Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors
This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. Fifty-seven patients wit...
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| Veröffentlicht in: | Annals of oncology 2012-09, Vol.23 (9), p.2399-2408 |
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| creator | Markman, B. Tabernero, J. Krop, I. Shapiro, G.I. Siu, L. Chen, L.C. Mita, M. Melendez Cuero, M. Stutvoet, S. Birle, D. Anak, Ö. Hackl, W. Baselga, J. |
| description | This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor.
Fifty-seven patients with advanced solid tumors received BGT226 2.5–125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples.
Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6–9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose–positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent.
The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure. |
| doi_str_mv | 10.1093/annonc/mds011 |
| format | Article |
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Fifty-seven patients with advanced solid tumors received BGT226 2.5–125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples.
Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6–9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose–positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent.
The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mds011</identifier><identifier>PMID: 22357447</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Adult ; Aged ; Aged, 80 and over ; anticancer agent ; Antineoplastic agents ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; BGT226 ; Biological and medical sciences ; Breast Neoplasms - diagnostic imaging ; Breast Neoplasms - drug therapy ; Colonic Neoplasms - diagnostic imaging ; Colonic Neoplasms - drug therapy ; Diarrhea - chemically induced ; dual inhibitor ; Female ; Fluorodeoxyglucose F18 ; Humans ; Imidazoles - adverse effects ; Imidazoles - pharmacokinetics ; Imidazoles - therapeutic use ; Male ; Maximum Tolerated Dose ; Medical sciences ; Middle Aged ; mTOR catalytic inhibitor ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Nausea - chemically induced ; Pharmacology. Drug treatments ; Phosphoinositide-3 Kinase Inhibitors ; PI3K pathway ; Prostatic Neoplasms - diagnostic imaging ; Prostatic Neoplasms - drug therapy ; Quinolines - adverse effects ; Quinolines - pharmacokinetics ; Quinolines - therapeutic use ; Radionuclide Imaging ; Radiopharmaceuticals ; solid tumors ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Treatment Outcome ; Tumors ; Young Adult</subject><ispartof>Annals of oncology, 2012-09, Vol.23 (9), p.2399-2408</ispartof><rights>2012 European Society for Medical Oncology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-fb9b38748a77253090747a5743b196cc8c6c1466401ea9c26c63d9e44baf1e803</citedby><cites>FETCH-LOGICAL-c410t-fb9b38748a77253090747a5743b196cc8c6c1466401ea9c26c63d9e44baf1e803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26294793$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22357447$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Markman, B.</creatorcontrib><creatorcontrib>Tabernero, J.</creatorcontrib><creatorcontrib>Krop, I.</creatorcontrib><creatorcontrib>Shapiro, G.I.</creatorcontrib><creatorcontrib>Siu, L.</creatorcontrib><creatorcontrib>Chen, L.C.</creatorcontrib><creatorcontrib>Mita, M.</creatorcontrib><creatorcontrib>Melendez Cuero, M.</creatorcontrib><creatorcontrib>Stutvoet, S.</creatorcontrib><creatorcontrib>Birle, D.</creatorcontrib><creatorcontrib>Anak, Ö.</creatorcontrib><creatorcontrib>Hackl, W.</creatorcontrib><creatorcontrib>Baselga, J.</creatorcontrib><title>Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors</title><title>Annals of oncology</title><addtitle>Ann Oncol</addtitle><description>This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor.
Fifty-seven patients with advanced solid tumors received BGT226 2.5–125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples.
Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6–9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose–positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent.
The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>anticancer agent</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>BGT226</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - diagnostic imaging</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - diagnostic imaging</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Diarrhea - chemically induced</subject><subject>dual inhibitor</subject><subject>Female</subject><subject>Fluorodeoxyglucose F18</subject><subject>Humans</subject><subject>Imidazoles - adverse effects</subject><subject>Imidazoles - pharmacokinetics</subject><subject>Imidazoles - therapeutic use</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>mTOR catalytic inhibitor</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Nausea - chemically induced</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>PI3K pathway</subject><subject>Prostatic Neoplasms - diagnostic imaging</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Quinolines - adverse effects</subject><subject>Quinolines - pharmacokinetics</subject><subject>Quinolines - therapeutic use</subject><subject>Radionuclide Imaging</subject><subject>Radiopharmaceuticals</subject><subject>solid tumors</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Young Adult</subject><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM1u1DAURi1E1Q6lS7bIG3YN9d_Y8RIqKJUqFaFhHd3YjmJI7JHtaZUH4j3xKKWsurJ0fe6n-x2E3lHykRLNryCEGMzVbDOh9BXa0K3UTUsEfY02RDPeqC0XZ-hNzr8IIVIzfYrOGONbJYTaoD_fR8gO3-IMgyvLJd6PkGYw8bcPrnhziSHY56FdAsze4FwOdsFxwGV0OCaYKhFzpYq3y-RDzL7EqeFNTTnGHzPm3f0P7MPo-_qX8OebHWOyDvC-brlQMn70ZcRgHyAYZ3GOk7e4HOaY8lt0MsCU3cXTe45-fv2yu_7W3N3f3F5_umuMoKQ0Q6973irRglJsy4kmSiioTXlPtTSmNdJQIaUg1IE2TBrJrXZC9DBQ1xJ-jpo116SYc3JDt09-hrR0lHRH3d2qu1t1V_79yu8P_ezsM_3PbwU-PAGQDUxDqt18_s9JpoXSvHJq5Vxt9-Bd6rKpUqoHn5wpnY3-hRP-AoqGoJk</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Markman, B.</creator><creator>Tabernero, J.</creator><creator>Krop, I.</creator><creator>Shapiro, G.I.</creator><creator>Siu, L.</creator><creator>Chen, L.C.</creator><creator>Mita, M.</creator><creator>Melendez Cuero, M.</creator><creator>Stutvoet, S.</creator><creator>Birle, D.</creator><creator>Anak, Ö.</creator><creator>Hackl, W.</creator><creator>Baselga, J.</creator><general>Elsevier Ltd</general><general>Oxford University Press</general><scope>6I.</scope><scope>AAFTH</scope><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></search><sort><creationdate>20120901</creationdate><title>Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors</title><author>Markman, B. ; Tabernero, J. ; Krop, I. ; Shapiro, G.I. ; Siu, L. ; Chen, L.C. ; Mita, M. ; Melendez Cuero, M. ; Stutvoet, S. ; Birle, D. ; Anak, Ö. ; Hackl, W. ; Baselga, J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-fb9b38748a77253090747a5743b196cc8c6c1466401ea9c26c63d9e44baf1e803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>anticancer agent</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>BGT226</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - diagnostic imaging</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - diagnostic imaging</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Diarrhea - chemically induced</topic><topic>dual inhibitor</topic><topic>Female</topic><topic>Fluorodeoxyglucose F18</topic><topic>Humans</topic><topic>Imidazoles - adverse effects</topic><topic>Imidazoles - pharmacokinetics</topic><topic>Imidazoles - therapeutic use</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>mTOR catalytic inhibitor</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Nausea - chemically induced</topic><topic>Pharmacology. 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Fifty-seven patients with advanced solid tumors received BGT226 2.5–125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples.
Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6–9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose–positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent.
The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>22357447</pmid><doi>10.1093/annonc/mds011</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Aged, 80 and over anticancer agent Antineoplastic agents Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use BGT226 Biological and medical sciences Breast Neoplasms - diagnostic imaging Breast Neoplasms - drug therapy Colonic Neoplasms - diagnostic imaging Colonic Neoplasms - drug therapy Diarrhea - chemically induced dual inhibitor Female Fluorodeoxyglucose F18 Humans Imidazoles - adverse effects Imidazoles - pharmacokinetics Imidazoles - therapeutic use Male Maximum Tolerated Dose Medical sciences Middle Aged mTOR catalytic inhibitor Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Nausea - chemically induced Pharmacology. Drug treatments Phosphoinositide-3 Kinase Inhibitors PI3K pathway Prostatic Neoplasms - diagnostic imaging Prostatic Neoplasms - drug therapy Quinolines - adverse effects Quinolines - pharmacokinetics Quinolines - therapeutic use Radionuclide Imaging Radiopharmaceuticals solid tumors TOR Serine-Threonine Kinases - antagonists & inhibitors Treatment Outcome Tumors Young Adult |
| title | Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors |
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