Background: Although anti-angiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. SDF-1 is a known mediator of cancer cell invasion, vasculogenesis and vessel co-option. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in orthotopic glioblastoma xenografts. Methods: We conducted an open-label Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab 10 mg/kg every two weeks in patients with recurrent HGG. In Part 1 of the study, plerixafor was dosed on Days 1-21 of each 28 day cycle. A 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle was used. Dose limiting toxicities (DLTs) were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Results: 17 patients have been enrolled into Part 1 of the study to date: median age was 54 (23-67), median Karnofsky Performance Status was 90 (70-100), 9 were women (52.9%) , 9 had grade 4 glioma (52.9%), 8 had grade 3 glioma (47.1%), median number of prior therapies 1 (1-3). One DLT (grade 3 rectal fistula) was seen at a dose level of plerixafor 240 µg/kg + bevacizumab and the cohort was expanded to from 4 to 8 patients. Because no further DLTs were seen at the 240 µg/kg dose level, the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb opened and 6 patients have been treated to date. Since no DLTs have been seen, the cohort has now been expanded to 12 patients. There are no other treatment-related grade 3 and no grade 4 toxicities. One grade 1 stroke (attributed to bevacizumab, unrelated to plerixafor) was found incidentally on imaging and the patient was removed from active treatment. Conclusions: Combination treatment with bevacizumab and plerixafor is well tolerated in HGG patients. No DLT has been seen in the first 6 patients treated at the maximum planned dose level (plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle) and the cohort has been expanded to 12 patients. Updated results will be presented. Clinical trial information: NCT01339039.