Phase 2 mirdametinib MEK1/2 inhibitor with radiotherapy in NF1-altered high‑grade glioma

University of Alabama at Birmingham (UAB) is running this Phase 2, open-label, parallel, multi-arm study testing mirdametinib—an oral small-molecule MEK1/MEK2 inhibitor (MAPK-pathway blockade downstream of RAS)—either combined with radiotherapy (Cohorts 1–2) or as monotherapy (Cohort 3). Cohort 1 enrolls adults with recurrent, sporadic IDH-wildtype grade 4 glioblastoma that harbors a pathogenic NF1 loss-of-function alteration but without a clinical NF1 diagnosis, and pairs re-irradiation with twice-daily mirdametinib. Cohorts 2–3 enroll participants with germline NF1 (≥12 years): Cohort 2 is newly diagnosed NF1-associated GBM/HGG (including select TP53-mutant HGG) treated with concurrent RT + mirdametinib followed by continued cycles; Cohort 3 treats NF1-associated HGAP or other non-GBM HGG with mirdametinib alone, using RANO 2.0 criteria. Scientifically, it is a biomarker-led attempt to exploit NF1-driven MAPK dependence in tumors where MEK inhibition has been inconsistent, while also probing whether MEK blockade can radiosensitize NF1-altered GBM. For newly diagnosed GBM/HGG, today’s care is maximal safe resection followed by radiotherapy with temozolomide (and sometimes tumor-treating fields), while recurrent GBM typically receives clinical trials, bevacizumab-based approaches, re-irradiation in select patients, and/or additional chemotherapy.