Background: Glioblastoma (GBM) is the most aggressive primary brain tumor with inevitable local relapse and no standard treatment. Hypofractionated stereotactic radiotherapy (hFSRT) has shown signs of efficacy with tolerable safety with PFS ranging from 3.4 to 5 months, but needs improvement. Radiotherapy (RT) causes immunogenic tumor cell death but also induces PDL1 and PD1 expression on tumors and immune cells, potentially evoking resistance to RT. Pre-clinical studies combining hFSRT with an anti-PD-1 antibody in GBM have shown increased efficacy of the combination. Clinical studies also show encouraging results when checkpoint inhibitors have been combined with high dose RT. We hypothesized that combining the anti PD-L1 Durvalumab (Durva) with hFSRT will be an effective regimen for patients with recurrent GBM. We designed a phase I and a phase II clinical trials studying the combination of hFSRT with Durva for recurrent GBM≤35 mm diameter. Results of the phase I are presented. Methods: A standard 3+3 dose escalation design was used. Patients were treated by hFSRT 24 Gy, 8 Gy/fraction at 80% isodose, every other day, combined with Durva infusion 1500mg first dose (Level 1) or 750 mg (Level -1) delivered on the last hFSRT, day followed by 1500 mg Durva infusion every four weeks until relapse and for a maximum of 12 months. The schema was defined as safe if one patient or less among 6 presents a dose limiting toxicity (DLT). DLT period started on the first Durva infusion with radiotherapy until 4 weeks. Brain MRI were performed before RT and then every 8 weeks until relapse. Results: Among the 6 patients (3 methylated MGMT, 3 unmethylated MGMT) included at the level 1, all completed the hFSRT course, only one had a DLT which was an immune related grade 3 vestibular neuritis. No DLT related to hFSRT or the Durva combination was reported. No other serious adverse event (SAE), immune-related AE or AE of special interest was reported. Conclusions: Combining three 8 Gy fractions of hFSRT with 1500 mg Durvalumab on the 3^rd fraction hFSRT and every 4 weeks for recurrent GBM is well tolerated justifying exploration of its efficacy in the phase II component of the study. Clinical trial information: NCT02866747