Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma.
Identifieur interne : 000619 ( Main/Exploration ); précédent : 000618; suivant : 000620Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma.
Auteurs : Jean-Pierre Delord [France] ; Caroline Robert [France] ; Marta Nyakas [Norvège] ; Grant A. Mcarthur [Australie] ; Ragini Kudchakar [Géorgie (pays)] ; Amit Mahipal [États-Unis] ; Yasuhide Yamada [Japon] ; Ryan Sullivan [États-Unis] ; Ana Arance [Espagne] ; Richard F. Kefford [Australie] ; Matteo S. Carlino [Australie] ; Manuel Hidalgo [Espagne] ; Carlos Gomez-Roca [France] ; Daniela Michel [Suisse] ; Abdelkader Seroutou [Suisse] ; Vassilios Aslanis [Suisse] ; Giordano Caponigro [États-Unis] ; Darrin D. Stuart [États-Unis] ; Laure Moutouh-De Parseval [Suisse] ; Tim Demuth [Suisse] ; Reinhard Dummer [Suisse]Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2017.
Abstract
Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4-not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7).Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339-48. ©2017 AACR.
DOI: 10.1158/1078-0432.CCR-16-2923
PubMed: 28611198
Affiliations:
- Australie, Espagne, France, Géorgie (pays), Japon, Norvège, Suisse, États-Unis
- Catalogne, Communauté de Madrid, Floride, Massachusetts, Midi-Pyrénées, Nouvelle-Galles du Sud, Occitanie (région administrative), Région de Kantō
- Barcelone, Madrid, Sydney, Tokyo, Toulouse
- Université de Sydney
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Stuart</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Moutouh De Parseval, Laure" sort="Moutouh De Parseval, Laure" uniqKey="Moutouh De Parseval L" first="Laure" last="Moutouh-De Parseval">Laure Moutouh-De Parseval</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Demuth, Tim" sort="Demuth, Tim" uniqKey="Demuth T" first="Tim" last="Demuth">Tim Demuth</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name><affiliation wicri:level="1"><nlm:affiliation>University Hospital Zurich, Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>University Hospital Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28611198</idno><idno type="pmid">28611198</idno><idno type="doi">10.1158/1078-0432.CCR-16-2923</idno><idno type="wicri:Area/PubMed/Corpus">000545</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000545</idno><idno type="wicri:Area/PubMed/Curation">000543</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000543</idno><idno type="wicri:Area/PubMed/Checkpoint">000543</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000543</idno><idno type="wicri:Area/Ncbi/Merge">004972</idno><idno type="wicri:Area/Ncbi/Curation">004972</idno><idno type="wicri:Area/Ncbi/Checkpoint">004972</idno><idno type="wicri:doubleKey">1078-0432:2017:Delord J:phase:i:dose</idno><idno type="wicri:Area/Main/Merge">000614</idno><idno type="wicri:Area/Main/Curation">000619</idno><idno type="wicri:Area/Main/Exploration">000619</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma.</title><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"><nlm:affiliation>Institut Universitaire du Cancer, Toulouse, France. delord.jean-pierre@iuct-oncopole.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut Universitaire du Cancer, Toulouse</wicri:regionArea><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="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy and Paris-Sud University, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy and Paris-Sud University, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Nyakas, Marta" sort="Nyakas, Marta" uniqKey="Nyakas M" first="Marta" last="Nyakas">Marta Nyakas</name><affiliation wicri:level="1"><nlm:affiliation>Oslo University Hospital, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Oslo University Hospital</wicri:regionArea></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name><affiliation wicri:level="1"><nlm:affiliation>Peter MacCallum Cancer Centre and the University of Melbourne, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Peter MacCallum Cancer Centre and the University of Melbourne</wicri:regionArea></affiliation></author><author><name sortKey="Kudchakar, Ragini" sort="Kudchakar, Ragini" uniqKey="Kudchakar R" first="Ragini" last="Kudchakar">Ragini Kudchakar</name><affiliation wicri:level="1"><nlm:affiliation>Winship Cancer Institute of Emory University, Atlanta, Georgia.</nlm:affiliation><country xml:lang="fr">Géorgie (pays)</country><wicri:regionArea>Winship Cancer Institute of Emory University, Atlanta</wicri:regionArea><wicri:noRegion>Atlanta</wicri:noRegion></affiliation></author><author><name sortKey="Mahipal, Amit" sort="Mahipal, Amit" uniqKey="Mahipal A" first="Amit" last="Mahipal">Amit Mahipal</name><affiliation wicri:level="2"><nlm:affiliation>Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>Lee Moffitt Cancer Center and Research Institute, Tampa</wicri:cityArea></affiliation></author><author><name sortKey="Yamada, Yasuhide" sort="Yamada, Yasuhide" uniqKey="Yamada Y" first="Yasuhide" last="Yamada">Yasuhide Yamada</name><affiliation wicri:level="3"><nlm:affiliation>National Cancer Center Hospital, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>National Cancer Center Hospital, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Sullivan, Ryan" sort="Sullivan, Ryan" uniqKey="Sullivan R" first="Ryan" last="Sullivan">Ryan Sullivan</name><affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital, Boston, Massachusetts.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Massachusetts General Hospital, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Arance, Ana" sort="Arance, Ana" uniqKey="Arance A" first="Ana" last="Arance">Ana Arance</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology and Translational Genomics and Targeted Therapeutics in Solid Tumors, Hospital Clínic, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Medical Oncology and Translational Genomics and Targeted Therapeutics in Solid Tumors, Hospital Clínic, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Kefford, Richard F" sort="Kefford, Richard F" uniqKey="Kefford R" first="Richard F" last="Kefford">Richard F. Kefford</name><affiliation wicri:level="4"><nlm:affiliation>Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Carlino, Matteo S" sort="Carlino, Matteo S" uniqKey="Carlino M" first="Matteo S" last="Carlino">Matteo S. Carlino</name><affiliation wicri:level="4"><nlm:affiliation>Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Hidalgo, Manuel" sort="Hidalgo, Manuel" uniqKey="Hidalgo M" first="Manuel" last="Hidalgo">Manuel Hidalgo</name><affiliation wicri:level="3"><nlm:affiliation>Spanish National Cancer Research Centre (CNIO) and Centro Integral Oncologico Clara Campal, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Spanish National Cancer Research Centre (CNIO) and Centro Integral Oncologico Clara Campal, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></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="3"><nlm:affiliation>Institut Universitaire du Cancer, Toulouse, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut Universitaire du Cancer, Toulouse</wicri:regionArea><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="Michel, Daniela" sort="Michel, Daniela" uniqKey="Michel D" first="Daniela" last="Michel">Daniela Michel</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Seroutou, Abdelkader" sort="Seroutou, Abdelkader" uniqKey="Seroutou A" first="Abdelkader" last="Seroutou">Abdelkader Seroutou</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Aslanis, Vassilios" sort="Aslanis, Vassilios" uniqKey="Aslanis V" first="Vassilios" last="Aslanis">Vassilios Aslanis</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Caponigro, Giordano" sort="Caponigro, Giordano" uniqKey="Caponigro G" first="Giordano" last="Caponigro">Giordano Caponigro</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Stuart, Darrin D" sort="Stuart, Darrin D" uniqKey="Stuart D" first="Darrin D" last="Stuart">Darrin D. Stuart</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Moutouh De Parseval, Laure" sort="Moutouh De Parseval, Laure" uniqKey="Moutouh De Parseval L" first="Laure" last="Moutouh-De Parseval">Laure Moutouh-De Parseval</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Demuth, Tim" sort="Demuth, Tim" uniqKey="Demuth T" first="Tim" last="Demuth">Tim Demuth</name><affiliation wicri:level="1"><nlm:affiliation>Novartis Pharma AG, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name><affiliation wicri:level="1"><nlm:affiliation>University Hospital Zurich, Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>University Hospital Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author></analytic><series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title><idno type="ISSN">1078-0432</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4-not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7).Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339-48. ©2017 AACR.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Espagne</li><li>France</li><li>Géorgie (pays)</li><li>Japon</li><li>Norvège</li><li>Suisse</li><li>États-Unis</li></country><region><li>Catalogne</li><li>Communauté de Madrid</li><li>Floride</li><li>Massachusetts</li><li>Midi-Pyrénées</li><li>Nouvelle-Galles du Sud</li><li>Occitanie (région administrative)</li><li>Région de Kantō</li></region><settlement><li>Barcelone</li><li>Madrid</li><li>Sydney</li><li>Tokyo</li><li>Toulouse</li></settlement><orgName><li>Université de Sydney</li></orgName></list><tree><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Delord, Jean Pierre" sort="Delord, Jean Pierre" uniqKey="Delord J" first="Jean-Pierre" last="Delord">Jean-Pierre Delord</name></region><name sortKey="Gomez Roca, Carlos" sort="Gomez Roca, Carlos" uniqKey="Gomez Roca C" first="Carlos" last="Gomez-Roca">Carlos Gomez-Roca</name><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name></country><country name="Norvège"><noRegion><name sortKey="Nyakas, Marta" sort="Nyakas, Marta" uniqKey="Nyakas M" first="Marta" last="Nyakas">Marta Nyakas</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name></noRegion><name sortKey="Carlino, Matteo S" sort="Carlino, Matteo S" uniqKey="Carlino M" first="Matteo S" last="Carlino">Matteo S. Carlino</name><name sortKey="Kefford, Richard F" sort="Kefford, Richard F" uniqKey="Kefford R" first="Richard F" last="Kefford">Richard F. Kefford</name></country><country name="Géorgie (pays)"><noRegion><name sortKey="Kudchakar, Ragini" sort="Kudchakar, Ragini" uniqKey="Kudchakar R" first="Ragini" last="Kudchakar">Ragini Kudchakar</name></noRegion></country><country name="États-Unis"><region name="Floride"><name sortKey="Mahipal, Amit" sort="Mahipal, Amit" uniqKey="Mahipal A" first="Amit" last="Mahipal">Amit Mahipal</name></region><name sortKey="Caponigro, Giordano" sort="Caponigro, Giordano" uniqKey="Caponigro G" first="Giordano" last="Caponigro">Giordano Caponigro</name><name sortKey="Stuart, Darrin D" sort="Stuart, Darrin D" uniqKey="Stuart D" first="Darrin D" last="Stuart">Darrin D. Stuart</name><name sortKey="Sullivan, Ryan" sort="Sullivan, Ryan" uniqKey="Sullivan R" first="Ryan" last="Sullivan">Ryan Sullivan</name></country><country name="Japon"><region name="Région de Kantō"><name sortKey="Yamada, Yasuhide" sort="Yamada, Yasuhide" uniqKey="Yamada Y" first="Yasuhide" last="Yamada">Yasuhide Yamada</name></region></country><country name="Espagne"><region name="Catalogne"><name sortKey="Arance, Ana" sort="Arance, Ana" uniqKey="Arance A" first="Ana" last="Arance">Ana Arance</name></region><name sortKey="Hidalgo, Manuel" sort="Hidalgo, Manuel" uniqKey="Hidalgo M" first="Manuel" last="Hidalgo">Manuel Hidalgo</name></country><country name="Suisse"><noRegion><name sortKey="Michel, Daniela" sort="Michel, Daniela" uniqKey="Michel D" first="Daniela" last="Michel">Daniela Michel</name></noRegion><name sortKey="Aslanis, Vassilios" sort="Aslanis, Vassilios" uniqKey="Aslanis V" first="Vassilios" last="Aslanis">Vassilios Aslanis</name><name sortKey="Demuth, Tim" sort="Demuth, Tim" uniqKey="Demuth T" first="Tim" last="Demuth">Tim Demuth</name><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name><name sortKey="Moutouh De Parseval, Laure" sort="Moutouh De Parseval, Laure" uniqKey="Moutouh De Parseval L" first="Laure" last="Moutouh-De Parseval">Laure Moutouh-De Parseval</name><name sortKey="Seroutou, Abdelkader" sort="Seroutou, Abdelkader" uniqKey="Seroutou A" first="Abdelkader" last="Seroutou">Abdelkader Seroutou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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