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Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II Studies

From the Pascale National Cancer Institute, Naples, Italy; Phoenix Pharmacologics, Inc; University of Kentucky, Lexington, KY; Hematology and Oncology Division, University of Miami; Miami Veterans Affairs Medical Center, Miami, FL; and Hematology and Oncology Division, Indiana University, Indianapolis, IN.

Address reprint requests to John S. Bomalaski, MD, Phoenix Pharmacologics, Inc, 115 John Robert Thomas Dr, Exton, PA 19341; e-mail: jbomalaski{at}phoenixpharmaco.com

PURPOSE: Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this auxotrophy may be therapeutically exploited. A novel amino acid–degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma.

PATIENTS AND METHODS: Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m². The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw.

RESULTS: PK and PD studies indicated that a dose of 160 U/m² lowered plasma arginine from a resting level of approximately 130 µmol/L to less than 2 µmol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival.

CONCLUSION: Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.

Supported in part by grants from the US Food and Drug Administration and National Institutes of Health to Phoenix Pharmacologics, Inc.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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