Background: vascular endothelial growth factor receptor (VEGFR) signal transduction mediates glioblastoma (GB) associated neo-angiogenesis. Axitinib, a small molecule TKI with high affinity and specificity for the VEGFRs, has demonstrated anti-tumor activity in patients with recurrent GB (J Clin Oncol 32:5s, 2014 [suppl; abstr 2018]). We investigated whether the combination of axitinib with lomustine (LOM) improves the outcome of pts with rGB as opposed to axitinib monotherapy. Methods: pts with rGB were randomized between single agent axitinib (AXI) vs. axitinib in combination with LOM (AXILOM) in an open label, randomized, phase II clinical trial. Pts in the AXI arm were allowed to cross over to AXILOM at progression. Six-month PFS served as the primary endpoint. Results: between February 2014 and July 2015, 56 pts were randomized 1:1 to AXI and AXILOM. Baseline characteristics were well balanced between both study arms (median age 56y [range 18-75]; 35M/21F; 15, 19, 11 and 11 pts had a WHO-PS of 0, 1, 2 and 3 respectively; MGMT promoter methylation: 11 pts methylated, 35- unmethylated, 10- unknown). All pts had failed prior therapy with RT and temozolomide. Six-mth PFS% did not differ between both study arms (AXI: 21% (95% CI 7-37] vs. AXILOM: 17% [95% CI 2-32]; neither did OS differ between both study arms (6-mths OS AXI 57% [95% CI 38-76] vs. AXILOM 53% [95% CI 34-73]). Pts with a methylated MGMT-promoter had a superior PFS and OS on the AXIG-arm but not in the AXILOM-arm. The best response (by RANO criteria) was 0 CR/ 6 PR/ 8 SD in the AXI arm (BORR 21%) vs. 1 CR/ 9 PR/ 3 SD in the AXILOM arm (BORR 38%). Among the 12 pts in the AXI arm who crossed-over at the time of progression, BORR was 0%, following cross-over SD was documented in 8 pts, median PFS 14wks (range 11 to 34). AXILOM pts were at higher risk for grade 3/4 adverse events (most frequent gr3/4 AE on AXILOM vs AXI were: thrombocytopenia 3- vs 0 pts, hypertension 2 vs 2 pts, anorexia 3 vs 3 pts). Conclusions: combination of axitinib and lomustine does not improve the outcome of pts with rGB as compared to axitinib monotherapy, regardless of the MGMT promoter methylation status. The previously reported activity and safety profile of axitinib monotherapy in pts with rGB was confirmed. Clinical trial information: NCT01562197