Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma

Abstract

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.

Fig 1

NY 10- MIP images (upper panel) and transaxial images (lower panel) of FDG PET scans on a patient with metastatic disease in the liver. The baseline study (a) shows intense uptake in a liver lesion (SUV 10.1); a 4-day post-treatment scan (b) shows decrease in the uptake (SUV 7.9) with persistent uptake in the day 50 scan c with an SUV of 8.5

Fig 2

The relationship of mean arginine and ADI-PEG 20 plasma concentrations over time is illustrated for each dose cohort (cohort 1: n=6; cohort 2: n=6; cohort 3: n=19)

Fig 3

The proportion of patients in which arginine levels were completely depleted (<2 μM, blue line) and percentages of patients with ADI-PEG concentration of >12 nM (red line) are shown for the first treatment cycle plasma levels below a critical threshold around 12 nM. The observation that there is a threshold of ADI-PEG 20 which leads to complete arginine depletion, measured on day 8 after the prior injection, is consistent with the findings in the prior US and Italian ADI-PEG 20 melanoma studies, which

Fig 4

Median ADI-PEG 20 plasma antibody titers of the entire study population (31 patients) over time are demonstrated

Fig 5

Immunohistochemical expression analysis for ASS: epidermis with ASS-positive basal keratinocytes (a), ASS positive hepatocytes in the peripheral areas of a liver lobule (b), ASS-negative melanoma, low magnification (c), ASS-negative melanoma cells (asterisk), ASS-positive endothelia in blood vessel of tumor stroma (interal positive control), high magnification (d)