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

Horsley, Laura and Cummings, Jeff and Middleton, Mark and Ward, Tim and Backen, Alison and Clamp, Andrew and Dawson, Martin and Farmer, Hayley and Fisher, Nita and Halbert, Gavin and Halford, Sarah and Harris, Adrian and Hasan, Jurjees and Hogg, Philip and Kumaran, Gireesh and Little, Ross and Parker, Geoff J. M. and Potter, Paula and Saunders, Mark and Roberts, Caleb and Shaw, Danielle and Smith, Nigel and Smythe, Jon and Taylor, Andrew and Turner, Helen and Watson, Yvonne and Dive, Caroline and Jayson, Gordon C., 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). pp. 1343-1352. ISSN 1432-0843

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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.