Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas

Abstract

Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.

Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin

“…In a phase III clinical trial of advanced soft tissue sarcomas (STS) in a relapsed or refractory setting (2014, NCT02049905), AlDox showed superior progression‐free survival (PFS) compared to the standard of care regimen and showed minimal cardiotoxicity—the major dose‐limiting safety concern associated with free Dox . However, in a phase II clinical trial in patients with previously untreated STS (2012, NCT01514188), despite superior PFS and no evidence of cardiotoxicity in the AlDox arm, the overall survival was not considerably different between AlDox and the free Dox arms.…”

“…Aldoxorubicin (AlDox) is a promising product in the in vivo albumin approach category . Formerly known as INNO‐206, it is an albumin‐binding prodrug of the anticancer drug doxorubicin (Dox), in which Dox is derivatized at its C‐13 keto position with the thiol‐binding 3,3′‐ N ‐(ε‐maleimidocaproic acid)hydrazide (EMCH) linker.…”

Recent trends in protein and peptide-based biomaterials for advanced drug delivery

“…Aldoxorubicin, also known as DOX-EMCH ( Fig. 9 B & C) is currently under various phases of clinical trial for the treatment of soft tissue sarcomas ( NCT01673438 and [ 152 ]) and small cell lung cancer ( NCT02235688 ). Inspired by DOX-EMCH, many other albumin-binding prodrugs have been developed.…”

Advances in systemic treatment of advanced soft tissue sarcomas

“…Following intravenous administration, aldoxorubicin binds to albumin; this happens with the help of a highly selective connection between the thiol group of cysteine at position 34 (Cys34) and a maleimide group. The aldoxorubicin-albumin conjugate moves to the tumour under the influence of acidic tumour environment, and is followed by the disintegration of the hydrazine link, and thus delivery of doxorubicin to tumour cells [55].…”