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Clinical Trial
. 2017 Oct;35(5):599-607.
doi: 10.1007/s10637-017-0433-4. Epub 2017 Feb 1.

ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer

Simon J Crabb  1 , Alison J Birtle  2 , Karen Martin  3 , Nichola Downs  3 , Ian Ratcliffe  3 , Tom Maishman  3 , Mary Ellis  3 , Gareth Griffiths  3 , Stuart Thompson  3   4 , Lidia Ksiazek  5 , Vincent Khoo  6 , Robert J Jones  7
Affiliations
Clinical Trial

ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer

Simon J Crabb et al. Invest New Drugs. 2017 Oct.

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.

Trial registration: ClinicalTrials.gov NCT02121639.

Keywords: AKT; AZD5363; Castration resistant prostate cancer; Docetaxel; Metastatic; Phase I.

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Conflict of interest statement

SJC has undertaken consulting or advisory roles for Bayer, Sanofi, Astellas, Janssen, Pfizer and Roche and has received research funding from AstraZeneca, Astex Pharmaceuticals and Plexxikon. GG has undertaken consulting or advisory roles for Sirtex, GlaxoSmithKline and Pfizer. All other authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of the days of dosing (blue crossed boxes) for each of the indicated drugs at the following doses: docetaxel, 75 mg/m2 by one hour intravenous infusion on day 1; dexamethasone 8 mg orally, at 12, 3 and 1 h prior to each docetaxel infusion; AZD5363, dosed according to dose level cohort, BID, orally, taken 4 days on/3 days off, continuously from cycle 1 day 2; prednisolone, 5 mg BID orally days 1–21
Fig. 2
Fig. 2
Individual patient data for a plasma glucose, b insulin and (c) C-peptide levels at the indicated time points during cycle 1 of treatment. Samples on day 3, 9 and 16 of the cycle were taken prior to the morning AZD5363 dose
Fig. 3
Fig. 3
Percentage change from baseline of individual patient prostate specific antigen (PSA) level after 12 weeks of therapy
See this image and copyright information in PMC

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