Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma Journal Article
| Authors: | Ott, P. A.; Carvajal, R. D.; Pandit-Taskar, N.; Jungbluth, A. A.; Hoffman, E. W.; Wu, B. W.; Bomalaski, J. S.; Venhaus, R.; Pan, L.; Old, L. J.; Pavlick, A. C.; Wolchok, J. D. |
| Article Title: | Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma |
| Abstract: | Summary: 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. © 2012 Springer Science+Business Media, LLC. |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; treatment outcome; aged; aged, 80 and over; middle aged; survival rate; unclassified drug; fatigue; advanced cancer; drug efficacy; drug safety; monotherapy; treatment duration; positron emission tomography; follow-up studies; antineoplastic agent; neoplasm staging; anorexia; treatment indication; melanoma; computer assisted tomography; drug eruption; phase 2 clinical trial; cohort studies; skin neoplasms; tumor volume; protein depletion; nausea; myalgia; cohort analysis; dose-response relationship, drug; recombinant enzyme; abdominal pain; arthralgia; drug dose escalation; pruritus; lymphedema; immunoenzyme techniques; drug uptake; tissue distribution; immunogenicity; fluorodeoxyglucose f 18; limb pain; injection site pain; open study; seizure; amino acid blood level; drug metabolism; skin induration; drug blood level; maximum tolerated dose; phase 1 clinical trial; cancer tissue; uvea melanoma; uveal neoplasms; polyethylene glycols; antibody titer; metastatic; hydrolases; injection site rash; injection site edema; argininosuccinate synthase; arginine deiminase; argininosuccinate synthetase; auxotrophy; arginine deiminase polyethylene glycol conjugate; enzyme antibody |
| Journal Title: | Investigational New Drugs |
| Volume: | 31 |
| Issue: | 2 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2013-04-01 |
| Start Page: | 425 |
| End Page: | 434 |
| Language: | English |
| DOI: | 10.1007/s10637-012-9862-2 |
| PROVIDER: | scopus |
| PUBMED: | 22864522 |
| PMCID: | PMC4169197 |
| DOI/URL: | |
| Notes: | "Export Date: 19 July 2013" - "CODEN: INNDD" - "Source: Scopus" |
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