Abstract BACKGROUND In the randomized phase 2 REGOMA trial, regorafenib has shown promising activity in recurrent glioblastoma patients with a significantly longer survival compared to the standard lomustine therapy. Subsequently, in Italy regorafenib was approved as second-line therapy by the Italian Medicines Agency. We performed a large multicenter, prospective and observational study to confirm REGOMA data in the real-world setting. METHODS Based on the REGOMA results, at least 150 patients had to be enrolled to estimate a 1-year survival rate with a precision of 7.8% and a confidence interval of 95%. Major inclusion criteria were: histologically confirmed diagnosis of glioblastoma according to WHO 2016, radiologically documented first relapse/progression after Stupp treatment, good performance status (ECOG PS 0-1), adequate hepatic and hematological function, stable or decreasing corticosteroid use within 7 days before starting regorafenib.Regorafenib has been administered at the standard dose of 160 mg/die for 3 weeks on/1 week off, until disease progression or unacceptable toxicity. Brain MRI has been performed within 14 days before starting regorafenib and then every 8-12 weeks. Primary endpoint is overall survival. Secondary endpoints include: progression-free survival, objective response rate, toxicity and quality of life. RANO criteria is used for response evaluation, CTCAE v. 5.0 for adverse events, EORTC QLQ-C30 and brain module BN20 for quality of life. Recruitment started in September 2020 and finished in October 2022. 191 recurrent glioblastoma patients were prospectively enrolled from 29 cancer centers in Italy: median age was 59 years (IQR 52.6-66.9), 68% male and 32% female, ECOG PS was 0 in 84 (44%), 115 pts (60%) undertook steroids at baseline. MGMT was methylated in 43% and IDH1/2 was wild-type in 92% of patients. The results from this large multicenter Italian study are expected in the second half of 2023.