Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m², IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639