A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma
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 DO...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-06-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.2136 |
| _version_ | 1828806633428353024 |
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| author | Brian A. Van Tine Mark Agulnik Richard D. Olson Gerald M. Walsh Arthur Klausner Nicole E. Frank Todd T. Talley Mohammed M. Milhem |
| author_facet | Brian A. Van Tine Mark Agulnik Richard D. Olson Gerald M. Walsh Arthur Klausner Nicole E. Frank Todd T. Talley Mohammed M. Milhem |
| author_sort | Brian A. Van Tine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T08:12:40Z |
| format | Article |
| id | doaj.art-6736cc86265f4013b5503c366edeaf37 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-12-12T08:12:40Z |
| publishDate | 2019-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-6736cc86265f4013b5503c366edeaf372022-12-22T00:31:43ZengWileyCancer Medicine2045-76342019-06-01862994300310.1002/cam4.2136A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcomaBrian A. Van Tine0Mark Agulnik1Richard D. Olson2Gerald M. Walsh3Arthur Klausner4Nicole E. Frank5Todd T. Talley6Mohammed M. Milhem7Division of Medical Oncology Washington University in St. Louis St Louis MissouriDivision of Hematology/Oncology, Feinberg School of Medicine Northwestern University Chicago IllinoisGem Pharmaceuticals LLC Birmingham AlabamaGem Pharmaceuticals LLC Birmingham AlabamaGem Pharmaceuticals LLC Birmingham AlabamaCollege of Pharmacy Idaho State University Meridian IdahoCollege of Pharmacy Idaho State University Meridian IdahoDivision of Hematology/Oncology University of Iowa Hospitals and Clinics Iowa City IowaAbstract 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.https://doi.org/10.1002/cam4.2136anthracyclinescardiotoxicitydoxorubicinGPX‐150phase IIsoft tissue sarcoma |
| spellingShingle | Brian A. Van Tine Mark Agulnik Richard D. Olson Gerald M. Walsh Arthur Klausner Nicole E. Frank Todd T. Talley Mohammed M. Milhem A phase II clinical study of 13‐deoxy, 5‐iminodoxorubicin (GPX‐150) with metastatic and unresectable soft tissue sarcoma Cancer Medicine anthracyclines cardiotoxicity doxorubicin GPX‐150 phase II 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 | anthracyclines cardiotoxicity doxorubicin GPX‐150 phase II soft tissue sarcoma |
| url | https://doi.org/10.1002/cam4.2136 |
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