Tumor delivery and exposure of aldoxorubicin compared with doxorubicin: Integrated clinical and preclinical analysis.

Abstract

e15134 Background: Doxorubicin is widely used across solid tumors and sarcomas but is limited by dose-dependent cardiotoxicity and suboptimal tumor delivery. Aldoxorubicin is an albumin-binding prodrug of doxorubicin designed to enhance tumor uptake through albumin transport pathways and to release active doxorubicin in the acidic tumor microenvironment and in tumor cells. Prior studies have independently demonstrated tumor accumulation of aldoxorubicin or its released doxorubicin. We conducted the first integrated analysis comparing tumor-site exposure of aldoxorubicin with doxorubicin using clinical intratumor pharmacokinetics and nonclinical biodistribution and efficacy data. Methods: Tumor and paired skin biopsies were obtained 24–48 hours after dosing from patients with Kaposi’s sarcoma treated with aldoxorubicin (Study ALDOX-P2-KS-01; NCT02029430). Total drug (aldoxorubicin + doxorubicin) was quantified and normalized by administered dose and doxorubicin-equivalent dose. Published Kaposi’s sarcoma intratumor doxorubicin concentrations (Northfelt 1996) served as clinical comparators. Because measured concentrations could not distinguish prodrug from released doxorubicin, two bounding potency scenarios were evaluated: (1) “All Aldox,” assuming all tumor drug was aldoxorubicin and applying a 10-fold lower in-vitro potency (Kratz 2002 and 2007); and (2) “All Dox,” assuming complete conversion to native doxorubicin. Mouse tumor xenograft data (Kratz 2007) comparing aldoxorubicin and doxorubicin were extracted, including tumor AUC 0-24 following 14 C-labeled dosing and tumor growth inhibition at equivalent doses. Exposure and potency-normalized metrics were compared across datasets. Results: Aldoxorubicin was detectable in all human tumor lesions, with linear dose-dependent increases in intratumor concentrations. Dose-normalized tumor exposure was substantially greater for aldoxorubicin compared with published doxorubicin values. Under the All Aldox scenario, potency-normalized exposure was comparable to doxorubicin; under the All Dox scenario, tumor exposure was up to an order of magnitude higher. In mouse xenografts, aldoxorubicin produced higher tumor AUC 0-24 than doxorubicin (92.2 vs 54.0 %ID·h/g) and demonstrated comparable antitumor activity at equivalent exposures and superior activity at higher tolerated doses. Conclusions: Across integrated human and mouse datasets, aldoxorubicin achieved consistently higher tumor exposure than doxorubicin when normalized for dose, with potency-adjusted analyses supporting at least comparable active exposure. Together, these findings support aldoxorubicin as a tumor-targeted anthracycline capable of delivering greater active drug levels to tumors with improved tolerability, offering the potential for enhanced therapeutic index compared with doxorubicin.