A Study to Investigate the Biological Effects of AZD9833 in Women with ER-positive, HER2 Negative Primary Breast Cancer - SERENA-3

Study identifier:D8530C00003

ClinicalTrials.gov identifier:NCT04588298

EudraCT identifier:2020-001079-33

CTIS identifier:N/A

Study Complete

Official Title

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)

Medical condition

HER2-negative breast cancer

Phase

Phase 2

Healthy volunteers

Study drug

AZD9833

Sex

Female

Actual Enrollment

135

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 02 Nov 2020

Primary Completion Date: 19 Jun 2023

Study Completion Date: 19 Jun 2023

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Dec 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

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:
(a) Have undergone a bilateral oophorectomy
(b) Age ≥ 60 years
(c) 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:
(a) ER positive breast cancer
(b) 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:
a) Use of sex-hormone-containing drugs within 6 months prior to the first dose of study treatment
b) 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
c) 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

Location

Research Site

Tbilisi, Georgia, '0112

Location

Research Site

Batumi, Georgia, 6000

Location

Research Site

Tbilisi, Georgia, '0186

Location

Research Site

Manchester, United Kingdom, M23 9LT

Location

Research Site

Tbilisi, Georgia, 0179

Location

Research Site

Tbilisi, Georgia, 0159

Location

Research Site

Mexico City, Mexico, '14080

Location

Research Site

Aguascalientes, Mexico, 20230

Arms	Assigned Interventions
Experimental: Stage 1: AZD9833 Dose A Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 1 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 1: AZD9833 Dose B Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 1 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 2: AZD9833 Dose A Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 2 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 2: AZD9833 Dose B Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 2 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 2: AZD9833 Dose C Post-menopausal participants will receive once daily oral dose C of AZD9833 in stage 2 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 3: AZD9833 Dose A Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 3 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.
Experimental: Stage 3: AZD9833: Dose B Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 3 of the study.	Drug: AZD9833 AZD9833 tablets will be administered orally.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted at 13 sites in 3 countries between November 2, 2020 and June 19, 2023.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Participant Flow: Overall Study

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
STARTED	30	33	13	30	29
COMPLETED	29	33	12	29	27
NOT COMPLETED	1	0	1	1	2
Adverse Event	0	0	1	0	2
Withdrawal by Subject	1	0	0	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Safety Analysis Set was defined as all patients who received any amount of study treatment, regardless of whether that was the randomized therapy intended.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Baseline Measures

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)	Total
Number of Participants [units: Participants]	30	33	13	30	29	135
Age Continuous [units: Years] Mean ± Standard Deviation	62.0 ± 7.35	65.7 ± 7.53	66.3 ± 8.20	64.0 ± 8.65	67.2 ± 10.03	64.9 ± 8.49
Sex: Female, Male [units: Participants]
Female	30	33	13	30	29	135
Male	0	0	0	0	0	0
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0
White	30	33	13	30	29	135
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0
Race/Ethnicity, Customized [units: Participants]
Hispanic or Latino	0	0	0	4	5	9
Not Hispanic or Latino	29	32	13	26	24	124
Other	1	1	0	0	0	2

Outcome Measures

1. Primary Outcome Measure: Percentage change from baseline in estrogen receptor (ER) expression between pre- and on-treatment tumour samples (Primary analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Primary
Measure Name	Percentage change from baseline in estrogen receptor (ER) expression between pre- and on-treatment tumour samples (Primary analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	26	31	11	24	26
Percentage change from baseline in estrogen receptor (ER) expression between pre- and on-treatment tumour samples (Primary analysis) [units: Percentage change from baseline] Least Squares Mean (80% Confidence Interval)	-62.7 (-67.46 to -57.93)	-62.8 (-67.13 to -58.43)	-67.1 (-74.49 to -59.74)	-66.9 (-72.34 to -61.46)	-65.0 (-70.27 to -59.81)

No statistical analysis provided for Percentage change from baseline in estrogen receptor (ER) expression between pre- and on-treatment tumour samples (Primary analysis)

2. Primary Outcome Measure: Percentage change from baseline in ER expression between pre- and on-treatment tumour samples (Sensitivity analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Primary
Measure Name	Percentage change from baseline in ER expression between pre- and on-treatment tumour samples (Sensitivity analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	25	31	11	24	26
Percentage change from baseline in ER expression between pre- and on-treatment tumour samples (Sensitivity analysis) [units: Percentage change from baseline] Least Squares Mean (80% Confidence Interval)	-62.1 (-67.00 to -57.25)	-62.3 (-66.64 to -57.88)	-66.6 (-74.00 to -59.14)	-66.9 (-72.34 to -61.46)	-65.0 (-70.27 to -59.81)

No statistical analysis provided for Percentage change from baseline in ER expression between pre- and on-treatment tumour samples (Sensitivity analysis)

3. Secondary Outcome Measure: Percentage change from baseline in progesterone receptor (PgR) expression between pre- and on-treatment tumour samples (Primary analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Secondary
Measure Name	Percentage change from baseline in progesterone receptor (PgR) expression between pre- and on-treatment tumour samples (Primary analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	26	31	11	24	26
Percentage change from baseline in progesterone receptor (PgR) expression between pre- and on-treatment tumour samples (Primary analysis) [units: Percentage change from baseline] Least Squares Mean (80% Confidence Interval)	194.8 (25.50 to 364.03)	-3.0 (-158.37 to 152.36)	170.3 (-89.67 to 430.33)	-24.2 (-547.03 to 498.69)	463.8 (-38.45 to 966.02)

No statistical analysis provided for Percentage change from baseline in progesterone receptor (PgR) expression between pre- and on-treatment tumour samples (Primary analysis)

4. Secondary Outcome Measure: Percentage change from baseline in PgR expression between pre- and on-treatment tumour samples (Sensitivity analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Secondary
Measure Name	Percentage change from baseline in PgR expression between pre- and on-treatment tumour samples (Sensitivity analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	19	26	8	23	20
Percentage change from baseline in PgR expression between pre- and on-treatment tumour samples (Sensitivity analysis) [units: Percentage change from baseline] Least Squares Mean (80% Confidence Interval)	-35.2 (-45.86 to -24.57)	-44.0 (-53.09 to -34.90)	-36.7 (-52.96 to -20.52)	-61.8 (-76.93 to -46.62)	-55.0 (-71.29 to -38.78)

No statistical analysis provided for Percentage change from baseline in PgR expression between pre- and on-treatment tumour samples (Sensitivity analysis)

5. Secondary Outcome Measure: Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Primary analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Secondary
Measure Name	Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Primary analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	26	31	11	24	26
Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Primary analysis) [units: Percentage change from baseline] Geometric Least Squares Mean (80% Confidence Interval)	-40.3 (-52.78 to -24.49)	-79.4 (-83.37 to -74.55)	-78.2 (-84.82 to -68.77)	-73.0 (-79.42 to -64.64)	-77.5 (-82.68 to -70.86)

No statistical analysis provided for Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Primary analysis)

6. Secondary Outcome Measure: Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Sensitivity analysis) [ Time Frame: Baseline (Screening Day -21 to 1) to Biopsy Day (Days 5-7 [Stage 1 and 2] or Days 12-15 [Stage 3]) ]

Measure Type	Secondary
Measure Name	Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Sensitivity analysis)
Measure Description	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])
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	17	28	11	18	20
Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Sensitivity analysis) [units: Percentage change from baseline] Geometric Least Squares Mean (80% Confidence Interval)	-49.3 (-62.18 to -31.96)	-81.3 (-85.14 to -76.49)	-78.9 (-85.37 to -69.46)	-81.7 (-86.45 to -75.24)	-81.9 (-86.38 to -75.88)

No statistical analysis provided for Percentage change from baseline in Ki-67 labelling index between pre- and on-treatment tumour samples (Sensitivity analysis)

7. Secondary Outcome Measure: Number of patients with adverse events (AEs) [ Time Frame: From screening (Day -21 to 1) through 28-day follow-up (Upto 2 months) ]

Measure Type	Secondary
Measure Name	Number of patients with adverse events (AEs)
Measure Description	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)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	30	33	13	30	29
Number of patients with adverse events (AEs) [units: Participants]
Any AE	9	17	9	11	19
Any AE possibly related to treatment	4	14	6	10	17
Any AE of CTCAE grade 3 or higher	0	1	0	0	0
Any AE of CTCAE grade 3 or higher, possibly related to treatment	0	1	0	0	0
Any AE with outcome = death	0	0	0	0	0
Any AE with outcome = death, possibly related to treatment	0	0	0	0	0
Any SAE (including events with outcome = death)	0	0	0	0	0
Any SAE (including events with outcome = death), possibly related to treatment	0	0	0	0	0
Any SAE leading to discontinuation of treatment	0	0	0	0	0
Any SAE leading to discontinuation of treatment, possibly related to treatment	0	0	0	0	0
Any AE leading to discontinuation of treatment	0	0	1	0	2
Any AE leading to discontinuation of treatment, possibly related to treatment	0	0	0	0	2
Any AE leading to dose modification of treatment	0	0	0	0	0
Any AE leading to dose modification of treatment, possibly related to treatment	0	0	0	0	0
Any other significant AEs	0	0	0	0	0

No statistical analysis provided for Number of patients with adverse events (AEs)

8. Secondary Outcome Measure: Plasma concentrations of AZD9833 [ Time Frame: Days 5-7 or Days 12-15 (Pre and Post biopsy) ]

Measure Type	Secondary
Measure Name	Plasma concentrations of AZD9833
Measure Description	The plasma concentration of AZD9833 in this participant population was evaluated
Time Frame	Days 5-7 or Days 12-15 (Pre and Post biopsy)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Measured Values

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Number of Participants Analyzed [units:participants]	29	33	12	28	27
Plasma concentrations of AZD9833 [units: Nanograms per milliliter] Geometric Mean (Geometric Coefficient of Variation)
Days 5-7 or Days 12-15 (Pre-biopsy)	50.712 (74.1%)	122.134 (103.8%)	180.773 (173.3%)	46.939 (56.3%)	120.516 (70.0%)
Days 5-7 or Days 12-15 (Post-biopsy)	58.304 (62.2%)	142.916 (102.4%)	213.446 (175.6%)	54.075 (42.8%)	137.687 (55.4%)

No statistical analysis provided for Plasma concentrations of AZD9833

Serious Adverse Events

Time Frame	From screening (Day -21 to 1) through 28-day follow-up (Up to 2 months)
Additional Description	No text entered.

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Serious Adverse Events

	AZD9833 75 mg (Stage 1 + 2)	AZD9833 150 mg (Stage 1 + 2)	AZD9833 300 mg (Stage 2)	AZD9833 75 mg (Stage 3)	AZD9833 150 mg (Stage 3)
Total, serious adverse events
# participants affected / at risk	0/30 (0.00%)	0/33 (0.00%)	0/13 (0.00%)	0/30 (0.00%)	0/29 (0.00%)

Other Adverse Events

Time Frame	From screening (Day -21 to 1) through 28-day follow-up (Up to 2 months)
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
AZD9833 75 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 75 mg for 5 to 7 days, during the study.
AZD9833 150 mg (Stage 1 + 2)	Patients received once daily oral dose of AZD9833 150 mg for 5 to 7 days, during the study.
AZD9833 300 mg (Stage 2)	Patients received once daily oral dose of AZD9833 300 mg for 5 to 7 days , during the study
AZD9833 75 mg (Stage 3)	Patients received once daily oral dose of AZD9833 75 mg for 12 to 15 days , during the study
AZD9833 150 mg (Stage 3)	Patients received once daily oral dose of AZD9833 150 mg for 12 to 15 days , during the study

Other Adverse Events

AZD9833 75 mg (Stage 1 + 2)

AZD9833 150 mg (Stage 1 + 2)

AZD9833 300 mg (Stage 2)

AZD9833 75 mg (Stage 3)

AZD9833 150 mg (Stage 3)

Total, other (not including serious) adverse events

# participants affected / at risk

7/30 (23.33%)

17/33 (51.52%)

9/13 (69.23%)

11/30 (36.67%)

19/29 (65.52%)

Eye disorders

Visual impairment¹

# participants affected / at risk

0/30 (0.00%)

5/33 (15.15%)

3/13 (23.08%)

6/30 (20.00%)

7/29 (24.14%)

# events

Eye disorders

Photopsia¹

# participants affected / at risk

2/30 (6.67%)

4/33 (12.12%)

2/13 (15.38%)

3/30 (10.00%)

4/29 (13.79%)

# events

Nervous system disorders

Headache¹

# participants affected / at risk

2/30 (6.67%)

3/33 (9.09%)

1/13 (7.69%)

3/30 (10.00%)

3/29 (10.34%)

# events

Vascular disorders

Hypertension¹

# participants affected / at risk

1/30 (3.33%)

2/33 (6.06%)

3/13 (23.08%)

1/30 (3.33%)

4/29 (13.79%)

# events

Gastrointestinal disorders

Nausea¹

# participants affected / at risk

4/30 (13.33%)

3/33 (9.09%)

1/13 (7.69%)

2/30 (6.67%)

1/29 (3.45%)

# events

Eye disorders

Diplopia¹

# participants affected / at risk

0/30 (0.00%)

4/33 (12.12%)

1/13 (7.69%)

0/30 (0.00%)

5/29 (17.24%)

# events

Nervous system disorders

Dizziness¹

# participants affected / at risk

0/30 (0.00%)

2/33 (6.06%)

1/13 (7.69%)

2/30 (6.67%)

3/29 (10.34%)

# events

General disorders

Fatigue¹

# participants affected / at risk

2/30 (6.67%)

3/33 (9.09%)

0/13 (0.00%)

0/30 (0.00%)

0/29 (0.00%)

# events

Cardiac disorders

Sinus bradycardia¹

# participants affected / at risk

0/30 (0.00%)

0/33 (0.00%)

0/13 (0.00%)

0/30 (0.00%)

3/29 (10.34%)

# events

Eye disorders

Vision blurred¹

# participants affected / at risk

0/30 (0.00%)

2/33 (6.06%)

0/13 (0.00%)

0/30 (0.00%)

0/29 (0.00%)

# events

Infections and infestations

COVID-19¹

# participants affected / at risk

0/30 (0.00%)

0/33 (0.00%)

1/13 (7.69%)

0/30 (0.00%)

0/29 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹

# participants affected / at risk

0/30 (0.00%)

1/33 (3.03%)

1/13 (7.69%)

0/30 (0.00%)

0/29 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 25.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: This document contains trade secrets and confidential commercial information, disclosure of which is prohibited without providing advance notice to AstraZeneca and opportunity to object.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

BreastCancerStudyLocator.com
Download
CSP_Redacted
Download
SAP_Redacted
Download
CSR Synopsis Redacted
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

AZ Breast Cancer Study Navigators

+1-877-400-4656

AstraZeneca@CareboxHealth.com

Investigators

Principal Investigator

John Robertson

Graduate Entry Medicine & Health School, University of Nottingham, Royal Derby Hospital

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

BreastCancerStudyLocator.com

CSP_Redacted

SAP_Redacted

CSR Synopsis Redacted

Trial Results Summaries