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dc.contributor.authorSlovin, S
dc.contributor.authorHussain, S
dc.contributor.authorSaad, F
dc.contributor.authorGarcia, J
dc.contributor.authorPicus, J
dc.contributor.authorFerraldeschi, R
dc.contributor.authorCrespo, M
dc.contributor.authorFlohr, P
dc.contributor.authorRiisnaes, R
dc.contributor.authorLin, C
dc.contributor.authorKeer, H
dc.contributor.authorOganesian, A
dc.contributor.authorWorkman, P
dc.contributor.authorde Bono, J
dc.date.accessioned2019-06-19T15:16:11Z
dc.date.issued2019-08-01
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (15), pp. 4624 - 4633
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3262
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-18-3212
dc.description.abstractPURPOSE: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P. PATIENTS AND METHODS: Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m2 on day 1 and day 2 weekly for 3 of 4 weeks (regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTC) and in fresh tumor tissue biopsies. RESULTS: Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose limiting at 260 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients showed an objective or PSA response. CONCLUSIONS: Onalespib in combination with AA/P showed mild evidence of some biological effect; however, this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
dc.formatPrint-Electronic
dc.format.extent4624 - 4633
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectBenzamides
dc.subjectPrednisolone
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectTreatment Outcome
dc.subjectSurvival Rate
dc.subjectTissue Distribution
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectIsoindoles
dc.subjectPatient Safety
dc.subjectProstatic Neoplasms, Castration-Resistant
dc.subjectAbiraterone Acetate
dc.titlePharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-05-17
rioxxterms.versionofrecord10.1158/1078-0432.ccr-18-3212
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue15
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublished
pubs.volume25
pubs.embargo.termsNot known
icr.researchteamCancer Biomarkers
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorWorkman, Paul
dc.contributor.icrauthorDe Bono, Johann


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