Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma.

Abstract

PURPOSE:

It is well known that hepatocellular carcinoma (HCC) is an arginine auxotroph due to argininosuccinate synthetase I deficiency. This study's purpose was to evaluate the effects of pegylated arginine deiminase (ADI) in terms of toxicity, tumor response, alpha-fetoprotein (AFP) levels, and serum arginine levels.

PATIENTS AND METHODS:

Eighty patients were randomly assigned to receive either 80 IU/m(2) or 160 IU/m(2) of ADI weekly for up to 6 months. Adverse events, serum arginine, AFP levels, and antibody production against ADI were measured on a regular basis. In addition, disease response and time to progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) and survival rates were evaluated.

RESULTS:

Four patients were excluded from the survival analysis because they developed exclusion criteria after randomization, but before first treatment. The number of patients in the two cohorts were similar (n = 37 in the low-dose cohort, n = 39 in the high-dose cohort). Mean (+/-SE) survival for all subjects was 15.8 months (474 days +/- 39 days) from time of diagnosis of unresectable disease. Arginine levels remained below baseline for 50 days while antibodies against ADI reached a plateau at approximately the same time. There were no deaths attributed to ADI treatment. Only two patients were withdrawn for immunogenic-related adverse events. Grade 2, 3, or 4 toxicities were recorded in 92, 19, and 0 patients, respectively.

CONCLUSION:

Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

• Authors: Evan S Glazer, Mauro Piccirillo, Vittorio Albino, Raimondo Di Giacomo, Raffaele Palaia, Angelo A Mastro, Gerardo Beneduce, Giuseppe Castello, Vincenzo De Rosa, Antonella Petrillo, Paolo A Ascierto, Steven A Curley, Francesco Izzo
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 28 Issue 13 Pg. 2220-6 (May 01 2010) ISSN: 1527-7755 [Electronic] United States
• PMID: 20351325 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• AFP protein, human
• Antibodies
• Antineoplastic Agents
• Biomarkers
• alpha-Fetoproteins
• Polyethylene Glycols
• Arginine
• Hydrolases
• ADI PEG20

Topics

• Aged
• Aged, 80 and over
• Antibodies (blood)
• Antineoplastic Agents (administration & dosage, adverse effects, immunology)
• Arginine (blood)
• Biomarkers (blood)
• Carcinoma, Hepatocellular (drug therapy, metabolism, mortality, secondary)
• Chi-Square Distribution
• Female
• Humans
• Hydrolases (administration & dosage, adverse effects, immunology)
• Injections, Intramuscular
• Kaplan-Meier Estimate
• Liver Neoplasms (drug therapy, metabolism, mortality, pathology)
• Male
• Middle Aged
• Polyethylene Glycols (administration & dosage, adverse effects)
• Time Factors
• Treatment Outcome
• alpha-Fetoproteins (metabolism)