Pegylated arginine deiminase treatment of patients with metastatic melanoma: Results from phase I and II studies

Paolo A. Ascierto, Stefania Scala, Giuseppe Castello, Antonio Daponte, Ester Simeone, Alessandro Ottaiano, Gerardo Beneduce, Vincenzo De Rosa, Francesco Izzo, Maria Teresa Melucci, C. Mark Ensor, Archie W. Prestayko, Frederick W. Holtsberg, John S. Bomalaski, Mike A. Clark, Niramol Savaraj, Lynn G. Feun, Theodore F. Logan

Research output: Contribution to journalArticlepeer-review


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/m 2. 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/m 2 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.

Original languageEnglish
Pages (from-to)7660-7668
Number of pages9
JournalJournal of Clinical Oncology
Issue number30
Publication statusPublished - 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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