Background: The overall survival (OS) of newly diagnosed glioblastoma (GB) patients (pts) treated with RT and TMZ is correlated with the methylation status of the MGMT-promoter. Pts with an unmethylated MGMT-promoter in particular have a poor prognosis and are in need of new active treatment options. Cilengitide, a selective αvβ_3/5 integrin inhibitor, and cetuximab, a monoclonal EGFR-targeted antibody, have demonstrated anti-tumor activity against GB and can be safely combined with RT and TMZ. Methods: CeCil is an academia sponsored, multi-center, randomized phase II clinical trial of postoperative RT with daily concomitant TMZ (75 mg/m²/day) followed by 6 adjuvant cycles of TMZ (75-100 mg/m²/d x21d q 28d). Pts are randomized (1:1) to additional treatment with either cilengitide 2000 mg 2x weekly i.v., or cetuximab 1x weekly i.v. (400 mg/m² for the 1st administration and 250mg/m² for subsequent administrations). Cilengitide and cetuximab administration is started 1 week prior to RT/TMZ and is continued for up to 52 consecutive weeks in non-progressive pts. The 1-year OS-rate is the primary endpoint. Secondary endpoints include the PFS, and safety. Eligibility criteria include histologically confirmed, newly diagnosed GB without a methylated MGMT promoter (pts with an “unmethylated” or “invalid” test result are eligible), age ≥ 18 year, performance status of 0-1, and prior tumor resection or open biopsy. Recruitment is a 2-step process: after informed consent, histopathological diagnosis of glioblastoma and MGMT–promoter methylation status are centrally determined; GB-confirmed patients with an “unmethylated” or “invalid” test result are randomized (stratification by RPA classes: III vs. IV-V) between the two treatment arms. According to a one-stage Fleming design (a: 0.05; b: 0.05), with P0=60% and P1=80%, 54 pts will be recruited per study-arm. At least 39 pts must be alive at 12 months to validate the predefined hypothesis of activity. Accrual is ongoing in 7 medical centers in Belgium. ClinicalTrials.gov identifier: NCT01044225.