Show simple item record

dc.contributor.authorJuric, D
dc.contributor.authorde Bono, JS
dc.contributor.authorLoRusso, PM
dc.contributor.authorNemunaitis, J
dc.contributor.authorHeath, EI
dc.contributor.authorKwak, EL
dc.contributor.authorMacarulla Mercadé, T
dc.contributor.authorGeuna, E
dc.contributor.authorJose de Miguel-Luken, M
dc.contributor.authorPatel, C
dc.contributor.authorKuida, K
dc.contributor.authorSankoh, S
dc.contributor.authorWestin, EH
dc.contributor.authorZohren, F
dc.contributor.authorShou, Y
dc.contributor.authorTabernero, J
dc.date.accessioned2018-06-28T08:40:42Z
dc.date.issued2017-09
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (17), pp. 5015 - 5023
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1957
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-16-2888
dc.description.abstractPurpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg ( n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg ( n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg ( n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted. Clin Cancer Res; 23(17); 5015-23. ©2017 AACR .
dc.formatPrint-Electronic
dc.format.extent5015 - 5023
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectImidazoles
dc.subjectMorpholines
dc.subjectPyridines
dc.subjectBenzoxazoles
dc.subjectProtein Kinase Inhibitors
dc.subjectNeoplasm Staging
dc.subjectDose-Response Relationship, Drug
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.titleA First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.
dc.typeOther
rioxxterms.versionofrecord10.1158/1078-0432.ccr-16-2888
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeOther
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue17
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublished
pubs.volume23
pubs.embargo.termsNot known
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorDe Bono, Johann


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record