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

• Published in: Cancer chemotherapy and pharmacology Vol. 72; no. 6; pp. 1343 - 1352
• Main Authors: Horsley, Laura, Cummings, Jeff, Middleton, Mark, Ward, Tim, Backen, Alison, Clamp, Andrew, Dawson, Martin, Farmer, Hayley, Fisher, Nita, Halbert, Gavin, Halford, Sarah, Harris, Adrian, Hasan, Jurjees, Hogg, Philip, Kumaran, Gireesh, Little, Ross, Parker, Geoff J. M., Potter, Paula, Saunders, Mark, Roberts, Caleb, Shaw, Danielle, Smith, Nigel, Smythe, Jon, Taylor, Andrew, Turner, Helen, Watson, Yvonne, Dive, Caroline, Jayson, Gordon C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Arsenicals - administration & dosage; Arsenicals - adverse effects; Arsenicals - pharmacokinetics; Biological and medical sciences; Cancer Research; Cell Proliferation - drug effects; Clinical Trial Report; Dose-Response Relationship, Drug; Female; Glutathione - administration & dosage; Glutathione - adverse effects; Glutathione - analogs & derivatives; Glutathione - pharmacokinetics; Humans; Infusions, Intravenous; Liver Function Tests; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - pathology; Neovascularization, Pathologic - pathology; Oncology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Tumors; Clinical trial; DCE-MRI; Phase 1; GSAO; Novel arsenic compound; Human; Solid tumor; Intravenous administration; Arsenic compound; Malignant tumor; Phase I; Phase I trial; Advanced stage; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2320-9

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/m 2 ). 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/m 2 dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation). Conclusions The MTD of GSAO was 22.0 mg/m 2 /day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.