A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma
Identifieur interne : 008703 ( Main/Exploration ); précédent : 008702; suivant : 008704A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma
Auteurs : F. Morschhauser [France] ; J. F. Seymour [Australie] ; H. C. Kluin-Nelemans [Pays-Bas] ; A. Grigg [Australie] ; M. Wolf ; M. Pfreundschuh [Allemagne] ; H. Tilly [France] ; J. Raemaekers [Pays-Bas] ; M. B. Van T Veer [Pays-Bas] ; N. Milpied ; G. Cartron [France] ; A. Pezzutto [Allemagne] ; A. Spencer [Australie] ; F. Reyes [France] ; M. Dreyling [Allemagne]Source :
- Annals of Oncology [ 0923-7534 ] ; 2007-09-28.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
Background: Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Patients and methods: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. Results: Sixty patients, median age 66 years (range 45–85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3–5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for ≥3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. Conclusion: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.
Url:
DOI: 10.1093/annonc/mdm463
Affiliations:
- Allemagne, Australie, France, Pays-Bas
- Berlin, Groningue (province), Gueldre, Hauts-de-France, Hollande-Méridionale, Nord-Pas-de-Calais, Victoria (État)
- Berlin, Groningue (ville), Lille, Melbourne, Nimègue, Rotterdam
- Université de Groningue, Université de Melbourne
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Le document en format XML
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Morschhauser</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Hematology, Hopital C. Huriez Centre Hospitalier Universitaire, Lille</wicri:regionArea><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country></affiliation></author><author><name sortKey="Seymour, J F" sort="Seymour, J F" uniqKey="Seymour J" first="J. F." last="Seymour">J. F. Seymour</name><affiliation wicri:level="4"><country xml:lang="fr">Australie</country><wicri:regionArea>Hematology, Peter Maccallum Cancer Center, East Melbourne, and University of Melbourne</wicri:regionArea><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Kluin Nelemans, H C" sort="Kluin Nelemans, H C" uniqKey="Kluin Nelemans H" first="H. C." last="Kluin-Nelemans">H. C. Kluin-Nelemans</name><affiliation wicri:level="4"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Hematology, University Medical Center Groningen, University of Groningen</wicri:regionArea><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName><orgName type="university">Université de Groningue</orgName></affiliation></author><author><name sortKey="Grigg, A" sort="Grigg, A" uniqKey="Grigg A" first="A." last="Grigg">A. Grigg</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Clinical Hematology and Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Wolf, M" sort="Wolf, M" uniqKey="Wolf M" first="M." last="Wolf">M. Wolf</name><affiliation><wicri:noCountry code="subField">Kassel</wicri:noCountry></affiliation></author><author><name sortKey="Pfreundschuh, M" sort="Pfreundschuh, M" uniqKey="Pfreundschuh M" first="M." last="Pfreundschuh">M. Pfreundschuh</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Onkologie, Hematology, Klin Immunologie & Rheumatologie, Universitatskliniken Des Saarlandes, Homburg/Saar</wicri:regionArea><wicri:noRegion>Homburg/Saar</wicri:noRegion><wicri:noRegion>Homburg/Saar</wicri:noRegion></affiliation></author><author><name sortKey="Tilly, H" sort="Tilly, H" uniqKey="Tilly H" first="H." last="Tilly">H. Tilly</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Centre Henri Becquerel, Rouen Cedex</wicri:regionArea><wicri:noRegion>Rouen Cedex</wicri:noRegion><wicri:noRegion>Rouen Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Raemaekers, J" sort="Raemaekers, J" uniqKey="Raemaekers J" first="J." last="Raemaekers">J. Raemaekers</name><affiliation wicri:level="3"><country>Pays-Bas</country><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName><wicri:orgArea>Hematology, University Medical Centre Nijmegen</wicri:orgArea></affiliation></author><author><name sortKey="Van T Veer, M B" sort="Van T Veer, M B" uniqKey="Van T Veer M" first="M. B." last="Van T Veer">M. B. Van T Veer</name><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Hematology, Erasmus Medisch Centrum, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Milpied, N" sort="Milpied, N" uniqKey="Milpied N" first="N." last="Milpied">N. Milpied</name><affiliation><wicri:noCountry code="subField">Cedex</wicri:noCountry></affiliation></author><author><name sortKey="Cartron, G" sort="Cartron, G" uniqKey="Cartron G" first="G." last="Cartron">G. Cartron</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Hematology, and Cell Therapy, Chru De Tours Hopital Bretonneau, Tours Cedex</wicri:regionArea><wicri:noRegion>Tours Cedex</wicri:noRegion><wicri:noRegion>Tours Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Pezzutto, A" sort="Pezzutto, A" uniqKey="Pezzutto A" first="A." last="Pezzutto">A. Pezzutto</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Med Klinic M.S.Hematologie/Oncologie, Universitatsklinikum Charite Med, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Spencer, A" sort="Spencer, A" uniqKey="Spencer A" first="A." last="Spencer">A. Spencer</name><affiliation wicri:level="3"><country xml:lang="fr">Australie</country><wicri:regionArea>Hematology and BMT, The Alfred Hospital, Melbourne</wicri:regionArea><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Reyes, F" sort="Reyes, F" uniqKey="Reyes F" first="F." last="Reyes">F. Reyes</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Clinical Hematology, Hopital Henri Mondor, Creteil Cedex</wicri:regionArea><wicri:noRegion>Creteil Cedex</wicri:noRegion><wicri:noRegion>Creteil Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Dreyling, M" sort="Dreyling, M" uniqKey="Dreyling M" first="M." last="Dreyling">M. Dreyling</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Klinikum Grosshadern der Ludwig-Maximilians-Universitat, Munchen</wicri:regionArea><wicri:noRegion>Munchen</wicri:noRegion><wicri:noRegion>Munchen</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Oncology</title><idno type="ISSN">0923-7534</idno><idno type="eISSN">1569-8041</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2007-09-28">2007-09-28</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="247">247</biblScope><biblScope unit="page" to="253">253</biblScope></imprint><idno type="ISSN">0923-7534</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0923-7534</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>B cell neoplasm</term><term>B-Lymphocyte</term><term>Enzastaurin</term><term>Human</term><term>Inhibitor</term><term>Mantle cell lymphoma</term><term>Phase II trial</term><term>Protein kinase C</term><term>Protein kinase Cβ</term><term>Relapse</term><term>Treatment</term><term>Treatment resistance</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Enzastaurine</term><term>Essai clinique phase II</term><term>Homme</term><term>Hémopathie lymphoïde B</term><term>Inhibiteur</term><term>Lymphocyte B</term><term>Lymphome centrocytique</term><term>Protein kinase C</term><term>Protein kinase Cβ</term><term>Récidive</term><term>Résistance traitement</term><term>Traitement</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">Background: Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Patients and methods: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. Results: Sixty patients, median age 66 years (range 45–85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3–5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for ≥3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. Conclusion: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Pays-Bas</li></country><region><li>Berlin</li><li>Groningue (province)</li><li>Gueldre</li><li>Hauts-de-France</li><li>Hollande-Méridionale</li><li>Nord-Pas-de-Calais</li><li>Victoria (État)</li></region><settlement><li>Berlin</li><li>Groningue (ville)</li><li>Lille</li><li>Melbourne</li><li>Nimègue</li><li>Rotterdam</li></settlement><orgName><li>Université de Groningue</li><li>Université de Melbourne</li></orgName></list><tree><noCountry><name sortKey="Milpied, N" sort="Milpied, N" uniqKey="Milpied N" first="N." last="Milpied">N. Milpied</name><name sortKey="Wolf, M" sort="Wolf, M" uniqKey="Wolf M" first="M." last="Wolf">M. Wolf</name></noCountry><country name="France"><region name="Hauts-de-France"><name sortKey="Morschhauser, F" sort="Morschhauser, F" uniqKey="Morschhauser F" first="F." last="Morschhauser">F. Morschhauser</name></region><name sortKey="Cartron, G" sort="Cartron, G" uniqKey="Cartron G" first="G." last="Cartron">G. Cartron</name><name sortKey="Morschhauser, F" sort="Morschhauser, F" uniqKey="Morschhauser F" first="F." last="Morschhauser">F. Morschhauser</name><name sortKey="Morschhauser, F" sort="Morschhauser, F" uniqKey="Morschhauser F" first="F." last="Morschhauser">F. Morschhauser</name><name sortKey="Reyes, F" sort="Reyes, F" uniqKey="Reyes F" first="F." last="Reyes">F. Reyes</name><name sortKey="Tilly, H" sort="Tilly, H" uniqKey="Tilly H" first="H." last="Tilly">H. Tilly</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Seymour, J F" sort="Seymour, J F" uniqKey="Seymour J" first="J. F." last="Seymour">J. F. Seymour</name></region><name sortKey="Grigg, A" sort="Grigg, A" uniqKey="Grigg A" first="A." last="Grigg">A. Grigg</name><name sortKey="Spencer, A" sort="Spencer, A" uniqKey="Spencer A" first="A." last="Spencer">A. Spencer</name></country><country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Kluin Nelemans, H C" sort="Kluin Nelemans, H C" uniqKey="Kluin Nelemans H" first="H. C." last="Kluin-Nelemans">H. C. Kluin-Nelemans</name></region><name sortKey="Raemaekers, J" sort="Raemaekers, J" uniqKey="Raemaekers J" first="J." last="Raemaekers">J. Raemaekers</name><name sortKey="Van T Veer, M B" sort="Van T Veer, M B" uniqKey="Van T Veer M" first="M. B." last="Van T Veer">M. B. Van T Veer</name></country><country name="Allemagne"><noRegion><name sortKey="Pfreundschuh, M" sort="Pfreundschuh, M" uniqKey="Pfreundschuh M" first="M." last="Pfreundschuh">M. Pfreundschuh</name></noRegion><name sortKey="Dreyling, M" sort="Dreyling, M" uniqKey="Dreyling M" first="M." last="Dreyling">M. Dreyling</name><name sortKey="Pezzutto, A" sort="Pezzutto, A" uniqKey="Pezzutto A" first="A." last="Pezzutto">A. Pezzutto</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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