Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors
Identifieur interne : 006838 ( Main/Exploration ); précédent : 006837; suivant : 006839Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors
Auteurs : Luis G. Paz-Ares [Espagne] ; Carlos Gomez-Roca [France] ; Jean-Pierre Delord [France] ; Andres Cervantes [Espagne] ; Ben Markman [Espagne, Australie] ; Jesus Corral [Espagne] ; Jean-Charles Soria [France] ; Yann Berge [France] ; Desamparados Roda [Espagne] ; Fiona Russell-Yarde [Royaume-Uni] ; Simon Hollingsworth [Royaume-Uni] ; José Baselga [Espagne] ; Pablo Umana [Suisse] ; Luigi Manenti [Suisse] ; Josep Tabernero [Espagne]Source :
- Journal of clinical oncology [ 0732-183X ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201 a humanized and glycoengineered immunoglobulin G, anti-epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patients), infusion-related reactions (77%), and hypomagnesemia (56%). Grades 3 and 4 AEs were rash (grade 3, 25%), infusion-related reaction (grade 3, 7%; grade 4, 1%), paronychia (grade 3, 3%), and hypomagnesemia (grade 3, 1%; grade 4, 1%). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients. Conclusion RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.
Affiliations:
- Australie, Espagne, France, Royaume-Uni, Suisse
- Catalogne, Midi-Pyrénées, Occitanie (région administrative), Victoria (État)
- Barcelone, Melbourne, Toulouse
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors</title><author><name sortKey="Paz Ares, Luis G" sort="Paz Ares, Luis G" uniqKey="Paz Ares L" first="Luis G." last="Paz-Ares">Luis G. Paz-Ares</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</s1><s2>Seville</s2><s3>ESP</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</wicri:noRegion></affiliation></author><author><name sortKey="Gomez Roca, Carlos" sort="Gomez Roca, Carlos" uniqKey="Gomez Roca C" first="Carlos" last="Gomez-Roca">Carlos Gomez-Roca</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></affiliation></author><author><name sortKey="Delord, Jean Pierre" sort="Delord, Jean Pierre" uniqKey="Delord J" first="Jean-Pierre" last="Delord">Jean-Pierre Delord</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>3 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Cervantes, Andres" sort="Cervantes, Andres" uniqKey="Cervantes A" first="Andres" last="Cervantes">Andres Cervantes</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Fundación Investigación Hospital Clinico Valencia, University of Valencia</s1><s2>Valencia</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Valencia</wicri:noRegion></affiliation></author><author><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Monash Institute of Medical Research, Monash University</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>5 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Corral, Jesus" sort="Corral, Jesus" uniqKey="Corral J" first="Jesus" last="Corral">Jesus Corral</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</s1><s2>Seville</s2><s3>ESP</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</wicri:noRegion></affiliation></author><author><name sortKey="Soria, Jean Charles" sort="Soria, Jean Charles" uniqKey="Soria J" first="Jean-Charles" last="Soria">Jean-Charles Soria</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></affiliation></author><author><name sortKey="Berge, Yann" sort="Berge, Yann" uniqKey="Berge Y" first="Yann" last="Berge">Yann Berge</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>3 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Roda, Desamparados" sort="Roda, Desamparados" uniqKey="Roda D" first="Desamparados" last="Roda">Desamparados Roda</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Fundación Investigación Hospital Clinico Valencia, University of Valencia</s1><s2>Valencia</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Valencia</wicri:noRegion></affiliation></author><author><name sortKey="Russell Yarde, Fiona" sort="Russell Yarde, Fiona" uniqKey="Russell Yarde F" first="Fiona" last="Russell-Yarde">Fiona Russell-Yarde</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>F. Hoffmann-La Roche</s1><s2>Welwyn Garden City</s2><s3>GBR</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Hollingsworth, Simon" sort="Hollingsworth, Simon" uniqKey="Hollingsworth S" first="Simon" last="Hollingsworth">Simon Hollingsworth</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>F. Hoffmann-La Roche</s1><s2>Welwyn Garden City</s2><s3>GBR</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="José" last="Baselga">José Baselga</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Umana, Pablo" sort="Umana, Pablo" uniqKey="Umana P" first="Pablo" last="Umana">Pablo Umana</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Roche Glycart</s1><s2>Schlieren</s2><s3>CHE</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Roche Glycart</wicri:noRegion></affiliation></author><author><name sortKey="Manenti, Luigi" sort="Manenti, Luigi" uniqKey="Manenti L" first="Luigi" last="Manenti">Luigi Manenti</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Roche Glycart</s1><s2>Schlieren</s2><s3>CHE</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Roche Glycart</wicri:noRegion></affiliation></author><author><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0455861</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0455861 INIST</idno><idno type="RBID">Pascal:11-0455861</idno><idno type="wicri:Area/PascalFrancis/Corpus">001892</idno><idno type="wicri:Area/PascalFrancis/Curation">004664</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">001800</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">001800</idno><idno type="wicri:doubleKey">0732-183X:2011:Paz Ares L:phase:i:pharmacokinetic</idno><idno type="wicri:Area/Main/Merge">006C51</idno><idno type="wicri:Area/Main/Curation">006838</idno><idno type="wicri:Area/Main/Exploration">006838</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors</title><author><name sortKey="Paz Ares, Luis G" sort="Paz Ares, Luis G" uniqKey="Paz Ares L" first="Luis G." last="Paz-Ares">Luis G. Paz-Ares</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</s1><s2>Seville</s2><s3>ESP</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</wicri:noRegion></affiliation></author><author><name sortKey="Gomez Roca, Carlos" sort="Gomez Roca, Carlos" uniqKey="Gomez Roca C" first="Carlos" last="Gomez-Roca">Carlos Gomez-Roca</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></affiliation></author><author><name sortKey="Delord, Jean Pierre" sort="Delord, Jean Pierre" uniqKey="Delord J" first="Jean-Pierre" last="Delord">Jean-Pierre Delord</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>3 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Cervantes, Andres" sort="Cervantes, Andres" uniqKey="Cervantes A" first="Andres" last="Cervantes">Andres Cervantes</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Fundación Investigación Hospital Clinico Valencia, University of Valencia</s1><s2>Valencia</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Valencia</wicri:noRegion></affiliation></author><author><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Monash Institute of Medical Research, Monash University</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>5 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Corral, Jesus" sort="Corral, Jesus" uniqKey="Corral J" first="Jesus" last="Corral">Jesus Corral</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</s1><s2>Seville</s2><s3>ESP</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio</wicri:noRegion></affiliation></author><author><name sortKey="Soria, Jean Charles" sort="Soria, Jean Charles" uniqKey="Soria J" first="Jean-Charles" last="Soria">Jean-Charles Soria</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></affiliation></author><author><name sortKey="Berge, Yann" sort="Berge, Yann" uniqKey="Berge Y" first="Yann" last="Berge">Yann Berge</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>3 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Roda, Desamparados" sort="Roda, Desamparados" uniqKey="Roda D" first="Desamparados" last="Roda">Desamparados Roda</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Fundación Investigación Hospital Clinico Valencia, University of Valencia</s1><s2>Valencia</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Espagne</country><wicri:noRegion>Valencia</wicri:noRegion></affiliation></author><author><name sortKey="Russell Yarde, Fiona" sort="Russell Yarde, Fiona" uniqKey="Russell Yarde F" first="Fiona" last="Russell-Yarde">Fiona Russell-Yarde</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>F. Hoffmann-La Roche</s1><s2>Welwyn Garden City</s2><s3>GBR</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Hollingsworth, Simon" sort="Hollingsworth, Simon" uniqKey="Hollingsworth S" first="Simon" last="Hollingsworth">Simon Hollingsworth</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>F. Hoffmann-La Roche</s1><s2>Welwyn Garden City</s2><s3>GBR</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="José" last="Baselga">José Baselga</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Umana, Pablo" sort="Umana, Pablo" uniqKey="Umana P" first="Pablo" last="Umana">Pablo Umana</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Roche Glycart</s1><s2>Schlieren</s2><s3>CHE</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Roche Glycart</wicri:noRegion></affiliation></author><author><name sortKey="Manenti, Luigi" sort="Manenti, Luigi" uniqKey="Manenti L" first="Luigi" last="Manenti">Luigi Manenti</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Roche Glycart</s1><s2>Schlieren</s2><s3>CHE</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Roche Glycart</wicri:noRegion></affiliation></author><author><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>12 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Advanced stage</term><term>Cancerology</term><term>Epidermal growth factor receptor</term><term>Growth factor receptor</term><term>Human</term><term>Increasing dose</term><term>Monoclonal antibody</term><term>Pharmacodynamics</term><term>Pharmacokinetics</term><term>Solid tumor</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Pharmacocinétique</term><term>Dose croissante</term><term>Anticorps monoclonal</term><term>Récepteur facteur croissance</term><term>Récepteur facteur croissance épiderme</term><term>Homme</term><term>Stade avancé</term><term>Tumeur solide</term><term>Cancérologie</term><term>Pharmacodynamie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201 a humanized and glycoengineered immunoglobulin G, anti-epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patients), infusion-related reactions (77%), and hypomagnesemia (56%). Grades 3 and 4 AEs were rash (grade 3, 25%), infusion-related reaction (grade 3, 7%; grade 4, 1%), paronychia (grade 3, 3%), and hypomagnesemia (grade 3, 1%; grade 4, 1%). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients. Conclusion RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Espagne</li><li>France</li><li>Royaume-Uni</li><li>Suisse</li></country><region><li>Catalogne</li><li>Midi-Pyrénées</li><li>Occitanie (région administrative)</li><li>Victoria (État)</li></region><settlement><li>Barcelone</li><li>Melbourne</li><li>Toulouse</li></settlement></list><tree><country name="Espagne"><noRegion><name sortKey="Paz Ares, Luis G" sort="Paz Ares, Luis G" uniqKey="Paz Ares L" first="Luis G." last="Paz-Ares">Luis G. Paz-Ares</name></noRegion><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="José" last="Baselga">José Baselga</name><name sortKey="Cervantes, Andres" sort="Cervantes, Andres" uniqKey="Cervantes A" first="Andres" last="Cervantes">Andres Cervantes</name><name sortKey="Corral, Jesus" sort="Corral, Jesus" uniqKey="Corral J" first="Jesus" last="Corral">Jesus Corral</name><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name><name sortKey="Roda, Desamparados" sort="Roda, Desamparados" uniqKey="Roda D" first="Desamparados" last="Roda">Desamparados Roda</name><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name></country><country name="France"><noRegion><name sortKey="Gomez Roca, Carlos" sort="Gomez Roca, Carlos" uniqKey="Gomez Roca C" first="Carlos" last="Gomez-Roca">Carlos Gomez-Roca</name></noRegion><name sortKey="Berge, Yann" sort="Berge, Yann" uniqKey="Berge Y" first="Yann" last="Berge">Yann Berge</name><name sortKey="Delord, Jean Pierre" sort="Delord, Jean Pierre" uniqKey="Delord J" first="Jean-Pierre" last="Delord">Jean-Pierre Delord</name><name sortKey="Soria, Jean Charles" sort="Soria, Jean Charles" uniqKey="Soria J" first="Jean-Charles" last="Soria">Jean-Charles Soria</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name></region></country><country name="Royaume-Uni"><noRegion><name sortKey="Russell Yarde, Fiona" sort="Russell Yarde, Fiona" uniqKey="Russell Yarde F" first="Fiona" last="Russell-Yarde">Fiona Russell-Yarde</name></noRegion><name sortKey="Hollingsworth, Simon" sort="Hollingsworth, Simon" uniqKey="Hollingsworth S" first="Simon" last="Hollingsworth">Simon Hollingsworth</name></country><country name="Suisse"><noRegion><name sortKey="Umana, Pablo" sort="Umana, Pablo" uniqKey="Umana P" first="Pablo" last="Umana">Pablo Umana</name></noRegion><name sortKey="Manenti, Luigi" sort="Manenti, Luigi" uniqKey="Manenti L" first="Luigi" last="Manenti">Luigi Manenti</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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