Abstract
Background13‐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 MethodsAn 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).ResultsGPX‐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.ConclusionThese 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.
Highlights
Doxorubicin (DOX) as a single agent or in combination with ifosfamide has been the mainstay of first‐line treatment for advanced or metastatic soft tissue sarcoma (STS) for more than 40 years.[1,2,3,4] Recently, DOX in combination with olaratumab, a monoclonal antibody against platelet‐derived growth factor receptor alpha, demonstrated superiority over DOX alone and was granted accelerated approval by the FDA in 2016 as the first‐line therapy for metastatic STS.[5]
The secondary objective was to describe the effects of GPX‐150 on STS as assessed by secondary efficacy measures: (a) PFR at 6 months, (b) progression‐free survival (PFS, defined as time to disease progression or death, (c) time to progression (TTP), (d) overall survival (OS), defined as time to death, (e) tumor response defined as complete response (CR), partial response (PR), or stable disease (SD), (f) duration of response, (g) duration of overall response (CR or PR), (h) best response during study, and (i) duration of best response
There has been an intense effort over the last five decades to remove the cardiotoxicity of DOX while retaining its anticancer activity or to develop cardioprotective strategies
Summary
Doxorubicin (DOX) as a single agent or in combination with ifosfamide has been the mainstay of first‐line treatment for advanced or metastatic soft tissue sarcoma (STS) for more than 40 years.[1,2,3,4] Recently, DOX in combination with olaratumab, a monoclonal antibody against platelet‐derived growth factor receptor alpha, demonstrated superiority over DOX alone and was granted accelerated approval by the FDA in 2016 as the first‐line therapy for metastatic STS.[5]. GPX‐150 demonstrated stable disease in five out of seven patients, including three patients with STS. This provided the opportunity to evaluate the safety, including that of irreversible, cumulative cardiotoxicity, of up to 16 cycles of GPX‐150 administered every 3 weeks at the MTD defined in the phase I clinical trial. Other criteria for patient exclusion were any malignancy other than STS within the last 5 years prior to screening, with the exception of cervical carcinoma in situ, basal cell carcinoma, or superficial bladder tumors that were successfully and curatively treated with no evidence of recurrent or residual disease, currently pregnant or nursing women or known allergy to any of the study drugs or their excipients
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