A phase I study of elesclomol sodium in patients with acute myeloid leukemia

Elesclomol is a novel, injectable, small molecule chemotherapeutic agent that has demonstrated preclinical efficacy in AML. [1,2] Mechanistically, elesclomol binds copper (Cu) in the form of Cu in the serum and enables the reduction reaction of Cu (II) to Cu (I) once inside the malignant cell. This redox reaction disrupts mitochondrial respiration and elevates the level of reactive oxygen species (ROS) beyond sustainable levels. [3] Ultimately, elesclomol perturbs cellular energy production and metabolism and triggers the mitochondrial apoptosis pathway in cancer cells resulting in cell death. [4] We and others have previously shown that AML cells and stem cells are uniquely dependent on mitochondrial metabolism and function. [5–7] Thus, elesclomol-mediated mitochondrial disruption could be efficacious for a subset of AML patients. Due to the mechanism of action of elesclomol, it is most effective under oxygen conditions where mitochondrial respiration is active. In contrast, under hypoxic conditions, where the energy production of a cell shifts to glycolysis in the cytoplasm, elesclomol’s anti-cancer activity is diminished. [8,9] This shift in cellular respiration is often associated with high lactate dehydrogenase (LDH) levels in the cell, and may be reflected by high levels in the serum as well. [10] In support of this hypothesis, preliminary findings in a phase 3 metastatic melanoma study showed a differential response to treatment with elesclomol based on baseline levels of LDH. Improved progression-free survival was achieved in patients with normal LDH. In contrast, patients with high LDH levels had no difference in progression-free survival, and in fact, had decreased overall survival. [11] We therefore conducted a phase I dose escalation study assessing the safety and efficacy of elesclomol in patients with relapsed or refractory AML. A total of nine patients with relapsed and refractory AML with LDH 0.8 times the upper limit of normal (ULN) were enrolled in the study from February 2011 to September 2013. Baseline characteristics are shown in Table 1. Patients at least 18 years of age with adequate performance status and renal and hepatic function were eligible to participate in this study. Patients were removed from study treatment if they developed unacceptable toxicity or adverse events, progressive disease, or a sustained increase in LDH 1.2 times the ULN (see Supplementary materials and methods for more details). The Ethics Review Board at the University Health Network as well as Health Canada approved this study before it commenced. All patients provided written consent and written authorization permitting the use of protected health information prior to the initiation of any study related procedures. The study is registered at clinicaltrials.gov (NCT01280786). A sodium salt formulation of elesclomol sodium was used in this study at a starting dose of 200 mg/m via a 60 min infusion once weekly (days 1, 8, 15, and 22) based on prior studies. [11–13] Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity possibly related to elesclomol occurring during the first four-week cycle of therapy. The primary study objective was to characterize the safety and tolerability of elesclomol administered to subjects with AML. The secondary objectives were to determine the optimal phase II dose and schedule for elesclomol in subjects with AML and evaluate response to the drug by pharmacodynamic assessment. Efficacy of elesclomol was evaluated based on bone marrow aspirate at cycle 1, day 29. Responses were recorded as defined by Cheson et al.[14] In the event of disease progression during cycle 1, study drug dosing was stopped and the bone marrow aspirate was not performed. Of the nine patients enrolled in the trial, six received one complete cycle of elesclomol. Two of the nine