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 Roberts; Danielle Shaw; Nigel Smith; Jon Smythe; Andrew Taylor; Helen Turner; Yvonne Watson; Caroline Dive; Gordon C. Jayson

doi:10.1007/s00280-013-2320-9

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 Manchester Institute

Research output: Contribution to journal › Article › peer-review

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/m 2 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. © 2013 Springer-Verlag Berlin Heidelberg.

Original language	English
Pages (from-to)	1343-1352
Number of pages	9
Journal	Cancer Chemotherapy and Pharmacology
Volume	72
Issue number	6
DOIs	https://doi.org/10.1007/s00280-013-2320-9
Publication status	Published - Dec 2013

Keywords

Clinical trial
DCE-MRI
GSAO
Novel arsenic compound
Phase 1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00280-013-2320-9

Cite this

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., ... Jayson, G. C. (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

@article{57e166e63ff84ae5bfb9a67cfc5e883a,

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/m2). 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/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. {\textcopyright} 2013 Springer-Verlag Berlin Heidelberg.",

keywords = "Clinical trial, DCE-MRI, GSAO, Novel arsenic compound, Phase 1",

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

year = "2013",

month = dec,

doi = "10.1007/s00280-013-2320-9",

language = "English",

volume = "72",

pages = "1343--1352",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

publisher = "Springer Nature",

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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, GJM, Potter, P, Saunders, M, Roberts, C, Shaw, D, Smith, N, Smythe, J, Taylor, A, Turner, H, Watson, Y, Dive, C & Jayson, GC 2013, 'A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours', Cancer Chemotherapy and Pharmacology, vol. 72, no. 6, pp. 1343-1352. https://doi.org/10.1007/s00280-013-2320-9

TY - JOUR

T1 - A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours

AU - Horsley, Laura

AU - Cummings, Jeff

AU - Middleton, Mark

AU - Ward, Tim

AU - Backen, Alison

AU - Clamp, Andrew

AU - Dawson, Martin

AU - Farmer, Hayley

AU - Fisher, Nita

AU - Halbert, Gavin

AU - Halford, Sarah

AU - Harris, Adrian

AU - Hasan, Jurjees

AU - Hogg, Philip

AU - Kumaran, Gireesh

AU - Little, Ross

AU - Parker, Geoff J M

AU - Potter, Paula

AU - Saunders, Mark

AU - Roberts, Caleb

AU - Shaw, Danielle

AU - Smith, Nigel

AU - Smythe, Jon

AU - Taylor, Andrew

AU - Turner, Helen

AU - Watson, Yvonne

AU - Dive, Caroline

AU - Jayson, Gordon C.

PY - 2013/12

Y1 - 2013/12

N2 - 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/m 2 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. © 2013 Springer-Verlag Berlin Heidelberg.

AB - 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/m 2 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. © 2013 Springer-Verlag Berlin Heidelberg.

KW - Clinical trial

KW - DCE-MRI

KW - GSAO

KW - Novel arsenic compound

KW - Phase 1

U2 - 10.1007/s00280-013-2320-9

DO - 10.1007/s00280-013-2320-9

M3 - Article

C2 - 24141375

SN - 0344-5704

VL - 72

SP - 1343

EP - 1352

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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