Background: Despite demonstrated chemosensitivity with PCV and TMZ, improvement of chemotherapy regimen need to be explored in AOG. Promising activity of BCNU and TMZ combination has been reported in GBM. We conducted a phase II study to evaluate safety and efficacy of BCNU-TMZ prior to RT in newly diagnosed AOG. Methods: This single arm multicenter phase II study assessed efficacy and safety of BCNU (150 mg/m2, day 1) and TMZ (110 mg/m2, D1-D5), every 6 weeks, up to 6 cycles, before conventional RT (60 Gy/30f). Eligibility criteria included histology of WHO 2000 grade 3 oligodendroglioma (AO) and mixed oligoastrocytoma (AOA), measurable contrast enhancing disease after initial surgery, no prior RT or CT. Histologic and MRI review were centrally performed. IDH1 mutation, internexin α (INA), p53 and MGMT expression were assed by IHC. Primary end point was response rate (RR). Secondary end-points included PFS and OS. Results: From 12/2005 to 9/2009, 54 pts were included and define the intend to treat population (ITTP). Median age was 53.3y. Surgery consists of biopsy in 37 pts and partial surgery in 17 pts. After central review, 43 patients constituted the per-protocol population (PPP) including AO n=14 and AOA n=29. In ITTP, RR was 38.5% including 7 (13.5%) CR and 13 (25%) PR. Median PFS was 15 mo (95% CI, 2 to 28.2) and 15.4 mo (95% CI, 3 to 27.6) in the ITTP and PPP respectively. Median PFS was 2.4, 14, 18.6 mo in case of PD, SD, and PR. Median OS was 25 mo (95% CI, 17.6 to 32.4). R132H mutated IDHI, INA and MGMT were expressed in 26/ 49 (53%), 12/50 (24%) and 8/44 (18%). In ITTP and PPP, IDH1, INA and MGMT strongly impact PFS and OS. Grade 3-4 toxicities included thrombopenia n=20, neutropenia n=13, elevated transaminases n=5. Treatment discontinuation for toxicity concerned 4 pts. 3 treatment possibly related deaths were reported (1 thrombopenia, 1 pulmonary fibrosis, 1 acute leukaemia). Conclusions: BCNU and TMZ combination is effective in this AOG population, despite pejorative prognostic characteristics, and is associated with prolonged tumor control in pts with negative INA. However, significant toxicity of the combination should be taken into account for further development.