A phase I study of chemo-radiotherapy with plerixafor for newly diagnosed glioblastoma (GB).

Thomas, Reena; Nagpal, Seema; Michael, Cassia; Soltys, Scott G.; Corbin, Zachary; Xu, Linda; Recht, Cathy Kahn; Bertrand, Sophie; Jain, Vani; Acevedo, Brenda; Brown, Martin; Recht, Lawrence D.

doi:10.1200/jco.2016.34.15_suppl.2068

Cited by 8 publications

(9 citation statements)

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“…had previously shown median PFS of 6.9 months and 6‐month PFS rate of ∼60% in the temozolomide plus radiotherapy arm 89 . Magnetic resonance imaging showed a marked decrease in relative cerebral blood volume in the radiation treatment field, suggesting enhanced local treatment effect in support of the investigators’ hypothesis that inhibition of the CXCR4/CXCL12‐mediated vasculogenesis pathway in the post‐radiotherapy period enhances radiation 90 . The same center has expanded this study into a phase 2 study (NCT03746080) with the addition of whole brain irradiation.…”

Section: Therapeutic Use Of Cxcr4 Inhibition In Solid Tumorssupporting

confidence: 57%

“…Given the high specificity of the therapeutic vector for human CXCR4, the therapy is generally safe and well-tolerated. 30 The largest studies so far examined the use of pentixather, labeled with betaemitters 177 Lutetium or 90 Yttrium, for ERT of advanced stage MM patients. Although initial response rates were high, and adverse effects were limited, no overall survival (OS) benefit could be observed in this cohort of heavily pretreated MM patients.…”

Section: Cxcr4-targeted Radionuclide Therapymentioning

confidence: 99%

“…89 Magnetic resonance imaging showed a marked decrease in relative cerebral blood volume in the radiation treatment field, suggesting enhanced local treatment effect in support of the investigators' hypothesis that inhibition of the CXCR4/CXCL12mediated vasculogenesis pathway in the post-radiotherapy period enhances radiation. 90 The same center has expanded this study into a phase 2 study (NCT03746080) with the addition of whole brain irradiation. Plerixafor was given by continuous infusion (400 µg/kg/day) for 4 weeks, beginning 7 days before the completion of whole brain radiation therapy.…”

Section: Small Molecule Cxcr4 Inhibitorsmentioning

confidence: 99%

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At the Bedside: Profiling and treating patients with CXCR4-expressing cancers

Martı́n

Mayer

Walenkamp

et al. 2020

Journal of Leukocyte Biology

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The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization).However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, Bio-LineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach.The current status and future directions for radioimaging and treating patients with CXCR4expressing hematologic and solid malignancies are reviewed. See related review -At the Bench:

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Section: Therapeutic Use Of Cxcr4 Inhibition In Solid Tumorssupporting

confidence: 57%

Section: Cxcr4-targeted Radionuclide Therapymentioning

confidence: 99%

Section: Small Molecule Cxcr4 Inhibitorsmentioning

confidence: 99%

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At the Bedside: Profiling and treating patients with CXCR4-expressing cancers

Martı́n

Mayer

Walenkamp

et al. 2020

Journal of Leukocyte Biology

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“…Its current use has been largely restricted to acute doses to mobilize hematopoietic stem cells from the bone marrow. However In a report of a phase 1 trial, Thomas and colleagues infused Plerixafor for 4 weeks in conjunction with standard therapy for newly diagnosed glioblastoma patients, and reported at target plasma levels no dose-limiting toxicities with promising indications of activity (113). In a phase II study with recurrent glioblastoma Butowski and colleagues reported that the CSF-1R Inhibitor PLX3397 was well tolerated but showed no efficacy (114).…”

Section: Clinical Datamentioning

confidence: 99%

The Promise of Targeting Macrophages in Cancer Therapy

Brown

Recht

Strober

2017

Clinical Cancer Research

271

225

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Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this Review we outline the importance of tumor associated macrophages (TAMs), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs and their role in blunting the efficacy to cancer treatment by radiation and anticancer drugs both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy.

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“…However, there is less experience combining Plerixafor with high‐dose RT and chemotherapy as curative treatment for cancer. However, the results of a phase I study in glioblastoma patients are reassuring, as a 4‐week infusion of Plerixafor was well tolerated with RT and concurrent temozolomide . In our pre‐clinical studies, Plerixafor was administered by continuous infusion over 3 weeks at the same time as RT and cisplatin with no evidence of increased acute or late toxicity .…”

Section: Opportunities and Future Directionmentioning

confidence: 82%

Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer

Lecavalier-Barsoum

Chaudary

Han

et al. 2018

Intl Journal of Cancer

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Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.

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A phase I study of chemo-radiotherapy with plerixafor for newly diagnosed glioblastoma (GB).

Cited by 8 publications

References 0 publications

At the Bedside: Profiling and treating patients with CXCR4-expressing cancers

At the Bedside: Profiling and treating patients with CXCR4-expressing cancers

The Promise of Targeting Macrophages in Cancer Therapy

Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer

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