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.
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.
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).
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.
- antineoplastic agents
- cell proliferation
- dose-response relationship, drug
- infusions, intravenous
- liver function tests
- magnetic resonance imaging
- maximum tolerated dose
- middle aged
- neovascularization, pathologic