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A phase II clinical study of 13-deoxy, 5-iminodoxorubicin (GPX-150) with metastatic and unresectable soft tissue sarcoma
Journal article   Open access   Peer reviewed

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

Brian A Van Tine, Mark Agulnik, Richard D Olson, Gerald M Walsh, Arthur Klausner, Nicole E Frank, Todd T Talley and Mohammed M Milhem
Cancer medicine (Malden, MA), Vol.8(6), pp.2994-3003
06/2019
DOI: 10.1002/cam4.2136
PMCID: PMC6558450
PMID: 31016866
url
https://doi.org/10.1002/cam4.2136View
Published (Version of record) Open Access

Abstract

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. 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). GPX-150 was administered at 265 mg/m 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. 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 .
 Adult Aged Aged, 80 and over Doxorubicin - analogs & derivatives Doxorubicin - pharmacology Doxorubicin - therapeutic use Female Humans Male Middle Aged Neoplasm Metastasis Sarcoma - drug therapy Sarcoma - mortality Soft Tissue Neoplasms - drug therapy Soft Tissue Neoplasms - mortality

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