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dc.contributor.authorYap, TA
dc.contributor.authorKristeleit, R
dc.contributor.authorMichalarea, V
dc.contributor.authorPettitt, SJ
dc.contributor.authorLim, JSJ
dc.contributor.authorCarreira, S
dc.contributor.authorRoda, D
dc.contributor.authorMiller, R
dc.contributor.authorRiisnaes, R
dc.contributor.authorMiranda, S
dc.contributor.authorFigueiredo, I
dc.contributor.authorRodrigues, DN
dc.contributor.authorWard, S
dc.contributor.authorMatthews, R
dc.contributor.authorParmar, M
dc.contributor.authorTurner, A
dc.contributor.authorTunariu, N
dc.contributor.authorChopra, N
dc.contributor.authorGevensleben, H
dc.contributor.authorTurner, NC
dc.contributor.authorRuddle, R
dc.contributor.authorRaynaud, FI
dc.contributor.authorDecordova, S
dc.contributor.authorSwales, KE
dc.contributor.authorFinneran, L
dc.contributor.authorHall, E
dc.contributor.authorRugman, P
dc.contributor.authorLindemann, JPO
dc.contributor.authorFoxley, A
dc.contributor.authorLord, CJ
dc.contributor.authorBanerji, U
dc.contributor.authorPlummer, R
dc.contributor.authorBasu, B
dc.contributor.authorLopez, JS
dc.contributor.authorDrew, Y
dc.contributor.authorde Bono, JS
dc.date.accessioned2020-06-22T15:12:30Z
dc.date.issued2020-10
dc.identifier.citationCancer discovery, 2020, 10 (10), pp. 1528 - 1543
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3762
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-20-0163
dc.description.abstractPreclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 ( BRCA1/2) -deficient and BRCA1/2 -proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2 -mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations. This article is highlighted in the In This Issue feature, p. 1426 .
dc.formatPrint-Electronic
dc.format.extent1528 - 1543
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titlePhase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non-<i>BRCA1/2</i>-Mutant Cancers.
dc.typeJournal Article
dcterms.dateAccepted2020-06-09
rioxxterms.versionofrecord10.1158/2159-8290.cd-20-0163
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue10
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
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/Cancer Therapeutics/Medicine (de Bono Prostate)
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/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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
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/Cancer Therapeutics/Medicine (de Bono Prostate)
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/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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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.volume10
pubs.embargo.termsNot known
icr.researchteamMolecular Oncologyen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicine (de Bono Prostate)en_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical PD Biomarker Groupen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorSwales, Karenen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorMiranda, Susanaen
dc.contributor.icrauthorHall, Emmaen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorTunariu, Ninaen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorCarreira, Suzanneen
dc.contributor.icrauthorLopez, Juanitaen


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