Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors
Identifieur interne : 004022 ( Main/Exploration ); précédent : 004021; suivant : 004023Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors
Auteurs : Kyriakos P. Papadopoulos [États-Unis] ; Josep Tabernero [Espagne] ; Ben Markman [Espagne, Australie] ; Amita Patnaik [États-Unis] ; Anthony W. Tolcher [États-Unis] ; José Baselga [États-Unis] ; WEILIANG SHI [États-Unis] ; Coumaran Egile [France] ; Rodrigo Ruiz-Soto [États-Unis] ; A. Douglas Laird [États-Unis] ; Dale Miles [États-Unis] ; Patricia M. Lorusso [États-Unis]Source :
- Clinical cancer research : (Print) [ 1078-0432 ] ; 2014.
Descripteurs français
- KwdFr :
- Administration par voie orale, Adulte, Adulte d'âge moyen, Antinéoplasiques (pharmacologie), Antinéoplasiques (usage thérapeutique), Dose maximale tolérée, Femelle, Humains, Jeune adulte, Mâle, Phosphatidylinositol 3-kinases (antagonistes et inhibiteurs), Quinoxalines (pharmacologie), Quinoxalines (usage thérapeutique), Résultat thérapeutique, Stade de la tumeur, Sujet âgé, Sujet âgé de 80 ans ou plus, Sulfonamides (pharmacologie), Sulfonamides (usage thérapeutique), Surveillance pharmacologique, Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Transduction du signal (), Tumeurs (anatomopathologie), Tumeurs (métabolisme), Tumeurs (traitement médicamenteux).
- MESH :
- anatomopathologie : Tumeurs.
- antagonistes et inhibiteurs : Phosphatidylinositol 3-kinases, Sérine-thréonine kinases TOR.
- métabolisme : Tumeurs.
- pharmacologie : Antinéoplasiques, Quinoxalines, Sulfonamides.
- traitement médicamenteux : Tumeurs.
- usage thérapeutique : Antinéoplasiques, Quinoxalines, Sulfonamides.
- Pascal (Inist)
- Administration par voie orale, Adulte, Adulte d'âge moyen, Dose maximale tolérée, Femelle, Humains, Jeune adulte, Mâle, Résultat thérapeutique, Stade de la tumeur, Sujet âgé, Sujet âgé de 80 ans ou plus, Surveillance pharmacologique, Toxicité, Relation pharmacocinétique pharmacodynamie, Transduction du signal, Voie orale, 1-Phosphatidylinositol 3-kinase, Homme, Stade avancé, Tumeur solide, Inhibiteur mTOR.
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
- 1-Phosphatidylinositol 3-kinase, Administration, Oral, Adult, Advanced stage, Aged, Aged, 80 and over, Antineoplastic Agents (pharmacology), Antineoplastic Agents (therapeutic use), Drug Monitoring, Female, Human, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Staging, Neoplasms (drug therapy), Neoplasms (metabolism), Neoplasms (pathology), Oral administration, Pharmacokinetic pharmacodynamic relationship, Phosphatidylinositol 3-Kinases (antagonists & inhibitors), Quinoxalines (pharmacology), Quinoxalines (therapeutic use), Signal Transduction (drug effects), Solid tumor, Sulfonamides (pharmacology), Sulfonamides (therapeutic use), TOR Serine-Threonine Kinases (antagonists & inhibitors), Toxicity, Treatment Outcome, Young Adult, mTOR inhibitor.
- MESH :
- chemical , antagonists & inhibitors : Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antineoplastic Agents, Quinoxalines, Sulfonamides.
- chemical , therapeutic use : Antineoplastic Agents, Quinoxalines, Sulfonamides.
- drug effects : Signal Transduction.
- drug therapy : Neoplasms.
- metabolism : Neoplasms.
- pathology : Neoplasms.
- Administration, Oral, Adult, Aged, Aged, 80 and over, Drug Monitoring, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Staging, Treatment Outcome, Young Adult.
Abstract
Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3 + 3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96- 7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥ 16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/ mTORC2 pathway signaling and was associated with clinically relevant stable disease.
Affiliations:
- Australie, Espagne, France, États-Unis
- Californie, Catalogne, Massachusetts, Michigan, Texas, État de New York
- Barcelone
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Le document en format XML
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Papadopoulos</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>South Texas Accelerated Research Therapeutics</s1><s2>San Antonio, Texas</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Monash Institute of Medical Research, Monash University</s1><s2>Melbourne, Victoria</s2><s3>AUS</s3><sZ>3 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Melbourne, Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Patnaik, Amita" sort="Patnaik, Amita" uniqKey="Patnaik A" first="Amita" last="Patnaik">Amita Patnaik</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>South Texas Accelerated Research Therapeutics</s1><s2>San Antonio, Texas</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Tolcher, Anthony W" sort="Tolcher, Anthony W" uniqKey="Tolcher A" first="Anthony W." last="Tolcher">Anthony W. Tolcher</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>South Texas Accelerated Research Therapeutics</s1><s2>San Antonio, Texas</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="José" last="Baselga">José Baselga</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Memorial Sloan-Kettering Cancer Center, Memorial Hospital</s1><s2>New York, New York</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Weiliang Shi" sort="Weiliang Shi" uniqKey="Weiliang Shi" last="Weiliang Shi">WEILIANG SHI</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Sanofi</s1><s2>Cambridge, Massachusetts</s2><s3>USA</s3><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Egile, Coumaran" sort="Egile, Coumaran" uniqKey="Egile C" first="Coumaran" last="Egile">Coumaran Egile</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Sanofi</s1><s2>Vitry-sur-Seine</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Vitry-sur-Seine</wicri:noRegion><wicri:noRegion>Sanofi</wicri:noRegion><wicri:noRegion>Sanofi</wicri:noRegion></affiliation></author><author><name sortKey="Ruiz Soto, Rodrigo" sort="Ruiz Soto, Rodrigo" uniqKey="Ruiz Soto R" first="Rodrigo" last="Ruiz-Soto">Rodrigo Ruiz-Soto</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Sanofi</s1><s2>Cambridge, Massachusetts</s2><s3>USA</s3><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Laird, A Douglas" sort="Laird, A Douglas" uniqKey="Laird A" first="A. Douglas" last="Laird">A. Douglas Laird</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Exelixis Inc.</s1><s2>South San Francisco, California</s2><s3>USA</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Miles, Dale" sort="Miles, Dale" uniqKey="Miles D" first="Dale" last="Miles">Dale Miles</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Exelixis Inc.</s1><s2>South San Francisco, California</s2><s3>USA</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Lorusso, Patricia M" sort="Lorusso, Patricia M" uniqKey="Lorusso P" first="Patricia M." last="Lorusso">Patricia M. Lorusso</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Karmanos Cancer Institute, Wayne State University School of Medicine</s1><s2>Detroit, Michigan</s2><s3>USA</s3><sZ>12 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Michigan</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Clinical cancer research : (Print)</title><title level="j" type="abbreviated">Clin. cancer res. : (Print)</title><idno type="ISSN">1078-0432</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Clinical cancer research : (Print)</title><title level="j" type="abbreviated">Clin. cancer res. : (Print)</title><idno type="ISSN">1078-0432</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Phosphatidylinositol 3-kinase</term><term>Administration, Oral</term><term>Adult</term><term>Advanced 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Adult</term><term>mTOR inhibitor</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Administration par voie orale</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Antinéoplasiques (pharmacologie)</term><term>Antinéoplasiques (usage thérapeutique)</term><term>Dose maximale tolérée</term><term>Femelle</term><term>Humains</term><term>Jeune adulte</term><term>Mâle</term><term>Phosphatidylinositol 3-kinases (antagonistes et inhibiteurs)</term><term>Quinoxalines (pharmacologie)</term><term>Quinoxalines (usage thérapeutique)</term><term>Résultat thérapeutique</term><term>Stade de la tumeur</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Sulfonamides (pharmacologie)</term><term>Sulfonamides (usage thérapeutique)</term><term>Surveillance pharmacologique</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Transduction du signal ()</term><term>Tumeurs (anatomopathologie)</term><term>Tumeurs (métabolisme)</term><term>Tumeurs (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term><term>Quinoxalines</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antineoplastic Agents</term><term>Quinoxalines</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Phosphatidylinositol 3-kinases</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term><term>Quinoxalines</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antinéoplasiques</term><term>Quinoxalines</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Administration, Oral</term><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Drug Monitoring</term><term>Female</term><term>Humans</term><term>Male</term><term>Maximum Tolerated Dose</term><term>Middle Aged</term><term>Neoplasm Staging</term><term>Treatment Outcome</term><term>Young Adult</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Administration par voie orale</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Dose maximale tolérée</term><term>Femelle</term><term>Humains</term><term>Jeune adulte</term><term>Mâle</term><term>Résultat thérapeutique</term><term>Stade de la tumeur</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Surveillance pharmacologique</term><term>Toxicité</term><term>Relation pharmacocinétique pharmacodynamie</term><term>Transduction du signal</term><term>Voie orale</term><term>1-Phosphatidylinositol 3-kinase</term><term>Homme</term><term>Stade avancé</term><term>Tumeur solide</term><term>Inhibiteur mTOR</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3 + 3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96- 7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥ 16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/ mTORC2 pathway signaling and was associated with clinically relevant stable disease.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Espagne</li><li>France</li><li>États-Unis</li></country><region><li>Californie</li><li>Catalogne</li><li>Massachusetts</li><li>Michigan</li><li>Texas</li><li>État de New York</li></region><settlement><li>Barcelone</li></settlement></list><tree><country name="États-Unis"><region name="Texas"><name sortKey="Papadopoulos, Kyriakos P" sort="Papadopoulos, Kyriakos P" uniqKey="Papadopoulos K" first="Kyriakos P." last="Papadopoulos">Kyriakos P. Papadopoulos</name></region><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="José" last="Baselga">José Baselga</name><name sortKey="Laird, A Douglas" sort="Laird, A Douglas" uniqKey="Laird A" first="A. Douglas" last="Laird">A. Douglas Laird</name><name sortKey="Lorusso, Patricia M" sort="Lorusso, Patricia M" uniqKey="Lorusso P" first="Patricia M." last="Lorusso">Patricia M. Lorusso</name><name sortKey="Miles, Dale" sort="Miles, Dale" uniqKey="Miles D" first="Dale" last="Miles">Dale Miles</name><name sortKey="Patnaik, Amita" sort="Patnaik, Amita" uniqKey="Patnaik A" first="Amita" last="Patnaik">Amita Patnaik</name><name sortKey="Ruiz Soto, Rodrigo" sort="Ruiz Soto, Rodrigo" uniqKey="Ruiz Soto R" first="Rodrigo" last="Ruiz-Soto">Rodrigo Ruiz-Soto</name><name sortKey="Tolcher, Anthony W" sort="Tolcher, Anthony W" uniqKey="Tolcher A" first="Anthony W." last="Tolcher">Anthony W. Tolcher</name><name sortKey="Weiliang Shi" sort="Weiliang Shi" uniqKey="Weiliang Shi" last="Weiliang Shi">WEILIANG SHI</name></country><country name="Espagne"><region name="Catalogne"><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name></region><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name></country><country name="Australie"><noRegion><name sortKey="Markman, Ben" sort="Markman, Ben" uniqKey="Markman B" first="Ben" last="Markman">Ben Markman</name></noRegion></country><country name="France"><noRegion><name sortKey="Egile, Coumaran" sort="Egile, Coumaran" uniqKey="Egile C" first="Coumaran" last="Egile">Coumaran Egile</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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