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Clinical Cancer Research

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Clinical Trials: Targeted Therapy

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

Reena P. Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith S. Pelpola, Robyn Ball, Jaden Yang, Vandana Sundaram, Jonathan Lavezo, Donald Born, Hannes Vogel, J. Martin Brown and Lawrence D. Recht
Reena P. Thomas
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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  • For correspondence: reenat@stanford.edu
Seema Nagpal
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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Michael Iv
Department of Radiology, Division of Neuro Radiology, Stanford, California.
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Scott G. Soltys
Department of Radiation Oncology, Stanford, California.
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Sophie Bertrand
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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Judith S. Pelpola
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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Robyn Ball
Department of Medicine, Quantitative Sciences Unit, Stanford, California.
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Jaden Yang
Department of Medicine, Quantitative Sciences Unit, Stanford, California.
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Vandana Sundaram
Department of Medicine, Quantitative Sciences Unit, Stanford, California.
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Jonathan Lavezo
Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California.
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Donald Born
Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California.
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Hannes Vogel
Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California.
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J. Martin Brown
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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Lawrence D. Recht
Department of Neurology, Division of Neuro Oncology, Stanford, California.
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DOI: 10.1158/1078-0432.CCR-19-1421 Published December 2019
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Abstract

Purpose: 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.

Patients and Methods: 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.

Results: 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.

Conclusions: 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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2019;25:6948–57

  • Received April 30, 2019.
  • Revision received July 17, 2019.
  • Accepted September 11, 2019.
  • Published first September 19, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 25 (23)
December 2019
Volume 25, Issue 23
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Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma
Reena P. Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith S. Pelpola, Robyn Ball, Jaden Yang, Vandana Sundaram, Jonathan Lavezo, Donald Born, Hannes Vogel, J. Martin Brown and Lawrence D. Recht
Clin Cancer Res December 1 2019 (25) (23) 6948-6957; DOI: 10.1158/1078-0432.CCR-19-1421

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Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma
Reena P. Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith S. Pelpola, Robyn Ball, Jaden Yang, Vandana Sundaram, Jonathan Lavezo, Donald Born, Hannes Vogel, J. Martin Brown and Lawrence D. Recht
Clin Cancer Res December 1 2019 (25) (23) 6948-6957; DOI: 10.1158/1078-0432.CCR-19-1421
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