title: ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer.
abstract: Background 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.
authors.affiliation: Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK. S.J.Crabb@southampton.ac.uk.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Crabb
authors.affiliation: Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Birtle
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Martin
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Nichola
authors.initials: N
authors.lastname: Downs
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ratcliffe
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Maishman
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Ellis
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.|Patient and Public Involvement Representative, Southampton, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ksiazek
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Khoo
authors.affiliation: The Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D011239:Prednisolone; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen; C575618:capivasertib
keywords: AKT; AZD5363; Castration resistant prostate cancer; Docetaxel; Metastatic; Phase I