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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02</title><author><name sortKey="Wen, Patrick Y" sort="Wen, Patrick Y" uniqKey="Wen P" first="Patrick Y." last="Wen">Patrick Y. Wen</name></author><author><name sortKey="Chang, Susan M" sort="Chang, Susan M" uniqKey="Chang S" first="Susan M." last="Chang">Susan M. Chang</name></author><author><name sortKey="Lamborn, Kathleen R" sort="Lamborn, Kathleen R" uniqKey="Lamborn K" first="Kathleen R." last="Lamborn">Kathleen R. Lamborn</name></author><author><name sortKey="Kuhn, John G" sort="Kuhn, John G" uniqKey="Kuhn J" first="John G." last="Kuhn">John G. Kuhn</name></author><author><name sortKey="Norden, Andrew D" sort="Norden, Andrew D" uniqKey="Norden A" first="Andrew D." last="Norden">Andrew D. Norden</name></author><author><name sortKey="Cloughesy, Timothy F" sort="Cloughesy, Timothy F" uniqKey="Cloughesy T" first="Timothy F." last="Cloughesy">Timothy F. Cloughesy</name></author><author><name sortKey="Robins, H Ian" sort="Robins, H Ian" uniqKey="Robins H" first="H. Ian" last="Robins">H. Ian Robins</name></author><author><name sortKey="Lieberman, Frank S" sort="Lieberman, Frank S" uniqKey="Lieberman F" first="Frank S." last="Lieberman">Frank S. Lieberman</name></author><author><name sortKey="Gilbert, Mark R" sort="Gilbert, Mark R" uniqKey="Gilbert M" first="Mark R." last="Gilbert">Mark R. Gilbert</name></author><author><name sortKey="Mehta, Minesh P" sort="Mehta, Minesh P" uniqKey="Mehta M" first="Minesh P." last="Mehta">Minesh P. Mehta</name></author><author><name sortKey="Drappatz, Jan" sort="Drappatz, Jan" uniqKey="Drappatz J" first="Jan" last="Drappatz">Jan Drappatz</name></author><author><name sortKey="Groves, Morris D" sort="Groves, Morris D" uniqKey="Groves M" first="Morris D." last="Groves">Morris D. Groves</name></author><author><name sortKey="Santagata, Sandro" sort="Santagata, Sandro" uniqKey="Santagata S" first="Sandro" last="Santagata">Sandro Santagata</name></author><author><name sortKey="Ligon, Azra H" sort="Ligon, Azra H" uniqKey="Ligon A" first="Azra H." last="Ligon">Azra H. Ligon</name></author><author><name sortKey="Yung, W K Alfred" sort="Yung, W K Alfred" uniqKey="Yung W" first="W. K. Alfred" last="Yung">W. K. Alfred Yung</name></author><author><name sortKey="Wright, John J" sort="Wright, John J" uniqKey="Wright J" first="John J." last="Wright">John J. Wright</name></author><author><name sortKey="Dancey, Janet" sort="Dancey, Janet" uniqKey="Dancey J" first="Janet" last="Dancey">Janet Dancey</name></author><author><name sortKey="Aldape, Kenneth D" sort="Aldape, Kenneth D" uniqKey="Aldape K" first="Kenneth D." last="Aldape">Kenneth D. Aldape</name></author><author><name sortKey="Prados, Michael D" sort="Prados, Michael D" uniqKey="Prados M" first="Michael D." last="Prados">Michael D. Prados</name></author><author><name sortKey="Ligon, Keith L" sort="Ligon, Keith L" uniqKey="Ligon K" first="Keith L." last="Ligon">Keith L. Ligon</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24470557</idno><idno type="pmc">3956354</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956354</idno><idno type="RBID">PMC:3956354</idno><idno type="doi">10.1093/neuonc/not247</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000B60</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B60</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02</title><author><name sortKey="Wen, Patrick Y" sort="Wen, Patrick Y" uniqKey="Wen P" first="Patrick Y." last="Wen">Patrick Y. Wen</name></author><author><name sortKey="Chang, Susan M" sort="Chang, Susan M" uniqKey="Chang S" first="Susan M." last="Chang">Susan M. Chang</name></author><author><name sortKey="Lamborn, Kathleen R" sort="Lamborn, Kathleen R" uniqKey="Lamborn K" first="Kathleen R." last="Lamborn">Kathleen R. Lamborn</name></author><author><name sortKey="Kuhn, John G" sort="Kuhn, John G" uniqKey="Kuhn J" first="John G." last="Kuhn">John G. Kuhn</name></author><author><name sortKey="Norden, Andrew D" sort="Norden, Andrew D" uniqKey="Norden A" first="Andrew D." last="Norden">Andrew D. Norden</name></author><author><name sortKey="Cloughesy, Timothy F" sort="Cloughesy, Timothy F" uniqKey="Cloughesy T" first="Timothy F." last="Cloughesy">Timothy F. Cloughesy</name></author><author><name sortKey="Robins, H Ian" sort="Robins, H Ian" uniqKey="Robins H" first="H. Ian" last="Robins">H. Ian Robins</name></author><author><name sortKey="Lieberman, Frank S" sort="Lieberman, Frank S" uniqKey="Lieberman F" first="Frank S." last="Lieberman">Frank S. Lieberman</name></author><author><name sortKey="Gilbert, Mark R" sort="Gilbert, Mark R" uniqKey="Gilbert M" first="Mark R." last="Gilbert">Mark R. Gilbert</name></author><author><name sortKey="Mehta, Minesh P" sort="Mehta, Minesh P" uniqKey="Mehta M" first="Minesh P." last="Mehta">Minesh P. Mehta</name></author><author><name sortKey="Drappatz, Jan" sort="Drappatz, Jan" uniqKey="Drappatz J" first="Jan" last="Drappatz">Jan Drappatz</name></author><author><name sortKey="Groves, Morris D" sort="Groves, Morris D" uniqKey="Groves M" first="Morris D." last="Groves">Morris D. Groves</name></author><author><name sortKey="Santagata, Sandro" sort="Santagata, Sandro" uniqKey="Santagata S" first="Sandro" last="Santagata">Sandro Santagata</name></author><author><name sortKey="Ligon, Azra H" sort="Ligon, Azra H" uniqKey="Ligon A" first="Azra H." last="Ligon">Azra H. Ligon</name></author><author><name sortKey="Yung, W K Alfred" sort="Yung, W K Alfred" uniqKey="Yung W" first="W. K. Alfred" last="Yung">W. K. Alfred Yung</name></author><author><name sortKey="Wright, John J" sort="Wright, John J" uniqKey="Wright J" first="John J." last="Wright">John J. Wright</name></author><author><name sortKey="Dancey, Janet" sort="Dancey, Janet" uniqKey="Dancey J" first="Janet" last="Dancey">Janet Dancey</name></author><author><name sortKey="Aldape, Kenneth D" sort="Aldape, Kenneth D" uniqKey="Aldape K" first="Kenneth D." last="Aldape">Kenneth D. Aldape</name></author><author><name sortKey="Prados, Michael D" sort="Prados, Michael D" uniqKey="Prados M" first="Michael D." last="Prados">Michael D. Prados</name></author><author><name sortKey="Ligon, Keith L" sort="Ligon, Keith L" uniqKey="Ligon K" first="Keith L." last="Ligon">Keith L. Ligon</name></author></analytic><series><title level="j">Neuro-Oncology</title><idno type="ISSN">1522-8517</idno><idno type="eISSN">1523-5866</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.</p></sec><sec><title>Methods</title><p>We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.</p></sec><sec><title>Results</title><p>Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6<sup>S235/236</sup> but possible compensatory increase in phospho-Akt<sup>S473</sup>. Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho–extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.</p></sec><sec><title>Conclusion</title><p>Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Neuro Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Neuro-oncology</journal-id><journal-id journal-id-type="publisher-id">neuonc</journal-id><journal-id journal-id-type="hwp">neuonc</journal-id><journal-title-group><journal-title>Neuro-Oncology</journal-title></journal-title-group><issn pub-type="ppub">1522-8517</issn><issn pub-type="epub">1523-5866</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24470557</article-id><article-id pub-id-type="pmc">3956354</article-id><article-id pub-id-type="doi">10.1093/neuonc/not247</article-id><article-id pub-id-type="publisher-id">not247</article-id><article-categories><subj-group subj-group-type="heading"><subject>Clinical Investigations</subject></subj-group></article-categories><title-group><article-title>Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wen</surname><given-names>Patrick Y.</given-names></name><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author"><name><surname>Chang</surname><given-names>Susan M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lamborn</surname><given-names>Kathleen R.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kuhn</surname><given-names>John G.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Norden</surname><given-names>Andrew D.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Cloughesy</surname><given-names>Timothy F.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Robins</surname><given-names>H. Ian</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lieberman</surname><given-names>Frank S.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Gilbert</surname><given-names>Mark R.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Mehta</surname><given-names>Minesh P.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Drappatz</surname><given-names>Jan</given-names></name></contrib><contrib contrib-type="author"><name><surname>Groves</surname><given-names>Morris D.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Santagata</surname><given-names>Sandro</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ligon</surname><given-names>Azra H.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Yung</surname><given-names>W.K. Alfred</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wright</surname><given-names>John J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Dancey</surname><given-names>Janet</given-names></name><role>*</role></contrib><contrib contrib-type="author"><name><surname>Aldape</surname><given-names>Kenneth D.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Prados</surname><given-names>Michael D.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ligon</surname><given-names>Keith L.</given-names></name></contrib></contrib-group><aff><addr-line>Center for Neuro-Oncology</addr-line>,<institution>Dana Farber/Brigham and Women's Cancer Center</institution>,<addr-line>Boston, Massachusetts</addr-line> (P.Y.W., A.D.N., J.D.);<addr-line>Department of Neurosurgery</addr-line>,<institution>University of California</institution>,<addr-line>San Francisco, San Francisco, California</addr-line> (S.M.C., K.R.L., M.D.P.);<institution>University of Texas Health Science Center</institution>,<addr-line>San Antonio, Texas</addr-line> (J.G.K.);<addr-line>Division of Neuro-Oncology, Department of Neurology</addr-line>,<institution>University of California</institution>,<addr-line>Los Angeles, Los Angeles, California</addr-line> (T.F.C.);<institution>University of Wisconsin</institution>,<addr-line>Madison Wisconsin</addr-line> (H.I.R., M.P.M.);<addr-line>Neurooncology Program, Division of Hematology/Oncology</addr-line>,<institution>University of Pittsburgh Medical Center Cancer Pavilion</institution>,<addr-line>Pittsburgh, Pennsylvania</addr-line> (F.S.L.);<addr-line>Division of Neuro-Oncology, MD Anderson Cancer Center</addr-line>,<addr-line>Houston, Texas</addr-line> (M.R.G., M.D.G., W.K.A.Y., K.D.A.);<addr-line>Center for Molecular Oncologic Pathology</addr-line>,<institution>Dana Farber/Brigham and Women's Cancer Center</institution>,<addr-line>Boston, Massachusetts</addr-line> (S.S., A.H.L.);<addr-line>Department of Pathology</addr-line>,<institution>Brigham and Women's Hospital</institution>,<addr-line>Boston, Massachusetts</addr-line> (S.S., A.H.L., K.L.L.);<addr-line>Investigational Drug Branch, Cancer Therapy Evaluation Program</addr-line>,<institution>National Cancer Institute</institution>,<addr-line>Bethesda, Maryland</addr-line> (J.D.*, J.J.W.)</aff><author-notes><corresp id="cor1"><bold>Corresponding Author:</bold> Patrick Y. Wen, MD, Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, MA 02215 (<email>pwen@partners.org</email>).</corresp></author-notes><pub-date pub-type="ppub"><month>4</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>26</day><month>1</month><year>2014</year></pub-date><volume>16</volume><issue>4</issue><fpage>567</fpage><lpage>578</lpage><history><date date-type="received"><day>13</day><month>10</month><year>2013</year></date><date date-type="accepted"><day>11</day><month>11</month><year>2013</year></date></history><permissions><copyright-statement>© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</copyright-statement><copyright-year>2014</copyright-year></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="not247.pdf"></self-uri><abstract><sec><title>Background</title><p>Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.</p></sec><sec><title>Methods</title><p>We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.</p></sec><sec><title>Results</title><p>Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6<sup>S235/236</sup> but possible compensatory increase in phospho-Akt<sup>S473</sup>. Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho–extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.</p></sec><sec><title>Conclusion</title><p>Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.</p></sec></abstract><kwd-group><kwd>anaplastic glioma</kwd><kwd>clinical trial</kwd><kwd>epidermal growth factor</kwd><kwd>erlotinib</kwd><kwd>glioblastoma</kwd><kwd>temsirolimus</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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