HER2-negative Breast Cancer
Conditions
Keywords
Breast cancer, Breast carcinoma, Estrogen-Receptor-positive breast cancer, HER2-negative breast cancer
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
Interventions
DRUGAZD9833
AZD9833 tablets will be administered orally.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a randomised, open-label, parallel-group study. The study is divided into three stages as follows: 1. 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. 2. 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. 3. 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
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: 1. Have undergone a bilateral oophorectomy 2. Age ≥ 60 years 3. 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: 1. ER positive breast cancer 2. 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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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 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. |
Countries
Georgia, Mexico, United Kingdom
Participant flow
Recruitment details
The study was conducted at 13 sites in 3 countries between November 2, 2020 and June 19, 2023.
Pre-assignment details
Patients were enrolled according to the inclusion/exclusion criteria, with a 21 day screening period. Assessments were performed as per schedule. The study consists of 3 stages with different patients in each stage. Results pool data from the 75mg and 150mg arms of stages 1 and 2. This is per the predefined statistical analysis plan, which describes the combination of identical treatments in terms of dose and treatment duration. Stage 3 explored a different duration so is reported separately.
Participants by arm
| Arm | Count |
|---|---|
| AZD9833 75 mg (Stage 1 + 2) Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study. | 30 |
| AZD9833 150 mg (Stage 1 + 2) Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study. | 33 |
| AZD9833 300 mg (Stage 2) Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study | 13 |
| AZD9833 75 mg (Stage 3) Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study | 30 |
| AZD9833 150 mg (Stage 3) Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study | 29 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | AZD9833 150 mg (Stage 3) | AZD9833 75 mg (Stage 3) | AZD9833 300 mg (Stage 2) | AZD9833 150 mg (Stage 1 + 2) | AZD9833 75 mg (Stage 1 + 2) |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.9 Years STANDARD_DEVIATION 8.49 | 67.2 Years STANDARD_DEVIATION 10.03 | 64.0 Years STANDARD_DEVIATION 8.65 | 66.3 Years STANDARD_DEVIATION 8.2 | 65.7 Years STANDARD_DEVIATION 7.53 | 62.0 Years STANDARD_DEVIATION 7.35 |
| Race/Ethnicity, Customized Hispanic or Latino | 9 Participants | 5 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 124 Participants | 24 Participants | 26 Participants | 13 Participants | 32 Participants | 29 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 135 Participants | 29 Participants | 30 Participants | 13 Participants | 33 Participants | 30 Participants |
| Sex: Female, Male Female | 135 Participants | 29 Participants | 30 Participants | 13 Participants | 33 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 33 | 0 / 13 | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 7 / 30 | 17 / 33 | 9 / 13 | 11 / 30 | 19 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 33 | 0 / 13 | 0 / 30 | 0 / 29 |
Outcome results
Primary
Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for ER measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -62.1 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -62.3 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -66.6 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -66.9 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in ER Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -65.0 Percentage change from baseline |
Primary
Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for ER measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -62.7 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -62.8 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -67.1 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -66.9 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in Estrogen Receptor (ER) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -65.0 Percentage change from baseline |
Secondary
Number of Patients With Adverse Events (AEs)
The safety and tolerability of AZD9833 in this patient population was evaluated.
Time frame: From screening (Day -21 to 1) through 28-day follow-up (Upto 2 months)
Population: Safety Analysis Set is defined as all patients who received any amount of study treatment, regardless of whether that was the randomized therapy at intended.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE possibly related to treatment | 4 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE | 9 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any other significant AEs | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 0 Participants |
| AZD9833 75 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE | 17 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher | 1 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any other significant AEs | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 1 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE possibly related to treatment | 14 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment | 0 Participants |
| AZD9833 150 mg (Stage 1 + 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any other significant AEs | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE possibly related to treatment | 6 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment, possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 0 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment | 1 Participants |
| AZD9833 300 mg (Stage 2) | Number of Patients With Adverse Events (AEs) | Any AE | 9 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE | 11 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE possibly related to treatment | 10 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment, possibly related to treatment | 0 Participants |
| AZD9833 75 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any other significant AEs | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any other significant AEs | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE | 19 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to dose modification of treatment, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher | 0 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment | 2 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE possibly related to treatment | 17 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any AE leading to discontinuation of treatment, possibly related to treatment | 2 Participants |
| AZD9833 150 mg (Stage 3) | Number of Patients With Adverse Events (AEs) | Any SAE leading to discontinuation of treatment, possibly related to treatment | 0 Participants |
Secondary
Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for Ki-67 measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -40.3 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -79.4 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -78.2 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -73.0 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -77.5 Percentage change from baseline |
Secondary
Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for ki-67 measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -49.3 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -81.3 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -78.9 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -81.7 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in Ki-67 Labelling Index Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -81.9 Percentage change from baseline |
Secondary
Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for PgR measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -35.2 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -44.0 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -36.7 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -61.8 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in PgR Expression Between Pre- and On-treatment Tumour Samples (Sensitivity Analysis) | -55.0 Percentage change from baseline |
Secondary
Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis)
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.
Time frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3])
Population: PD analysis set included: all the patient who had taken at least 5 consecutive daily doses (Stage 1 and 2) or at least 12 consecutive daily doses (Stage 3) of AZD9833. The patient received last AZD9833 dose within 12 hours of the on-treatment biopsy, diagnostic and on-treatment biopsy pair was considered evaluable by central pathology assessment (\>100 tumor cells per FFPE biopsy, and minimum of 2 slides for PgR measurement), with no protocol deviations affecting the biomarker analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | 194.8 Percentage change from baseline |
| AZD9833 150 mg (Stage 1 + 2) | Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -3.0 Percentage change from baseline |
| AZD9833 300 mg (Stage 2) | Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | 170.3 Percentage change from baseline |
| AZD9833 75 mg (Stage 3) | Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | -24.2 Percentage change from baseline |
| AZD9833 150 mg (Stage 3) | Percentage Change From Baseline in Progesterone Receptor (PgR) Expression Between Pre- and On-treatment Tumour Samples (Primary Analysis) | 463.8 Percentage change from baseline |
Secondary
Plasma Concentrations of AZD9833
The plasma concentration of AZD9833 in this participant population was evaluated
Time frame: Days 5-7 or Days 12-15 (Pre and Post biopsy)
Population: The Pharmacokinetic (PK) Analysis Set is defined as all patients who received at least one dose of AZD9833 per protocol, for whom there is at least one reportable PK concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9833 75 mg (Stage 1 + 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Pre-biopsy) | 50.712 Nanograms per milliliter | Geometric Coefficient of Variation 74.1 |
| AZD9833 75 mg (Stage 1 + 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Post-biopsy) | 58.304 Nanograms per milliliter | Geometric Coefficient of Variation 62.2 |
| AZD9833 150 mg (Stage 1 + 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Pre-biopsy) | 122.134 Nanograms per milliliter | Geometric Coefficient of Variation 103.8 |
| AZD9833 150 mg (Stage 1 + 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Post-biopsy) | 142.916 Nanograms per milliliter | Geometric Coefficient of Variation 102.4 |
| AZD9833 300 mg (Stage 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Pre-biopsy) | 180.773 Nanograms per milliliter | Geometric Coefficient of Variation 173.3 |
| AZD9833 300 mg (Stage 2) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Post-biopsy) | 213.446 Nanograms per milliliter | Geometric Coefficient of Variation 175.6 |
| AZD9833 75 mg (Stage 3) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Post-biopsy) | 54.075 Nanograms per milliliter | Geometric Coefficient of Variation 42.8 |
| AZD9833 75 mg (Stage 3) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Pre-biopsy) | 46.939 Nanograms per milliliter | Geometric Coefficient of Variation 56.3 |
| AZD9833 150 mg (Stage 3) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Pre-biopsy) | 120.516 Nanograms per milliliter | Geometric Coefficient of Variation 70 |
| AZD9833 150 mg (Stage 3) | Plasma Concentrations of AZD9833 | Days 5-7 or Days 12-15 (Post-biopsy) | 137.687 Nanograms per milliliter | Geometric Coefficient of Variation 55.4 |