A Study to Investigate the Biological Effects of AZD9833 in Women With ER-positive, HER2 Negative Primary Breast Cancer

Study Overview
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Brief Summary
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This is a randomised, open-label, parallel-group, pre-surgical study aimed to investigate the biological effects, safety, tolerability, and pharmacokinetics (PK) of different doses of oral AZD9833 in post-menopausal women with primary breast cancer

Detailed Description
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The study will be conducted in approximately 20 study centers across 3 countries and will be conducted in three stages (stage 1, stage 2 and stage 3). After the screening visit and confirmation of eligibility, evaluable participants will be enrolled across treatment groups. In stage 1, up to 24 evaluable participants across two treatment groups will be enrolled. A Safety and Data Monitoring Committee will convene to review stage 1 data and decide whether further treatment groups are required in stage 2. Stage 2 will include participants across up to 3 treatment groups. Stage 3 will include two treatment groups: Stage 1 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily Stage 2 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily Group 3: AZD9833 Dose C once daily Stage 3 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily Adverse events and concomitant medications information will be collected throughout the study. Thereafter there will be 28-day follow-up visit after discontinuation of study treatment

Official Title
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A Randomised, Open-Label, Parallel-Group, Pre-surgical Study to Investigate the Biological Effects of AZD9833 in Women With ER-positive, HER2-negative Primary Breast Cancer (SERENA-3)

Conditions
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HER2-negative Breast Cancer

Intervention / Treatment
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* Drug: AZD9833


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Provision of written informed consent prior to study entry Female participants aged at least 18 years Post-menopausal status defined as meeting at least one of the following criteria: Have undergone a bilateral oophorectomy Age ≥ 60 years Age ≥ 50 and < 60 years and with cessation of menses ≥ 12 months and follicle-stimulating hormone and oestradiol levels in the post-menopausal range and with an intact uterus in the absence of oral contraception or hormone replacement therapy prior to the diagnosis of breast cancer Female participants with newly diagnosed primary breast cancer scheduled to undergo treatment with curative intent by surgery and irrespective of clinical node status Histologically confirmed invasive breast cancer involving a palpable tumour of any size, or a tumour with an ultrasound assessed diameter of ≥ 1.0 cm Participants with adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 3 months can be considered for the study According to the local laboratory participants must have: ER positive breast cancer HER2-negative breast cancer Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Exclusion Criteria: Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments) Intervention with any of the following: Use of sex-hormone-containing drugs within 6 months prior to the first dose of study treatment Medications or herbal supplements known to be strong inhibitors/inducers of CYP3A4/5, sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index Drugs that are known to prolong QT and have a known risk of torsades de pointes Inflammatory breast cancer Any evidence of severe or uncontrolled systemic diseases which in the investigator's opinion makes it undesirable for the participant to participate in the study Any of the following cardiovascular criteria: Mean resting QTcF > 470 msec; resting heart rate of < 50 bpm for stages 1 and 2 at screening;resting heart rate <60 bpm at screening for Stage 3; 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; known left ventricular ejection fraction < 50%; significant cardiovascular procedure or event within the last 6 months; uncontrolled hypertension or symptomatic hypotension Inadequate bone marrow reserve or organ function Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833 History of hypersensitivity to active or inactive excipients of AZD9833 Previous randomisation in the present study Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Interventional Model Description: This is a randomised, open-label, parallel-group study. The study is divided into three stages as follows: Stage 1: In this stage post-menopausal participants will be randomised in 2 cohorts in 1:1 ratio to receive AZD9833 with 12 evaluable participants in each cohort. Stage 2: In this stage post-menopausal participants may be randomised in up to 3 cohorts, which may include up to 3 doses of AZD9833. Stage 3 : In this stage post-menopausal participants may be randomised in up to 2 cohorts in 1:1 ratio, which may include up to 2 doses of AZD9833.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: AZD9833 Dose A<br>Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 1 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 1: AZD9833 Dose B<br>Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 1 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 2: AZD9833 Dose A<br>Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 2 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 2: AZD9833 Dose B<br>Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 2 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 2: AZD9833 Dose C<br>Post-menopausal participants will receive once daily oral dose C of AZD9833 in stage 2 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 3: AZD9833 Dose A<br>Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 3 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|
| Experimental: Stage 3: AZD9833: Dose B<br>Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 3 of the study. | Drug: AZD9833<br>* AZD9833 tablets will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in estrogen receptor (ER) expression between pre- and on-treatment tumour samples measured by immunohistochemistry (IHC) | To explore the ER pharmacodynamic (PD) effects of AZD9833 between pre- and on-treatment tumour samples in women with early breast cancer after AZD9833 treatment. | Baseline (Screening Day -21 to 1) to Days 5-7 or Days 12-15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in progesterone receptor (PgR) expression between pre- and on-treatment tumour samples measured by IHC | To explore the PgR PD effects of AZD9833 between pre- and on-treatment tumour samples in women with early breast cancer after AZD9833. | Baseline (Screening Day -21 to 1) to Days 5-7 or Days 12-15 | 
| Change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples measured by IHC | To explore the Ki-67 PD effects of AZD9833 between pre- and on-treatment tumour samples in women with early breast cancer after AZD9833. | Baseline (Screening Day -21 to 1) to Days 5-7 or Days 12-15 | 
| Number of adverse events (AEs) experienced by participants | Safety and tolerability will be assessed through the incidence of AEs. | From screening (Day -21 to 1) through 28-day follow-up (Upto 2 months) | 
| Plasma concentrations of AZD9833 on the biopsy day | To evaluate the PK of AZD9833 in this participant population. | Days 5-7 or Days 12-15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Breast carcinoma, Estrogen-Receptor-positive breast cancer, HER2-negative breast cancer