Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma

Abstract

To report the interim analysis of the phase II single arm noninferiority trial testing the upfront use of dexrazoxane with doxorubicin on progression free survival (PFS) and cardiac function in soft tissue sarcoma (STS). Patients and MethodsPatients with metastatic or unresectable STS who were candidates for first line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33/65 patients were enrolled. Using the historical control of 4.6 months progression free survival (PFS) for doxorubicin in the front-line setting, we tested if the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered non-inferior. Secondary aims included cardiac related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including 3D echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m 2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. ResultsAt interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1 -11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m 2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m 2 (interquartile range 300-750 mg/m 2 ). April 4, 2021. Conclusions on

Fatal heart disease in patients with bone and soft tissue sarcoma

“…In addition to prolonging survival rates, clinicians are now increasingly concerned about complications caused by sarcoma therapy ( 20 , 23 ). Several small sample or single-center clinical cohort studies reported that antineoplastic agents such as anthracyclines increased the risk of dying from HD in sarcoma patients ( 14 , 15 ). However, due to low sarcoma incidence rates and limitations with small sample or single center studies, no robust data are available to inform clinical practice.…”

“…However, a worrisome adverse side effect is ventricular dysfunction and heart failure ( 25 ). Due to low sarcoma incidence rates, previous cardio-toxicity studies in sarcoma patients receiving chemotherapy were conducted in small sample or at single centers ( 13 – 15 ). In a recent comparative study of 95 patients with sarcoma, approximately 17% developed cardio-toxicity after receiving doxorubicin ( 26 ).…”

Doxorubicin-Dexrazoxane from Day 1 for Soft-tissue Sarcomas: The Road to Cardioprotection

“…Early cardiac protection permits oncologic decisions to determine when to stop or whether to reinstitute anthracycline therapy, rather than binding to some magic number. The papers by Jones et al (1) and Van Tine et al, (2) substantiating the known cardioprotective effect of this agent and emphasizing that the antitumor activity of dexrazoxane-protected doxorubicin against adult sarcomas is not impaired when dexrazoxane is started with course 1, lend further support to the routine use of dexrazoxane in sarcomas, or wherever there may be potential benefit from giving additional doxorubicin at some point in time. Although Jones et al (1) did not demonstrate specifically the effects of dexrazoxane from day 1, since the time of initiation was left at the investigator's discretion, the study of Van Tine et al optimized cardiac protection by routinely starting dexrazoxane at day 1.…”

“…In this issue of Clinical Cancer Research, Jones et al (1) and Van Tine et al (2) question the traditional maximum lifetime cumulative dose of doxorubicin and lend support to protecting against doxorubicin cardiac toxicity by initiating dexrazoxane prior to the first anthracycline dose in patients with soft-tissue sarcomas. Is it time to re-evaluate the maximum lifetime dose of doxorubicin?…”

Luteolin Prevents Cardiac Dysfunction and Improves the Chemotherapeutic Efficacy of Doxorubicin in Breast Cancer

“…Dexrazoxane is the only drug currently approved by the FDA that provides protection against Dox-induced cardiotoxicity. However, dexrazoxane not only causes side effects, such as hematological toxicity and myelosuppression, but also decreases the antitumor efficacy of Dox ( 11 , 12 ). For instance, the activation of hypoxia-inducible transcription factor, an oncogene, may contribute to the protective effect of dexrazoxane against anthracycline cardiotoxicity in dexrazoxane-treated H9c2 cardiomyocytes ( 13 ).…”