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A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours
Authors: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 Roberts  Danielle Shaw  Nigel Smith  Jon Smythe  Andrew Taylor  Helen Turner  Yvonne Watson  Caroline Dive  Gordon C. Jayson
Affiliation:1. Institute for Cancer Studies Christie Hospital NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
10. University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, UK
2. Paterson Institute for Cancer Research, Wilmslow Road, Withington, Manchester, M20 4BX, UK
3. Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
4. Drug Development Office Cancer Research UK, Angel Building, 407 St John Street, London, EC1V 4AD, UK
5. NHS Blood and Transplant Unit, John Radcliffe Hospital, Oxford, UK
6. Cancer Research UK Formulation Unit, University of Strathclyde, 16 Richmond Street, Glasgow, G1 1XQ, UK
7. Lowry Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, Australia
8. Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK
9. The Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guilford, GU2 7XX, UK
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/m2). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/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 22.0 mg/m2/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.
Keywords:
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