Phase I Study of Copper-Binding Agent ATN-224 in Patients with Advanced Solid Tumors

Abstract

Purpose: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities. Patients and Methods: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose. Results: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was doselimiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (>90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of >6 months was observed in 2 patients.Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

“…In addition, the copper chelator ATN-224, which interferes with the activation of SOD1 (and other cellular processes), inhibits growth of tumor cells and blocks angiogenesis in animal models (15), suggesting a role for SOD1 in regulating tumorigenesis and angiogenesis. ATN-224 is currently being tested in clinical trials for the treatment of late stage solid tumors (16). However, there has been no clear evidence pointing to a specific role for SOD1 in tumorigenesis, and we are unaware of any previously reported SOD1 inhibitors known to be effective in cells, other than copper chelators.…”

Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224)

“…The SOD activity can be measured in blood pellets and tumour lysates, and is quickly inhibited upon ATN-224 dosing. The PK of ATN-224 is followed by tracking Mo in plasma (Berenson et al, 2006;Lowndes et al, 2006). This approach, however, does not distinguish the active compound from its metabolites.…”

“…This suggests that longer treatments than those used in this study may lower the threshold of ATN-224 needed for inhibiting blood cell SOD1. Indeed, data from a phase I trial showed a profound and persistent inhibition of SOD1 in blood pellets in patients treated at several ATN-224 doses below and at the maximal tolerated dose (Lowndes et al, 2006).…”

“…All other parameters measured, for example, red and white blood cell counts, platelets and haemoglobin levels were not affected by treatment (data not shown). Although we did not measure blood cell SOD in the macaque study, the recently completed phase I study with ATN-224 (Lowndes et al, 2006) indicated that substantial and maintained inhibition of blood cell SOD was associated with haematologic toxicities. As we observed significant depletion of EPCs in the macaques at a dose of ATN-224 that does not affect haematologic parameters, it is unlikely that we had significant inhibition of blood cell SOD in that study, further supporting the hypothesis that doses at which red blood cell (RBC) SOD activity is inhibited exceed the threshold required for antiangiogenic activity.…”

“…The ability of TM to inhibit angiogenesis has been attributed to the depletion of systemic copper, which has been described to affect multiple key regulators of angiogenesis (Brewer et al, 2000;Pan et al, 2002Pan et al, , 2003aRedman et al, 2003;Goodman et al, 2005;Hassouneh et al, 2007). ATN-224 is a second-generation choline salt of TM with improved stability, which has been tested in two phase I clinical trials (solid tumours and haematological malignancies) (Berenson et al, 2006;Lowndes et al, 2006) and is currently being investigated in three phase II trials (melanoma, prostate and multiple myeloma). We have recently identified the copperdependent enzyme superoxide dismutase 1 (SOD1) as the main target for the antiproliferative activity of ATN-224 in endothelial and tumour cells (Juarez et al, 2006).…”