Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors

Sarah A. Lowndes, Avril Adams, Anthony Timms, Nita Fisher, Jon Smythe, Suzanne M. Watt, Simon Joel, Fernando Donate, Carolyn Hayward, Steven Reich, Mark Middleton, Andrew Mazar, Adrian L. Harris

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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, asmeasured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, 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 dosel-imiting. 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 andmore 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 300mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.

Original languageEnglish (US)
Pages (from-to)7526-7534
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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