Background: The vaccine (VXM01) is a VEGFR-2 coding DNA vaccine, using a Salmonella Ty21a carrier for oral application. VEGFR-2 is over-expressed in glioblastoma and serves as a promising target for VEGFR-2 primed T cells with the potential to alter tumor angiogenesis and/or eliminate VEGFR-2 expressing tumor cells. VXM01 was well tolerated in a previous phase I/II study involving 14 patients with progressive glioblastoma multiforme. Immunological correlates of vaccination and anti-tumor immunity in the blood and in the tumor were detected. At least one objective clinical response was attributed to vaccine monotherapy, with one more PR achieved in combination with nivolumab. Prolonged overall survival was associated with peripheral immune responses against VEGFR-2, J Clin Oncol 36, 2018 (suppl; abstr 2017). A combination study with the anti PD-L1 checkpoint inhibitor monoclonal antibody avelumab is currently underway. Methods: A multicentre, open-label phase I/II study (EudraCT.gov no.2017-003076-31), will enrol 30 patients with progressive glioblastoma, previously treated with temozolomide/radiotherapy. The primary objective is to evaluate safety and tolerability of the vaccine in combination with avelumab. In a 1+2 safety run in, two cohorts of non-reoperable patients will be vaccinated with one of 2 doses of the oral vaccine (10⁶ or 10⁷ CFU) with concurrent intravenous avelumab. After safety evaluation and recommendation of study continuation by the Data Safety Monitoring Board, 18 non-re-operable and 6 re-operable patients will be treated with 10⁷ CFU of the vaccine + avelumab. Vaccinations for all patients will be on day 1, 3, 5, and 7, followed by 4-weekly boosts until progression. Avelumab 800 mg will be administered every two weeks until progression. The enrolment of cohort 1 started with inclusion of the 1st patient in November 2018. The end of study is week 60. Follow up visits will be on months 1, 3, 6, 12 and 24. Objective response rate (ORR), clinical response using iRano criteria, immunological correlates before and after treatment using ELISpot, FACS, TCR-sequencing, IF, and IHC laboratory methods. Clinical trial information: NCT03750071