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

Phase 2

Completed

Conditions: HER2-negative Breast Cancer

Interventions: Drug: AZD9833

Registration Number: NCT04588298

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 135

Inclusion Criteria

Not provided

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:
1. Use of sex-hormone-containing drugs within 6 months prior to the first dose of study treatment
2. 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
3. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stage 1: AZD9833 Dose B	AZD9833	Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 1 of the study.
Stage 2: AZD9833 Dose B	AZD9833	Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 2 of the study.
Stage 2: AZD9833 Dose A	AZD9833	Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 2 of the study.
Stage 3: AZD9833 Dose A	AZD9833	Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 3 of the study.
Stage 2: AZD9833 Dose C	AZD9833	Post-menopausal participants will receive once daily oral dose C of AZD9833 in stage 2 of the study.
Stage 3: AZD9833: Dose B	AZD9833	Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 3 of the study.
Stage 1: AZD9833 Dose A	AZD9833	Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 1 of the study.

Primary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis)	Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The pharmacodynamic (PD) effect of AZD9833 on ER expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by immunohistochemistry (IHC) method. The percentage change was calculated from an analysis of covariance (ANCVOA) model adjusting for baseline ER score and day of on-treatment biopsy.
Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)	Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The PD effect of AZD9833 on ER expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by IHC method. The sensitivity analysis excluded any patients who were HER2-positive patient by central assessment as well as patients with baseline ER H-score \< 10. The percentage change was calculated from ANCVOA model adjusting for baseline ER score and day of on-treatment biopsy.

Secondary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis)	Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The PD effects of AZD9833 on PgR expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by IHC method. The percentage change was calculated from an ANCOVA model adjusting for baseline PgR score and day of on-treatment biopsy.
Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)	Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The PD effects of AZD9833 on PgR expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by IHC method. The sensitivity analysis excluded any patients who were HER2-positive patient by central assessment as well as patients with baseline PgR H-score \< 10. The percentage change was calculated from an ANCOVA model adjusting for baseline PgR score and day of on-treatment biopsy.
Number of Patients With Adverse Events (AEs)	From screening (Day -21 to 1) through 28-day follow-up (Upto 2 months)	The safety and tolerability of AZD9833 in this patient population was evaluated.
Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis)	Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The PD effect of AZD9833 on antigen Ki-67 expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by IHC method. The percentage change was calculated from an ANCOVA model adjusting for log baseline Ki67 index and day of on-treatment biopsy. The Ki-67 index data were log transformed prior to analysis, with results back-transformed to represent percentage change.
Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)	Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])	The PD effect of AZD9833 on antigen Ki-67 expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days of AZD9833 treatment was assessed. The assessment was done by IHC method. The sensitivity analysis excluded any patients who were HER2-positive patient by central assessment as well as patients with baseline Ki67 labelling index \<5%. The percentage change was calculated from an ANCOVA model adjusting for log baseline Ki67 index and day of on-treatment biopsy. The Ki-67 index data were log transformed prior to analysis, with results back-transformed to represent percentage change.
Plasma Concentrations of AZD9833	Days 5-7 or Days 12-15 (Pre and Post biopsy)	The plasma concentration of AZD9833 in this participant population was evaluated