Phase I and Biomarker Study of Plerixafor and Bevacizumab in Recurrent High-Grade Glioma

Purpose: Although antiangiogenic therapy for high-grade glioma (HOG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1 alpha/CXCR4 axis may mediate resistance to VEGFR inhibition. Predinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGC. Patients and Methods: Part 1 enrolled 23 patients with a 3 x 3 dose escalation design to a maximum planned dose of plerixafor 320 mu g/kg subcutaneously on days 1 to 21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. Cerebrospinal fluid (CSF) and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular bio markers were evaluated before and after treatment, Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue. Results: In Part 1, no dose-limiting toxicities were seen at the maximum planned dose of plerixafor + bevacizumab. Treatment was well tolerated. After plerixafor 320 mu g/kg treatment, the average CSF drug concentration was 26.8 +/- 19.6 ng/mL. Plerixafor concentration in resected tumor tissue from patients pretreated with plerixafor was 10 to 12 mu g/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF-1 alpha and placental growth factor. Progression-free survival correlated with pretreatment plasma soluble mesenchymal-epithelial transition receptor and sVEGFR1, and overall survival with the change during treatment in CD34(+) progenitor/stem cells and CD8 T cells. Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with bio-marker changes consistent with VEGF and CXCR4 inhibition. (C) 2018 AACR.