Study to Compare the Effects of AZD9496 vs Fulvestrant in Breast Cancer.
Study to Compare the Effects of AZD9496 vs Fulvestrant in Breast Cancer.
This is an open label randomised multicentre pre-surgical pharmacodynamics study to compare
 and assess the biological effects of AZD9496 and fulvestrant in postmenopausal women with
 estrogen receptor (ER) positive (ER+), human epidermal growth factor receptor 2 (HER-2)
 negative (HER2-) primary breast cancer.

 Patients will receive AZD9496 or fulvestrant and will have an on-treatment image

 -guided core biopsy after 5-14 days of commencing treatment.
This is an open label, randomized, multi-centre study in postmenopausal women with primary
 ER+ HER2- breast cancer. Patients will be randomised to an oral dose of 250 mg bd AZD9496 or
 500mg fulvestrant i.m. administered on one occasion. Patients diagnosed with primary breast
 cancer who are scheduled for surgery with curative intent will be consented to the study
 including consent to use the formalin fixed paraffin embedded (FFPE) diagnostic tumor biopsy
 sample and fresh frozen tumor biopsy sample (if available) for research purposes. Patients
 may also consent to provide an optional pretreatment fresh frozen tumor biopsy sample if this
 was not obtained at the time of initial diagnostic biopsy. If the diagnostic biopsy was taken
 ≥ 6 weeks prior to starting treatment or was not of sufficient quality, new tumor core
 biopsies (FFPE and fresh frozen) must be taken. Following the screening visit, eligible
 patients will be randomised to receive one of the following study treatments:

 -  AZD9496 administered at 250 mg bd orally for 5-14 days commencing on Day 1, and
 continuing up to the day of biopsy OR

 -  fulvestrant 500 mg administered as two consecutive 5 ml intramuscular injections on Day
 1, one in each buttock.

 After the morning dose of AZD9496 on the day of biopsy dosing will be stopped. If following
 initiation of AZD9496 treatment, dosing will be stopped if biopsy is postponed beyond Day 14.
 Patients will be considered not evaluable for the study if biopsy is postponed beyond day 14
 of AZD9496/fulvestrant treatment initiation. Core tumor biopsies will be taken at either the
 time of definitive surgery or at a separate visit prior to surgery in the period between (and
 including) day 5 and day 14. Subjects who are scheduled to start a subsequent neoadjuvant
 therapy must have their core tumor biopsies performed before commencing neoadjuvant
 treatment.
Inclusion criteria:

 1. Signed and dated informed consent form (ICF)

 2. Women >=18 years

 3. Patients with newly diagnosed resectable primary breast cancer scheduled to undergo
 treatment with curative intent by surgery

 4. Histologically confirmed invasive breast cancer involving a palpable tumor of any
 size, or a tumor with an ultrasound assessed diameter of ≥ 1.0 cm

 5. Any clinical nodal status

 6. ER+breast cancer

 7. HER2- breast cancer defined as a negative in situ hybridization test or an
 immno-histochemistry (IHC) status of 0 or 1+

 8. Eastern Co-operative Oncology group (ECOG) performance status 0-1

 9. Post-menopausal status defined as meeting at least one of the following criteria: Have
 undergone a bilateral oophorectomy; Age ≥60 years; Age ≥50 years and with cessation of
 regular menses ≥12 months and with an intact uterus in the absence of oral
 contraception or hormone-replacement therapy (HRT) prior to the diagnosis of breast
 cancer; Age <60 years and with cessation of regular menses ≥12 months and follicle
 stimulating hormone (FSH) and oestradiol levels in the postmenopausal range

 Exclusion criteria:

 1. Pre-treatment biopsy sample not likely to provide adequate tissue sections for the
 biomarker assays

 2. Previous systemic or local treatment for the new primary breast cancer currently under
 investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments)

 3. Inflammatory breast cancer

 4. Evidence of metastases

 5. Patients currently receiving medications or herbal supplements known to be strong
 inhibitors/inducers of CYP3A4/5 or strong inhibitors of CYP2C8 or that are sensitive
 substrates of CYP2C8 inhibition

 6. Concurrent treatment with other experimental drugs within 4 weeks prior to receiving
 study treatment

 7. Use of hormone-replacement therapy from <4 weeks of the diagnostic/baseline core
 biopsy to the start of trial treatment

 8. Patients with second primary cancer. Any endocrine therapies or other anti-cancer
 therapies must have been ceased at least 12 months prior to enrollment.

 9. Any of the following cardiac criteria:

 -  Mean resting QT interval corrected for heart rate (QTc) > 470 msec obtained from
 3 ECGs using Fridericia's formula

 -  Any clinically important abnormalities in rhythm, conduction or morphology of
 resting ECG

 -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
 events

 10. Experience of any of the following in the preceding 6 months: coronary artery bypass
 graft (CABG), angioplasty, vascular stent, myocardial infarction (MI), angina
 pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥2,
 cerebrovascular accident (CVA), transient ischaemic attack (TIA), deep venous or
 arterial thrombosis, pulmonary embolism, bleeding diathesis (i.e., disseminated
 intravascular coagulation, clotting factor deficiency) or requirement of anticoagulant
 therapy

 11. As judged by the Investigator, any evidence of severe or uncontrolled systemic
 diseases,

 12. Uncontrolled symptomatic thyroid dysfunction (hyperthyroidism or hypothyroidism).

 13. Unexplained symptomatic endometrial disorders.

 14. Refractory nausea and vomiting, uncontrolled chronic GI diseases, inability to swallow
 the formulated product or previous significant bowel resection that would preclude
 adequate absorption of AZD9496.

 15. Inadequate bone marrow reserve or organ function as demonstrated by any of the
 following laboratory values: absolute neutrophil count < 1.5 x 109/L, Platelet count <
 100 x 109/L, Haemoglobin < 90 g/L, alanine aminotransferase (ALT) > 2.5x upper limit
 of normal (ULN), aspartate aminotransferase (AST) > 2.5 x ULN, Total bilirubin > 1.5 x
 ULN or > 3 x in case of Gilbert's Syndrome, glomerular filtration rate < 50 mL/min

 16. Direct involvement in the planning and conduct of the study

 17. History of hypersensitivity to AZD9496

 18. History of hypersensitivity to fulvestrant and/or castor oil

 19. Judgment by the investigator that the patient should not participate in the study if
 unlikely to comply with study procedures, restrictions and requirements In addition,
 the following is considered a criterion for exclusion from the exploratory genetic
 research: Previous allogeneic bone marrow transplant; Non-leukocyte depleted whole
 blood transfusion within 120 days of the date of the genetic sample collection