Clinical Trials /

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

NCT03243461

Description:

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).

Related Conditions:
  • Anaplastic Astrocytoma
  • Diffuse Glioma
  • Diffuse Intrinsic Pontine Glioma
  • Glioblastoma
  • Gliomatosis Cerebri
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 01153
  • SECONDARY ID: 2013-004187-56
  • NCT ID: NCT03243461

Conditions

  • Glioblastoma WHO Grade IV
  • Diffuse Midline Glioma Histone 3 K27M WHO Grade IV
  • Anaplastic Astrocytoma WHO Grade III
  • Diffuse Intrinsic Pontine Glioma
  • Gliomatosis Cerebri

Interventions

DrugSynonymsArms
Temozolomide + Valproic AcidTemozolomide + Valproic acid
Temozolomide + ChloroquineTemozolomide + Chloroquine

Purpose

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).

Detailed Description

      Indication:

      First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis
      cerebri in paediatric patients < 18 years of age.

      Background:

      Based on published results regarding the potential therapeutic benefit of adult and pediatric
      high grade glioma patients receiving either the histone deacetylase (HDAC) inhibitor valproic
      acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et al. 2011; Su et al. 2011;
      Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller et al. 2011) or the
      autophagy inhibitor chloroquine (CQ; Briceño et al. 2003, 2007; Sotelo et al. 2006) in
      addition to radiochemotherapy, the present trial is aimed to investigate if the addition of
      VPA or CQ to radiochemo- and maintenance therapy with temozolomide (Stupp et al. 2005; Cohen
      et al. 2011a, b) 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 VPA and CQ will be evaluated in a randomized fashion
      followed by 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.

      Therapy:

      TMZ, VPA, and CQ will be studied as investigational medicinal products in the present trial.

      ▪ Trial treatment will be performed as follows: Surgery with best possible extent of tumour
      resection

        -  Depending on the randomisation result:

        -  Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses as
           NON-RETARDED FORMULA (please use Valproat-neuraxpharm®, Valproatneuraxpharm® Lösung,
           Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft), increase by 10 mg/kg/d once per week up
           until recommended target serum level of 75-100 μg/ml is reached.

        -  Start as soon as diagnosis is confirmed with CQ. Please use Resochin junior®.

      Please use the following two dosing regimes to avoid to go beyond the maximum cumulative dose
      of [1000 mg/kg] as recommended by the SmPC:

      1. For the whole treatment period before and after radiochemotherapy (for radiochemotherapy
      see dosing scheme below): 50% of the recommended maximum doses in dependence of body weight
      according to SmPc: 11-20 kg: ½ tablet every SECOND day (= 40.5 mg CQ phosphate/25 mg CQ every
      SECOND day); 21-30 kg: 1/2 tablet every day (=40.5 mg CQ phosphate/25 mg CQ every day); 31-40
      kg: 1 tablet every day (= 81 mg CQ phosphate/50 mg CQ every day); 41-50 kg: 1 1/2 tablets
      every day (= 120.5 mg CQ phosphate/75 mg CQ every day); 51-60 kg: 2 tablets every day (= 162
      mg CQ phosphate/100 mg CQ every day); 61-70 kg: 2 ½ tablets every day (= 202.5 mg CQ
      phosphate/125 mg CQ every day). 2. ONLY for the 6-7 weeks of radiochemotherapy: 100% of the
      recommended maximum doses in dependence of body weight according to SmPc: 11-20 kg: ½ tablet
      every day (= 40.5 mg CQ phosphate/25 mg CQ every day); 21-30 kg: 1 tablet every day (= 81 mg
      CQ phosphate/50 mg CQ every day); 31-40 kg: 1 1/2 tablets every day (= 120.5 mg CQ
      phosphate/75 mg CQ every day); 41-50 kg: 2 tablets every day (= 162 mg CQ phosphate/100 mg CQ
      every day); 51-60 kg: 2 ½ tablets every day (= 202.5 mg CQ phosphate/125 mg CQ every day);
      61-70 kg: 3 tablets every day (= 241.5 mg CQ phosphate/150 mg CQ every day). Before and upon
      CQ treatment, an opthalmological examination including visus, visual fields, retinal fundus,
      colour vision, and cornea should at least be performed at treatment start and then every 3
      months!

        -  After start of VPA or CQ induction with simultaneous radiochemotherapy

        -  Fractionated, locoregional radiotherapy, total dose 54-60 Gy

        -  Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d,
           starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral
           temozolomide treatment may be started in single cases at maximum 7 days before
           radiotherapy if the 49 days treatment period still fully covers radiotherapy).

        -  Please, use Temodal® capsules (for oral application) and Temodal® powder (for
           preparation of an intravenously applicable solution).

        -  Maintenance therapy with daily VPA or CQ and

        -  four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral
           temozolomide [150-200 mg/m2/d], repeated every 28 days for in total 12 courses

        -  VPA or CQ treatment is performed until day 28 of the 12. course of temozolomide.

        -  Treatment doses may vary according to available medication formulations and sizes. Thus,
           deviances of +/- 15% of the recommended doses may be acceptable if not stated
           otherwise.The starting points of treatment may also vary in single cases. Thus,
           deviances of +/- 7 days of the recommended time periods to start treatment may be
           acceptable if not stated otherwise.

      Biometry (regarding the primary objectives):

        1. Confirmatory statistical design:

             1. Difference between the treatment with additional VPA and the treatment with
                additional CQ with respect to EFS (two sided test). Each of those planned
                statistical comparisons between two groups can be considered a combination of two
                one-sided tests. Accordingly, a superiority of one treatment group compared to the
                other treatment group will be interpreted, if a significant difference will be
                detected.

                Adaptive design with one interim analysis planned after 87 observed events, final
                analysis after 173 observed events.

             2. Difference between the treatment with additional VPA and the historic sample from
                the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as
                a significant difference between VPA treatment and the historic sample. A
                directional interpretation will detect either a superiority of the VPA-treatment
                compared to the historic sample, or a superiority of the historic sample compared
                to the VPA treatment sample.

             3. Difference between the treatment with additional CQ and the historic sample from
                the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as
                a significant difference between CQ-treatment and the historic sample. A
                directional interpretation will detect either a superiority of the CQ-treatment
                compared to the historic sample, or a superiority of the historic sample compared
                to the CQ-treatment sample.

           Statistical tests: adaptive Log-rank test / (conventional) Log-rank test Multiple
           Significance level α(overall) = 5%, Power = 80%, Assumed 6 months EFS-rates = 55% vs.
           70% Multiple Testing: Bonferroni-Holm adjustment will be performed.

        2. Estimated sample sizes:

      About 142 recruitments (after 87 observed events) at interim analysis, about 198 recruitments
      (after 173 observed events) at final analysis.

      Patient recruitment will be performed for 3.8 years. Individual follow-up (including study
      treatment) is required for this protocol for at least 1 year and 30 days after study entry.
      Long-term follow-up is strongly recommended and will be organised according to national
      guidelines and recommendations.

      Financial support:

      Deutsche Kinderkrebsstiftung, Bonn, Germany
    

Trial Arms

NameTypeDescriptionInterventions
Temozolomide + Valproic acidExperimentalValproat-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).
  • Temozolomide + Valproic Acid
Temozolomide + ChloroquineExperimentalResochin 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).
  • Temozolomide + Chloroquine

Eligibility 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
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Comparison of effects of valproine acid and chloroquine.
Time Frame:4.8 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Göttingen

Trial Keywords

  • Glioblastoma
  • high grade glioma
  • brain tumor
  • Anaplastic astrocytoma
  • DIPG
  • Gliomatosis cerebri
  • Diffuse midline glioma

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