N2M2 (NOA20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma

Abstract

Background

Patients with glioblastoma without O6-methyl guanine O6-methylatransferase (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 and analysis

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 in 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 four weeks, allowing a timely initiation of postoperative treatment. Stratification for TREATMENT takes place in five 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 six months is used as endpoint for efficacy.