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dc.contributor.authorCrabb, SJen_US
dc.contributor.authorBirtle, AJen_US
dc.contributor.authorMartin, Ken_US
dc.contributor.authorDowns, Nen_US
dc.contributor.authorRatcliffe, Ien_US
dc.contributor.authorMaishman, Ten_US
dc.contributor.authorEllis, Men_US
dc.contributor.authorGriffiths, Gen_US
dc.contributor.authorThompson, Sen_US
dc.contributor.authorKsiazek, Len_US
dc.contributor.authorKhoo, Ven_US
dc.contributor.authorJones, RJen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2017-04-03T09:30:54Z
dc.date.issued2017-10en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/28144789en_US
dc.identifier.citationInvest New Drugs, 2017, 35 (5), pp. 599 - 607en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/538
dc.identifier.eissn1573-0646en_US
dc.identifier.doi10.1007/s10637-017-0433-4en_US
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/m2, 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.en_US
dc.format.extent599 - 607en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAKTen_US
dc.subjectAZD5363en_US
dc.subjectCastration resistant prostate canceren_US
dc.subjectDocetaxelen_US
dc.subjectMetastaticen_US
dc.subjectPhase Ien_US
dc.subjectAgeden_US
dc.subjectAntineoplastic Combined Chemotherapy Protocolsen_US
dc.subjectDocetaxelen_US
dc.subjectDose-Response Relationship, Drugen_US
dc.subjectHumansen_US
dc.subjectMaleen_US
dc.subjectMaximum Tolerated Doseen_US
dc.subjectMiddle Ageden_US
dc.subjectPrednisoloneen_US
dc.subjectProstate-Specific Antigenen_US
dc.subjectProstatic Neoplasms, Castration-Resistanten_US
dc.subjectProto-Oncogene Proteins c-akten_US
dc.subjectPyrimidinesen_US
dc.subjectPyrrolesen_US
dc.subjectTaxoidsen_US
dc.titleProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer.en_US
dc.typeConference Proceeding
dcterms.dateAccepted2017-01-16en_US
rioxxterms.versionofrecord10.1007/s10637-017-0433-4en_US
rioxxterms.licenseref.startdate2017-10en_US
rioxxterms.typeConference Paper/Proceeding/Abstracten_US
dc.relation.isPartOfInvest New Drugsen_US
pubs.issue5en_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume35en_US
pubs.embargo.termsNo embargoen_US
dc.contributor.icrauthorKhoo, Vincenten_US
dc.contributor.icrauthorMarsden,en_US


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