dc.contributor.author | Juric, D | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | LoRusso, PM | |
dc.contributor.author | Nemunaitis, J | |
dc.contributor.author | Heath, EI | |
dc.contributor.author | Kwak, EL | |
dc.contributor.author | Macarulla Mercadé, T | |
dc.contributor.author | Geuna, E | |
dc.contributor.author | Jose de Miguel-Luken, M | |
dc.contributor.author | Patel, C | |
dc.contributor.author | Kuida, K | |
dc.contributor.author | Sankoh, S | |
dc.contributor.author | Westin, EH | |
dc.contributor.author | Zohren, F | |
dc.contributor.author | Shou, Y | |
dc.contributor.author | Tabernero, J | |
dc.date.accessioned | 2018-06-28T08:40:42Z | |
dc.date.issued | 2017-09 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (17), pp. 5015 - 5023 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1957 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-16-2888 | |
dc.description.abstract | Purpose: 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.format | Print-Electronic | |
dc.format.extent | 5015 - 5023 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Imidazoles | |
dc.subject | Morpholines | |
dc.subject | Pyridines | |
dc.subject | Benzoxazoles | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Neoplasm Staging | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Aged, 80 and over | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Class I Phosphatidylinositol 3-Kinases | |
dc.title | A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies. | |
dc.type | Other | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-16-2888 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Other | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 17 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 23 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | en_US |
dc.contributor.icrauthor | De Bono, Johann | |