Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma

• Published in: Clinical cancer research 2019-12, Vol.25 (23), p.6948-6957
• Main Authors: Thomas, Reena P, Nagpal, Seema, Iv, Michael, Soltys, Scott G, Bertrand, Sophie, Pelpola, Judith S, Ball, Robyn, Yang, Jaden, Sundaram, Vandana, Lavezo, Jonathan, Born, Donald, Vogel, Hannes, Brown, J Martin, Recht, Lawrence D
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anti-HIV Agents; Benzylamines; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Chemoradiotherapy - mortality; Cyclams; Female; Follow-Up Studies; Glioblastoma - pathology; Glioblastoma - therapy; Heterocyclic Compounds - therapeutic use; Humans; Macrophages; Male; Middle Aged; Prognosis; Receptors, CXCR4 - antagonists & inhibitors; Survival Rate; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-19-1421

Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.