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dc.contributor.authorKolinsky, MP
dc.contributor.authorRescigno, P
dc.contributor.authorBianchini, D
dc.contributor.authorZafeiriou, Z
dc.contributor.authorMehra, N
dc.contributor.authorMateo, J
dc.contributor.authorMichalarea, V
dc.contributor.authorRiisnaes, R
dc.contributor.authorCrespo, M
dc.contributor.authorFigueiredo, I
dc.contributor.authorMiranda, S
dc.contributor.authorNava Rodrigues, D
dc.contributor.authorFlohr, P
dc.contributor.authorTunariu, N
dc.contributor.authorBanerji, U
dc.contributor.authorRuddle, R
dc.contributor.authorSharp, A
dc.contributor.authorWelti, J
dc.contributor.authorLambros, M
dc.contributor.authorCarreira, S
dc.contributor.authorRaynaud, FI
dc.contributor.authorSwales, KE
dc.contributor.authorPlymate, S
dc.contributor.authorLuo, J
dc.contributor.authorTovey, H
dc.contributor.authorPorta, N
dc.contributor.authorSlade, R
dc.contributor.authorLeonard, L
dc.contributor.authorHall, E
dc.contributor.authorde Bono, JS
dc.date.accessioned2020-03-16T10:33:12Z
dc.date.issued2020-05
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2020, 31 (5), pp. 619 - 625
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3548
dc.identifier.eissn1569-8041
dc.identifier.doi10.1016/j.annonc.2020.01.074
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.
dc.formatPrint-Electronic
dc.format.extent619 - 625
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectPhenylthiohydantoin
dc.subjectPyrimidines
dc.subjectPyrroles
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectTreatment Outcome
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectProstatic Neoplasms, Castration-Resistant
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.
dc.typeJournal Article
dcterms.dateAccepted2020-01-29
rioxxterms.versionofrecord10.1016/j.annonc.2020.01.074
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2020-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue5
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
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/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublished
pubs.volume31en_US
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical PD Biomarker Groupen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamTranslational Therapeuticsen_US
dc.contributor.icrauthorSwales, Karenen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorRescigno, Pasqualeen
dc.contributor.icrauthorSharp, Adamen
dc.contributor.icrauthorHall, Emmaen
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorCarreira, Suzanneen
dc.contributor.icrauthorTovey, Hollyen
dc.contributor.icrauthorPorta, Nuriaen
dc.contributor.icrauthorCrespo, Mateusen


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