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dc.contributor.authorKolinsky, MPen_US
dc.contributor.authorRescigno, Pen_US
dc.contributor.authorBianchini, Den_US
dc.contributor.authorZafeiriou, Zen_US
dc.contributor.authorMehra, Nen_US
dc.contributor.authorMateo, Jen_US
dc.contributor.authorMichalarea, Ven_US
dc.contributor.authorRiisnaes, Ren_US
dc.contributor.authorCrespo, Men_US
dc.contributor.authorFigueiredo, Ien_US
dc.contributor.authorMiranda, Sen_US
dc.contributor.authorNava Rodrigues, Den_US
dc.contributor.authorFlohr, Pen_US
dc.contributor.authorTunariu, Nen_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorRuddle, Ren_US
dc.contributor.authorSharp, Aen_US
dc.contributor.authorWelti, Jen_US
dc.contributor.authorLambros, Men_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorSwales, KEen_US
dc.contributor.authorPlymate, Sen_US
dc.contributor.authorLuo, Jen_US
dc.contributor.authorTovey, Hen_US
dc.contributor.authorPorta, Nen_US
dc.contributor.authorSlade, Ren_US
dc.contributor.authorLeonard, Len_US
dc.contributor.authorHall, Een_US
dc.contributor.authorde Bono, JSen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2020-03-16T10:33:12Z
dc.date.issued2020-02-21en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/32205016en_US
dc.identifierS0923-7534(20)36037-3en_US
dc.identifier.citationAnn Oncol, 2020en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3548
dc.identifier.eissn1569-8041en_US
dc.identifier.doi10.1016/j.annonc.2020.01.074en_US
dc.description.abstractBACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAKT inhibitoren_US
dc.subjectAZD5363en_US
dc.subjectbiomarkersen_US
dc.subjectcapivasertiben_US
dc.subjectenzalutamideen_US
dc.subjectprostate canceren_US
dc.titleA phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-01-29en_US
rioxxterms.versionofrecord10.1016/j.annonc.2020.01.074en_US
rioxxterms.licenseref.startdate2020-02-21en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfAnn Oncolen_US
pubs.notesNot knownen_US
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/ICR-CTSU Urology and Head and Neck Trials Team
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
dc.contributor.icrauthorHall, Emmaen_US


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