A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse
The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (cli...
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| Veröffentlicht in: | Leukemia 2013-07, Vol.27 (7), p.1479-1486 |
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| creator | Park, S Chapuis, N Saint Marcoux, F Recher, C Prebet, T Chevallier, P Cahn, J-Y Leguay, T Bories, P Witz, F Lamy, T Mayeux, P Lacombe, C Demur, C Tamburini, J Merlat, A Delepine, R Vey, N Dreyfus, F Béné, M C Ifrah, N Bouscary, D |
| description | The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10–70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with |
| doi_str_mv | 10.1038/leu.2013.17 |
| format | Article |
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We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10–70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2013.17</identifier><identifier>PMID: 23321953</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject><![CDATA[631/154/436/108 ; 692/699/67/1059/99 ; 692/699/67/1990/283/1897 ; Acute myeloid leukemia ; Adult ; Aged ; Allosteric properties ; Antibiotics, Antineoplastic - administration & dosage ; Antibiotics, Antineoplastic - adverse effects ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Cancer ; Cancer Research ; Chemotherapy ; Clinical trials ; Critical Care Medicine ; Cytarabine ; Cytarabine - administration & dosage ; Cytarabine - adverse effects ; Daunorubicin ; Daunorubicin - administration & dosage ; Daunorubicin - adverse effects ; Diseases ; Enzyme inhibitors ; Everolimus ; Female ; Gastrointestinal system ; Gastrointestinal tract ; Health aspects ; Hematology ; Humans ; Inhibitors ; Intensive ; Internal Medicine ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Life Sciences ; Male ; Medical prognosis ; Medicine ; Medicine & Public Health ; Middle Aged ; Oncology ; Oral administration ; original-article ; Patients ; Recurrence ; Relapse ; Signal transduction ; Signal Transduction - drug effects ; Sirolimus - administration & dosage ; Sirolimus - adverse effects ; Sirolimus - analogs & derivatives ; Stem cell transplantation ; Stem cells ; TOR protein ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Toxicity ; Treatment Outcome ; Verbal communication ; Young Adult]]></subject><ispartof>Leukemia, 2013-07, Vol.27 (7), p.1479-1486</ispartof><rights>Macmillan Publishers Limited 2013</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2013</rights><rights>Macmillan Publishers Limited 2013.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c617t-680e7fac1a8f6f7c945f58ce383798db4e4b449dfc92af16b1dea9c202a4aaed3</citedby><cites>FETCH-LOGICAL-c617t-680e7fac1a8f6f7c945f58ce383798db4e4b449dfc92af16b1dea9c202a4aaed3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2013.17$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2013.17$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23321953$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00849677$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, S</creatorcontrib><creatorcontrib>Chapuis, N</creatorcontrib><creatorcontrib>Saint Marcoux, F</creatorcontrib><creatorcontrib>Recher, C</creatorcontrib><creatorcontrib>Prebet, T</creatorcontrib><creatorcontrib>Chevallier, P</creatorcontrib><creatorcontrib>Cahn, J-Y</creatorcontrib><creatorcontrib>Leguay, T</creatorcontrib><creatorcontrib>Bories, P</creatorcontrib><creatorcontrib>Witz, F</creatorcontrib><creatorcontrib>Lamy, T</creatorcontrib><creatorcontrib>Mayeux, P</creatorcontrib><creatorcontrib>Lacombe, C</creatorcontrib><creatorcontrib>Demur, C</creatorcontrib><creatorcontrib>Tamburini, J</creatorcontrib><creatorcontrib>Merlat, A</creatorcontrib><creatorcontrib>Delepine, R</creatorcontrib><creatorcontrib>Vey, N</creatorcontrib><creatorcontrib>Dreyfus, F</creatorcontrib><creatorcontrib>Béné, M C</creatorcontrib><creatorcontrib>Ifrah, N</creatorcontrib><creatorcontrib>Bouscary, D</creatorcontrib><creatorcontrib>GOELAMS (Groupe Ouest Est d’Etude des Leucémies aiguës et Autres Maladies du Sang)</creatorcontrib><title>A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10–70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.</description><subject>631/154/436/108</subject><subject>692/699/67/1059/99</subject><subject>692/699/67/1990/283/1897</subject><subject>Acute myeloid leukemia</subject><subject>Adult</subject><subject>Aged</subject><subject>Allosteric properties</subject><subject>Antibiotics, Antineoplastic - administration & dosage</subject><subject>Antibiotics, Antineoplastic - adverse effects</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Critical Care Medicine</subject><subject>Cytarabine</subject><subject>Cytarabine - administration & dosage</subject><subject>Cytarabine - adverse effects</subject><subject>Daunorubicin</subject><subject>Daunorubicin - administration & dosage</subject><subject>Daunorubicin - adverse effects</subject><subject>Diseases</subject><subject>Enzyme inhibitors</subject><subject>Everolimus</subject><subject>Female</subject><subject>Gastrointestinal system</subject><subject>Gastrointestinal tract</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Oral administration</subject><subject>original-article</subject><subject>Patients</subject><subject>Recurrence</subject><subject>Relapse</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - adverse effects</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Toxicity</subject><subject>Treatment Outcome</subject><subject>Verbal communication</subject><subject>Young 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phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse</title><author>Park, S ; Chapuis, N ; Saint Marcoux, F ; Recher, C ; Prebet, T ; Chevallier, P ; Cahn, J-Y ; Leguay, T ; Bories, P ; Witz, F ; Lamy, T ; Mayeux, P ; Lacombe, C ; Demur, C ; Tamburini, J ; Merlat, A ; Delepine, R ; Vey, N ; Dreyfus, F ; Béné, M C ; Ifrah, N ; Bouscary, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c617t-680e7fac1a8f6f7c945f58ce383798db4e4b449dfc92af16b1dea9c202a4aaed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/154/436/108</topic><topic>692/699/67/1059/99</topic><topic>692/699/67/1990/283/1897</topic><topic>Acute myeloid leukemia</topic><topic>Adult</topic><topic>Aged</topic><topic>Allosteric properties</topic><topic>Antibiotics, Antineoplastic - administration & dosage</topic><topic>Antibiotics, Antineoplastic - adverse effects</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Critical Care Medicine</topic><topic>Cytarabine</topic><topic>Cytarabine - administration & dosage</topic><topic>Cytarabine - adverse effects</topic><topic>Daunorubicin</topic><topic>Daunorubicin - administration & dosage</topic><topic>Daunorubicin - adverse effects</topic><topic>Diseases</topic><topic>Enzyme inhibitors</topic><topic>Everolimus</topic><topic>Female</topic><topic>Gastrointestinal system</topic><topic>Gastrointestinal tract</topic><topic>Health aspects</topic><topic>Hematology</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Oral administration</topic><topic>original-article</topic><topic>Patients</topic><topic>Recurrence</topic><topic>Relapse</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - adverse effects</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Toxicity</topic><topic>Treatment Outcome</topic><topic>Verbal 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association with chemotherapy for AML patients in first relapse</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>27</volume><issue>7</issue><spage>1479</spage><epage>1486</epage><pages>1479-1486</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10–70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23321953</pmid><doi>10.1038/leu.2013.17</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2013-07, Vol.27 (7), p.1479-1486 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_00849677v1 |
| source | MEDLINE; Nature; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | 631/154/436/108 692/699/67/1059/99 692/699/67/1990/283/1897 Acute myeloid leukemia Adult Aged Allosteric properties Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - adverse effects Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Cancer Cancer Research Chemotherapy Clinical trials Critical Care Medicine Cytarabine Cytarabine - administration & dosage Cytarabine - adverse effects Daunorubicin Daunorubicin - administration & dosage Daunorubicin - adverse effects Diseases Enzyme inhibitors Everolimus Female Gastrointestinal system Gastrointestinal tract Health aspects Hematology Humans Inhibitors Intensive Internal Medicine Leukemia Leukemia, Myeloid, Acute - drug therapy Life Sciences Male Medical prognosis Medicine Medicine & Public Health Middle Aged Oncology Oral administration original-article Patients Recurrence Relapse Signal transduction Signal Transduction - drug effects Sirolimus - administration & dosage Sirolimus - adverse effects Sirolimus - analogs & derivatives Stem cell transplantation Stem cells TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors Toxicity Treatment Outcome Verbal communication Young Adult |
| title | A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T19%3A56%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phase%20Ib%20GOELAMS%20study%20of%20the%20mTOR%20inhibitor%20RAD001%20in%20association%20with%20chemotherapy%20for%20AML%20patients%20in%20first%20relapse&rft.jtitle=Leukemia&rft.au=Park,%20S&rft.aucorp=GOELAMS%20(Groupe%20Ouest%20Est%20d%E2%80%99Etude%20des%20Leuc%C3%A9mies%20aigu%C3%ABs%20et%20Autres%20Maladies%20du%20Sang)&rft.date=2013-07-01&rft.volume=27&rft.issue=7&rft.spage=1479&rft.epage=1486&rft.pages=1479-1486&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2013.17&rft_dat=%3Cgale_hal_p%3EA338779251%3C/gale_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1399107136&rft_id=info:pmid/23321953&rft_galeid=A338779251&rfr_iscdi=true |