Background: Activation of the PI3K/AKT/mTOR pathway may contribute to resistance to androgen receptor targeted therapies in metastatic CRPC (mCRPC). The phase I/II RE-AKT trial (NCT02525068) investigates the safety and activity of enzalutamide (enza) in combination with the AKT inhibitor, AZD5363, in patients (pts) with mCRPC. Results of the phase I run-in are reported. Methods: mCRPC pts progressing after 1-2 lines of taxane chemotherapy and at least 12 weeks (wks) of abiraterone or enza were treated with enza (160mg od) and AZD5363 bid 4-days on, 3-days off, in a 3+3 dose escalation design. Co-primary endpoints were to assess toxicity (CTCAE), and identify the recommended phase II dose (RP2D) of AZD5363; antitumour activity and pharmacokinetics (PK) were secondary endpoints. Response was assessed by PSA, RECIST v1.1 and circulating tumor cell (CTC) conversion. Pts were considered evaluable for response if they completed 12 wks of treatment. Results: 16 pts were enrolled between 12/2014 & 04/2016 with 15 receiving treatment. At the AZD5363 320mg dose 3 pts were treated with no dose limiting toxicity (DLT). At the AZD5363 480mg dose, 5 pts were treated with 2 DLTs of grade (G) 3 maculopapular rash (MPR) related to AZD5363. An intermediate dose level of AZD5363 400mg was selected with 7 pts treated. 1 pt withdrew consent prior to completing the DLT window. 1 DLT of G3 MPR occurred and this dose was selected as the RP2D. Non-DLT treatment related (TR) G3/4 adverse events (AEs) were hyperglycaemia (n = 4, 26.7%), neutropenia (n = 1, 6.7%) & diarrhea (n = 1, 6.7%). All other TR AEs were G1 or G2, with diarrhea (n = 9, 60%), anorexia (n = 8, 53.3%) & nausea (n = 7, 46.7%) being most common. Of the 10 pts who completed 12 wks of treatment, 3 met at least one of the criteria for response. 1 pt (AZD5363 320mg) who had previously progressed on enza exhibited RECIST v1.1 partial response, > 50% PSA response, and CTC conversion by wk 13. Enza decreased AZD5363 PK exposure; robust modulation of pS6, pGSK3b and pPRAS40 was demonstrated. Conclusions: AZD5363 at the RP2D of 400mg bid 4 days on, 3 days off combined with enza 160mg od is safe and tolerable. Antitumor activity is reported, suggesting that AZD5363 may be able to overcome resistance to enza. Clinical trial information: NCT02525068