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To compare the effect of four and a half days treatment of a range of doses of AZD5363 on selected markers of the AKT pathway and anti-proliferation compared with placebo in oestrogen receptor positive breast cancers.
To assess the tolerability of four and a half days treatment of AZD5363.
Full description
The principal research questions to be addressed are whether (or not) AZD5363 is "hitting its therapeutic target" sufficiently and to the extent that is required to produce efficacy in pre-clinical experiments.
The primary endpoint markers have been selected to determine this.
Reductions in markers of the AKT pathway and increases in markers of anti-proliferation will characterise the degree of biological activity arising from the inhibition of AKT across a range of doses of AZD5363.
Enrollment
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Inclusion criteria
Written informed consent
WHO performance status 0-1.
Able to swallow & retain oral medication.
Patients who fall in to either category (a) or (b):
i) hysterectomy or bilateral fallopian tube ligation at least 6 weeks ago plus a negative pregnancy test.
ii) true abstinence iii) willing to have pregnancy testing and use 2 forms of contraception
Female patients, aged 18 years and over, with histological confirmation of ER positive invasive breast carcinoma.
Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies. New primary breast tumours (ipsi- or contra-lateral) despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1 are eligible.
Scheduled to have chemotherapy based on tumour characteristics and local treatment protocols.
Tumours large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy to provide tissue sections for the marker assays.
Exclusion criteria
Prior treatment for breast cancer except new primary breast tumours arising despote prior endocrine treatment for an earlier primary breas tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1 (see inclusion criteria 6).
Known ER negative tumour.
Female patients with histological confirmation of ER+ve invasive breast carcinoma 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 Johns 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 disease.
Any of the following cardiac criteria:
Absolute neutrophil count <1.5 x 10,000,000,000/L
Platelet count <100 x 10,000,000,000/L.
Haemoglobin <90 g/L
ALT >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
Elevated ALP is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate
Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of liver metastases.
Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min; confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN
Proteinuria >3+ on dipstick analysis.
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.
History of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a similar chemical structure or class to AZD5363.
Current disease or condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
Evidence of 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.
Pregnant or lactating patients
Primary purpose
Allocation
Interventional model
Masking
48 participants in 4 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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