Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

NCT Neuro Master Match - N²M² (NOA-20) (N²M²)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03158389
Recruitment Status : Recruiting
First Posted : May 18, 2017
Last Update Posted : May 17, 2018
Sponsor:
Collaborators:
German Cancer Aid
German Cancer Research Center
National Center for Tumor Diseases, Heidelberg
Information provided by (Responsible Party):
Prof. Dr. Wolfgang Wick, University Hospital Heidelberg

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.

Condition or disease Intervention/treatment Phase
Glioblastoma, Adult Drug: APG101 Drug: Alectinib Drug: Idasanutlin Drug: Atezolizumab Drug: Vismodegib Drug: Temsirolimus Drug: Palbociclib Phase 1 Phase 2

  Hide Detailed Description

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 a 450k (epigenomewide) Illumina 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 match/no 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; i.e. there may be some linear relations between an alteration, e.g. 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 450k (epigenomewide) 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 (n=43) 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 I/IIa 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 13 sites in Germany. 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, panels/arrays only and it would be desirable that data from these initiatives are looked at in a joined manner.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Umbrella Protocol for Phase I/IIa 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)
Actual Study Start Date : May 7, 2018
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : September 30, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Subtrial A: APG101
  • weekly application of 400/600/800 mg i.v. until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: APG101
weekly i.v.

Experimental: Subtrial B: Alectinib
  • 600 mg orally twice daily (bid) for 6 until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: Alectinib
twice daily
Other Name: Alecensa

Experimental: Subtrial C: Idasanutlin
  • at escalating doses from 100 mg until maximum tolerated dose daily administered (orally) on five consecutive days of a 28-day cycle until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: Idasanutlin
on 5 days of a 28 days cycle

Experimental: Subtrial D: Atezolizumab
  • application of 1200 mg i.v. every three weeks until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: Atezolizumab
i.v. every 3 weeks

Experimental: Subtrial E: Vismodegib
  • daily application of 150 mg orally until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: Vismodegib
daily orally
Other Name: Erivedge

Experimental: Subtrial F: Palbociclib
  • 75/100/125 mg orally once daily on 21/28 days
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions)
  • followed by a 4 weeks break (after last dose of 2nd cycle)
  • and with maintenance therapy with palbociclib at 125 mg daily until progression
Drug: Palbociclib
orally on 21 days of a 28 days cycle
Other Name: Ibrance

Experimental: Subtrial G: Temsirolimus
  • weekly application of 25 mg i.v. until progression
  • in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
Drug: Temsirolimus
weekly i.v.
Other Name: Troisel




Primary Outcome Measures :
  1. PFS-6 rate [ Time Frame: 6 months ]
    defined as the proportion of patients free of progression at 6 months after study entry. PFS will be calculated from study entry until clinical or radiographic progression or death, whichever comes first.Progression will be evaluated according to Response Assessment in Neurooncology (RANO) criteria or Immunotherapy Response Assessment in Neurooncology (iRANO) criteria.


Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events (AE) [ Time Frame: 6 months ]
    Toxic effects will be graded according to CTCAE v4.03.

  2. Overall survival (OS) [ Time Frame: 6 months ]
    defined as the time from first administration of the investigational medicinal product (IMP) to time of death from any cause.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Main Inclusion Criteria:

  • Histologically confirmed, newly diagnosed glioblastoma (astrocytoma World Health Organization (WHO) grade IV) with unmethylated MGMT promoter determined by one of the accepted methods (qPCR, pyrosequencing, 450k array) and without mutation of the isocitrate dehydrogenase genes
  • Open biopsy or resection
  • Craniotomy or intracranial biopsy site must be adequately healed
  • Informed consent
  • Standard MRI ≤ 48 (+ 6 h) post-surgery according to the present national and international guidelines
  • Availability of fresh-frozen tissue, formalin-fixed, paraffin-embedded (FFPE) tissue, and blood
  • Age: ≥18 years
  • Karnofsky performance status (KPS) ≥70%
  • Life expectancy > 6 months
  • All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within 6 days prior to start of therapy. All female patients must be surgically sterile or must agree to use adequate contraception during the period of therapy and 6 months after the end of study treatment, or women must be postmenopausal for at least 2 years. Acceptable methods of contraception comprise barrier contraception combined with a medically accepted contraceptive method for the female patient (e.g. intra-uterine device with spermicide, hormonal contraceptive since at least 2 month). Female patients must agree not to donate lactation during treatment and until 6 months after end of treatment
  • Male patients willing to use contraception (condoms with spermicidal jellies or cream) upon study entry and during the course of the study and 3 months after the end of the study, have undergone vasectomy, or are practicing total abstinence. Sperm donation is not permitted for the same time interval.

Main Exclusion Criteria:

  • Abnormal (≥ Grade 2 CTCAE v4.03) laboratory values for hematology, liver or renal function.
  • HIV infection or active Hepatitis B or C infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies).
  • Prior therapy for glioma (except surgery and steroids) including but not limited to carmustine wafers and immunotherapy.
  • Concurrent participation in another interventional clinical trial studying a drug or treatment regimen.
  • Insufficient tumor material for molecular diagnostics
  • Pregnant and lactating women
  • History of hypersensitivity to any of the additives of the study drug formulations
  • Co-administration of anti-cancer therapies other than those administered/allowed in this study
  • Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study
  • Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry

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): NCT03158389


Contacts
Layout table for location contacts
Contact: Wolfgang Wick, Prof. Dr. +49 (0)6221 56 ext 7075 wolfgang.wick@med.uni-heidelberg.de

Locations
Layout table for location information
Germany
Charité Berlin, Neurosurgery Not yet recruiting
Berlin, Germany
Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic Not yet recruiting
Bochum, Germany
University Hospital Bonn, Neurology Clinic Not yet recruiting
Bonn, Germany
University Hospital Cologne, Neurosurgery Not yet recruiting
Cologne, Germany
University Hospital Dresden, Neurosurgery Not yet recruiting
Dresden, Germany
University Hospital Essen, Neurology Clinic Not yet recruiting
Essen, Germany
University Hospital Frankfurt, Neurooncology Not yet recruiting
Frankfurt am Main, Germany
University Hospital Heidelberg, Neurology Clinic Recruiting
Heidelberg, Germany
University Hospital Saarland, Neurosurgery Not yet recruiting
Homburg, Germany
University Hospital Mainz, Neurosurgery Not yet recruiting
Mainz, Germany
University Hospital Mannheim, Neurology Clinic Not yet recruiting
Mannheim, Germany
University Hospital Regensburg, Neurology Clinic Not yet recruiting
Regensburg, Germany
University Hospital Tuebingen, Neurooncology Not yet recruiting
Tübingen, Germany
Sponsors and Collaborators
University Hospital Heidelberg
German Cancer Aid
German Cancer Research Center
National Center for Tumor Diseases, Heidelberg
Investigators
Layout table for investigator information
Principal Investigator: Wolfgang Wick, Prof. Dr. University Hospital Heidelberg

Layout table for additonal information
Responsible Party: Prof. Dr. Wolfgang Wick, Coordinating Investigator, University Hospital Heidelberg
ClinicalTrials.gov Identifier: NCT03158389     History of Changes
Other Study ID Numbers: NCT-2014-0235/N2M2
2015-002752-27 ( EudraCT Number )
First Posted: May 18, 2017    Key Record Dates
Last Update Posted: May 17, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prof. Dr. Wolfgang Wick, University Hospital Heidelberg:
MGMT methylation
targeted therapy
umbrella protocol

Additional relevant MeSH terms:
Layout table for MeSH terms
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Atezolizumab
Palbociclib
Everolimus
Sirolimus
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents