Abstract Background Treatment options in progressive glioblastoma (GBM) are limited, especially in patients who have experienced disease progression while receiving bevacizumab therapy. This phase 2 study was conducted to evaluate the efficacy and safety of regorafenib monotherapy in patients with GBM. Methods Eligible patients had radiographic progression of histologically confirmed GBM following second- or third-line bevacizumab therapy. They received regorafenib monotherapy using the dose escalation strategy demonstrated in the ReDOS phase 2 clinical trial evaluating regorafenib in metastatic colon cancer. The target dose was 160 mg once daily, administered for 3 weeks on/1 week off in 28-day cycles. Patients underwent brain magnetic resonance imaging (MRI) every 8 weeks and were assessed via modified Response Assessment in Neuro-Oncology (RANO) criteria. Patients continued treatment with regorafenib therapy until they experienced progression or excessive toxicity. Results Based on the analysis of 13 enrolled patients, there were no responses and 12 of 13 (92.3%) had progressive disease (PD) on brain MRI; 1 patient went off study due to an adverse event (AE) occurring before assessment. The median OS was 4.1 months (95% CI 2.0—7.3). The OS at 12 months was 23% (0.2—46). The PFS at both 3 and 6 months was 7.7% (0.0—22.2%) with a median PFS of 1.0 month, (0.4—1.8). There was a total of 14 Grade 3 or 4 adverse events and no Grade 5 adverse events. Conclusions Regorafenib did not improve OS or PFS in bevacizumab-refractory recurrent glioblastoma. The study was halted early due to futility. Trial Registration NCT04051606
Lucas et al. (Mon,) studied this question.