A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours

Laura Horsley, Jeff Cummings, Mark Middleton, Tim Ward, Alison Backen, Andrew Clamp, Martin Dawson, Hayley Farmer, Nita Fisher, Gavin Halbert, Sarah Halford, Adrian Harris, Jurjees Hasan, Philip Hogg, Gireesh Kumaran, Ross Little, Geoff J. M. Parker, Paula Potter, Mark Saunders, Caleb RobertsDanielle Shaw, Nigel Smith, Jon Smythe, Andrew Taylor, Helen Turner, Yvonne Watson, Caroline Dive, Gordon C. Jayson, Cancer Research UK Drug Development Office Phase I clinical trial

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background

4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds toadenine nucleotide translocase in the inner mitochondrial membrane, therebytargeting cell proliferation. This phase 1 study investigated safety,dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) andpharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamiccontrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markersof angiogenesis.

Methods

Patients with advanced solidtumours 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, byarsenic PK data.

Results

A total of 34 patients were treatedwith GSAO across 9 dose levels (1.3-44.0 mg/m2). Treatment was well toleratedwith few adverse events. An additional three patients were enrolled at the 12.4mg/m2 dose level following a DLT of derangement of liver function tests(grade 4). At the 44.0 mg/m2 dose level, two out of three patients had DLTs(reversible encephalopathy; paroxysmal atrial fibrillation).

Conclusions

The MTD of GSAO was 22.0mg/m2/day. There was no biomarker evidence from DCE-MRI or circulatingmarkers of angiogenesis of an anti-vascular effect of GSAO.

Original languageEnglish
Pages (from-to)1343-1352
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume72
Issue number6
Early online date20 Oct 2013
DOIs
Publication statusPublished - 1 Dec 2013

Keywords

  • adult
  • aged
  • antineoplastic agents
  • arsenicals
  • cell proliferation
  • dose-response relationship, drug
  • female
  • glutathione
  • humans
  • infusions, intravenous
  • liver function tests
  • magnetic resonance imaging
  • male
  • maximum tolerated dose
  • middle aged
  • neoplasms
  • neovascularization, pathologic

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    Horsley, L., Cummings, J., Middleton, M., Ward, T., Backen, A., Clamp, A., Dawson, M., Farmer, H., Fisher, N., Halbert, G., Halford, S., Harris, A., Hasan, J., Hogg, P., Kumaran, G., Little, R., Parker, G. J. M., Potter, P., Saunders, M., ... Cancer Research UK Drug Development Office Phase I clinical trial (2013). A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours. Cancer Chemotherapy and Pharmacology, 72(6), 1343-1352. https://doi.org/10.1007/s00280-013-2320-9