Background: VEGFR2 overexpression in glioblastoma serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed that detection of VEGFR2 specific T cells as well as altered intra-tumoral immunity is correlated with prolonged overall survival, one partial response was reported with VXM01 alone. Three patients received nivolumab in addition to VXM01, which resulted in one complete and one partial clinical response. Based on these findings, a trial combining VXM01 and avelumab was designed. Methods: A multicentre, open-label phase I/II study (EudraCT 2017-003076-31) in progressive glioblastoma includes 30 patients (24 non-resectable, 6 resectable) previously treated with temozolomide/radiotherapy. VXM01 is administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab 800mg is given intravenously q2w. Treatment continues up to week 48 followed by a 2 year observation period. The safety run-in phase of dose groups treated with VXM01 10⁶ or 10⁷ CFU plus avelumab was completed with 9 patients. Safety evaluation by the Data Safety Monitoring Board was performed after 3 and 9 patients treated for at least 5 weeks. Endpoints include safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, TCR-sequencing and tumor stainings. Results: No treatment-related toxicities were observed. Three partial responses with tumor reductions of 58, 81 and 95% to baseline were reported in 9 patients according to iRANO. Two of these patients are progression-free > 6 months. Significant VEGFR2 specific T cell responses were measured in several patients, and pre-existing intra-tumoral T cells are positively associated with the effectiveness of the immunotherapy combination. Conclusions: VXM01 in combination with avelumab was safe and produces detectable peripheral VEGFR-2 specific immune responses. Three patients had an objective response. Clinical trial information: NCT03750071.