dc.contributor.author | Mateo, J | |
dc.contributor.author | Ganji, G | |
dc.contributor.author | Lemech, C | |
dc.contributor.author | Burris, HA | |
dc.contributor.author | Han, S-W | |
dc.contributor.author | Swales, K | |
dc.contributor.author | Decordova, S | |
dc.contributor.author | DeYoung, MP | |
dc.contributor.author | Smith, DA | |
dc.contributor.author | Kalyana-Sundaram, S | |
dc.contributor.author | Wu, J | |
dc.contributor.author | Motwani, M | |
dc.contributor.author | Kumar, R | |
dc.contributor.author | Tolson, JM | |
dc.contributor.author | Rha, SY | |
dc.contributor.author | Chung, HC | |
dc.contributor.author | Eder, JP | |
dc.contributor.author | Sharma, S | |
dc.contributor.author | Bang, Y-J | |
dc.contributor.author | Infante, JR | |
dc.contributor.author | Yan, L | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Arkenau, H-T | |
dc.date.accessioned | 2017-08-14T13:54:06Z | |
dc.date.issued | 2017-10-01 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (19), pp. 5981 - 5992 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/773 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-17-0725 | |
dc.description.abstract | Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. ©2017 AACR. | |
dc.format | Print-Electronic | |
dc.format.extent | 5981 - 5992 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
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 | Protein Kinase Inhibitors | |
dc.subject | Neoplasm Staging | |
dc.subject | Drug Administration Schedule | |
dc.subject | Maximum Tolerated Dose | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Phosphoinositide-3 Kinase Inhibitors | |
dc.title | A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-06-19 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-17-0725 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 19 | |
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/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
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/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 23 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical PD Biomarker Group | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
dc.contributor.icrauthor | Swales, Karen | |
dc.contributor.icrauthor | De Bono, Johann | |