TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors

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Despite impressive progress in the fields of surgical and immunological cancer therapies, most late-stage cancer treatments still heavily depend on conventional chemotherapeutics, which are often effective but also toxic, resulting in severe adverse effects limiting the dose and duration of therapy....

Despite impressive progress in the fields of surgical and immunological cancer therapies, most late-stage cancer treatments still heavily depend on conventional chemotherapeutics, which are often effective but also toxic, resulting in severe adverse effects limiting the dose and duration of therapy. Consequently, there remains a high unmet medical need for new innovative systemic treatments with an improved risk-benefit-profile. Doxorubicin is a potent anthracycline used as a systemic treatment against several solid tumor including breast, ovarian and bladder cancer, small cell lung cancer and various types of sarcoma. However, Doxorubicin use is often limited due to hematological and non-hematological toxicity including cumulative cardiotoxicity with myocardial damage. Cardiotoxicity has been substantially mitigated through the introduction of liposomal formulations such as Myocet and Caelyx/Doxil. Both products are associated with substantially lower rates of cardiac dysfunction during or post-treatment. Whereas Myocet's clinical use remains limited due to the intricate "bedside" reconstitution process, Caelyx has been associated with a high incidence of Palmar-Plantar Erythrodysesthesia (PPE) (also called hand-foot-syndrome), likely due to its long plasma half-life. The development of TLD-1 (Talidox) aimed at combining the cardio-preserving properties of the liposomal delivery system with shorter blood circulation time in order to reduce the risk of PPE. Even though the pathophysiology of PPE is not yet fully understood, studies analyzing the correlation of dose and pharmacokinetic parameters with PLD toxic effects revealed that the severity of PPE correlated significantly with plasma half-life (t1/2). Given its performance in preclinical trials, TLD-1 bears the potential for an improved benefit/risk profile compared to established liposomal doxorubicin formulations including Caelyx. This first-in-human phase-I trial will evaluate the safety and will establish the maximal tolerated dose (MTD) and recommended phase II dose of TLD-1, and characterize specific dose limiting toxicities (DLT) of TLD-1. Moreover, the trial shall yield information on tolerability, adverse events profile, pharmacokinetics and preliminary efficacy.

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