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dc.contributor.authorCrabb, SJ
dc.contributor.authorBirtle, AJ
dc.contributor.authorMartin, K
dc.contributor.authorDowns, N
dc.contributor.authorRatcliffe, I
dc.contributor.authorMaishman, T
dc.contributor.authorEllis, M
dc.contributor.authorGriffiths, G
dc.contributor.authorThompson, S
dc.contributor.authorKsiazek, L
dc.contributor.authorKhoo, V
dc.contributor.authorJones, RJ
dc.date.accessioned2017-04-03T09:30:54Z
dc.date.issued2017-10
dc.identifier.citationInvestigational new drugs, 2017, 35 (5), pp. 599 - 607
dc.identifier.issn0167-6997
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/538
dc.identifier.eissn1573-0646
dc.identifier.doi10.1007/s10637-017-0433-4
dc.description.abstractBackground Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP. Eligibility criteria included chemotherapy naive mCRPC, PSA or radiographic disease progression and ECOG performance status 0 or 1. Treatment comprised DP (75 mg/m<sup>2</sup>, IV, day 1 and 5 mg BID, PO, day 1-21 respectively for ten cycles) and AZD5363 to disease progression for all patients. We utilised a 3 + 3 dose escalation design to determine a maximum tolerated dose according to defined dose limiting toxicity criteria assessed using CTCAE version 4.03. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from day 2 of each cycle. Results 10 patients were treated. Dose limiting toxicities affected 2 patients (grade 3 rash ≥5 days; grade 3 diarrhoea) in DL2. The commonest grade 3 or 4, AZD5363 related, symptomatic adverse events were rash and diarrhoea. Hyperglycaemia affected all patients but was self-limiting. PSA reduction to <50% at 12 weeks occurred in 7 patients. Conclusions The RP2D for AZD5363 is 320 mg BID, 4 days on/3 days off, in combination with full dose DP for mCRPC.
dc.formatPrint-Electronic
dc.format.extent599 - 607
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectTaxoids
dc.subjectPyrimidines
dc.subjectPyrroles
dc.subjectPrednisolone
dc.subjectProstate-Specific Antigen
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectMaximum Tolerated Dose
dc.subjectDose-Response Relationship, Drug
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectProstatic Neoplasms, Castration-Resistant
dc.subjectDocetaxel
dc.titleProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer.
dc.typeJournal Article
dcterms.dateAccepted2017-01-16
rioxxterms.versionofrecord10.1007/s10637-017-0433-4
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfInvestigational new drugs
pubs.issue5
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume35en_US
pubs.embargo.termsNo embargo
dc.contributor.icrauthorKhoo, Vincenten
dc.contributor.icrauthorMarsden,en


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