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

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

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References

  1. Brookes K, Cummings J, Backen A, Greystoke A, Ward T, Jayson GC, Dive C (2010) Issues on fit-for-purpose validation of a panel of ELISAs for application as biomarkers in clinical trials of anti-Angiogenic drugs. Br J Cancer 102:1524–1532

    Article  PubMed  CAS  Google Scholar 

  2. Cummings J, Langdon SP, Ritchie AA, Burns DJ, Mackay J, Stockman P, Leonard RC, Miller WR (1996) Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3′,5′-monophosphate in breast cancer patients and xenograft bearing mice. Ann Oncol 7:291–296

    Article  PubMed  CAS  Google Scholar 

  3. Cummings J, Ranson M, Lacasse E, Ganganagari JR, St-Jean M, Jayson G, Durkin J, Dive C (2006) Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 95:42–48

    Article  PubMed  CAS  Google Scholar 

  4. Cummings J, Ward TH, Lacasse E, Lefebvre C, St-Jean M, Durkin J, Ranson M, Dive C (2005) Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 92:532–538

    PubMed  CAS  Google Scholar 

  5. Dilda PJ, Decollogne S, Weerakoon L, Norris MD, Haber M, Allen JD, Hogg PJ (2009) Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. J Med Chem 52:6209–6216

    Article  PubMed  CAS  Google Scholar 

  6. Dilda PJ, Don AS, Tanabe KM, Higgins VJ, Allen JD, Dawes IW, Hogg PJ (2005) Mechanism of selectivity of an angiogenesis inhibitor from screening a genome-wide set of Saccharomyces cerevisiae deletion strains. J Natl Cancer Inst 97:1539–1547

    Article  PubMed  CAS  Google Scholar 

  7. Dilda PJ, Ramsay EE, Corti A, Pompella A, Hogg PJ (2008) Metabolism of the tumor angiogenesis inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous acid. J Biol Chem 283:35428–35434

    Article  PubMed  CAS  Google Scholar 

  8. Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, Creighton B, Flynn E, Folkman J, Hogg PJ (2003) A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 3:497–509

    Article  PubMed  CAS  Google Scholar 

  9. Ellerhorn M (1997) Ellenhorn’s Medical Toxicology: diagnosis and treatment of human poisoning,. Williams & Wilkins

  10. Greystoke A, Cummings J, Ward T, Simpson K, Renehan A, Butt F, Moore D, Gietema J, Blackhall F, Ranson M, Hughes A, Dive C (2008) Optimisation of circulating biomarkers of cell death for routine clinical use. Ann Oncol 19:990–995

    Article  PubMed  CAS  Google Scholar 

  11. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  PubMed  CAS  Google Scholar 

  12. Hughes MF (2002) Arsenic toxicity and potential mechanisms of action. Toxicol Lett 133:1–16

    Article  PubMed  CAS  Google Scholar 

  13. Kramer G, Erdal H, Mertens HJ, Nap M, Mauermann J, Steiner G, Marberger M, Biven K, Shoshan MC, Linder S (2004) Differentiation between cell death modes using measurements of different soluble forms of extracellular cytokeratin 18. Cancer Res 64:1751–1756

    Article  PubMed  CAS  Google Scholar 

  14. Nordberg F, Nordberg Friberg ML (2007) Handbook on the toxicology of metals. AP/Elsevier, Amsterdam

    Google Scholar 

  15. Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K, Shinjo K, Fujita Y, Matsui H, Takeshita A, Sugiyama S, Satoh H, Terada H, Ohno R (2000) Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 133:881–885

    Article  PubMed  CAS  Google Scholar 

  16. Park D, Chiu J, Perrone GG, Dilda PJ, Hogg PJ (2012) The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase. Cancer Cell Int 12:11

    Article  PubMed  CAS  Google Scholar 

  17. Park D, Dilda PJ (2010) Mitochondria as targets in angiogenesis inhibition. Mol Aspects Med 31:113–131

    Article  PubMed  CAS  Google Scholar 

  18. Ramsay EE, Hogg PJ, Dilda PJ (2011) Mitochondrial metabolism inhibitors for cancer therapy. Pharm Res 28:2731–2744

    Article  PubMed  CAS  Google Scholar 

  19. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY (1997) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360

    PubMed  CAS  Google Scholar 

  20. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341–1348

    Article  PubMed  CAS  Google Scholar 

  21. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  22. Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 7:91–101

    Article  PubMed  CAS  Google Scholar 

  23. Tsimberidou AM, Camacho LH, Verstovsek S, Ng C, Hong DS, Uehara CK, Gutierrez C, Daring S, Stevens J, Komarnitsky PB, Schwartz B, Kurzrock R (2009) A phase I clinical trial of darinaparsin in patients with refractory solid tumors. Clin Cancer Res 15:4769–4776

    Article  PubMed  CAS  Google Scholar 

  24. Waxman S, Anderson KC (2001) History of the development of arsenic derivatives in cancer therapy. Oncologist 6(Suppl 2):3–10

    Article  PubMed  CAS  Google Scholar 

  25. Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, Luger SM, Ma MK, Ley TJ, DiPersio JF (2001) Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 98:266–271

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This phase I clinical trial was funded, sponsored and managed by the Cancer Research UK Drug Development Office. The following institutions were also involved in this study: Cancer Research UK Formulation Unit, University of Strathclyde; New South Innovations Pty and Oxford NHS Biomedical Research Centre. We thank all of the patients who participated in this trial. The study was supported by CR-UK core funding to the Paterson Institute for Cancer Research (C147/A12328) to C. Dive. The Manchester Experimental Cancer Medicine Centre provides financial support for G. Jayson and J. Cummings. G Jayson also receives financial support from the Manchester Academic Health Centre. Thanks to Dilly Goonetilleke for help with the manuscript.

Conflict of interest

G.J.M. Parker has a shareholding and part time appointment and directorship at Bioxydyn Limited which provides DCE-MRI services.

Author information

Authors and Affiliations

  1. Institute for Cancer Studies Christie Hospital NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK

    Laura Horsley, Andrew Clamp, Jurjees Hasan, Gireesh Kumaran, Paula Potter, Mark Saunders, Danielle Shaw & Gordon C. Jayson

  2. Paterson Institute for Cancer Research, Wilmslow Road, Withington, Manchester, M20 4BX, UK

    Jeff Cummings, Tim Ward, Alison Backen, Martin Dawson, Nigel Smith & Caroline Dive

  3. Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK

    Mark Middleton & Adrian Harris

  4. Drug Development Office Cancer Research UK, Angel Building, 407 St John Street, London, EC1V 4AD, UK

    Hayley Farmer, Sarah Halford & Helen Turner

  5. NHS Blood and Transplant Unit, John Radcliffe Hospital, Oxford, UK

    Nita Fisher & Jon Smythe

  6. Cancer Research UK Formulation Unit, University of Strathclyde, 16 Richmond Street, Glasgow, G1 1XQ, UK

    Gavin Halbert

  7. Lowry Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, Australia

    Philip Hogg

  8. Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Ross Little, Geoff J. M. Parker, Caleb Roberts & Yvonne Watson

  9. The Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guilford, GU2 7XX, UK

    Andrew Taylor

  10. University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, UK

    Laura Horsley, Andrew Clamp, Jurjees Hasan, Gireesh Kumaran, Mark Saunders, Danielle Shaw & Gordon C. Jayson

Authors
  1. Laura Horsley
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  2. Jeff Cummings
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  3. Mark Middleton
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  11. Sarah Halford
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  12. Adrian Harris
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  16. Ross Little
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  18. Paula Potter
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  28. Gordon C. Jayson
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Consortia

A Cancer Research UK Drug Development Office Phase I clinical trial

Corresponding author

Correspondence to Gordon C. Jayson.

Additional information

Laura Horsley and Jeff Cummings have contributed equally to the manuscript.

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Horsley, L., Cummings, J., Middleton, M. et al. A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours. Cancer Chemother Pharmacol 72, 1343–1352 (2013). https://doi.org/10.1007/s00280-013-2320-9

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  • DOI: https://doi.org/10.1007/s00280-013-2320-9

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