dc.contributor.author | Kolinsky, MP | |
dc.contributor.author | Rescigno, P | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Zafeiriou, Z | |
dc.contributor.author | Mehra, N | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Michalarea, V | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Flohr, P | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Ruddle, R | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Welti, J | |
dc.contributor.author | Lambros, M | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Swales, KE | |
dc.contributor.author | Plymate, S | |
dc.contributor.author | Luo, J | |
dc.contributor.author | Tovey, H | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Slade, R | |
dc.contributor.author | Leonard, L | |
dc.contributor.author | Hall, E | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2020-03-16T10:33:12Z | |
dc.date.issued | 2020-02-21 | |
dc.identifier.citation | Annals of oncology : official journal of the European Society for Medical Oncology, 2020, 31 (5), pp. 619 - 625 | |
dc.identifier.issn | 0923-7534 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3548 | |
dc.identifier.eissn | 1569-8041 | |
dc.identifier.doi | 10.1016/j.annonc.2020.01.074 | |
dc.description.abstract | BACKGROUND: 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.format | Print-Electronic | |
dc.format.extent | 619 - 625 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Phenylthiohydantoin | |
dc.subject | Pyrimidines | |
dc.subject | Pyrroles | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Treatment Outcome | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.title | A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-01-29 | |
rioxxterms.versionofrecord | 10.1016/j.annonc.2020.01.074 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc-nd/4.0 | |
rioxxterms.licenseref.startdate | 2020-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Annals of oncology : official journal of the European Society for Medical Oncology | |
pubs.issue | 5 | |
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/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-status | Published | |
pubs.volume | 31 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical PD Biomarker Group | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | ICR-CTSU Urology and Head and Neck Trials Team | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Banerji, Udai | |
dc.contributor.icrauthor | Ruddle, Ruth | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Swales, Karen | |
dc.contributor.icrauthor | Tovey, Holly | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Hall, Emma | |
dc.contributor.icrauthor | De Bono, Johann | |