title: Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors.
abstract: OBJECTIVE
  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 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities.
  
  
  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 dose-limiting. 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.
authors.affiliation: Cancer Research UK Department of Medical Oncology, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Lowndes
authors.forename: Avril
authors.initials: A
authors.lastname: Adams
authors.forename: Anthony
authors.initials: A
authors.lastname: Timms
authors.forename: Nita
authors.initials: N
authors.lastname: Fisher
authors.forename: Jon
authors.initials: J
authors.lastname: Smythe
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Watt
authors.forename: Simon
authors.initials: S
authors.lastname: Joel
authors.forename: Fernando
authors.initials: F
authors.lastname: Donate
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hayward
authors.forename: Steven
authors.initials: S
authors.lastname: Reich
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.forename: Andrew
authors.initials: A
authors.lastname: Mazar
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D002570:Ceruloplasmin / Q000187:drug effects; D002614:Chelating Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015913:Chelation Therapy; D002794:Choline / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003300:Copper / Q000097:blood*; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008982:Molybdenum / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000097:blood / Q000187:drug effects
chemical_list: D002614:Chelating Agents; D016207:Cytokines; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D002570:Ceruloplasmin; D002794:Choline