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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
49
500 mg Fulvestrant administered as two consecutive 5 ml intramuscular injections on Day 1, one in each buttock
Administered at 250 mg bd orally for 5-14 days commencing on Day 1, and continuing up to the day of biopsy
Research Site
Erlangen, Germany
Research Site
Minden, Germany
Research Site
München, Germany
Research Site
Schwerin, Germany
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
Time frame: 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 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: From first dose until 28 days after fulvestrant
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Research Site
Derby, United Kingdom
Research Site
Edinburgh, United Kingdom
Research Site
London, United Kingdom
Research Site
London, United Kingdom
Research Site
London, United Kingdom
Research Site
Manchester, United Kingdom
...and 2 more locations
Plasma concentration of AZD9496 - stand alone biopsy visit option
Determination of AZD9496 concentrations in plasma
Time frame: 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
Time frame: A blood sample will be collected anytime before biopsy.
Plasma concentration of AZD9496 - on the table biopsy option
Determination of AZD9496 concentration in plasma
Time frame: 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