Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma
Identifieur interne : 004022 ( Main/Exploration ); précédent : 004021; suivant : 004023Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma
Auteurs : Patrick A. Ott ; 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. WolchokSource :
- Investigational new drugs [ 0167-6997 ] ; 2012.
Abstract
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 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.
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.
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.
Url:
DOI: 10.1007/s10637-012-9862-2
PubMed: 22864522
PubMed Central: 4169197
Affiliations:
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Hoffman</name></author><author><name sortKey="Wu, Bor Wen" sort="Wu, Bor Wen" uniqKey="Wu B" first="Bor-Wen" last="Wu">Bor-Wen Wu</name></author><author><name sortKey="Bomalaski, John S" sort="Bomalaski, John S" uniqKey="Bomalaski J" first="John S." last="Bomalaski">John S. Bomalaski</name></author><author><name sortKey="Venhaus, Ralph" sort="Venhaus, Ralph" uniqKey="Venhaus R" first="Ralph" last="Venhaus">Ralph Venhaus</name></author><author><name sortKey="Pan, Linda" sort="Pan, Linda" uniqKey="Pan L" first="Linda" last="Pan">Linda Pan</name></author><author><name sortKey="Old, Lloyd J" sort="Old, Lloyd J" uniqKey="Old L" first="Lloyd J." last="Old">Lloyd J. Old</name></author><author><name sortKey="Pavlick, Anna C" sort="Pavlick, Anna C" uniqKey="Pavlick A" first="Anna C." last="Pavlick">Anna C. Pavlick</name></author><author><name sortKey="Wolchok, Jedd D" sort="Wolchok, Jedd D" uniqKey="Wolchok J" first="Jedd D." last="Wolchok">Jedd D. 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Ott</name></author><author><name sortKey="Carvajal, Richard D" sort="Carvajal, Richard D" uniqKey="Carvajal R" first="Richard D." last="Carvajal">Richard D. Carvajal</name></author><author><name sortKey="Pandit Taskar, Neeta" sort="Pandit Taskar, Neeta" uniqKey="Pandit Taskar N" first="Neeta" last="Pandit-Taskar">Neeta Pandit-Taskar</name></author><author><name sortKey="Jungbluth, Achim A" sort="Jungbluth, Achim A" uniqKey="Jungbluth A" first="Achim A." last="Jungbluth">Achim A. Jungbluth</name></author><author><name sortKey="Hoffman, Eric W" sort="Hoffman, Eric W" uniqKey="Hoffman E" first="Eric W." last="Hoffman">Eric W. Hoffman</name></author><author><name sortKey="Wu, Bor Wen" sort="Wu, Bor Wen" uniqKey="Wu B" first="Bor-Wen" last="Wu">Bor-Wen Wu</name></author><author><name sortKey="Bomalaski, John S" sort="Bomalaski, John S" uniqKey="Bomalaski J" first="John S." last="Bomalaski">John S. Bomalaski</name></author><author><name sortKey="Venhaus, Ralph" sort="Venhaus, Ralph" uniqKey="Venhaus R" first="Ralph" last="Venhaus">Ralph Venhaus</name></author><author><name sortKey="Pan, Linda" sort="Pan, Linda" uniqKey="Pan L" first="Linda" last="Pan">Linda Pan</name></author><author><name sortKey="Old, Lloyd J" sort="Old, Lloyd J" uniqKey="Old L" first="Lloyd J." last="Old">Lloyd J. Old</name></author><author><name sortKey="Pavlick, Anna C" sort="Pavlick, Anna C" uniqKey="Pavlick A" first="Anna C." last="Pavlick">Anna C. Pavlick</name></author><author><name sortKey="Wolchok, Jedd D" sort="Wolchok, Jedd D" uniqKey="Wolchok J" first="Jedd D." last="Wolchok">Jedd D. Wolchok</name></author></analytic><series><title level="j">Investigational new drugs</title><idno type="ISSN">0167-6997</idno><idno type="eISSN">1573-0646</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec id="S2"><title>Background</title><p id="P1">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.</p></sec><sec id="S3"><title>Patients and methods</title><p id="P2">Patients with advanced melanoma were treated with 40, 80 or 160 IU/m<sup>2</sup> ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by <sup>18</sup>FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry.</p></sec><sec id="S4"><title>Results</title><p id="P3">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.</p></sec><sec id="S5"><title>Conclusions</title><p id="P4">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.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Bomalaski, John S" sort="Bomalaski, John S" uniqKey="Bomalaski J" first="John S." last="Bomalaski">John S. Bomalaski</name><name sortKey="Carvajal, Richard D" sort="Carvajal, Richard D" uniqKey="Carvajal R" first="Richard D." last="Carvajal">Richard D. Carvajal</name><name sortKey="Hoffman, Eric W" sort="Hoffman, Eric W" uniqKey="Hoffman E" first="Eric W." last="Hoffman">Eric W. Hoffman</name><name sortKey="Jungbluth, Achim A" sort="Jungbluth, Achim A" uniqKey="Jungbluth A" first="Achim A." last="Jungbluth">Achim A. Jungbluth</name><name sortKey="Old, Lloyd J" sort="Old, Lloyd J" uniqKey="Old L" first="Lloyd J." last="Old">Lloyd J. Old</name><name sortKey="Ott, Patrick A" sort="Ott, Patrick A" uniqKey="Ott P" first="Patrick A." last="Ott">Patrick A. Ott</name><name sortKey="Pan, Linda" sort="Pan, Linda" uniqKey="Pan L" first="Linda" last="Pan">Linda Pan</name><name sortKey="Pandit Taskar, Neeta" sort="Pandit Taskar, Neeta" uniqKey="Pandit Taskar N" first="Neeta" last="Pandit-Taskar">Neeta Pandit-Taskar</name><name sortKey="Pavlick, Anna C" sort="Pavlick, Anna C" uniqKey="Pavlick A" first="Anna C." last="Pavlick">Anna C. Pavlick</name><name sortKey="Venhaus, Ralph" sort="Venhaus, Ralph" uniqKey="Venhaus R" first="Ralph" last="Venhaus">Ralph Venhaus</name><name sortKey="Wolchok, Jedd D" sort="Wolchok, Jedd D" uniqKey="Wolchok J" first="Jedd D." last="Wolchok">Jedd D. Wolchok</name><name sortKey="Wu, Bor Wen" sort="Wu, Bor Wen" uniqKey="Wu B" first="Bor-Wen" last="Wu">Bor-Wen Wu</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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