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, Mohammed M. Milhem

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Abstract

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/m2 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/m2.

Original languageEnglish
Pages (from-to)2994-3003
Number of pages10
JournalCancer medicine
Volume8
Issue number6
DOIs
StatePublished - Jun 2019
Externally publishedYes

Keywords

  • GPX-150
  • anthracyclines
  • cardiotoxicity
  • doxorubicin
  • phase II
  • soft tissue sarcoma

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    Van Tine, B. A., Agulnik, M., Olson, R. D., Walsh, G. M., Klausner, A., Frank, N. E., Talley, T. T., & Milhem, M. M. (2019). A phase II clinical study of 13-deoxy, 5-iminodoxorubicin (GPX-150) with metastatic and unresectable soft tissue sarcoma. Cancer medicine, 8(6), 2994-3003. https://doi.org/10.1002/cam4.2136