title: Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies.
abstract: OBJECTIVE
  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.
  
  
  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 micromol/L to less than 2 micromol/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.
authors.affiliation: Pascale National Cancer Institute, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Antonio
authors.initials: A
authors.lastname: Daponte
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ottaiano
authors.forename: Gerardo
authors.initials: G
authors.lastname: Beneduce
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Rosa
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Melucci
authors.forename: C Mark
authors.initials: CM
authors.lastname: Ensor
authors.forename: Archie W
authors.initials: AW
authors.lastname: Prestayko
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.forename: John S
authors.initials: JS
authors.lastname: Bomalaski
authors.forename: Mike A
authors.initials: MA
authors.lastname: Clark
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000097:blood; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007558:Italy; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary*; D015996:Survival Rate; D016896:Treatment Outcome; D014481:United States
chemical_list: D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C019723:arginine deiminase