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Neuro Oncol. 2019 Jan 1;21(1):95-105. doi: 10.1093/neuonc/noy161.

N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma.

Author information

1
Clinical Cooperation Unit Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center(DKFZ), Heidelberg, Germany.
2
Department of Neurology and Neuro-oncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
3
NCT Trial Center, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Division of Pediatric Neuro-oncology, DKFZ, German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
5
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
6
Division of Applied Bioinformatics, DKFZ, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
7
DKTK.
8
Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany.
9
National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany.
10
Clinical Cooperation Unit Radiation Oncology, DKFZ, Heidelberg, Germany.
11
Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.
12
DKFZ, Heidelberg, Germany.
13
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
14
Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
15
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
16
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
17
Clinical Cooperation Unit Neuropathology, DKTK.
18
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZ, Heidelberg, Germany.
19
Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract

Background:

Patients with glioblastoma without O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation are unlikely to benefit from alkylating chemotherapy with temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in unselected patient populations have failed to demonstrate any improvement of survival. Advances in molecular understanding and diagnostic precision enable identification of key genetic alterations in a timely manner and in principle allow treatments with targeted compounds based on molecular markers.

Methods:

The NCT Neuro Master Match (N2M2) trial is an open-label, multicenter, phase I/IIa umbrella trial for patients with newly diagnosed isocitrate dehydrogenase (IDH) wildtype glioblastoma without MGMT promoter hypermethylation to show safety, feasibility, and preliminary efficacy of treatment with targeted compounds in addition to standard radiotherapy based on molecular characterization. N2M2 is formally divided into a Discovery and a Treatment part. Discovery includes broad molecular neuropathological diagnostics to detect predefined biomarkers for targeted treatments. Molecular diagnostics and bioinformatic evaluation are performed within 4 weeks, allowing a timely initiation of postoperative treatment. Stratification for Treatment takes place in 5 subtrials, including alectinib, idasanutlin, palbociclib, vismodegib, and temsirolimus as targeted therapies, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asinercept (APG101) and the standard of care, TMZ. For the phase I parts, a Bayesian criterion is used for continuous monitoring of toxicity. In the phase II trials, progression-free survival at 6 months is used as endpoint for efficacy.

Results:

Molecular diagnostics and bioinformatic evaluation are performed within 4 weeks, allowing a timely initiation of postoperative treatment. Stratification for Treatment takes place in 5 subtrials, including alectinib, idasanutlin, palbociclib, vismodegib, and temsirolimus as targeted therapies, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asinercept (APG101) and the standard of care, TMZ. For the phase I parts, a Bayesian criterion is used for continuous monitoring of toxicity. In the phase II trials, progression-free survival at 6 months is used as endpoint for efficacy.

Discussion:

Molecularly informed trials may provide the basis for the development of predictive biomarkers and help to understand and select patient subgroups who will benefit.

PMID:
30277538
PMCID:
PMC6303534
[Available on 2020-01-01]
DOI:
10.1093/neuonc/noy161

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