Study to Compare the Effects of AZD9496 vs Fulvestrant in Breast Cancer.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open Label, Randomised, Pre-surgical, Pharmacodynamics Study to Compare the Biological Effects of AZD9496 Versus Fulvestrant in Postmenopausal Women With ER Positive HER-2 Negative Primary Breast Cancer

Conditions
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Postmenopausal Women With ER+ HER2- Primary Breast Cancer

Intervention / Treatment
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* Drug: Standard Arm - Fulvestrant
* Drug: AZD9496


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated informed consent form (ICF) Women >=18 years Patients with newly diagnosed resectable primary breast cancer scheduled to undergo treatment with curative intent by surgery Histologically confirmed invasive breast cancer involving a palpable tumor of any size, or a tumor with an ultrasound assessed diameter of ≥ 1.0 cm Any clinical nodal status ER+breast cancer HER2- breast cancer defined as a negative in situ hybridization test or an immno-histochemistry (IHC) status of 0 or 1+ Eastern Co-operative Oncology group (ECOG) performance status 0-1 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: Pre-treatment biopsy sample not likely to provide adequate tissue sections for the biomarker assays Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments) Inflammatory breast cancer Evidence of metastases 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 Concurrent treatment with other experimental drugs within 4 weeks prior to receiving study treatment Use of hormone-replacement therapy from <4 weeks of the diagnostic/baseline core biopsy to the start of trial treatment Patients with second primary cancer. Any endocrine therapies or other anti-cancer therapies must have been ceased at least 12 months prior to enrollment. 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 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 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, Uncontrolled symptomatic thyroid dysfunction (hyperthyroidism or hypothyroidism). Unexplained symptomatic endometrial disorders. 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. 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 Direct involvement in the planning and conduct of the study History of hypersensitivity to AZD9496 History of hypersensitivity to fulvestrant and/or castor oil 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard arm<br>Fulvestrant, 500 mg | Drug: Standard Arm - Fulvestrant<br>* 500 mg Fulvestrant administered as two consecutive 5 ml intramuscular injections on Day 1, one in each buttock<br>* Other names: Fulvestrant;|
| Experimental: AZD9496<br>250 mg bd taken orally for 5-14 days | Drug: AZD9496<br>* Administered at 250 mg bd orally for 5-14 days commencing on Day 1, and continuing up to the day of biopsy<br>* Other names: Study drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics changes to estrogen receptor (ER) expression following treatment with AZD9496 or fulvestrant | Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. ER expression | Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics changes to progesterone receptor (PgR) expression following treatment with AZD9496 or fulvestrant | Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. PgR expression | Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment | 
| Pharmacodynamics changes to Ki67 protein biomarker expression following treatment with AZD9496 or fulvestrant | Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. Ki67 protein biomarker expression | Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment | 
| Safety and tolerability of AZD9496 | Safety and tolerability will be assessed in terms of adverse events (AEs), laboratory data, vital signs and ECG changes. | From first dose until 28 days after last dose of AZD9496 | 
| Safety and tolerability of fulvestrant | Safety and tolerability will be assessed in terms of adverse events (AEs), laboratory data and vital signs | From first dose until 28 days after fulvestrant | 
| Plasma concentration of AZD9496 - stand alone biopsy visit option | Determination of AZD9496 concentrations in plasma | Blood samples collected close as possible to time of biopsy, 1-2 hours after biopsy and optional 3-4 hours after biopsy | 
| Plasma concentration of fulvestrant | Determination of fulvestrant concentration in plasma | A blood sample will be collected anytime before biopsy. | 
| Plasma concentration of AZD9496 - on the table biopsy option | Determination of AZD9496 concentration in plasma | Blood samples collected close as possible to time of biopsy, at least 2 hours after biopsy and 8-12 hours after last dose or at discharge which is defined as up to 12 hours after last dose |