Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors
Purpose Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 gu...
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2016-08, Vol.78 (2), p.271-280 |
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| creator | Smith, David C. Powderly, John Lee, James J. Shepard, Dale R. Wallin, Johan Chaudhary, Archana Chao, Grace Yi Ng, Wee Teck Mitchell, Malcolm I. Grau, Gerrit Kurek, Raffael LoRusso, Patricia |
| description | Purpose
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.
Methods
Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.
Results
Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.
Conclusions
The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab. |
| doi_str_mv | 10.1007/s00280-016-3074-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1846420245</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1807901486</sourcerecordid><originalsourceid>FETCH-LOGICAL-c405t-bb327c51bed8d8f12c59426d9ffda14c839fa1def6fb99844ba820b0425586653</originalsourceid><addsrcrecordid>eNqNkc2L1TAUxYMoznP0D3AjATduqvcmt226lGH8gAERxnVI8-F0bJtnko68_9483igiCC7CTTi_c8LlMPYc4TUC9G8ygFDQAHaNhJ6awwO2Q5KiAUXyIduBJGraHuiMPcn5FgAIpXzMzkQvsR65Y98u78y8mTLFlcfAy43nPgRvy_G1ejuVbdkWM_KqH0UbU6qqd_zzNZ_W4lP11wvf1wy_lsx_TOWGG3dnVlupHOfJ8RoSU37KHgUzZ__sfp6zL-8ury8-NFef3n-8eHvVWIK2NOMoRW9bHL1TTgUUth1IdG4IwRkkq-QQDDofujAOgyIajRIwAom2VV3XynP26pS7T_H75nPRy5Stn2ez-rhljYo6EiDof1DoB0BSXUVf_oXexi2tdZFKISKIQchK4YmyKeacfND7NC0mHTSCPpamT6XpWpo-lqYP1fPiPnkbF-9-O361VAFxAnKV1q8-_fH1P1N_AqHTohU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1811102923</pqid></control><display><type>article</type><title>Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Smith, David C. ; Powderly, John ; Lee, James J. ; Shepard, Dale R. ; Wallin, Johan ; Chaudhary, Archana ; Chao, Grace Yi ; Ng, Wee Teck ; Mitchell, Malcolm I. ; Grau, Gerrit ; Kurek, Raffael ; LoRusso, Patricia</creator><creatorcontrib>Smith, David C. ; Powderly, John ; Lee, James J. ; Shepard, Dale R. ; Wallin, Johan ; Chaudhary, Archana ; Chao, Grace Yi ; Ng, Wee Teck ; Mitchell, Malcolm I. ; Grau, Gerrit ; Kurek, Raffael ; LoRusso, Patricia</creatorcontrib><description>Purpose
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.
Methods
Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.
Results
Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.
Conclusions
The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-016-3074-y</identifier><identifier>PMID: 27312733</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Cancer Research ; Electrocardiography ; Female ; Humans ; Long QT Syndrome - chemically induced ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Neoplasms - drug therapy ; Neoplasms - pathology ; Oncology ; Original Article ; Pharmacology/Toxicology</subject><ispartof>Cancer chemotherapy and pharmacology, 2016-08, Vol.78 (2), p.271-280</ispartof><rights>Springer-Verlag Berlin Heidelberg 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-bb327c51bed8d8f12c59426d9ffda14c839fa1def6fb99844ba820b0425586653</citedby><cites>FETCH-LOGICAL-c405t-bb327c51bed8d8f12c59426d9ffda14c839fa1def6fb99844ba820b0425586653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00280-016-3074-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00280-016-3074-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27312733$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, David C.</creatorcontrib><creatorcontrib>Powderly, John</creatorcontrib><creatorcontrib>Lee, James J.</creatorcontrib><creatorcontrib>Shepard, Dale R.</creatorcontrib><creatorcontrib>Wallin, Johan</creatorcontrib><creatorcontrib>Chaudhary, Archana</creatorcontrib><creatorcontrib>Chao, Grace Yi</creatorcontrib><creatorcontrib>Ng, Wee Teck</creatorcontrib><creatorcontrib>Mitchell, Malcolm I.</creatorcontrib><creatorcontrib>Grau, Gerrit</creatorcontrib><creatorcontrib>Kurek, Raffael</creatorcontrib><creatorcontrib>LoRusso, Patricia</creatorcontrib><title>Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.
Methods
Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.
Results
Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.
Conclusions
The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antibodies, Monoclonal - administration & dosage</subject><subject>Antibodies, Monoclonal - adverse effects</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Cancer Research</subject><subject>Electrocardiography</subject><subject>Female</subject><subject>Humans</subject><subject>Long QT Syndrome - chemically induced</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacology/Toxicology</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkc2L1TAUxYMoznP0D3AjATduqvcmt226lGH8gAERxnVI8-F0bJtnko68_9483igiCC7CTTi_c8LlMPYc4TUC9G8ygFDQAHaNhJ6awwO2Q5KiAUXyIduBJGraHuiMPcn5FgAIpXzMzkQvsR65Y98u78y8mTLFlcfAy43nPgRvy_G1ejuVbdkWM_KqH0UbU6qqd_zzNZ_W4lP11wvf1wy_lsx_TOWGG3dnVlupHOfJ8RoSU37KHgUzZ__sfp6zL-8ury8-NFef3n-8eHvVWIK2NOMoRW9bHL1TTgUUth1IdG4IwRkkq-QQDDofujAOgyIajRIwAom2VV3XynP26pS7T_H75nPRy5Stn2ez-rhljYo6EiDof1DoB0BSXUVf_oXexi2tdZFKISKIQchK4YmyKeacfND7NC0mHTSCPpamT6XpWpo-lqYP1fPiPnkbF-9-O361VAFxAnKV1q8-_fH1P1N_AqHTohU</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Smith, David C.</creator><creator>Powderly, John</creator><creator>Lee, James J.</creator><creator>Shepard, Dale R.</creator><creator>Wallin, Johan</creator><creator>Chaudhary, Archana</creator><creator>Chao, Grace Yi</creator><creator>Ng, Wee Teck</creator><creator>Mitchell, Malcolm I.</creator><creator>Grau, Gerrit</creator><creator>Kurek, Raffael</creator><creator>LoRusso, Patricia</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><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>7X8</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20160801</creationdate><title>Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors</title><author>Smith, David C. ; Powderly, John ; Lee, James J. ; Shepard, Dale R. ; Wallin, Johan ; Chaudhary, Archana ; Chao, Grace Yi ; Ng, Wee Teck ; Mitchell, Malcolm I. ; Grau, Gerrit ; Kurek, Raffael ; LoRusso, Patricia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-bb327c51bed8d8f12c59426d9ffda14c839fa1def6fb99844ba820b0425586653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Antibodies, Monoclonal - adverse effects</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Cancer Research</topic><topic>Electrocardiography</topic><topic>Female</topic><topic>Humans</topic><topic>Long QT Syndrome - chemically induced</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacology/Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, David C.</creatorcontrib><creatorcontrib>Powderly, John</creatorcontrib><creatorcontrib>Lee, James J.</creatorcontrib><creatorcontrib>Shepard, Dale R.</creatorcontrib><creatorcontrib>Wallin, Johan</creatorcontrib><creatorcontrib>Chaudhary, Archana</creatorcontrib><creatorcontrib>Chao, Grace Yi</creatorcontrib><creatorcontrib>Ng, Wee Teck</creatorcontrib><creatorcontrib>Mitchell, Malcolm I.</creatorcontrib><creatorcontrib>Grau, Gerrit</creatorcontrib><creatorcontrib>Kurek, Raffael</creatorcontrib><creatorcontrib>LoRusso, Patricia</creatorcontrib><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>ProQuest 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 Edition)</collection><collection>ProQuest Central UK/Ireland</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>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, David C.</au><au>Powderly, John</au><au>Lee, James J.</au><au>Shepard, Dale R.</au><au>Wallin, Johan</au><au>Chaudhary, Archana</au><au>Chao, Grace Yi</au><au>Ng, Wee Teck</au><au>Mitchell, Malcolm I.</au><au>Grau, Gerrit</au><au>Kurek, Raffael</au><au>LoRusso, Patricia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2016-08-01</date><risdate>2016</risdate><volume>78</volume><issue>2</issue><spage>271</spage><epage>280</epage><pages>271-280</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><abstract>Purpose
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.
Methods
Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.
Results
Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.
Conclusions
The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>27312733</pmid><doi>10.1007/s00280-016-3074-y</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Cancer chemotherapy and pharmacology, 2016-08, Vol.78 (2), p.271-280 |
| issn | 0344-5704 1432-0843 |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adult Aged Aged, 80 and over Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - adverse effects Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Cancer Research Electrocardiography Female Humans Long QT Syndrome - chemically induced Male Medicine Medicine & Public Health Middle Aged Neoplasms - drug therapy Neoplasms - pathology Oncology Original Article Pharmacology/Toxicology |
| title | Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors |
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