Ignite Creation Date:
2024-05-06 @ 10:05 AM
Last Modification Date:
2024-10-26 @ 12:24 PM
Study NCT ID:
NCT03158389
Status:
COMPLETED
Last Update Posted:
2023-09-28
First Post:
2017-05-16
Brief Title:
NCT Neuro Master Match - N²M² NOA-20
Sponsor:
University Hospital Heidelberg
Organization:
University Hospital Heidelberg
Study Overview
Official Title:
Umbrella Protocol for Phase IIIa Trials of Molecularly Matched Targeted Therapies Plus Radiotherapy in Patients With Newly Diagnosed Glioblastoma Without MGMT Promoter Methylation NCT Neuro Master Match - N²M² NOA-20
Status:
COMPLETED
Status Verified Date:
2023-09
Last Known Status:
None
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:
N²M²
Brief Summary:
The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design The progression-free survival rate at six months PFS-6 will be used to make decisions
Detailed Description:
Advances in the understanding of glioblastoma at a molecular level along with technological progress have led to the identification of key genetic alterations not only in scientific projects but also in every-day clinical practice These alterations increasingly refine the sub-classification of glioblastoma and the introduction of molecular markers in this classification which ultimately may allow defining subset specific treatments
The present umbrella concept for multiple biomarker-driven subtrials anchors at the Heidelberg-based INFORM registry trial in recurrent pediatric malignancies where in analogy to NCT Neuro Master Match N²M² whole-exome low-coverage whole-genome and transcriptome sequencing is used to identify targeted agents single or in combinations according to a dedicated algorithm It also shares conceptual similarities with international projects currently developed for lung and breast cancer Finally approaches to use molecular information in glioblastoma for the definition of a therapy at progression are also planned by the Defeat Glioma Consortium in the US and a group of excellence centers also in the US
The N²M² concept excels the aforementioned initiatives in the strict focus on newly diagnosed patients the option to cross-validate molecular biomarkers in an already analyzed contemporary cohort of glioblastoma patients analyzed in the German Consortium for Translational Cancer Research DKTK and the use of a parallel group treated with standard-of-care SOC Further restriction is made by the inclusion of patients only with a low likelihood to benefit from the SOC temozolomide TMZ chemotherapy on the basis of O6-methylguanine-DNA-methyltransferase MGMT promoter methylation allowing to replace TMZ with a molecularly targeted agent in combination with radiotherapy RT in each of the experimental subtrials Replacing TMZ by an experimental agent in the primary chemo-radiotherapy has been done in at least four completed trials albeit without pre-selection of a targeted therapy but the more opportunistic use of an available drug with no known MGMT interaction Focusing on newly diagnosed patients not only harbors the greater likelihood of impact on the disease but also allows addressing questions on acquired resistance in the more likely obtained tumor tissue at recurrence
N²M² is formally divided into a DISCOVERY and a TREATMENT aspect DISCOVERY starts with an epigenomewide Illumina methylation array and a panel sequencing followed by an appropriate and accepted standard method Sanger Sequencing or Immunohistochemistry within the scope of these methods for target validation prior to any suggestion for patient allocation into one of the subtrials Suggestions for patients allocation to one of the subtrials will be based on results of accepted standard methods These data will be generated from formaline-fixed paraffine embedded FFPE tissue within in 2-3 weeks after surgery The Heidelberg site has already established the next generation gene panel sequencing used for target discovery in case of N²M² and genome wide DNA methylation analyses for aiding daily routine To meet the criteria for a safe use of these data for decision-making the orthogonal standard methods performed in the Institute of Pathology are supplemented
DISCOVERY also includes the use of whole exome low-coverage whole-genome and transcriptome sequencing the methylome analysis and gene expression arrays to find new unexpected targets and get a more comprehensive view on affected pathways Discovery is also the driving force behind the work on resistant tumors The latter may result in individual treatment decisions at recurrence knowing there are no relevantly active treatments in this setting
TREATMENT is driven by a matchno match decision rendered in an algorithm that will be subject to refinement in the process of the project both by data generated in N²M² but also external evidence ie there may be some linear relations between an alteration eg BRAF V600E mutation and a distinct treatment or some others but it is expected that these linear relations will be replaced in a learning system by relations that take upstream and downstream target alterations and also parallel signaling pathways into account and may therefore already predict a certain likelihood of resistance development
In detail FFPE tissue and blood from patients diagnosed with a glioblastoma harboring an unmethylated MGMT promoter after informed consent will be subjected to a epigenomewide methylation array and panel sequencing as well as the appropriate methods to validate any of the trial immanent targets if they are present with results available within a maximum of 3 weeks postoperatively This allows for a timely decision at the molecular Neurooncology Tumor Board and a timely initiation within 4 to 6 weeks of the postoperative treatment Further examinations on fresh tumor tissue and blood such as whole exome low-coverage whole genome and transcriptome sequencing as well as expression arrays will be done to enhance the scientific background on the tumor tissue These data will not be used for decision-making Runs already done within the INFORM project with glioblastoma samples and also dry runs n43 for the N²M² project support the feasibility of the timelines and principal options for discovery
Matching will be defined as a molecular situation which makes treatment with RT and a matching targeted drug from a prespecified warehouse separated in subtrials meaningful Patients will be informed about the identified treatment option within the matching open-label parallel group Phase IIIa trial As for 2 of the experimental compounds APG101 and Atezolizumab no specific biomarker is validated at the moment the nonmatching patients will be equally allocated to receive either APG101 Atezolizumab or the current SOC radiochemotherapy with TMZ TMZ-group Patients allocated to the TMZ-group will serve as a meaningful control group with basic efficacy parameters documented if consent has been obtained
The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design The progression-free survival rate at six months PFS-6 will be used to make decisions
Parallel and ongoing translational projects within the DKTK will examine prognostic properties of the biomarkers identified to drive therapy decisions in this trial Trial accrual will be asymmetric into the different subtrials It is expected that 75-100 patients will be accrued into this trial per year at about 14 sites in Germany mainly Deutsches Konsortium für Translationale Krebsforschung DKTK and Neuroonkologische Arbeitsgemeinschaft NOA Importantly the parallel SPECTAbrain initiative of the European Organization for the Research and Treatment of Cancer EORTC is synergistic and not competitive to our study proposal since it is focused on the treatment at recurrence using paraffin-embedded tissues panelsarrays only and it would be desirable that data from these initiatives are looked at in a joined manner
The present umbrella concept for multiple biomarker-driven subtrials anchors at the Heidelberg-based INFORM registry trial in recurrent pediatric malignancies where in analogy to NCT Neuro Master Match N²M² whole-exome low-coverage whole-genome and transcriptome sequencing is used to identify targeted agents single or in combinations according to a dedicated algorithm It also shares conceptual similarities with international projects currently developed for lung and breast cancer Finally approaches to use molecular information in glioblastoma for the definition of a therapy at progression are also planned by the Defeat Glioma Consortium in the US and a group of excellence centers also in the US
The N²M² concept excels the aforementioned initiatives in the strict focus on newly diagnosed patients the option to cross-validate molecular biomarkers in an already analyzed contemporary cohort of glioblastoma patients analyzed in the German Consortium for Translational Cancer Research DKTK and the use of a parallel group treated with standard-of-care SOC Further restriction is made by the inclusion of patients only with a low likelihood to benefit from the SOC temozolomide TMZ chemotherapy on the basis of O6-methylguanine-DNA-methyltransferase MGMT promoter methylation allowing to replace TMZ with a molecularly targeted agent in combination with radiotherapy RT in each of the experimental subtrials Replacing TMZ by an experimental agent in the primary chemo-radiotherapy has been done in at least four completed trials albeit without pre-selection of a targeted therapy but the more opportunistic use of an available drug with no known MGMT interaction Focusing on newly diagnosed patients not only harbors the greater likelihood of impact on the disease but also allows addressing questions on acquired resistance in the more likely obtained tumor tissue at recurrence
N²M² is formally divided into a DISCOVERY and a TREATMENT aspect DISCOVERY starts with an epigenomewide Illumina methylation array and a panel sequencing followed by an appropriate and accepted standard method Sanger Sequencing or Immunohistochemistry within the scope of these methods for target validation prior to any suggestion for patient allocation into one of the subtrials Suggestions for patients allocation to one of the subtrials will be based on results of accepted standard methods These data will be generated from formaline-fixed paraffine embedded FFPE tissue within in 2-3 weeks after surgery The Heidelberg site has already established the next generation gene panel sequencing used for target discovery in case of N²M² and genome wide DNA methylation analyses for aiding daily routine To meet the criteria for a safe use of these data for decision-making the orthogonal standard methods performed in the Institute of Pathology are supplemented
DISCOVERY also includes the use of whole exome low-coverage whole-genome and transcriptome sequencing the methylome analysis and gene expression arrays to find new unexpected targets and get a more comprehensive view on affected pathways Discovery is also the driving force behind the work on resistant tumors The latter may result in individual treatment decisions at recurrence knowing there are no relevantly active treatments in this setting
TREATMENT is driven by a matchno match decision rendered in an algorithm that will be subject to refinement in the process of the project both by data generated in N²M² but also external evidence ie there may be some linear relations between an alteration eg BRAF V600E mutation and a distinct treatment or some others but it is expected that these linear relations will be replaced in a learning system by relations that take upstream and downstream target alterations and also parallel signaling pathways into account and may therefore already predict a certain likelihood of resistance development
In detail FFPE tissue and blood from patients diagnosed with a glioblastoma harboring an unmethylated MGMT promoter after informed consent will be subjected to a epigenomewide methylation array and panel sequencing as well as the appropriate methods to validate any of the trial immanent targets if they are present with results available within a maximum of 3 weeks postoperatively This allows for a timely decision at the molecular Neurooncology Tumor Board and a timely initiation within 4 to 6 weeks of the postoperative treatment Further examinations on fresh tumor tissue and blood such as whole exome low-coverage whole genome and transcriptome sequencing as well as expression arrays will be done to enhance the scientific background on the tumor tissue These data will not be used for decision-making Runs already done within the INFORM project with glioblastoma samples and also dry runs n43 for the N²M² project support the feasibility of the timelines and principal options for discovery
Matching will be defined as a molecular situation which makes treatment with RT and a matching targeted drug from a prespecified warehouse separated in subtrials meaningful Patients will be informed about the identified treatment option within the matching open-label parallel group Phase IIIa trial As for 2 of the experimental compounds APG101 and Atezolizumab no specific biomarker is validated at the moment the nonmatching patients will be equally allocated to receive either APG101 Atezolizumab or the current SOC radiochemotherapy with TMZ TMZ-group Patients allocated to the TMZ-group will serve as a meaningful control group with basic efficacy parameters documented if consent has been obtained
The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design The progression-free survival rate at six months PFS-6 will be used to make decisions
Parallel and ongoing translational projects within the DKTK will examine prognostic properties of the biomarkers identified to drive therapy decisions in this trial Trial accrual will be asymmetric into the different subtrials It is expected that 75-100 patients will be accrued into this trial per year at about 14 sites in Germany mainly Deutsches Konsortium für Translationale Krebsforschung DKTK and Neuroonkologische Arbeitsgemeinschaft NOA Importantly the parallel SPECTAbrain initiative of the European Organization for the Research and Treatment of Cancer EORTC is synergistic and not competitive to our study proposal since it is focused on the treatment at recurrence using paraffin-embedded tissues panelsarrays only and it would be desirable that data from these initiatives are looked at in a joined manner
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 |
|---|---|---|---|
| 2015-002752-27 | EUDRACT_NUMBER | None | None |