Phase-1 Study of ZIO-101: A New Organic Arsenic Active in Acute Myelogenous Leukemia (AML) and Multiple Myeloma (MM).
Authors: Berenson James R. , Boccia Ralph Vincent V. , Hussein Mohamad A. , Belch Andrew , Boise Lawrence , Schwartz Brian , Gale Robert Peter , Kornblau Steven M. 
Published: October 2019

Abstract
Background: Although arsenic trioxide (As2O3) is active in vitro against diverse hematological cancers, clinical data show activity only in acute progranulocytic leukemia (APL); there is little if any single-agent activity in multiple myeloma and other hematological cancers. This discordance may be because relatively little As2O3 can be given consequent to its substantial toxicity (especially QTc-prolongation) or because the mode of action (MOA) in APL (differentiation) is inoperative in other hematological cancers (or both). ZIO-101 (S-dimethylarsino-glutathione), a new organic arsenic, is active against diverse cancers in vitro and in animal models including AML and MM. Cell-killing by ZIO-101 is mediated by mitochondrial-disruption and apoptosis-induction rather than the differentiation MOA of As2O3. ZIO-101 can be given at doses ≥ 50-fold higher than As2O3 and achieves 5–10-fold higher intracellular concentrations at equimolar extracellular As concentrations. Gene-expression profiling data suggest different cellular responses to ZIO-101 and As2O3. These features make ZIO-101 attractive for evaluation in AML and MM.
Methods: 2 phase-1 studies evaluating safety, activity and pharmacokinetic (PK) profile of ZIO-101 in 21 subjects with advanced AML (N=8) or MM (N=13). Median age is 58 y (range, 41–85 y). Median N of prior therapies is 5 (range, 2–12) including 4 subjects failing prior As2O3 therapy. Starting dose was 78 mg/me2/d IV for 5 consecutive d every 4 w.
Results: Subjects received a median of 2 cycles (range, 1–6). Therapy was well-tolerated; adverse events ≥ grade-2 occurring in > 25% of subjects included neutropenia, hypokalemia and hyperglycemia. There was no clinically-important renal, liver or heart toxicity nor QTc-prolongation. Maximum tolerated dose (MTD) was 420 mg/me2/d. Pharmacokinetic (PK) studies at this dose showed a tmax=1 h (SD±0.9), Cmax=1.06 μg/mL (SD±0.07 μg/mL), t1/2=17.8 h (SD±1.4 h) and AUC0-∞=25.9 μg·h/mL (SD±0.8 μg·h/mL). 4 subjects with AML had stable disease (SD) after 1 cycle and received 2–4 more cycles before progressing. Blood myeloblasts decreased substantially in 1 subject and completely resolved in 2. Bone marrow myeloblasts decreased in 1. 1 subject with prior myelodysplastic syndrome (MDS) stopped requiring frequent RBC transfusions. 1 subject with rapidly-progressing As2O3- and bortezumib-resistant MM has stable disease (SD) >6 mo.
Conclusions: These early data suggest activity of ZIO-101 in advanced AML and MM. The MTD is 420 mg/me2/d, ≥ 50-fold higher than As2O3. Plasma levels exceed the IC50 for AML and MM cell in vitro and animal models. Clinically-important QTc-prolongation was not seen. Some subjects failing As2O3 responded to ZIO-101 indicating efficacy of a higher dose, different MOA or both. Because of these favorable results phase-2 studies in hematological cancers are in progress.