Investigational New Drugs

, Volume 31, Issue 2, pp 425–434 | Cite as

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

  • Patrick A. OttEmail author
  • Richard D. Carvajal
  • Neeta Pandit-Taskar
  • Achim A. Jungbluth
  • Eric W. Hoffman
  • Bor-Wen Wu
  • John S. Bomalaski
  • Ralph Venhaus
  • Linda Pan
  • Lloyd J. Old
  • Anna C. Pavlick
  • Jedd D. Wolchok


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/m2 ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by 18FDG-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.


Melanoma Metastatic Auxotrophy Arginine deiminase Argininosuccinate synthetase 



Ludwig Institute for Cancer Research

Financial disclosures

Eric W. Hoffman is the executive officer of the Ludwig Institute for Cancer Research, which has a royalty agreement with Polaris Pharmaceuticals for ADI-PEG20. He received honoraria from Polaris for presentations and participation in investor meetings. Jedd Wolchok is an advisory board member at Polaris Pharmaceuticals. Bor-Wen Wu and John Bomalaski are employees of Polaris Group, the maker of ADI-PEG 20, and hold stock and employee stock options in Polaris Group. All remaining authors have declared no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Patrick A. Ott
    • 1
    • 5
    Email author
  • Richard D. Carvajal
    • 2
  • Neeta Pandit-Taskar
    • 2
  • Achim A. Jungbluth
    • 3
  • Eric W. Hoffman
    • 3
  • Bor-Wen Wu
    • 4
  • John S. Bomalaski
    • 4
  • Ralph Venhaus
    • 3
  • Linda Pan
    • 3
  • Lloyd J. Old
    • 3
  • Anna C. Pavlick
    • 1
  • Jedd D. Wolchok
    • 2
    • 3
  1. 1.Department of Medical OncologyNew York University School of MedicineNew YorkUSA
  2. 2.Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Ludwig Institute for Cancer ResearchBranch at Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Polaris PharmaceuticalsSan DiegoUSA
  5. 5.Melanoma Disease CenterDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA

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