Open AccessA phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
Author(s) -
Van Tine Brian A.,
Agulnik Mark,
Olson Richard D.,
Walsh Gerald M.,
Klausner Arthur,
Frank Nicole E.,
Talley Todd T.,
Milhem Mohammed M.
Publication year - 2019
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.2136
Subject(s) - cardiotoxicity , medicine , ejection fraction , doxorubicin , soft tissue sarcoma , cumulative dose , neutropenia , pharmacology , phases of clinical research , leukopenia , sarcoma , gastroenterology , chemotherapy , oncology , heart failure , pathology
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 .