Background
Arginine deiminase (ADI) is an
enzyme that degrades
arginine, an
amino acid that is important for growth and development of normal and neoplastic cells.
Melanoma cells are auxotrophic for
arginine, because they lack argininosuccinatesynthetase (ASS), a key
enzyme required for the synthesis of
arginine. Patients and methods Patients with advanced
melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and
tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating
arginine levels, and
argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site
pain,
rash, and
fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had
uveal melanoma. PD analysis showed complete plasma
arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in
tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced
melanoma patients and leads to consistent, but transient,
arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in
uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this
melanoma subgroup.