Open Label Phase I/Randomised,Double Blind Phase II Study in mCRPC of AZD5363 In Combination With DP Chemotherapy

Inclusion Criteria: 1. Histologically or cytologically proven mCRPC with documented metastases (measurable or evaluable disease is acceptable) now eligible for treatment with docetaxel chemotherapy 2. Disease progression since the last change in therapy defined by one or more of the following according to the Prostate Cancer Working Group (PCWG2) criteria (J Clin Oncol 2008;26:1148-1159): i. PSA progression as defined by the prostate cancer working group (2) (PCWG2) criteria (Scher et al. 2008 J Clin Oncol. 26; 1148). This must be based on a series of at least 3 readings at least 7 days apart. The 3rd reading must be \>= 2ng/ml. In the event where an intermediate reading is lower than a previous reading, then the patient will still be eligible (ie. the 3 readings do not need to be consecutive). The first of the three readings must have been obtained after commencing the previous systemic therapy, or, in the case of androgen receptor antagonists, after discontinuing. ii. Radiographic progression of nodal or visceral metastases as defined by RECIST version 1.1 (Eur J Cancer 2009;45:228). See Appendix 5 iii. The appearance of two or more new bony metastases 3. Serum testosterone \<1.7 nmol/L (ongoing LHRH analogue or antagonist therapy is permitted to maintain a castrate state) 4. Discontinuation of prior therapies for prostate cancer ≥ 4 weeks prior to commencing study treatment (with the exception of an LHRH agonist or antagonist where required for ongoing testosterone suppression) 5. No current anti-androgen withdrawal response from bicalutamide or flutamide. Consistent with PCWG2 guidelines, investigators should evaluate patients to exclude withdrawal response for 6 weeks after stopping bicalutamide or flutamide. Investigators need not wait to assess for withdrawal response in patients who did not respond, or who showed a PSA decline for ≤ 3 months, after bicalutamide or flutamide was administered as a second-line or later intervention. 6. ECOG performance status 0 or 1 7. Hb ≥ 9g/dL; platelets ≥ 100 x 109/L; neutrophils ≥ 1.5 x109/L 8. Bilirubin ≤ ULN ; ALT and AST ≤ 1.5 x ULN 9. Sodium and potassium within the normal range for the site 10. Able to swallow study drugs (without crushing/opening in the case of AZD5363) 11. Life expectancy \> 3 months 12. Aged 18 years or over 13. Provision of written informed consent Exclusion Criteria: 1. Previous treatment with cytotoxic chemotherapy for castrate resistant prostate cancer. Patients may have received previous docetaxel for up to 6 cycles given in the 'hormone sensitive setting' or ongoing bisphosphonates or denosumab. There are no restrictions on prior use of second generation hormonal therapies e.g. abiraterone, enzalutamide as long as they have been discontinued ≥ 2 weeks prior to commencing study treatment. 2. Prior malignancy with an estimated ≥ 30% chance of relapse within 2 years following curative treatment 3. Previously identified brain metastases, or spinal cord compression unless treated with full functional recovery 4. Prior radiotherapy to \> 30% of bone marrow 5. Administration of an investigational agent within 30 days of first dose of study medication 6. Patients will be excluded with any of: i. Diabetes mellitus type I ii. Fasting plasma glucose \[fasting is defined as no calorific intake for at least 8 hours\] of either ≥ 7.0mmol/L (126 mg/dL) for those patients without a pre-existing diagnosis of Type 2 diabetes mellitus or ≥ 9.3 mmol/L (167mg/dL) for those patients with a pre-existing diagnosis of Type 2 diabetes mellitus iii. Glycosylated haemoglobin (HbA1C) ≥8.0% (63.9 mmol/mol) iv. Requirement for insulin for routine diabetic management and control v. Requirement for more than two oral hypoglycaemic medications for routine diabetic management and control. 7. Malabsorption syndrome, previous gastrointestinal surgery, or other gastrointestinal condition that may affect drug absorption 8. Coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris or congestive heart failure (NYHA ≥ grade 2) within the last 6 months 9. Abnormal echocardiogram or MUGA (LVEF should be normal according to the criteria used within the treating institution 10. Uncontrolled hypotension (systolic blood pressure \<90 mmHg and/or diastolic blood pressure \<50 mmHg) 11. QTc interval of \>480 msec at two or more time points within a 24 hour period 12. Proteinuria (either 3+ on dipstick analysis or \>500 mg/24 hours) or creatinine \>1.5 x ULN concurrent with creatinine clearance \<50 mL/min (assessed as per local practice e.g. by Cockcroft and Gault estimation) 13. Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort) 14. Unresolved toxicity ≥ grade 2 (except alopecia) from previous cancer therapy 15. Patients with a partner of child-bearing potential who are not using a highly effective method of contraception, who are unwilling to use condoms during the study and for 30 days after the last dose of study drug 16. Known hypersensitivity to AZD5363, its excipients, or drugs in its class 17. Previous exposure to agents with the following mechanisms of action: * inhibition of AKT (e.g., MK2206, GDC0068, GSK2110183, GSK2141795)any inhibitor with PI3K pharmacology (e.g., GDC0941, XL147, BKM120, PX866, BYL719, AMG319, GDC0032, INK1117, INK119) * any compound with mixed PI3K and mammalian target of rapamycin (mTOR) kinase pharmacology (e.g., BEZ235, GDC0980, PF04691502, PF05212384, GSK2126458, XL765) * or any mTOR kinase inhibitor (e.g., AZD8055, AZD2014, OSI027, INK128) Note: Do not exclude patients previously treated with a rapalogue (allosteric inhibitor of mTOR; mTORC1 complex inhibitor) - including temisirolimus (Torisel; Pfizer), everolimus (Affinitor; Novartis), ridoforolimus (Ariad).