A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer
Summary The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-cli...
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| Veröffentlicht in: | Investigational new drugs 2015-06, Vol.33 (3), p.710-719 |
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| creator | Azaro, Analia Rodon, Jordi Calles, Antonio Braña, Irene Hidalgo, Manuel Lopez-Casas, Pedro P. Munoz, Manuel Westwood, Paul Miller, Joel Moser, Brian A. Ohnmacht, Ute Bumgardner, William Benhadji, Karim A. Calvo, Emiliano |
| description | Summary
The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100–500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (
n
= 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (
n
= 1), and increased gamma-glutamyl transpeptidase (GGT) (
n
= 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies. |
| doi_str_mv | 10.1007/s10637-015-0241-7 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2695713080</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3687288791</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-7b808e75611282f6bec2e0f56274d4a782bda8104b6318bc3f77d77f46a97d453</originalsourceid><addsrcrecordid>eNp9kbFuFDEQhi1ERC6BB6BBlmhjMvZ6Pd7yFAU46SSKQEFleddezknOe9jeIGpePF5dQDRQjTTzzT8afYS85vCOA-Bl5qAaZMBbBkJyhs_IirfYMFBSPScr4AqZ6jo8JWc53wJA06F8QU5F24HoAFbk15qOIeXCQmS7eW8jPexs9nRDSwr2nk4j3X4VqKEBfkEtdXNtHhDojaJ3IS6ojY6u7wrdxF3oQ5nSBQ01xpbgY8n0Ryg7at2DjYN3dEp074vNpY4HOizN9JKcjPY--1dP9Zx8eX_9-eoj2376sLlab9kgEQrDXoP22CrOhRaj6v0gPIytEiidtKhF76zmIHvVcN0PzYjoEEepbIdOts05eXvMPaTp--xzMbfTnGI9aYTqWuQN1D__Q3GluVCou4XiR2pIU87Jj-aQwt6mn4aDWeSYoxxT5ZhFjsG68-Ypee733v3Z-G2jAuII5DqK33z66_Q_Ux8BhJuVwA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1681267890</pqid></control><display><type>article</type><title>A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Azaro, Analia ; Rodon, Jordi ; Calles, Antonio ; Braña, Irene ; Hidalgo, Manuel ; Lopez-Casas, Pedro P. ; Munoz, Manuel ; Westwood, Paul ; Miller, Joel ; Moser, Brian A. ; Ohnmacht, Ute ; Bumgardner, William ; Benhadji, Karim A. ; Calvo, Emiliano</creator><creatorcontrib>Azaro, Analia ; Rodon, Jordi ; Calles, Antonio ; Braña, Irene ; Hidalgo, Manuel ; Lopez-Casas, Pedro P. ; Munoz, Manuel ; Westwood, Paul ; Miller, Joel ; Moser, Brian A. ; Ohnmacht, Ute ; Bumgardner, William ; Benhadji, Karim A. ; Calvo, Emiliano</creatorcontrib><description>Summary
The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100–500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (
n
= 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (
n
= 1), and increased gamma-glutamyl transpeptidase (GGT) (
n
= 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-015-0241-7</identifier><identifier>PMID: 25902900</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adult ; Aged ; AKT protein ; Alanine ; Alanine transaminase ; Anemia ; Animals ; Anticancer properties ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Antitumor activity ; Aspartate aminotransferase ; Biopsy ; Cancer ; Cancer therapies ; Cell cycle ; Cell growth ; Constipation ; Diarrhea ; Drug dosages ; Enzyme inhibitors ; Epidermis ; Female ; Health services ; Humans ; International ; Kinases ; Male ; Medical research ; Medicine ; Medicine & Public Health ; Metabolites ; Metastases ; Metastasis ; Mice, Nude ; Middle Aged ; Nausea ; Neoplasm Metastasis ; Neoplasm Staging ; Neoplasms - drug therapy ; Neoplasms - enzymology ; Neoplasms - pathology ; Neutropenia ; Oncology ; p70 S6 kinase ; Patients ; Pharmaceutical industry ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Pharmacology/Toxicology ; Phase I Studies ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - therapeutic use ; Proteins ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; R&D ; Regulatory approval ; Research & development ; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors ; Ribosomal Protein S6 Kinases, 70-kDa - metabolism ; Skin ; Studies ; Toxicity ; Transaminases ; Tumors ; Xenograft Model Antitumor Assays ; Young Adult ; γ-Glutamyltransferase</subject><ispartof>Investigational new drugs, 2015-06, Vol.33 (3), p.710-719</ispartof><rights>Springer Science+Business Media New York 2015</rights><rights>Springer Science+Business Media New York 2015.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-7b808e75611282f6bec2e0f56274d4a782bda8104b6318bc3f77d77f46a97d453</citedby><cites>FETCH-LOGICAL-c470t-7b808e75611282f6bec2e0f56274d4a782bda8104b6318bc3f77d77f46a97d453</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/s10637-015-0241-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-015-0241-7$$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/25902900$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Azaro, Analia</creatorcontrib><creatorcontrib>Rodon, Jordi</creatorcontrib><creatorcontrib>Calles, Antonio</creatorcontrib><creatorcontrib>Braña, Irene</creatorcontrib><creatorcontrib>Hidalgo, Manuel</creatorcontrib><creatorcontrib>Lopez-Casas, Pedro P.</creatorcontrib><creatorcontrib>Munoz, Manuel</creatorcontrib><creatorcontrib>Westwood, Paul</creatorcontrib><creatorcontrib>Miller, Joel</creatorcontrib><creatorcontrib>Moser, Brian A.</creatorcontrib><creatorcontrib>Ohnmacht, Ute</creatorcontrib><creatorcontrib>Bumgardner, William</creatorcontrib><creatorcontrib>Benhadji, Karim A.</creatorcontrib><creatorcontrib>Calvo, Emiliano</creatorcontrib><title>A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100–500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (
n
= 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (
n
= 1), and increased gamma-glutamyl transpeptidase (GGT) (
n
= 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.</description><subject>Adult</subject><subject>Aged</subject><subject>AKT protein</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Anemia</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antitumor activity</subject><subject>Aspartate aminotransferase</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Constipation</subject><subject>Diarrhea</subject><subject>Drug dosages</subject><subject>Enzyme inhibitors</subject><subject>Epidermis</subject><subject>Female</subject><subject>Health services</subject><subject>Humans</subject><subject>International</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolites</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice, Nude</subject><subject>Middle Aged</subject><subject>Nausea</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Staging</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>p70 S6 kinase</subject><subject>Patients</subject><subject>Pharmaceutical industry</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>R&D</subject><subject>Regulatory approval</subject><subject>Research & development</subject><subject>Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors</subject><subject>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</subject><subject>Skin</subject><subject>Studies</subject><subject>Toxicity</subject><subject>Transaminases</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Young Adult</subject><subject>γ-Glutamyltransferase</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kbFuFDEQhi1ERC6BB6BBlmhjMvZ6Pd7yFAU46SSKQEFleddezknOe9jeIGpePF5dQDRQjTTzzT8afYS85vCOA-Bl5qAaZMBbBkJyhs_IirfYMFBSPScr4AqZ6jo8JWc53wJA06F8QU5F24HoAFbk15qOIeXCQmS7eW8jPexs9nRDSwr2nk4j3X4VqKEBfkEtdXNtHhDojaJ3IS6ojY6u7wrdxF3oQ5nSBQ01xpbgY8n0Ryg7at2DjYN3dEp074vNpY4HOizN9JKcjPY--1dP9Zx8eX_9-eoj2376sLlab9kgEQrDXoP22CrOhRaj6v0gPIytEiidtKhF76zmIHvVcN0PzYjoEEepbIdOts05eXvMPaTp--xzMbfTnGI9aYTqWuQN1D__Q3GluVCou4XiR2pIU87Jj-aQwt6mn4aDWeSYoxxT5ZhFjsG68-Ypee733v3Z-G2jAuII5DqK33z66_Q_Ux8BhJuVwA</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Azaro, Analia</creator><creator>Rodon, Jordi</creator><creator>Calles, Antonio</creator><creator>Braña, Irene</creator><creator>Hidalgo, 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first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer</title><author>Azaro, Analia ; Rodon, Jordi ; Calles, Antonio ; Braña, Irene ; Hidalgo, Manuel ; Lopez-Casas, Pedro P. ; Munoz, Manuel ; Westwood, Paul ; Miller, Joel ; Moser, Brian A. ; Ohnmacht, Ute ; Bumgardner, William ; Benhadji, Karim A. ; Calvo, Emiliano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-7b808e75611282f6bec2e0f56274d4a782bda8104b6318bc3f77d77f46a97d453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Aged</topic><topic>AKT protein</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Anemia</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antitumor activity</topic><topic>Aspartate aminotransferase</topic><topic>Biopsy</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Constipation</topic><topic>Diarrhea</topic><topic>Drug dosages</topic><topic>Enzyme inhibitors</topic><topic>Epidermis</topic><topic>Female</topic><topic>Health services</topic><topic>Humans</topic><topic>International</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolites</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice, Nude</topic><topic>Middle Aged</topic><topic>Nausea</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Staging</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>p70 S6 kinase</topic><topic>Patients</topic><topic>Pharmaceutical industry</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>R&D</topic><topic>Regulatory approval</topic><topic>Research & development</topic><topic>Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors</topic><topic>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</topic><topic>Skin</topic><topic>Studies</topic><topic>Toxicity</topic><topic>Transaminases</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Young Adult</topic><topic>γ-Glutamyltransferase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Azaro, Analia</creatorcontrib><creatorcontrib>Rodon, Jordi</creatorcontrib><creatorcontrib>Calles, Antonio</creatorcontrib><creatorcontrib>Braña, Irene</creatorcontrib><creatorcontrib>Hidalgo, Manuel</creatorcontrib><creatorcontrib>Lopez-Casas, Pedro P.</creatorcontrib><creatorcontrib>Munoz, Manuel</creatorcontrib><creatorcontrib>Westwood, Paul</creatorcontrib><creatorcontrib>Miller, Joel</creatorcontrib><creatorcontrib>Moser, Brian A.</creatorcontrib><creatorcontrib>Ohnmacht, Ute</creatorcontrib><creatorcontrib>Bumgardner, William</creatorcontrib><creatorcontrib>Benhadji, Karim A.</creatorcontrib><creatorcontrib>Calvo, Emiliano</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>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>ABI/INFORM Collection (ProQuest)</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM 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Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Global</collection><collection>ProQuest Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>One Business (ProQuest)</collection><collection>ProQuest One Business (Alumni)</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 Basic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Azaro, Analia</au><au>Rodon, Jordi</au><au>Calles, Antonio</au><au>Braña, Irene</au><au>Hidalgo, Manuel</au><au>Lopez-Casas, Pedro P.</au><au>Munoz, Manuel</au><au>Westwood, Paul</au><au>Miller, Joel</au><au>Moser, Brian A.</au><au>Ohnmacht, Ute</au><au>Bumgardner, William</au><au>Benhadji, Karim A.</au><au>Calvo, Emiliano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>33</volume><issue>3</issue><spage>710</spage><epage>719</epage><pages>710-719</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100–500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (
n
= 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (
n
= 1), and increased gamma-glutamyl transpeptidase (GGT) (
n
= 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>25902900</pmid><doi>10.1007/s10637-015-0241-7</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 2015-06, Vol.33 (3), p.710-719 |
| issn | 0167-6997 1573-0646 |
| language | eng |
| recordid | cdi_proquest_journals_2695713080 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adult Aged AKT protein Alanine Alanine transaminase Anemia Animals Anticancer properties Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Antitumor activity Aspartate aminotransferase Biopsy Cancer Cancer therapies Cell cycle Cell growth Constipation Diarrhea Drug dosages Enzyme inhibitors Epidermis Female Health services Humans International Kinases Male Medical research Medicine Medicine & Public Health Metabolites Metastases Metastasis Mice, Nude Middle Aged Nausea Neoplasm Metastasis Neoplasm Staging Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - pathology Neutropenia Oncology p70 S6 kinase Patients Pharmaceutical industry Pharmacodynamics Pharmacokinetics Pharmacology Pharmacology/Toxicology Phase I Studies Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - therapeutic use Proteins Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism R&D Regulatory approval Research & development Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors Ribosomal Protein S6 Kinases, 70-kDa - metabolism Skin Studies Toxicity Transaminases Tumors Xenograft Model Antitumor Assays Young Adult γ-Glutamyltransferase |
| title | A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T03%3A26%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20first-in-human%20phase%20I%20trial%20of%20LY2780301,%20a%20dual%20p70%20S6%20kinase%20and%20Akt%20Inhibitor,%20in%20patients%20with%20advanced%20or%20metastatic%20cancer&rft.jtitle=Investigational%20new%20drugs&rft.au=Azaro,%20Analia&rft.date=2015-06-01&rft.volume=33&rft.issue=3&rft.spage=710&rft.epage=719&rft.pages=710-719&rft.issn=0167-6997&rft.eissn=1573-0646&rft_id=info:doi/10.1007/s10637-015-0241-7&rft_dat=%3Cproquest_cross%3E3687288791%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1681267890&rft_id=info:pmid/25902900&rfr_iscdi=true |