BACKGROUND: Vandetanib is a selective VEGFR and EGFR inhibitor that targets these key pathways implicated in gliomagenesis. While single-agent vandetanib has not shown significant clinical activity in high grade glioma but preclinical experience supports potential synergistic efficacy in combination with carboplatin. METHODS: This randomized non-comparative phase-II trial evaluates the efficacy and safety of vandetanib (300 mg/d NEIAED, 400 mg/d EIAED) in combination with carboplatin (AUC 6 q 4 weeks) versus carboplatin alone (AUC 6 q 4 weeks) in adults with recurrent anaplastic glioma. Upon progression with single-agent carboplatin, single-agent vandetanib was offered. Contrast-enhanced-MRI before subsequent cycles were compared to baseline and response assessed using RANO criteria. Primary end-point was progression free survival at 6 months (PFS-6). RESULTS: 23 patients were accrued to each group (n = 46). Gender, median age, performance status, number of recurrences, 1p/19q co-deletion status, and baseline steroid doses were comparable. 60% of patients in each group had failed prior VEGF-inhibitor therapy. Most frequent treatment related grade ≥3 toxicities were lymphopenia (n = 7), thrombocytopenia (n = 4), neutropenia (n = 3), hypertension (n = 3) and transaminitis (n = 3). All grade 4 toxicities were observed in the combination-group. There were 3 partial responses in the combination group, and 1PR in the sequential-group. PFS-6 was 8.7% (95% CI: 2.3%, 32.7%) and 17.4 % (95% CI: 7.1%, 42.4%), median-PFS (months) was 1.8 (95% CI: 1.15, 2.66) and 0.95 (95% CI:0.92,2.04)while median-OS (months) was 6.5 (95% CI: 5.42, 11.7) and 9.27 (95% CI: 5.52, 43.86) in combination-group and sequential-group respectively. CONCLUSION: Although this study was not powered to detect differences between groups and did not complete accrual as planned, no meaningful differences in PFS-6, PFS or OS were observed compared to historical controls. Majority of patients were VEGF therapy resistant, which may have limited efficacy. Combination therapy was more toxic.