Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer
This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed. Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD...
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| Veröffentlicht in: | Annals of oncology 2009-09, Vol.20 (9), p.1565-1575 |
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| creator | Hanauske, A.-R. Lahn, M. Musib, L.C. Weigang-Köhler, K. Yilmaz, E. Graefe, T. Kuenen, B. Thornton, D. McNealy, P. Giaccone, G. |
| description | This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed.
Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by ∼25% in the presence of pemetrexed. Enzastaurin Cav,ss were ∼40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer. |
| doi_str_mv | 10.1093/annonc/mdp049 |
| format | Article |
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Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by ∼25% in the presence of pemetrexed. Enzastaurin Cav,ss were ∼40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mdp049</identifier><identifier>PMID: 19487488</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; enzastaurin ; Female ; Glutamates - administration & dosage ; Glutamates - adverse effects ; Glutamates - pharmacokinetics ; Guanine - administration & dosage ; Guanine - adverse effects ; Guanine - analogs & derivatives ; Guanine - pharmacokinetics ; Humans ; Indoles - administration & dosage ; Indoles - adverse effects ; Indoles - pharmacokinetics ; Male ; Middle Aged ; Neoplasms - drug therapy ; Pemetrexed ; pharmacokinetics ; phase I ; safety</subject><ispartof>Annals of oncology, 2009-09, Vol.20 (9), p.1565-1575</ispartof><rights>2009 European Society for Medical Oncology</rights><rights>The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org 2009</rights><rights>The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-44e6d0d6f7305f773f2c478b9a16be9efe4e6e5b4f1e242b79c7e1dd6f41ec683</citedby><cites>FETCH-LOGICAL-c476t-44e6d0d6f7305f773f2c478b9a16be9efe4e6e5b4f1e242b79c7e1dd6f41ec683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19487488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hanauske, A.-R.</creatorcontrib><creatorcontrib>Lahn, M.</creatorcontrib><creatorcontrib>Musib, L.C.</creatorcontrib><creatorcontrib>Weigang-Köhler, K.</creatorcontrib><creatorcontrib>Yilmaz, E.</creatorcontrib><creatorcontrib>Graefe, T.</creatorcontrib><creatorcontrib>Kuenen, B.</creatorcontrib><creatorcontrib>Thornton, D.</creatorcontrib><creatorcontrib>McNealy, P.</creatorcontrib><creatorcontrib>Giaccone, G.</creatorcontrib><title>Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer</title><title>Annals of oncology</title><addtitle>Ann Oncol</addtitle><description>This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed.
Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by ∼25% in the presence of pemetrexed. Enzastaurin Cav,ss were ∼40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</subject><subject>enzastaurin</subject><subject>Female</subject><subject>Glutamates - administration & dosage</subject><subject>Glutamates - adverse effects</subject><subject>Glutamates - pharmacokinetics</subject><subject>Guanine - administration & dosage</subject><subject>Guanine - adverse effects</subject><subject>Guanine - analogs & derivatives</subject><subject>Guanine - pharmacokinetics</subject><subject>Humans</subject><subject>Indoles - administration & dosage</subject><subject>Indoles - adverse effects</subject><subject>Indoles - pharmacokinetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neoplasms - drug therapy</subject><subject>Pemetrexed</subject><subject>pharmacokinetics</subject><subject>phase I</subject><subject>safety</subject><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9r3DAQxU1pabZpj70W0VMv7kq2LFnHEtIkEGgK_RNyEbI0ZpWsJVeSN0m_R79vZWzaUykIBs383jyYVxSvCX5PsKi3yjnv9HYwI6biSbEhDRNliyl5WmywqOqSNzU9Kl7EeIsxZqISz4sjImjLadtuil9XOxUBXXQoqh7SI1LOoHGnwqC0v7MOktUIDmo_qWS9Q75HRtn9wqV7q2H9-6D2CNxPFZOagnUoP-2HzrpFeG_TDo0wQArwAGYeK3NQToPZ5uYsm6303Akvi2e92kd4tdbj4uvH0y8n5-Xlp7OLkw-XpaacpZJSYAYb1vMaNz3ndV_lQdsJRVgHAnrIADQd7QlUtOq40ByIyQJKQLO2Pi7eLnvH4H9MEJO89VNw2VISwRgTbcUyVC6QDj7GAL0cgx1UeJQEyzkDuWQglwwy_2ZdOnUDmL_0evQMvFsAP43_3bV625jg4Q-swp1kvOaNPL--kZ-vrr-1Z99vJM88X3jIVztYCDJqC_ORbQCdpPH2H06_AeHyuYs</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>Hanauske, A.-R.</creator><creator>Lahn, M.</creator><creator>Musib, L.C.</creator><creator>Weigang-Köhler, K.</creator><creator>Yilmaz, E.</creator><creator>Graefe, T.</creator><creator>Kuenen, B.</creator><creator>Thornton, D.</creator><creator>McNealy, P.</creator><creator>Giaccone, G.</creator><general>Elsevier Ltd</general><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>6I.</scope><scope>AAFTH</scope><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope></search><sort><creationdate>20090901</creationdate><title>Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer</title><author>Hanauske, A.-R. ; Lahn, M. ; Musib, L.C. ; Weigang-Köhler, K. ; Yilmaz, E. ; Graefe, T. ; Kuenen, B. ; Thornton, D. ; McNealy, P. ; Giaccone, G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-44e6d0d6f7305f773f2c478b9a16be9efe4e6e5b4f1e242b79c7e1dd6f41ec683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</topic><topic>enzastaurin</topic><topic>Female</topic><topic>Glutamates - administration & dosage</topic><topic>Glutamates - adverse effects</topic><topic>Glutamates - pharmacokinetics</topic><topic>Guanine - administration & dosage</topic><topic>Guanine - adverse effects</topic><topic>Guanine - analogs & derivatives</topic><topic>Guanine - pharmacokinetics</topic><topic>Humans</topic><topic>Indoles - administration & dosage</topic><topic>Indoles - adverse effects</topic><topic>Indoles - pharmacokinetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neoplasms - drug therapy</topic><topic>Pemetrexed</topic><topic>pharmacokinetics</topic><topic>phase I</topic><topic>safety</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hanauske, A.-R.</creatorcontrib><creatorcontrib>Lahn, M.</creatorcontrib><creatorcontrib>Musib, L.C.</creatorcontrib><creatorcontrib>Weigang-Köhler, K.</creatorcontrib><creatorcontrib>Yilmaz, E.</creatorcontrib><creatorcontrib>Graefe, T.</creatorcontrib><creatorcontrib>Kuenen, B.</creatorcontrib><creatorcontrib>Thornton, D.</creatorcontrib><creatorcontrib>McNealy, P.</creatorcontrib><creatorcontrib>Giaccone, G.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Annals of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanauske, A.-R.</au><au>Lahn, M.</au><au>Musib, L.C.</au><au>Weigang-Köhler, K.</au><au>Yilmaz, E.</au><au>Graefe, T.</au><au>Kuenen, B.</au><au>Thornton, D.</au><au>McNealy, P.</au><au>Giaccone, G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer</atitle><jtitle>Annals of oncology</jtitle><addtitle>Ann Oncol</addtitle><date>2009-09-01</date><risdate>2009</risdate><volume>20</volume><issue>9</issue><spage>1565</spage><epage>1575</epage><pages>1565-1575</pages><issn>0923-7534</issn><eissn>1569-8041</eissn><abstract>This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed.
Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by ∼25% in the presence of pemetrexed. Enzastaurin Cav,ss were ∼40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>19487488</pmid><doi>10.1093/annonc/mdp049</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Oral Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics enzastaurin Female Glutamates - administration & dosage Glutamates - adverse effects Glutamates - pharmacokinetics Guanine - administration & dosage Guanine - adverse effects Guanine - analogs & derivatives Guanine - pharmacokinetics Humans Indoles - administration & dosage Indoles - adverse effects Indoles - pharmacokinetics Male Middle Aged Neoplasms - drug therapy Pemetrexed pharmacokinetics phase I safety |
| title | Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer |
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