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 1

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

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)

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

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‟s Wort) 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*

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

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)

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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