Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study
Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × ...
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| Veröffentlicht in: | Cancer medicine (Malden, MA) MA), 2015-01, Vol.4 (1), p.16-26 |
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| creator | Winer, Eric S. Safran, Howard Karaszewska, Boguslawa Richards, Donald A. Hartner, Lee Forget, Frederic Ramlau, Rodryg Kumar, Kirushna Mayer, Bhabita Johnson, Brendan M. Messam, Conrad A. Mostafa Kamel, Yasser |
| description | Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag‐treated patients versus 53 × 109/L and 103 × 109/L for placebo‐treated patients in Groups A and B, respectively. No dose‐limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose‐escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.
Eltrombopag, an oral thrombopoietin receptor agonist, was administered in patients receiving treatment with gemcitabine‐based therapy. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. Eltrombopag was well tolerated with an acceptable safety profile, and will be further tested. |
| doi_str_mv | 10.1002/cam4.326 |
| format | Article |
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Eltrombopag, an oral thrombopoietin receptor agonist, was administered in patients receiving treatment with gemcitabine‐based therapy. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. Eltrombopag was well tolerated with an acceptable safety profile, and will be further tested.</description><identifier>ISSN: 2045-7634</identifier><identifier>EISSN: 2045-7634</identifier><identifier>DOI: 10.1002/cam4.326</identifier><identifier>PMID: 25165041</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Anemia ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Benzoates - administration & dosage ; Benzoates - adverse effects ; Benzoates - pharmacokinetics ; Blood ; Blood platelets ; cancer ; Cancer Research ; Carboplatin ; Chemotherapy ; Cisplatin ; Deoxycytidine - administration & dosage ; Deoxycytidine - adverse effects ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacokinetics ; Drug Administration Schedule ; eltrombopag ; Female ; Gemcitabine ; Humans ; Hydrazines - administration & dosage ; Hydrazines - adverse effects ; Hydrazines - pharmacokinetics ; Male ; Middle Aged ; Neoplasm Staging ; Neoplasms - drug therapy ; Neoplasms - pathology ; Neutropenia ; Patients ; Platelet Count ; Platelets ; Pyrazoles - administration & dosage ; Pyrazoles - adverse effects ; Pyrazoles - pharmacokinetics ; Schedules ; Solid tumors ; Thrombocytopenia ; Thrombocytosis ; Thrombopoietin ; thrombosis ; Treatment Outcome ; Tumors</subject><ispartof>Cancer medicine (Malden, MA), 2015-01, Vol.4 (1), p.16-26</ispartof><rights>2014 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.</rights><rights>2015. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 The Authors. published by John Wiley & Sons Ltd. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4386-dac4f77c41e61de50ac0e7132f9c41ec492890709ece2503797da6cc46879b0e3</citedby><cites>FETCH-LOGICAL-c4386-dac4f77c41e61de50ac0e7132f9c41ec492890709ece2503797da6cc46879b0e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312114/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312114/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,1418,11567,27929,27930,45579,45580,46057,46481,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25165041$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Winer, Eric S.</creatorcontrib><creatorcontrib>Safran, Howard</creatorcontrib><creatorcontrib>Karaszewska, Boguslawa</creatorcontrib><creatorcontrib>Richards, Donald A.</creatorcontrib><creatorcontrib>Hartner, Lee</creatorcontrib><creatorcontrib>Forget, Frederic</creatorcontrib><creatorcontrib>Ramlau, Rodryg</creatorcontrib><creatorcontrib>Kumar, Kirushna</creatorcontrib><creatorcontrib>Mayer, Bhabita</creatorcontrib><creatorcontrib>Johnson, Brendan M.</creatorcontrib><creatorcontrib>Messam, Conrad A.</creatorcontrib><creatorcontrib>Mostafa Kamel, Yasser</creatorcontrib><title>Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study</title><title>Cancer medicine (Malden, MA)</title><addtitle>Cancer Med</addtitle><description>Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag‐treated patients versus 53 × 109/L and 103 × 109/L for placebo‐treated patients in Groups A and B, respectively. No dose‐limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose‐escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.
Eltrombopag, an oral thrombopoietin receptor agonist, was administered in patients receiving treatment with gemcitabine‐based therapy. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. Eltrombopag was well tolerated with an acceptable safety profile, and will be further tested.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Anemia</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Benzoates - administration & dosage</subject><subject>Benzoates - adverse effects</subject><subject>Benzoates - pharmacokinetics</subject><subject>Blood</subject><subject>Blood platelets</subject><subject>cancer</subject><subject>Cancer Research</subject><subject>Carboplatin</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - adverse effects</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - pharmacokinetics</subject><subject>Drug Administration Schedule</subject><subject>eltrombopag</subject><subject>Female</subject><subject>Gemcitabine</subject><subject>Humans</subject><subject>Hydrazines - administration & dosage</subject><subject>Hydrazines - adverse effects</subject><subject>Hydrazines - pharmacokinetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neoplasm Staging</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Neutropenia</subject><subject>Patients</subject><subject>Platelet Count</subject><subject>Platelets</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Schedules</subject><subject>Solid tumors</subject><subject>Thrombocytopenia</subject><subject>Thrombocytosis</subject><subject>Thrombopoietin</subject><subject>thrombosis</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>2045-7634</issn><issn>2045-7634</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kcFO3DAQhq2KqiCK1CdAlrhwCbUdJ95wQEIr2iJR9dKerYk9uzFK4mA7oO2pj9Bn5EnwaimiB3yx5fn8zVg_IZ84O-OMic8GBnlWivodORBMVoWqS7n36rxPjmK8ZXkpJmrFP5B9UfG6YpIfkHTVp-CH1k-wpg8udXSNg3EJWjfi45-_LUS01HQ4-NRhgGlD3UgnSA7HFHcvwN7DaDIWfe8sTfPgQzynQAOM1g_udy5NXRbRaxrTbDcfyfsV9BGPnvdD8uvL1c_lt-Lmx9fr5eVNYWS5qAsLRq6UMpJjzS1WDAxDxUuxarZ3RjZi0eRPNWhQVKxUjbJQGyPrhWpahuUhudh5p7kd0Jo8coBeT8ENEDbag9P_V0bX6bW_17LkgnOZBSfPguDvZoxJ3_o5jHlmLXJvnrGyydTpjjLBxxhw9dKBM72NSG8j0jmijB6_nugF_BdIBood8OB63Lwp0svL73IrfAI4Z515</recordid><startdate>201501</startdate><enddate>201501</enddate><creator>Winer, Eric S.</creator><creator>Safran, Howard</creator><creator>Karaszewska, Boguslawa</creator><creator>Richards, Donald A.</creator><creator>Hartner, Lee</creator><creator>Forget, Frederic</creator><creator>Ramlau, Rodryg</creator><creator>Kumar, Kirushna</creator><creator>Mayer, Bhabita</creator><creator>Johnson, Brendan M.</creator><creator>Messam, Conrad A.</creator><creator>Mostafa Kamel, Yasser</creator><general>John Wiley & Sons, Inc</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>WIN</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>5PM</scope></search><sort><creationdate>201501</creationdate><title>Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study</title><author>Winer, Eric S. ; Safran, Howard ; Karaszewska, Boguslawa ; Richards, Donald A. ; Hartner, Lee ; Forget, Frederic ; Ramlau, Rodryg ; Kumar, Kirushna ; Mayer, Bhabita ; Johnson, Brendan M. ; Messam, Conrad A. ; Mostafa Kamel, Yasser</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4386-dac4f77c41e61de50ac0e7132f9c41ec492890709ece2503797da6cc46879b0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Anemia</topic><topic>Antineoplastic Combined Chemotherapy Protocols - 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administration & dosage</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Schedules</topic><topic>Solid tumors</topic><topic>Thrombocytopenia</topic><topic>Thrombocytosis</topic><topic>Thrombopoietin</topic><topic>thrombosis</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Winer, Eric S.</creatorcontrib><creatorcontrib>Safran, Howard</creatorcontrib><creatorcontrib>Karaszewska, Boguslawa</creatorcontrib><creatorcontrib>Richards, Donald A.</creatorcontrib><creatorcontrib>Hartner, Lee</creatorcontrib><creatorcontrib>Forget, Frederic</creatorcontrib><creatorcontrib>Ramlau, Rodryg</creatorcontrib><creatorcontrib>Kumar, Kirushna</creatorcontrib><creatorcontrib>Mayer, Bhabita</creatorcontrib><creatorcontrib>Johnson, Brendan M.</creatorcontrib><creatorcontrib>Messam, Conrad A.</creatorcontrib><creatorcontrib>Mostafa Kamel, Yasser</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer medicine (Malden, MA)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Winer, Eric S.</au><au>Safran, Howard</au><au>Karaszewska, Boguslawa</au><au>Richards, Donald A.</au><au>Hartner, Lee</au><au>Forget, Frederic</au><au>Ramlau, Rodryg</au><au>Kumar, Kirushna</au><au>Mayer, Bhabita</au><au>Johnson, Brendan M.</au><au>Messam, Conrad A.</au><au>Mostafa Kamel, Yasser</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study</atitle><jtitle>Cancer medicine (Malden, MA)</jtitle><addtitle>Cancer Med</addtitle><date>2015-01</date><risdate>2015</risdate><volume>4</volume><issue>1</issue><spage>16</spage><epage>26</epage><pages>16-26</pages><issn>2045-7634</issn><eissn>2045-7634</eissn><abstract>Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag‐treated patients versus 53 × 109/L and 103 × 109/L for placebo‐treated patients in Groups A and B, respectively. No dose‐limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose‐escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.
Eltrombopag, an oral thrombopoietin receptor agonist, was administered in patients receiving treatment with gemcitabine‐based therapy. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. Eltrombopag was well tolerated with an acceptable safety profile, and will be further tested.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>25165041</pmid><doi>10.1002/cam4.326</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer medicine (Malden, MA), 2015-01, Vol.4 (1), p.16-26 |
| issn | 2045-7634 2045-7634 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | Adult Aged Aged, 80 and over Anemia Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzoates - administration & dosage Benzoates - adverse effects Benzoates - pharmacokinetics Blood Blood platelets cancer Cancer Research Carboplatin Chemotherapy Cisplatin Deoxycytidine - administration & dosage Deoxycytidine - adverse effects Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacokinetics Drug Administration Schedule eltrombopag Female Gemcitabine Humans Hydrazines - administration & dosage Hydrazines - adverse effects Hydrazines - pharmacokinetics Male Middle Aged Neoplasm Staging Neoplasms - drug therapy Neoplasms - pathology Neutropenia Patients Platelet Count Platelets Pyrazoles - administration & dosage Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Schedules Solid tumors Thrombocytopenia Thrombocytosis Thrombopoietin thrombosis Treatment Outcome Tumors |
| title | Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T23%3A04%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Eltrombopag%20with%20gemcitabine%E2%80%90based%20chemotherapy%20in%20patients%20with%20advanced%20solid%20tumors:%20a%20randomized%20phase%20I%20study&rft.jtitle=Cancer%20medicine%20(Malden,%20MA)&rft.au=Winer,%20Eric%20S.&rft.date=2015-01&rft.volume=4&rft.issue=1&rft.spage=16&rft.epage=26&rft.pages=16-26&rft.issn=2045-7634&rft.eissn=2045-7634&rft_id=info:doi/10.1002/cam4.326&rft_dat=%3Cproquest_pubme%3E2289131239%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2289131239&rft_id=info:pmid/25165041&rfr_iscdi=true |