Phase I Study of the [Cu, Zn] Superoxide Dismutase (SOD1) Inhibitor ATN-224 (Bis-Choline Tetrathiomolybdate) in Patients (pts) with Advanced Hematologic Malignancies.

Abstract

Abstract BACKGROUND: ATN-224 is an orally available, small molecule containing molybdenum (Mo) that specifically binds copper. ATN-224 inhibits multiple signaling pathways important to angiogenesis and tumor growth such as pathways mediated by growth factors, including vascular endothelial growth and epidermal growth factors and signaling molecules such as protein kinase B (PKB/Akt) and nuclear factor kappa B. ATN-224 exerts these effects through the inhibition of the enzyme copper-zinc superoxide dismutase (SOD1) in endothelial and tumor cells. Activity has been seen in a variety of animal tumor models including bortezomib-resistant myeloma. METHODS: Adult pts with recurrent or refractory hematologic malignanies or for which no standard therapy exists were enrolled. Pts had to have adequate performance status (PS 0–2) and have adequate hematologic and organ function. Pts were monitored for safety and efficacy and blood samples for pharmacokinetic and biomarker determinations were taken at specified intervals. At least 3 pts were to be enrolled at each dose level starting at 120 mg/day. Pts who left the study prior to 28 days for reasons other than toxicity were to be replaced. If 1 pt developed dose-limiting toxicity (DLT) as defined by the protocol, the cohort was to be expanded to up to 6 pts. Maximum tolerated dose (MTD) was defined as the highest dose where no more than 1 of 6 pts had DLT. Dose adjustments were made on the basis of toxicity and serum ceruloplasmin (Cp), a surrogate marker for total body copper. Pts received a loading dose for 2 weeks and then doses were titrated to keep Cp between 5 and 15 mg/dL. RESULTS: 17 pts (53% female), ages 43–79 (mean 63), with PS 0 or 1 were entered. 8 pts had myeloma, 5 leukemia, 3 lymphoma, and 1 myelodysplastic syndrome. Because of rapid progression in 5 pts who were replaced and 1 DLT (Grade [Gr] 4 neutropenia, Gr 3 anemia), 11 pts were entered in the 1st cohort. With information from a companion study in pts with solid tumors, the dose for the next cohort was increased to 300 mg. 1 of 6 pts had DLT (Gr 4 neutropenia). No further cohorts were entered as 300 mg/day was determined as MTD from the companion study. Pts who received long-acting antacids were found to have higher Mo concentrations than those without, so the protocol was amended to require all pts to receive daily antacid. Dose-dependent inhibition of SOD in red blood cells (a surrogate tissue for tumor) was observed. Major adverse events included reversible Gr 4 neutropenia, Gr 3 anemia, and Gr 3 thrombocytopenia. Gr 3 fatigue, which was DLT in the solid tumor study, was not observed in this trial. Mild to moderate symptoms such as gastrointestinal disorders, headache and lightheadedness were also observed. There were no responses but 1 pt with leukemia had stable disease for 5 months and a pt with myeloma had stable disease for 4.5 months. CONCLUSION: ATN-224, an antiangiogenesis and antitumor agent with a novel mechanism of action, has manageable, reversible toxicity. The dose recommended for Phase II studies is 300 mg/day with dose adjustment starting at 2 weeks to maintain Cp at 5–15 mg/dL.