Ignite Creation Date:
2024-05-06 @ 10:24 AM
Last Modification Date:
2024-10-26 @ 12:29 PM
Study NCT ID:
NCT03243461
Status:
UNKNOWN
Last Update Posted:
2022-06-06
First Post:
2017-08-04
Brief Title:
International Cooperative Phase III Trial of the HIT-HGG Study Group HIT-HGG-2013
Sponsor:
University of Göttingen
Organization:
University of Göttingen
Study Overview
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 YearsHIT-HGG-2013
Status:
UNKNOWN
Status Verified Date:
2022-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HIT-HGG-2013
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
In the present study it was originally planned to investigate the therapeutic efficiency and safety of valproic acid and the autophagy inhibitor chloroquine both in addition to temozolomide therapy Since distribution of Resochin junior chloroquine phosphate was terminated recruitment of new patients was stopped on August 8 2019 For continuation of the trial the chloroquine arm was closed but the patients already recruited in this arm will be followed up
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
In the present study it was originally planned to investigate the therapeutic efficiency and safety of valproic acid and the autophagy inhibitor chloroquine both in addition to temozolomide therapy Since distribution of Resochin junior chloroquine phosphate was terminated recruitment of new patients was stopped on August 8 2019 For continuation of the trial the chloroquine arm was closed but the patients already recruited in this arm will be followed up
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 preclinical and clinical results regarding the potential therapeutic benefit of adult and pediatric high grade glioma patients receiving 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 in addition to radiochemotherapy the present trial is aimed to investigate if the addition of VPA to radiochemo- and maintenance therapy with temozolomide Stupp et al 2005 Cohen et al 2011a b provides a survival advantage in comparison to radiochemo- and maintenance therapy with temozolomide alone Therapeutic efficiency of VPA will be evaluated 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 and VPA 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
Start as soon as diagnosis is confirmed with VPA 10 mgkgd in two daily doses preferencially as NONRETARDED FORMULA eg Valproat-neuraxpharm Valproat-neuraxpharm Lösung Ergenyl Ergenyl-Lösung or Orfiril Saft however any VPA preparation including generic drugs is allowed the use of a retarded formula might be helpful in some case as indicated below increase by 10 mgkgd once per week up until recommended target Serum level of 75-100 μgml 520-694 μmolL is reached If target serum levels cannot be reached with non-retarded formula andor side effects occur which might be connected to VPA change to a retarded formula may be helpful to obtain sufficient VPA serum levels andor reduce side effects If VPA target serum levels are still not reached andor side effects occur even with a retarded VPA formula please contact the HIT-HGG study office
After start of VPA induction with simultaneous radiochemotherapy
Fractionated locoregional radiotherapy total dose 54-60 Gy
Simultaneous chemotherapy with oral temozolomide 7 days per week at 75 mgm2d 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 temozolomide capsules for oral application and temozolomide powder for preparation of an intravenously applicable solution Any temozolomide preparation including generic drugs is allowed except for patients who are not able to swallow capsules and in whom the use of an intravenous solution is no Option only Temodal capsules must be used to generate a temozolomide suspension as described in the Appendix A11 Parents have to be advised how to prepare the Temodal suspension at the trial site PLEASE NOTE Capsules of generic temozolomide drugs other than Temodal MUST NOT be opened and used for generating temozolomide suspension
Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral temozolomide 150-200 mgm2d repeated every 28 days for in total 12 courses VPA treatment is performed until day 28 of the 12th 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 otherwiseThe 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
Primary end point Event-free survival
Biometry regarding the primary objectives
1 Confirmatory statistical design
1 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
Statistical tests adaptive Log-rank test conventional Log-rank test
Multiple Significance level αoverall 5 Power 80 Assumed 6 months EFS-rates 55 vs 70
Multiple Testing No Multiplicity Problem in this trial
2 Estimated sample sizes
About 167 recruitments at final analysis
Patient recruitment will be performed for 54 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
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 preclinical and clinical results regarding the potential therapeutic benefit of adult and pediatric high grade glioma patients receiving 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 in addition to radiochemotherapy the present trial is aimed to investigate if the addition of VPA to radiochemo- and maintenance therapy with temozolomide Stupp et al 2005 Cohen et al 2011a b provides a survival advantage in comparison to radiochemo- and maintenance therapy with temozolomide alone Therapeutic efficiency of VPA will be evaluated 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 and VPA 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
Start as soon as diagnosis is confirmed with VPA 10 mgkgd in two daily doses preferencially as NONRETARDED FORMULA eg Valproat-neuraxpharm Valproat-neuraxpharm Lösung Ergenyl Ergenyl-Lösung or Orfiril Saft however any VPA preparation including generic drugs is allowed the use of a retarded formula might be helpful in some case as indicated below increase by 10 mgkgd once per week up until recommended target Serum level of 75-100 μgml 520-694 μmolL is reached If target serum levels cannot be reached with non-retarded formula andor side effects occur which might be connected to VPA change to a retarded formula may be helpful to obtain sufficient VPA serum levels andor reduce side effects If VPA target serum levels are still not reached andor side effects occur even with a retarded VPA formula please contact the HIT-HGG study office
After start of VPA induction with simultaneous radiochemotherapy
Fractionated locoregional radiotherapy total dose 54-60 Gy
Simultaneous chemotherapy with oral temozolomide 7 days per week at 75 mgm2d 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 temozolomide capsules for oral application and temozolomide powder for preparation of an intravenously applicable solution Any temozolomide preparation including generic drugs is allowed except for patients who are not able to swallow capsules and in whom the use of an intravenous solution is no Option only Temodal capsules must be used to generate a temozolomide suspension as described in the Appendix A11 Parents have to be advised how to prepare the Temodal suspension at the trial site PLEASE NOTE Capsules of generic temozolomide drugs other than Temodal MUST NOT be opened and used for generating temozolomide suspension
Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral temozolomide 150-200 mgm2d repeated every 28 days for in total 12 courses VPA treatment is performed until day 28 of the 12th 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 otherwiseThe 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
Primary end point Event-free survival
Biometry regarding the primary objectives
1 Confirmatory statistical design
1 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
Statistical tests adaptive Log-rank test conventional Log-rank test
Multiple Significance level αoverall 5 Power 80 Assumed 6 months EFS-rates 55 vs 70
Multiple Testing No Multiplicity Problem in this trial
2 Estimated sample sizes
About 167 recruitments at final analysis
Patient recruitment will be performed for 54 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2013-004187-56 | EUDRACT_NUMBER | None | None |