistance against radiation and antineoplastic agents.

Studies in cell culture, animals and first clinical trials in adults as well provided evidence for efficacy of valproic acid and chloroquine 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. As common for clinical trials, the treatment of the patients will be settled in a randomized manner to ensure impartiality of the investigators.

One aim of the HIT-HGG-2013 trial will be to compare the effects of Valproat and Chloroquin to each other. Additionally, the results will be compared 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 Drug: Temozolomide + Chloroquine Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 198 participants
Allocation: Randomized
Intervention Model: Parallel 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 : January 1, 2022
Estimated Study Completion Date : June 1, 2023


Arm Intervention/treatment
Experimental: Temozolomide + Valproic acid
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

Experimental: Temozolomide + Chloroquine
Resochin junior® (Chloroquine), depending on patient weight and treatment scedule 1/2 to 3 tablets [25-150 mg] every day, p.o., 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 + Chloroquine
Chloroquine additionally to simultaneous radiochemotherapy with temozolomide




Primary Outcome Measures :
  1. Comparison of effects of valproine acid and chloroquine. [ Time Frame: 4.8 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 treated with additional CQ.

  2. Comparison of effects of valproine acid with respect to historical control group. [ Time Frame: 4.8 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.

  3. Comparison of effects of chloroquine with respect to historical control group. [ Time Frame: 4.8 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, DIPG, and gliomatosis cerebri differs for children treated with additional CQ 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 and/or any other 4-aminoquinoline compound (hydroxychloroquine, amodiaquine)
  • Prior chemotherapy 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. EXCEPTION: Patients may be eligible after a future amendment for a separate future targeted therapy protocol in addition to the current treatment protocol, i.e. radiotherapy and temozolomide plus VPA or CQ. These patients will then be stratified within the randomized arms of the current protocol.
  • 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
  • Severe manifest hepatic disease including hepatic porphyria as well as personal or family history of severe hepatic dysfunction, especially drug-related
  • Severe pancreatic disease
  • Severe hepatic disease
  • Lethal hepatic dysfunction in a sibling during valproic acid treatment
  • Known urea cycle defect
  • Severe coagulation disorders (in regards to thrombopenia see prerequisite for blood cell count before starting treatment)
  • Retinopathy and restricted visual fields (Exception: Brain tumour-related changes of visual fields)
  • Glucose-6-phosphate dehydrogenase deficiency (favism)
  • Myasthenia gravis
  • Known porphyria
  • Valproic acid as antiepileptc drug for any pre-existing epilepsy
  • Chloroquine or hydroxycloroquine as pre-existing and ongoing medication for malaria, lupus erythematodes, or any other medical reason

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
Contact: Christof Kramm, Prof., MD 49(0)551 3966201 christof.kramm@med.uni-goettingen.de

Locations
Germany
Klinikum Augsburg Recruiting
Augsburg, Germany
Contact: Michael Frühwald, Prof.         
Evangelisches Krankenhaus Bielefeld Recruiting
Bielefeld, Germany
Contact: Norbert Jorch, Dr.         
Universitätsklinikum Bonn Recruiting
Bonn, Germany
Contact: Carola Weber, Dr.         
Klinikum Bremen-Mitte gGmbH Recruiting
Bremen, Germany
Contact: Arnulf Pekrun, Prof.         
Klinikum Chemnitz gGmbH Recruiting
Chemnitz, Germany
Contact: André Hofmann, Dr.         
Carl-Thiem-Klinikum Cottbus gGmbH Recruiting
Cottbus, Germany
Contact: Georg Schwabe, PD Dr.         
Sana Kliniken Duisburg GmbH - Wedau Kliniken Recruiting
Duisburg, Germany
Contact: Tanja Höll, Dr.         
Universitätsklinikum Erlangen Recruiting
Erlangen, Germany
Contact: Markus Metzler, Prof.         
Universitätsklinikum Freiburg Recruiting
Freiburg, Germany
Contact: Charlotte Niemeyer, Prof.         
Universitätsmedizin Greifswald Recruiting
Greifswald, Germany
Contact: Holger Lode, Prof.         
Universitätsmedizin Göttingen Recruiting
Göttingen, Germany
Contact: Christof Kramm, Prof.         
Universitätsklinikum Halle Recruiting
Halle, Germany
Contact: Toralf Bernig, Dr.         
Universitätsklinikum des Saarlandes Recruiting
Homburg, Germany
Contact: Norbert Graf, Prof.         
Gesundheit Nordhessen - Klinikum Kassel Recruiting
Kassel, Germany
Contact: Michaela Nathrath, Prof.         
Universitätsklinikum Leipzig Recruiting
Leipzig, Germany
Contact: Holger Christiansen, Prof.         
UMM Universitätsmedizin Mannheim Recruiting
Mannheim, Germany
Contact: Matthias Dürken, PD Dr.         
Johannes Wesling Klinikum Minden Recruiting
Minden, Germany
Contact: Bernhard Erdlenbruch, Prof.         
Universitätsklinikum Münster Recruiting
Münster, Germany
Contact: Ronald Sträter, PD Dr.         
Klinikum Oldenburg gGmbH Recruiting
Oldenburg, Germany
Contact: Hermann Müller, Prof.         
Universitätsklinikum Regensburg Recruiting
Regensburg, Germany
Contact: Marcus Jakob, Dr.         
ASKLEPIOS Klinik St. Augustin Recruiting
Sankt Augustin, Germany
Contact: Harald Reinhard, PD Dr.         
Klinikum Stuttgart - Olgahospital Recruiting
Stuttgart, Germany
Contact: Stefan Bielack, Prof.         
Universitätsklinikum Tübingen Recruiting
Tübingen, Germany
Contact: Martin Ebinger, PD Dr.         
Sponsors and Collaborators
University of Göttingen
Deutsche Kinderkrebsstiftung
Hannover Clinical Trial Center GmbH
Investigators
Study Chair: Christof Kramm, Prof., MD University of Göttingen

Responsible Party: Prof. Dr. Christof Kramm, Coordinating investigator, University of Göttingen
ClinicalTrials.gov Identifier: NCT03243461     History of Changes
Other Study ID Numbers: 01153
2013-004187-56 ( EudraCT Number )
First Posted: August 9, 2017    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
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
Dacarbazine
Chloroquine
Chloroquine diphosphate
Valproic Acid
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents