Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma

Abstract Background and purpose This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) chemotherapy (TMZ), in treatment newly diagnosed glioblastoma (GBM) patients. Materials methods The study was designed as an open-label dose-escalation driven by Tite-CRM design followed expansion cohort. Ralimetinib administered orally every 12 h, 7 days week, for 2 cycles 2 weeks at 100, 200 or 300 mg/12 h. Patients received ralimetinib added standard concurrent RT (60 Gy 30 fractions) TMZ (75 mg/m2/day) 6 adjuvant (150–200 mg/m2 on days 1–5 28 days). Results MTD 100 mg/12 h chemoradiotherapy. three patients treated 200 mg/12 h presented dose-limiting toxicity: one patient had grade 3 face edema, two rash hepatic cytolysis (66%). Of 18 enrolled patients, 15 ralimetinib. At MTD, grade ? 3 adverse events during concomitant chemoradiotherapy were (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) nausea/vomiting (1/15). No interaction when administrated concomitantly has been observed. Inhibition pMAPKAP-K2 (?54%) observed peripheral blood mononuclear cells. Conclusion is first combination 100 mg/12 h. most frequent toxicities rash.