Cardiac safety of aldoxorubicin compared to doxorubicin: Integrated results from two randomized studies in advanced soft tissue sarcoma.

11565 Background: Doxorubicin clinical benefit is limited by cumulative, irreversible cardiotoxicity that restricts dosing. Aldoxorubicin is an albumin-binding prodrug of doxorubicin designed to enhance tumor delivery while reducing systemic exposure to cardiotoxic metabolites such as doxorubicinol. Prior reports suggest improved cardiac tolerability of aldoxorubicin, but no integrated analysis across randomized studies has been presented. Methods: Cardiac safety data were analyzed from two randomized studies, INNO-206-STS-P2-01 (NCT01514188) and ALDOXORUBICIN-P3-STS-01 (NCT02049905), comparing aldoxorubicin with doxorubicin in advanced soft tissue sarcoma. Left ventricular ejection fraction (LVEF) was assessed at baseline and prespecified intervals during and after treatment. Outcomes included mean and change-from-baseline LVEF, proportion of patients with LVEF <45%, treatment-emergent heart-failure and cardiovascular adverse events (AEs), and composite endpoints integrating LVEF decline and cardiac AEs. Cumulative doxorubicin-equivalent dose was calculated using a 0.74 conversion factor. Results: Across both studies (N≈383), baseline demographics and cardiac risk factors were balanced. Aldoxorubicin was administered at approximately 3.5-fold higher doxorubicin-equivalent cumulative doses than doxorubicin. Despite higher exposure, aldoxorubicin was associated with smaller mean LVEF declines (pooled lowest on-treatment change −3.17% vs −5.77%; nominal p<0.05). Approximately three-fold more doxorubicin-treated patients reached LVEF <45% (1.1% vs 3.8%). Composite endpoints favored aldoxorubicin, including HF-AE plus LVEF <45% (0.7% vs 3.4%), HF-AE plus ≥10-point decline (2.0% vs 4.6%), prespecified cardiovascular AE plus LVEF <45% (0.3% vs 1.1%), and prespecified cardiovascular AE plus ≥10-point decline (1.4% vs 4.6%). Treatment-emergent prespecified heart-failure events occurred less frequently with aldoxorubicin (3.0% vs 6.9%). LVEF–exposure plots showed higher LVEF with aldoxorubicin despite substantially higher cumulative exposure. In Phase 1 aldoxorubicin pharmacokinetic data, the doxorubicinol-to-doxorubicin exposure ratio was ~5–6%, compared with ~40–60% reported for conventional doxorubicin, consistent with lower systemic doxorubicinol burden and supporting the observed cardiac safety findings. Conclusions: Across two randomized studies, aldoxorubicin demonstrated a consistently more favorable cardiac safety profile than doxorubicin despite higher cumulative exposure, with smaller LVEF declines and fewer heart-failure–related events. These findings support aldoxorubicin as a potentially safer anthracycline option for patients requiring sustained exposure.