Background: Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. Methods: We are conducting a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in patients with recurrent HGG. In Part 1 of the study, 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. DLTs were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Part 2 of the study is a surgical study to determine if plerixafor penetrates tumor tissue. Results: Part 1 of the study has been completed with 23 patients enrolled. Part 2 of the study is now open with 3 patients enrolled to date. For all 26 patients, the median age is 59 (23-72), median KPS 90 (70-100), 11 women (42.3%). In Part 1, no DLTs were seen at the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb. Treatment has been well tolerated to date with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Preliminary pharmacokinetic data on plerixafor from the first two cohorts compares well with historical PK data. Conclusions: Combination treatment with bevacizumab and plerixafor is well tolerated in HGG patients. No DLTs were encountered at the maximum planned dose level. To date, 3 of 10 planned patients have enrolled in the surgical cohort to examine tumor tissue penetration. Updated results as well as preliminary circulating biomarker analysis will be presented. Clinical trial information: NCT01339039