title: A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours.
abstract: BACKGROUND
  4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis.
  
  
  METHODS
  Patients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard '3 + 3' design that was guided by toxicity and, for the final dose escalation, by arsenic PK data.
  
  
  RESULTS
  A total of 34 patients were treated with GSAO across 9 dose levels (1.3-44.0 mg/m(2)). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/m(2) dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0 mg/m(2) dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation).
  
  
  CONCLUSIONS
  The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.
authors.affiliation: Institute for Cancer Studies Christie Hospital NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Horsley
authors.forename: Jeff
authors.initials: J
authors.lastname: Cummings
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.forename: Andrew
authors.initials: A
authors.lastname: Clamp
authors.forename: Martin
authors.initials: M
authors.lastname: Dawson
authors.forename: Hayley
authors.initials: H
authors.lastname: Farmer
authors.forename: Nita
authors.initials: N
authors.lastname: Fisher
authors.forename: Gavin
authors.initials: G
authors.lastname: Halbert
authors.forename: Sarah
authors.initials: S
authors.lastname: Halford
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.forename: Jurjees
authors.initials: J
authors.lastname: Hasan
authors.forename: Philip
authors.initials: P
authors.lastname: Hogg
authors.forename: Gireesh
authors.initials: G
authors.lastname: Kumaran
authors.forename: Ross
authors.initials: R
authors.lastname: Little
authors.forename: Geoff J M
authors.initials: GJ
authors.lastname: Parker
authors.forename: Paula
authors.initials: P
authors.lastname: Potter
authors.forename: Mark
authors.initials: M
authors.lastname: Saunders
authors.forename: Caleb
authors.initials: C
authors.lastname: Roberts
authors.forename: Danielle
authors.initials: D
authors.lastname: Shaw
authors.forename: Nigel
authors.initials: N
authors.lastname: Smith
authors.forename: Jon
authors.initials: J
authors.lastname: Smythe
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.forename: Helen
authors.initials: H
authors.lastname: Turner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Watson
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001152:Arsenicals / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology
chemical_list: C426645:4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; D000970:Antineoplastic Agents; D001152:Arsenicals; D005978:Glutathione