Background: TMZ confers little benefit in newly diagnosed GBM with an unmethylated promoter of the MGMT (O6-methylguanine-DNA methyltransferase) gene. In this study, we address the chemoresistance in the MGMT unmethylated population, building on our preclinical data, prior experience with the integrin inhibitor cilengitide and the combination of low dose TMZ and PCB. Several trials have shown that cilengitide is active in GBM. There is evidence that protracted metronomic dosing of TMZ and the addition of low dose PCB may overcome TMZ resistance mediated by MGMT. Methods: Forty-eight newly diagnosed GBM patients with unmethylated MGMT gene promoter will be given cilengitide 2000 mg twice weekly over a period of 18 months without interruption. One week after the initiation of cilengitide, radiotherapy (60 Gy, 2 Gy per fraction) with concurrent daily TMZ (60 mg/m²) and daily PCB (50 mg if BSA < 1.7; 100 mg if BSA ≥ 1.7) is given over a period of 6 weeks. After a 4-week break, adjuvant TMZ (50mg/m² in first cycle, 60 mg/m² in subsequent cycles) and PCB (50 mg if BSA < 1.7; 100 mg if BSA ≥ 1.7) are then given daily D1 to 20. TMZ/PCB cycles are repeated every 28 days over a total of 6 cycles. The intensive safety-monitoring phase of 6 patients has already completed accrual. The primary endpoint is 12m overall survival. A one-stage design is used; with 95% probability of accepting the treatment if it’s true one-year survival were at least 65%, and 80% probability of rejecting the treatment if its true one-year survival were at most 45%. Secondary endpoints include 6-month progression-free survival, objective response and toxicity. Correlative studies will include measurement peripheral blood mononuclear cells MGMT as a surrogate for MGMT modulation and an exploration of biologic correlates of angiogenesis inhibition. ClinicalTrials.gov Identifier: NCT01124240.