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Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023
Purpose This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab,...
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| Published in: | Cancer chemotherapy and pharmacology 2013, Vol.71 (1), p.53-62 |
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| container_title | Cancer chemotherapy and pharmacology |
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| creator | Kerklaan, Bojana Milojkovic Diéras, Veronique Le Tourneau, Christophe Mergui-Roelvink, Marja Huitema, Alwin D. R. Rosing, Hilde Beijnen, Jos H. Marreaud, Sandrine Govaerts, Anne-Sophie Piccart-Gebhart, Martine J. Schellens, Jan H. M. Awada, Ahmad |
| description | Purpose
This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
Methods
Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle.
Results
The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients.
Conclusion
Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer. |
| doi_str_mv | 10.1007/s00280-012-1972-1 |
| format | article |
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This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
Methods
Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle.
Results
The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients.
Conclusion
Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-012-1972-1</identifier><identifier>PMID: 23053259</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adult ; Aged ; Antibodies, Monoclonal, Humanized - administration & dosage ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Cancer Research ; Dose-Response Relationship, Drug ; Female ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Maximum Tolerated Dose ; Medical sciences ; Medicine ; Medicine & Public Health ; Middle Aged ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Oncology ; Original Article ; Paclitaxel - administration & dosage ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Piperidines - administration & dosage ; Pyridines - administration & dosage ; Receptor, ErbB-2 - genetics ; Trastuzumab ; Treatment Outcome ; Tumors</subject><ispartof>Cancer chemotherapy and pharmacology, 2013, Vol.71 (1), p.53-62</ispartof><rights>Springer-Verlag Berlin Heidelberg 2012</rights><rights>2014 INIST-CNRS</rights><rights>Springer-Verlag Berlin Heidelberg 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-5219a731b2a0604dfcc8a4b1e2a0f0e7600d3f5c2c9c005c3c87032e63cb4ef43</citedby><cites>FETCH-LOGICAL-c402t-5219a731b2a0604dfcc8a4b1e2a0f0e7600d3f5c2c9c005c3c87032e63cb4ef43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27610442$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23053259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kerklaan, Bojana Milojkovic</creatorcontrib><creatorcontrib>Diéras, Veronique</creatorcontrib><creatorcontrib>Le Tourneau, Christophe</creatorcontrib><creatorcontrib>Mergui-Roelvink, Marja</creatorcontrib><creatorcontrib>Huitema, Alwin D. R.</creatorcontrib><creatorcontrib>Rosing, Hilde</creatorcontrib><creatorcontrib>Beijnen, Jos H.</creatorcontrib><creatorcontrib>Marreaud, Sandrine</creatorcontrib><creatorcontrib>Govaerts, Anne-Sophie</creatorcontrib><creatorcontrib>Piccart-Gebhart, Martine J.</creatorcontrib><creatorcontrib>Schellens, Jan H. M.</creatorcontrib><creatorcontrib>Awada, Ahmad</creatorcontrib><title>Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
Methods
Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle.
Results
The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients.
Conclusion
Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.</description><subject>Adult</subject><subject>Aged</subject><subject>Antibodies, Monoclonal, Humanized - administration & dosage</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Cancer Research</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Mammary gland diseases</subject><subject>Maximum Tolerated Dose</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Paclitaxel - administration & dosage</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Piperidines - administration & dosage</subject><subject>Pyridines - administration & dosage</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Trastuzumab</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp1kc9u1DAQxi0EokvhAbggSwgJDqFjj-Nke0OrwlaqVATlbDnecesq6wQ7gZbH4Inxapc_Fy5jjfz75hvNx9hzAW8FQHOSAWQLFQhZiWVTygO2EAplBa3Ch2wBqFRVN6CO2JOcbwFACcTH7Egi1Cjr5YL9_HhjM_Fznqd5c88Hz_shWm9TDB1__Xm11hpRv-EhcjdsuxDtFIbIv4fphk_JFtWPeWs7PvZz5qN1fZjsHfU7fk1JnkSa-fCNEt2NiXIO8Zp3iYqOOxsdpVN-dvnpanWwFxokPmWPvO0zPTu8x-zL-7Or1bq6uPxwvnp3UTkFcqpqKZa2QdFJCxrUxjvXWtUJKr0HajTABn3tpFs6gNqhaxtASRpdp8grPGYv93PHNHydKU_mdphTLJZG1IhKatnWhRJ7yqUh50TejClsbbo3AswuBbNPwZQUzC4FI4rmxWHy3G1p80fx--wFeHUAbHa296ncIuS_XKMFKCULJ_dcLl_xmtI_K_7X_RfYWZ3X</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Kerklaan, Bojana Milojkovic</creator><creator>Diéras, Veronique</creator><creator>Le Tourneau, Christophe</creator><creator>Mergui-Roelvink, Marja</creator><creator>Huitema, Alwin D. R.</creator><creator>Rosing, Hilde</creator><creator>Beijnen, Jos H.</creator><creator>Marreaud, Sandrine</creator><creator>Govaerts, Anne-Sophie</creator><creator>Piccart-Gebhart, Martine J.</creator><creator>Schellens, Jan H. M.</creator><creator>Awada, Ahmad</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</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>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>2013</creationdate><title>Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023</title><author>Kerklaan, Bojana Milojkovic ; Diéras, Veronique ; Le Tourneau, Christophe ; Mergui-Roelvink, Marja ; Huitema, Alwin D. R. ; Rosing, Hilde ; Beijnen, Jos H. ; Marreaud, Sandrine ; Govaerts, Anne-Sophie ; Piccart-Gebhart, Martine J. ; Schellens, Jan H. M. ; Awada, Ahmad</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-5219a731b2a0604dfcc8a4b1e2a0f0e7600d3f5c2c9c005c3c87032e63cb4ef43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antibodies, Monoclonal, Humanized - administration & dosage</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Cancer Research</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Mammary gland diseases</topic><topic>Maximum Tolerated Dose</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Paclitaxel - administration & dosage</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Piperidines - administration & dosage</topic><topic>Pyridines - administration & dosage</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Trastuzumab</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kerklaan, Bojana Milojkovic</creatorcontrib><creatorcontrib>Diéras, Veronique</creatorcontrib><creatorcontrib>Le Tourneau, Christophe</creatorcontrib><creatorcontrib>Mergui-Roelvink, Marja</creatorcontrib><creatorcontrib>Huitema, Alwin D. R.</creatorcontrib><creatorcontrib>Rosing, Hilde</creatorcontrib><creatorcontrib>Beijnen, Jos H.</creatorcontrib><creatorcontrib>Marreaud, Sandrine</creatorcontrib><creatorcontrib>Govaerts, Anne-Sophie</creatorcontrib><creatorcontrib>Piccart-Gebhart, Martine J.</creatorcontrib><creatorcontrib>Schellens, Jan H. M.</creatorcontrib><creatorcontrib>Awada, Ahmad</creatorcontrib><collection>Pascal-Francis</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>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</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)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kerklaan, Bojana Milojkovic</au><au>Diéras, Veronique</au><au>Le Tourneau, Christophe</au><au>Mergui-Roelvink, Marja</au><au>Huitema, Alwin D. R.</au><au>Rosing, Hilde</au><au>Beijnen, Jos H.</au><au>Marreaud, Sandrine</au><au>Govaerts, Anne-Sophie</au><au>Piccart-Gebhart, Martine J.</au><au>Schellens, Jan H. M.</au><au>Awada, Ahmad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2013</date><risdate>2013</risdate><volume>71</volume><issue>1</issue><spage>53</spage><epage>62</epage><pages>53-62</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Purpose
This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
Methods
Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle.
Results
The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients.
Conclusion
Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23053259</pmid><doi>10.1007/s00280-012-1972-1</doi><tpages>10</tpages></addata></record> |
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| ispartof | Cancer chemotherapy and pharmacology, 2013, Vol.71 (1), p.53-62 |
| issn | 0344-5704 1432-0843 |
| language | eng |
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| source | Springer Link |
| subjects | Adult Aged Antibodies, Monoclonal, Humanized - administration & dosage Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Breast Neoplasms - drug therapy Breast Neoplasms - genetics Cancer Research Dose-Response Relationship, Drug Female Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Maximum Tolerated Dose Medical sciences Medicine Medicine & Public Health Middle Aged Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Oncology Original Article Paclitaxel - administration & dosage Pharmacology. Drug treatments Pharmacology/Toxicology Piperidines - administration & dosage Pyridines - administration & dosage Receptor, ErbB-2 - genetics Trastuzumab Treatment Outcome Tumors |
| title | Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023 |
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