Clinical Efficacy of L-Annamycin, a Liposomal Formulated Non-Cross-Resistant and Non-Cardiotoxic Anthracycline in Relapsed/Refractory AML Patients

Introduction: An anthracycline combined with cytarabine remains the backbone for induction therapy in the treatment of AML. De novo and acquired multidrug resistance (MDR) limits efficacy of clinically used anthracyclines. L-Annamycin, a novel anthracycline formulated in multilamellar liposomes, has been shown to overcome MDR in preclinical in vitro and in vivo doxorubicin resistant models as well as in clinical studies. Furthermore, preclinical toxicology studies comparing L-Annamycin to doxorubicin determined that the drug displayed dramatically reduced cardiotoxicity. These promising properties justified initiation of Phase I/II clinical trials in both the US and Europe using L-Annamycin for the treatment of R/R AML.

Aims: The aim of the Phase I component is to determine the recommended Phase 2 dose (RP2D) of L-Annamycin for the treatment of R/R AML. The expansion Phase IIa studies are designed to assess L-Annamycin efficacy leading to a Phase II registration study for accelerated approval.

Methods: The Phase I component is a standard 3+3 design to determine the RP2D. An additional 21 patients expansion phase will be enrolled at the RP2D to confirm efficacy. A DMC will monitor all data and decide if the study should continue and if any changes to the protocol are needed. Cardiotoxicity is being closely studied with stress 2-D echocardiography and biomarkers such as troponin.

Results: This study is ongoing in both Europe and the USA. Even at a relatively low starting dose, two patients had sufficient response from a single 3-day course of L-Annamycin to qualify for a potentially curative bone marrow transplant. In total, 11 patients have completed at least one course of L-Annamycin with no signs of cardiotoxicity. Adverse events included one instance of Grade 2 mucositis, which resolved quickly.

Summary/Conclusion: Despite progress in the treatment of AML most patients will relapse and die from refractory disease. Properties of L-Annamycin, including the ability to overcome MDR, a critical mechanism of resistance, and the lack of cardiac toxicity, are highly promising and fully justify a Phase II clinical study designed to demonstrate L-Annamycin efficacy in all patients with R/R AML agnostic of mutational status.