Mr Kwok-Leung Cheung Clinical Associate Professor, University of Nottingham

1. The short term effects of an AKT inhibitor (AZD5363) on biomarkers of the AKT pathway and anti-tumour activity in a breast cancer paired biopsy study (STAKT trial) Patient Recruitment Mr Kwok-Leung Cheung Clinical Associate Professor, University of Nottingham STAKT Trial Co-investigator

2. Source of patients (1) • Paired biopsy study • 4.5 days of treatment • Postmenopausal women • ER+ invasive carcinoma • Expected to receive chemotherapy

3. Source of patients (2) • Breast and oncology clinics • ~15 centres in the UK • N=150 (60 and 90 from stages 1 and 2 respectively, with seamless transition) • Over ~15 mos (7 and 8 mos for stages 1 and 2 respectively)

4. Inclusion criteria • Informed consent • WHO performance status 0-1 with no deterioration over the previous 2 weeks • Able to swallow and retain oral medication • Post-menopausal* • Female patients with histological confirmation of ER+ invasive breast carcinoma • Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies • Scheduled to have chemotherapy (with or without surgery) based on tumour characteristics and local treatment protocols • Tumours large enough to provide sufficient tissue to be taken by core/tru-cut biopsy to provide tissue sections for the marker assays

5. Exclusion criteria (1) • Any prior treatment for breast cancer • HRT within 4 weeks prior to trial treatment • Known ER− tumour • Not scheduled to have chemotherapy • 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‟sWort) • Clinically significant abnormalities of glucose metabolism* • Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment • Spinal cord compression or brain metastases • Evidence of severe or uncontrolled systemic diseases* • Cardiac criteria*

6. Exclusion criteria (2) • Criteria based on haematology, LFT and renal function* • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5363 • Hypersensitivity to excipients of AZD5363 or drugs with a similar chemical structure or class to AZD5363 • Disease or condition known to interfere with absorption, distribution, metabolism or excretion of drugs • History of interstitial lung disease etc* • Dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent • Previous allogeneic bone marrow transplant • Known immunodeficiency syndrome

7. Pathway for patients scheduled for surgery (likely but not exclusively for patients with clinically stage 1/2 (and LN+) disease), followed by chemotherapy Consent, randomisation, pre-treatment biopsy etc  Treatment (including placebo)  ECGs on the day of surgery Post-treatment biopsy (any time before anaesthesia) taken (eg under image-guidance  as with pre-treatment biopsy) Post-treatment biopsy (within 12 hrs of last dose) taken at surgery  (within 12 hrs of last dose) ECGs on the day of surgery (any time before anaesthesia)  Surgery (no further biopsy required)

8. Pathway for patients scheduled for chemotherapy, which may (ie when used as neoadjuvant systemic therapy eg in patients with clinically stage 3 disease, though not exclusively) or may not (eg stage 4 disease) be followed by surgery Consent, randomisation, pre-treatment biopsy etc  Treatment (including placebo)  Post-treatment biopsy taken (eg under image-guidance as with pre-treatment biopsy) (within 12 hrs of last dose)  Chemotherapy

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