The German National Center for Tumor Diseases (NCT) has developed a noncomparative screening trial called Neuro Master Match (N2M2) for first-line unmethylated glioblastoma classification.
The NCT Neuro Master Match (N2M2) trial is an open-label, multicenter, phase 1/IIa umbrella trial for patients with newly diagnosed Glioblastoma IDH wildtype 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 bioinformatics 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 2trials, progression-free survival at 6 months is used as endpoint for efficacy.
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.
Molecularly informed trials may provide the basis for the development of predictive biomarkers and help to understand and select patient subgroups who will benefit 1).
The N2M2 study represents a significant advance in study design for evaluation of drugs in the early phase II space for newly diagnosed GBM. It will be of great interest to the field to see how this design plays out in “real life,” and whether any of the substudies show evidence of efficacy in their target populations. Furthermore, the practical experience of using extensive multiplatform biomarker data in a large, prospective platform study will aid other platform efforts in the field, including adaptive studies such as INSIGhT 2) 3) and GBM AGILE, 4) which target the later phase II and phase III areas of drug evaluation for both newly diagnosed and recurrent GBM 5).