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A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma

BACKGROUND: 13‐Deoxy, 5‐iminodoxorubicin (GPX‐150) is a doxorubicin (DOX) analog synthesized to reduce the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible, cumulative dose‐dependent cardiotoxicity of DOX. In a...

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Autores principales: Van Tine, Brian A., Agulnik, Mark, Olson, Richard D., Walsh, Gerald M., Klausner, Arthur, Frank, Nicole E., Talley, Todd T., Milhem, Mohammed M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558450/
https://www.ncbi.nlm.nih.gov/pubmed/31016866
http://dx.doi.org/10.1002/cam4.2136
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author Van Tine, Brian A.
Agulnik, Mark
Olson, Richard D.
Walsh, Gerald M.
Klausner, Arthur
Frank, Nicole E.
Talley, Todd T.
Milhem, Mohammed M.
author_facet Van Tine, Brian A.
Agulnik, Mark
Olson, Richard D.
Walsh, Gerald M.
Klausner, Arthur
Frank, Nicole E.
Talley, Todd T.
Milhem, Mohammed M.
author_sort Van Tine, Brian A.
collection PubMed
description BACKGROUND: 13‐Deoxy, 5‐iminodoxorubicin (GPX‐150) is a doxorubicin (DOX) analog synthesized to reduce the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible, cumulative dose‐dependent cardiotoxicity of DOX. In a preclinical chronic models and a phase I clinical study of GPX‐150, no irreversible, cumulative dose‐dependent cardiotoxicity was demonstrated. Recent studies suggest that DOX cardiotoxicity may be mediated, at least in part, by the poisoning of topoisomerase IIβ. PATIENTS AND METHODS: An open‐label, single‐arm phase II clinical study in metastatic and unresectable soft tissue sarcoma (STS) patients was initiated to further evaluate the efficacy and safety of GPX‐150, including cardiac function, specifically left ventricular ejection fraction (LVEF). RESULTS: GPX‐150 was administered at 265 mg/m(2) every 3 weeks for up to 16 doses with prophylactic G‐CSF until progression, death, or patient withdrawal from the study. GPX‐150 exhibited efficacy assessed as progression‐free survival (PFS) rates of 38% and 12% at 6 and 12 months and an overall survival rate of 74% and 45% at 6 and 12 months. GPX‐150–treated patients did not develop any evidence of irreversible, cumulative dose‐dependent chronic cardiotoxicity. Toxicities included grade 3 anemia, neutropenia, and one grade 4 leukopenia. Correlative analysis demonstrated that GPX‐150 was more selective than DOX for the inhibition of topoisomerase IIα over IIβ in vitro. CONCLUSION: These results suggest future studies are warranted to further evaluate the clinical efficacy of GPX‐150 in STS, perhaps at doses higher than 265 mg/m(2).
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spelling pubmed-65584502019-06-13 A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma Van Tine, Brian A. Agulnik, Mark Olson, Richard D. Walsh, Gerald M. Klausner, Arthur Frank, Nicole E. Talley, Todd T. Milhem, Mohammed M. Cancer Med Clinical Cancer Research BACKGROUND: 13‐Deoxy, 5‐iminodoxorubicin (GPX‐150) is a doxorubicin (DOX) analog synthesized to reduce the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible, cumulative dose‐dependent cardiotoxicity of DOX. In a preclinical chronic models and a phase I clinical study of GPX‐150, no irreversible, cumulative dose‐dependent cardiotoxicity was demonstrated. Recent studies suggest that DOX cardiotoxicity may be mediated, at least in part, by the poisoning of topoisomerase IIβ. PATIENTS AND METHODS: An open‐label, single‐arm phase II clinical study in metastatic and unresectable soft tissue sarcoma (STS) patients was initiated to further evaluate the efficacy and safety of GPX‐150, including cardiac function, specifically left ventricular ejection fraction (LVEF). RESULTS: GPX‐150 was administered at 265 mg/m(2) every 3 weeks for up to 16 doses with prophylactic G‐CSF until progression, death, or patient withdrawal from the study. GPX‐150 exhibited efficacy assessed as progression‐free survival (PFS) rates of 38% and 12% at 6 and 12 months and an overall survival rate of 74% and 45% at 6 and 12 months. GPX‐150–treated patients did not develop any evidence of irreversible, cumulative dose‐dependent chronic cardiotoxicity. Toxicities included grade 3 anemia, neutropenia, and one grade 4 leukopenia. Correlative analysis demonstrated that GPX‐150 was more selective than DOX for the inhibition of topoisomerase IIα over IIβ in vitro. CONCLUSION: These results suggest future studies are warranted to further evaluate the clinical efficacy of GPX‐150 in STS, perhaps at doses higher than 265 mg/m(2). John Wiley and Sons Inc. 2019-04-23 /pmc/articles/PMC6558450/ /pubmed/31016866 http://dx.doi.org/10.1002/cam4.2136 Text en © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Cancer Research
Van Tine, Brian A.
Agulnik, Mark
Olson, Richard D.
Walsh, Gerald M.
Klausner, Arthur
Frank, Nicole E.
Talley, Todd T.
Milhem, Mohammed M.
A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title_full A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title_fullStr A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title_full_unstemmed A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title_short A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
title_sort phase ii clinical study of 13‐deoxy, 5‐iminodoxorubicin (gpx‐150) with metastatic and unresectable soft tissue sarcoma
topic Clinical Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558450/
https://www.ncbi.nlm.nih.gov/pubmed/31016866
http://dx.doi.org/10.1002/cam4.2136
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