Trial of Olaparib in Combination With AZD5363 (ComPAKT)

Inclusion Criteria: 1. Part A: Patients with histologically or cytologically confirmed malignant advanced solid tumours refractory to standard therapy or for which no suitable effective standard therapy exists, including, but not limited to patients with: BRCA1/2 mutant cancers, TNBC, CRPC and HGSOC, and those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway. Part B: (1) BRCA1/2 mutation cohort: Patients with advanced germline BRCA1/2 mutant solid tumours; (2) Sporadic cancers cohort: This cohort will include advanced sporadic cancers that are not known to harbour germline BRCA1/2 mutations, but which may harbour homologous recombination (HR) defects, e.g. advanced TNBC, CRPC and HGSOC, and those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway. 2. Life expectancy of at least 12 weeks 3. WHO performance status of 0-1 with no significant deterioration over the previous 2 weeks 4. Evaluable or measurable disease as assessed by RECIST 1.1 5. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week. * Hb ≥ 10.0 g/dL * Absolute neutrophil count ≥ 1.5 x 109/L * Platelet count ≥ 100 x 109/L * Serum bilirubin ≤ 1.5 x upper limit of normal except for patient with documented Gilburt's disease * ALT or AST ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 times ULN is permissible If creatinine \> 1.5 times ULN then: Either: * Creatinine Clearance ≥ 50 mL/min (uncorrected value) * Isotope clearance measurement ≥ 50 mL/min (corrected) 6.18 years or over 7. Signed and dated informed consent and be capable of co-operating with treatment and follow-up Exclusion Criteria: 1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products before treatment, except for hormonal therapy with luteinizing hormone-releasing hormone analogues for medical castration in patients with CRPC, which are permitted. 2. Ongoing toxic manifestations of previous treatments. Exceptions to this are Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient. 3. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible. 4. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of study treatment. 6. At high medical risk because of severe or uncontrolled systemic disease including active bleeding diathesis or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. 7. Clinically significant abnormalities of glucose metabolism as defined by any of the following: * Diagnosis of diabetes mellitus type I or II (irrespective of management). * HbA1C ≥ 8.0% at screening (64 mmol/mol) (conversion equation for HbA1C \[IFCC-HbA1C (mmol/mol)\] = \[DCCT-HbA1C (%) - 2.15\] x 10.929) * Fasting Plasma Glucose ≥ 8.9mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours. 8. Proteinuria 3+ on dipstick analysis or \>500mg/24 hours. 9. Previous treatment with a PARP inhibitor or PI3K/AKT inhibitor (Part B: sporadic cancers arm of dose expansion cohort only). 10. Treatment with potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort). 11. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment 12. Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \> 470 msec obtained from 3 consecutive electrocardiograms * Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval * Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association \[NYHA0 Grade 2 * Uncontrolled hypotension - Systolic BP \<90mmHg and/or diastolic BP \<50mmHg * LVEF below institutional lower limit of normal. 13. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of olaparib and AZD5363. 14. History of hypersensitivity to active or inactive excipients of AZD5363 or olaparib or drugs with a similar chemical structure or class to AZD5363 and olaparib. 15. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study. Participation in an observational trial would be acceptable. 16. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. 17. Patients with myelodysplastic syndrome or acute myeloid leukaemia