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; Cancer Research UK Drug Development Office Phase I clinical trial

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 Drug Development Office Phase I clinical trial

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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

34 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 language	English
Pages (from-to)	1343-1352
Number of pages	10
Journal	Cancer Chemotherapy and Pharmacology
Volume	72
Issue number	6
Early online date	20 Oct 2013
DOIs	https://doi.org/10.1007/s00280-013-2320-9
Publication status	Published - 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

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., ... 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

@article{57ae60dcbfb84a20a163c370668ffe5b,

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

abstract = "Background4-(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.MethodsPatients 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.ResultsA 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).ConclusionsThe 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.",

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",

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.} and {Cancer Research UK Drug Development Office Phase I clinical trial}",

year = "2013",

month = dec,

day = "1",

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

language = "English",

volume = "72",

pages = "1343--1352",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

number = "6",

}

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 & 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, 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.

AU - Cancer Research UK Drug Development Office Phase I clinical trial

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Background4-(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.MethodsPatients 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.ResultsA 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).ConclusionsThe 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.

AB - Background4-(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.MethodsPatients 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.ResultsA 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).ConclusionsThe 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.

KW - adult

KW - aged

KW - antineoplastic agents

KW - arsenicals

KW - cell proliferation

KW - dose-response relationship, drug

KW - female

KW - glutathione

KW - humans

KW - infusions, intravenous

KW - liver function tests

KW - magnetic resonance imaging

KW - male

KW - maximum tolerated dose

KW - middle aged

KW - neoplasms

KW - neovascularization, pathologic

UR - http://link.springer.com/journal/280

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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