Clinical trial NCT04191382
Conditions: Breast Cancer
Sponsor: Sanofi
Start date: 2020-02-04; Completion date: 2021-05-28
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To determine whether amcenestrant given at 2 different doses improved the antiproliferative activity when compared to letrozole.

Secondary Objectives:

* To assess the proportion of participants with a relative decrease from Baseline in percentage of positive tumor cells tested by immunohistochemistry greater than or equal to (\>=) 50 percent (%) (Ki67 \>=50%) in the three treatment arms.
* To assess estrogen receptor (ER) degradation in biopsies in participants in the three treatment arms.
* To assess safety in the three treatment arms.

Detailed description:
Duration of the study, per participant, would include screening period of up to 14 days before randomization, treatment period of 14 days and post-treatment safety follow-up period of 30±7 days after last investigational medicinal product (IMP) intake.

Arms: arm 1: Participants received 4 capsules of 100 milligrams (mg) of amcenestrant once daily (QD) from Day 1 to Day 14. arm 2: Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14. arm 3: Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Interventions: intervention 1: Amcenestrant (SAR439859) intervention 2: Letrozole
Intervention descriptions: intervention 1: Pharmaceutical form: Capsules, Route of administration: Oral intervention 2: Pharmaceutical form: Tablets, Route of administration: Oral

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
Phase 2 window study of two dose levels of 
amcenestrant [SAR439859] (SERD) versus letrozole in 
newly diagnosed pre-operative post-menopausal 
patients with ER positive, HER2 negative primary 
breast cancer 
Protocol number: 
ACT16106 
Amendment number: 
02  
Compound number 
(INN/Trademark): 
SAR439859 (amcenestrant) 
Study phase: 
Phase 2 
Short title: 
Phase 2 window study of amcenestrant (SAR439859) 
versus letrozole in post-menopausal patients with ER+, 
HER2- pre-operative primary breast cancer  
(AMEERA-4)  
Sponsor name: 
Sanofi Research and Development 
Legal registered 
address: 
1, Avenue Pierre Brossolette, 91385 Chilly-Mazarin 
cedex, France 
Manufacturer: Sanofi 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifier number(s): 
IND: 
133204 
EudraCT: 
2019-002015-26 
NCT: 
NCT04191382 
WHO: 
U1111-1228-9473 
Other: 
Not applicable 
Approval Date: 
04-Feb-2021 
Total number of pages: 81 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 02 
All 
04 Feb 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 
All 
20 Jan 2020, version 1 (electronic 1.0) 
Original Protocol 
All 
28 Jun 2019, version 1 (electronic 1.0) 
Amended protocol 02 (04 Feb 2021) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The objectives of this amendment are to  
1. Incorporate mandated Clinical Trial Facilitation Group (CTFG) guidance to clarify the 
requirement of FSH measurements to confirm postmenopausal status; 
2. Include contingency measures for a regional or national emergency, as declared by 
a governmental agency; 
3. Update the inclusion/exclusion criteria, prohibited concomitant medications and AESI 
according to the new available data from ongoing amcenestrant studies; 
4. Optimize the PK assessment time points for amcenestrant. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
(SOA): notes of FSH test 
& 5.1 Inclusion criteria I04 b) 
Updated the protocol verbiage to reflect 
serial FSH measurements are required to 
confirm postmenopausal status for the 
patients who have received hormonal 
replacement therapy but have discontinued 
this treatment and in the absence of 
amenorrhea >12 months.  
In line with the recommended Clinical Trial 
Facilitation Group (CTFG) guidance dated 
2014, multiple FSH measurements (at least 
two) to confirm postmenopausal state should 
be conducted before including women in the 
absence of amenorrhea >12 months. 
1.3 Schedule of Activities 
(SOA): footnote d; 
& 8.6.1 Tumor biopsy Section 
8.8.1 Protein Biomarkers 
Added Cyclin D1 in the exploratory protein 
biomarker panel to be tested by IHC in 
tumor tissues.  
To complement data on impact of 
amcenestrant and letrozole on cell cycle arrest 
in addition to Ki67, since Cyclin D1 is regulated 
by ER. 
3 Objectives and endpoints: 
Table 1; 
& 8.6.1 Tumor biopsy 
Added Complete Cell Cycle Arrest (CCCA) 
as an exploratory endpoint to further 
assess impact on proliferation; and added 
digital assessment of protein biomarkers. 
To add some additional tools to evaluate 
impact on proliferation, and to explore 
increased reproducibility and objective 
measurement of protein expression. 
1.3 Schedule of Activities 
(SOA) 
Removed PK sampling on Day 1 and 
Day 7, and added PK sampling on Day 15. 
To optimize the PK sample collection time 
points. So that an on-site visit could be 
changed to a remote visit whenever possible 
(especially during pandemic). 
5.1 Inclusion criteria I01 
Added “or country's legal age of majority if 
the legal adult age is >18 years old”. 
To adapt some local country’s law. 
1.3 Schedule of Activities 
(SOA) 
& 5.2 Exclusion criteria E01 
& 10.2 Appendix 2: Clinical 
laboratory tests 
Added hepatitis A/B/C viral serologies at 
screening. And updated the exclusion 
criterion E01 to exclude participants with 
known active hepatitis A/B/C, or hepatic 
cirrhosis. 
As the study IMPs have a potential to induce 
hepatic toxicity, the implemented changes are 
added as part of risk minimization strategy. 
5.2 Exclusion criteria E04 
& 6.5 Concomitant therapy 
& 10.8 Appendix 8: List of 
Strong CYP3A Inducers 
Updated the exclusion criterion E04 to 
remove treatment with moderate CYP3A 
inducers; updated the list of CYP3A 
inducer and removed moderate CYP3A 
inducers from it. 
Availability of new data showing that no 
interaction is anticipated with moderate CYP3A 
inducers; availability of updated data from 
October 2020 extraction - from the DDI 
database of University of Washington. 
5.2 Exclusion criteria – E05  
& 6.5 Concomitant therapy 
& 10.9 Appendix 9 
Removed exclusion criterion E05 - 
'Treatment with strong or moderate 
CYP2C8 inducers within 2 weeks before 
first study treatment administration or 
5 elimination half-lives whichever is longest 
and cannot be replaced’. Removed the list 
of prohibited concomitant therapies with 
regards to CYP2C8 inducers from 
Appendix 9 and added the lists of CYP 
sensitive substrates.  
Availability of new data showing that no 
interaction is anticipated with moderate 
CYP2C8 inducers, and there is no known 
strong CYP2C8 inducers. And availability of 
updated data from October 2020 extraction - 
from the DDI database of University of 
Washington. 
5.2 Exclusion criteria E06 
& 6.5 Concomitant therapy 
Added BCRP substrate in prohibited 
concomitant medication. 
To be consistent with last IB update, as 
amcenestrant was identified as a potential 
BCRP inhibitor. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.3 Lifestyle considerations  
& 6.5 Concomitant therapy 
Added recommendation of using broad 
spectrum sunscreens filtering both the UVA 
and UVB light exposure. 
Risk minimization strategy for photosensitivity 
reactions. 
6.5 Concomitant Therapy 
Prolonged the duration of prior treatment 
which must be recorded in eCRF to “from 
30 days prior to randomization”. 
The prior treatment received within 30 days 
prior to randomization need to be recorded in 
eCRF for checking the patient’s eligibility. 
8.3 AEs and SAEs 
Added phototoxicity reaction in AESI. 
Preclinical toxicity studies using amcenestrant 
indicated a potential risk for phototoxicity. 
Therefore, photosensitivity has been added as 
an AESI in order to collect additional relevant 
information of these events. 
8.3 AEs and SAEs 
& 6.6 Dose Modification 
(Table 3) 
Added guidance on the management of 
Increase in alanine transaminase (ALT) ≥ 
Grade 2. 
As the study IMPs have a potential to induce 
hepatic toxicity, the implemented changes are 
added as part of risk minimization strategy. 
8 Study Assessment and 
Procedure;  
& 10.1.6 Data quality 
assurance 
& 10.14 Appendix 14: 
Contingency measures for a 
regional or national 
emergency that is declared by 
a governmental agency 
Added new section describing the 
contingency measures for a regional or 
national emergency that is declared by 
a government agency. 
These measures have been added to help 
manage the study conduct during an 
emergency (eg, COVID-19 pandemic). 
1.1 Synopsis: primary 
analysis 
& 9.4.1.1 Analysis of primary 
endpoint 
Changed the statistical model from t-test to 
analysis of covariance (ANCOVA) model. 
To add baseline Ki67 as a covariate when 
comparing the Ki67 log-proportional change 
after a 14-day treatment period between 
treatment groups. 
10.13 Appendix 13 
Abbreviated modification of 
diet in renal disease formula 
Updated the formula of eGFR calculation. 
Provided a linkage of eGFR calculator.  
To provide site with a calculator for eGFR 
based on creatinine in 2 different units. 
10.15 Appendix 15: Protocol 
amendment history 
Summary of Changes in Amendment 01 
was captured. 
Summary of protocol history is mandated. 
Throughout the Document  
Added the INN name amcenestrant. And 
Performed administrative and editorial 
updates and corrections. 
INN name was obtained. And to improve 
consistency and clarity. 
Throughout the amended 
protocol 
Performed administrative and editorial 
updates and corrections. 
To improve consistency and clarity. 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
2 
INTRODUCTION ............................................................................................................................ 20 
2.1 
STUDY RATIONALE...................................................................................................................... 20 
2.2 
BACKGROUND ............................................................................................................................. 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 22 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 22 
4 
STUDY DESIGN ............................................................................................................................ 23 
4.1 
OVERALL DESIGN ........................................................................................................................ 23 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 23 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 23 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 25 
5 
STUDY POPULATION .................................................................................................................. 26 
5.1 
INCLUSION CRITERIA .................................................................................................................. 26 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 27 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 29 
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5.4 
SCREEN FAILURES...................................................................................................................... 29 
6 
STUDY INTERVENTION ............................................................................................................... 30 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 30 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 30 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 31 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 32 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 32 
6.6 
DOSE MODIFICATION .................................................................................................................. 34 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 34 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 35 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 35 
7.1.1 
Definitive discontinuation ............................................................................................................... 35 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 35 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 36 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 37 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 37 
8.1.1 
Pathological complete response .................................................................................................... 37 
8.1.2 
ECOG response ............................................................................................................................. 38 
8.1.3 
Preoperative Endocrine Prognostic Index (PEPI) .......................................................................... 38 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 38 
8.2.1 
Physical examinations ................................................................................................................... 38 
8.2.2 
Vital signs ....................................................................................................................................... 38 
8.2.3 
Electrocardiograms ........................................................................................................................ 38 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 39 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 39 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 41 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 41 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 41 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 41 
8.3.5 
Pregnancy ...................................................................................................................................... 42 
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8.3.6 
Guidelines for reporting product complaints .................................................................................. 42 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 42 
8.5 
PHARMACOKINETICS .................................................................................................................. 43 
8.6 
PHARMACODYNAMICS ............................................................................................................... 43 
8.6.1 
Tumor biopsy ................................................................................................................................. 44 
8.7 
GENETICS ..................................................................................................................................... 45 
8.8 
BIOMARKERS ............................................................................................................................... 45 
8.8.1 
Protein biomarkers ......................................................................................................................... 45 
8.8.2 
RNA transcriptome research .......................................................................................................... 46 
8.8.3 
Future use of samples ................................................................................................................... 46 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 46 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 47 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 47 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 47 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 48 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 48 
9.4.1 
Efficacy/pharmacodynamics analyses ........................................................................................... 48 
9.4.1.1 
Analysis of primary endpoint .......................................................................................................... 49 
9.4.1.2 
Analysis of secondary endpoints ................................................................................................... 49 
9.4.2 
Safety analyses .............................................................................................................................. 50 
9.4.2.1 
Analysis of adverse events ............................................................................................................ 50 
9.4.2.2 
Analyses of clinical laboratory evaluations .................................................................................... 51 
9.4.3 
Other analyses ............................................................................................................................... 51 
9.5 
INTERIM ANALYSES .................................................................................................................... 51 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 52 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 52 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 52 
10.1.2 
Financial disclosure........................................................................................................................ 52 
10.1.3 
Informed consent process .............................................................................................................. 53 
10.1.4 
Data protection ............................................................................................................................... 53 
10.1.5 
Committees structure ..................................................................................................................... 54 
10.1.6 
Data quality assurance .................................................................................................................. 54 
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10.1.7 
Dissemination of clinical study data ............................................................................................... 55 
10.1.8 
Source documents ......................................................................................................................... 55 
10.1.9 
Study and site closure .................................................................................................................... 55 
10.1.10 Publication policy ........................................................................................................................... 56 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 57 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 58 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 62 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 63 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 63 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................... 64 
10.8 
APPENDIX 8: LIST OF STRONG CYP3A4 INDUCERS ............................................................... 66 
10.9 
APPENDIX 9: LIST OF CYP SENSITIVE SUBSTRATES ............................................................. 68 
10.10 
APPENDIX 10: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ......................................................................................................................................... 73 
10.11 
APPENDIX 11: EASTERN COOPERATIVE ONCOLOGY GROUP RESPONSE CRITERIA ...... 74 
10.12 
APPENDIX 12: PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX ...................................... 75 
10.13 
APPENDIX 13: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA ...................................................................................................................................... 75 
10.14 
APPENDIX 14: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 76 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY ................................................................ 78 
11 
REFERENCES ............................................................................................................................... 80 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 22 
Table 2 - Overview of study interventions administered ............................................................................... 30 
Table 3 - Dose modification for amcenestrant arms and letrozole arm ........................................................ 34 
Table 4 - Populations for analyses ................................................................................................................ 48 
Table 5 - Efficacy/pharmacodynamics analyses ........................................................................................... 49 
Table 6 - Safety analyses .............................................................................................................................. 50 
Table 7 - Protocol-required laboratory assessments .................................................................................... 57 
Table 8 - Strong CYP3A inducers ................................................................................................................. 67 
Table 9 - In vivo CYP3A sensitive substrate ................................................................................................. 69 
Table 10 - In vivo CYP2B6 sensitive substrate ............................................................................................. 71 
Table 11 - In vivo CYP2C8 sensitive substrate ............................................................................................. 71 
Table 12 - In vivo CYP2C9 sensitive substrate ............................................................................................. 71 
Table 13 - In vivo CYP2C9 sensitive substrate ............................................................................................. 72 
Table 14 - ECOG performance status scale ................................................................................................. 73 
Table 15 - ECOG response criteria ............................................................................................................... 74 
Table 16 - Preoperative endocrine prognostic index (PEPI) ......................................................................... 75 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Phase 2 window study of two dose levels of amcenestrant [SAR439859] 
(SERD) versus letrozole in newly diagnosed pre-operative post-menopausal 
patients with ER positive, HER2 negative primary breast cancer 
Short title: 
Phase 2 window study of SAR439859 (amcenestrant) versus letrozole in post-
menopausal patients with ER+, HER2- pre-operative primary breast cancer 
(AMEERA-4) 
Rationale: 
Short pre-surgical trials (also known as “window” trials) are non-therapeutic studies in which 
patients are treated for 2 to 3 weeks immediately after their diagnostic biopsy and before breast 
surgery (1). Biomarkers of cellular activity (Ki67) and/or drug target modulation are measured in 
intraoperative biopsies and/or the surgical specimen.  
Short-term preoperative ‘window’ studies of 2-3 weeks treatment are a validated strategy to 
provide rapid and cost-efficient proof-of-concept for novel treatment approaches by assessing the 
direct effects of the study treatment on the tumor tissue (1, 2). The principle is to have access to 
tumor tissue before, under and after treatment for pharmacodynamic assessment and correlative 
studies thus providing critical insight into the optimal patient population, differences in activity 
between agents, influence of the tumor biology on sensitivity, and molecular mechanisms of 
response or resistance (1). 
Detailed studies in the neoadjuvant setting in prospective randomized clinical trials have 
demonstrated the utility and validity of changes in Ki67 as a predictor of benefit from treatment 
and of long-term outcome (3, 4). Although Ki67 measurements in preoperative trials cannot 
replace the need for adjuvant trials with clinical endpoints, they can be highly instructive in 
selecting or rejecting candidate approaches for Phase 3 studies and defining the most appropriate 
patient populations.  
The purpose of this short term preoperative study is to evaluate the pharmacodynamic  
(anti-proliferation) activity of two dose levels of amcenestrant, a potent, orally bioavailable, and 
selective estrogen receptor (ER) inhibitor that belongs to the selective estrogen receptor degrader 
(SERD) class of compounds, in comparison with letrozole. amcenestrant antagonizes the binding 
of estradiol to ER and promotes the transition of ER to an inactive conformation that leads to up 
to 98% receptor degradation at nanomolar concentrations in cellular assays. These dual properties 
of amcenestrant translate to a deeper inhibition of ER pathways and a more effective 
anti-proliferative activity in ER-dependent breast cancer cell lines driven by mutant or wild type 
ER compared to fulvestrant, an approved SERD.  
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Amcenestrant recommended dose was established at 400 mg once daily (QD), based on the safety, 
pharmacokinetic (PK) and pharmacodynamic data review of the ongoing first in human 
study TED14856, from advanced breast cancer patients. As the patients in this study have early 
breast cancer, the 200 mg QD dose will also be explored.  
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To determine whether amcenestrant given at 2 different doses 
improves the antiproliferative activity when compared to 
letrozole  
Change in Ki67 (percentage of positive tumor cells tested by 
immunohistochemistry [IHC]) after a 14-day treatment period 
compared to baseline assessed by central reading  
Secondary 
To assess the proportion of participants with a relative 
decrease from baseline in Ki67 ≥50% in the three treatment 
arms 
The proportion of participants with relative decrease from 
baseline in the proliferation marker Ki67 (% positive tumor 
cells) ≥50% as tested by IHC after a 14-day treatment period 
compared to baseline  
To assess ER degradation in biopsies in participants in the 
three treatment arms 
Change in ER expression measured by H-Score after a 
14-day treatment period compared to baseline 
To assess safety in the three treatment arms 
AEs/SAEs and laboratory abnormalities 
Overall design: 
This is an international, prospective, open-label, Phase 2 randomized study of 2-week 
preoperative treatment in ER positive, human epidermal growth factor receptor (HER2) negative 
invasive primary breast cancer. After confirmation of eligibility criteria, postmenopausal women 
with early breast cancer will be randomly (1:1:1) assigned to one of the following treatment arms: 
amcenestrant 400 mg QD, amcenestrant 200 mg QD or letrozole 2.5 mg QD. Participants will be 
treated for 14 days. The surgery date should be fixed before randomization. The surgery is to be 
performed 1 (+1) day after the last dose of study treatment. Paired biopsies (before and after 
therapy) will be required for assessment of Ki67 and other biomarkers.  
Disclosure Statement: This is a Parallel, Treatment study with 3 arms that is only blinded for 
assessors of primary endpoint. 
Number of participants: 
Approximately 126 patients will be randomized such that 120 evaluable participants are reached. 
A total of 40 evaluable participants per treatment arm are expected. Evaluable participants are 
defined as participants who have baseline and post-treatment available biopsies with Ki67 values. 
Sufficient participants will be screened to achieve 126 participants randomly assigned to study 
intervention. 
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Intervention groups and duration: 
Participants will be treated with either amcenestrant 400 mg QD (dose regimen 1), amcenestrant 
200 mg QD (dose regimen 2) or letrozole 2.5 mg QD, depending on the randomization allocation. 
Study intervention(s) 
Investigational medicinal products (IMPs) 
Amcenestrant (SAR439859) 
• Formulation: 100 mg capsules. 
• Route of administration: PO. 
• Dose regimen 1: 4 capsules QD, given in the morning, either with or without meal. 
Capsules should be taken approximately at the same time every day. 
• Dose regimen 2: 2 capsules QD, given in the morning, either with or without meal. 
Capsules should be taken approximately at the same time every day. 
Letrozole 
• Formulation: 2.5 mg tablets. 
• Route of administration: PO. 
• Dose regimen: 1 tablet QD, given in the morning, either with or without meal. Tablets 
should be taken approximately at the same time every day. 
Post-trial access to study medication: There is no access to medication post trial. 
Statistical considerations: 
Sample size calculations: 
The sample size is determined based on the following assumptions:  
• The geometric mean of percentage change in Ki67 after a 14-day treatment period for the 
control arm is assumed to be 70%. 
• The geometric mean of reduction in Ki67 after a 14-day treatment period is increased to 
85% for each amcenestrant arm. Therefore the geometric means of residual Ki67 (defined 
as one minus the geometric mean of reduction) are assumed to be 30% for the control arm 
and 15% for treatment arms, corresponding to a log fold difference of -0.693  
(log(0.15)-log(0.3) under the alternative hypothesis.  
• The standard deviation of the log-fold change after a 14-day treatment period is assumed 
to be 1. 
A total of 40 evaluable participants per treatment arm will be needed to achieve 85% marginal 
power at the overall one-sided Type I error rate of 2.5% controlled with an Hochberg procedure, 
assuming a difference of at least 15% in geometric mean change of Ki67 between the control arm 
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and amcenestrant after a 14-day treatment period with a t-test (on the log-transformed data). The 
disjunctive power, ie, the probability to reject at least one null hypothesis associated with the 
comparison amcenestrant and the control arm, is estimated at 91.5%. 
Allowing for a 5% non-evaluable participant rate, the total sample size for randomization is 
126 participants (42 per treatment arm). 
Primary analysis: On the assumption of a log-normal distribution, the Ki67 values will be 
log-transformed before analysis. The change of log (Ki67) between baseline and after a 14-day 
treatment period will be compared between groups using an analysis of covariance (ANCOVA) 
model adjusting for baseline Ki67 expression. For each group, the geometric mean of Ki67 at 
baseline and after a 14-day treatment period and the geometric mean of percentage reduction in 
Ki67 will be provided along with the 95% confidence interval. The geometric mean ratio of the 
proportional change between groups and associated 95% confidence interval will be provided. 
Due to the multiplicity of tests as each amcenestrant dose/regimen will be compared to the control 
arm, a Hochberg step-up procedure will be used to control the overall one-sided Type I error rate 
of 2.5%. 
Analysis of secondary endpoints: The proportion of participants with a relative decrease from 
baseline in Ki67 ≥50% between baseline and after a 14-day treatment will be provided for each 
treatment arm along with the 95% CI computed using the Clopper-Pearson method. The ER 
expression in H-score at baseline and after a 14-day treatment, as well as the change from baseline 
will be summarized for each group. 
Analysis of safety endpoints 
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• The on-treatment period is defined as the time from the first dose of IMP up to the 
last dose of IMP.  
• The post-treatment safety follow-up period is defined as the time from the last 
administration of the IMP to last administration of the IMP +30 days. 
Emergence will be defined during the on-treatment period only and during the period which 
includes both the on-treatment and post-treatment periods. 
Number and percentage of participants experiencing treatment emergent adverse events (TEAEs) 
by Medical Dictionary for Regulatory Activities primary system organ class and preferred term 
will be summarized by National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v5.0 grade (all grades and Grade ≥3) for the safety population. Similar 
summaries will be prepared for treatment related TEAEs, TEAEs leading to definitive 
discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
AEs of special interest (AESI), and AEs/serious AEs (SAEs) occurring during the post treatment 
period. For participants with multiple occurrences of the same AE within the treatment period, the 
worst grade will be used. 
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Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the treatment period will be provided for the 
safety population.  
Data Monitoring Committee: No
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
IMP = investigational medicinal product, QD = once daily, R= randomization 
Screening period / 
baseline 
Treatment period 
(14 days)  
Post-treatment safety 
follow-up period 
(30 ±7 days)  
Surgery and 
tumor biopsy 
Up to 14 days 
before 
randomization 
D1 
1st IMP 
intake 
Amcenestrant 400 mg QD 
Amcenestrant 200 mg QD 
Letrozole 2.5 mg QD 
D7 (±2)  
D14 
Last IMP 
intake 
D15 (+1) 
30 (±7) days 
after last IMP 
intake 
Within 
3 days 
R 
Biopsy 
Baseline 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedurea 
Screening  
Treatment 
Period  
(14 days) 
Surgeryc 
Post treatment safety 
follow-up period 
Notes 
up to 14 days before 
randomization 
D1b 
D7  
(±2) 
D14 
 
D15  
(+1) 
30 (±7) days after last IMP 
intake 
 
Informed consent 
X 
 
 
 
 
 
Informed consent (including genetic sampling) may be signed more 
than 14 days prior to randomization. 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
Recheck clinical status before randomization, and before 1st dosing 
of IMP if 1st dosing and randomization are not on the same day. 
See Section 5.1 and Section 5.2 for details. 
Randomization 
X 
 
 
 
 
 
To take place once the consented participant has completed all the 
necessary screening procedures and is deemed eligible for study 
entry by the Investigator or designee and has already a breast 
conservative surgery scheduled per protocol timing requirement.  
All eligible participants must be randomized using IRT.  
Participants will be randomized within 3 days prior to first dosing of 
IMP.  
See Section 6.3 for details 
Demography 
X 
 
 
 
 
 
Demography includes age, year of birth, gender, race, ethnicity. 
Follicle stimulating hormone (FSH) 
test 
X 
 
 
 
 
 
Serial FSH measurements (at least 2) with at least 1-day interval 
between the measurements are required to confirm 
postmenopausal status for the patients who have received 
hormonal replacement therapy but have discontinued this treatment 
and in the absence of amenorrhea >12 months. FSH level in the 
postmenopausal range assessed prior to screening can be used as 
the first FSH measurement. 
Full physical examination including 
height / weight / ECOG PS 
X 
(X) 
 
X 
X 
X 
Height will only be assessed at screening.  
Other assessments will be repeated within 1 day prior to the first 
dosing of IMP if abnormal or if screening assessment >7 days of 
D1. See Section 8.2.1 for details. 
Past and current medical conditions  
X 
 
 
 
 
 
Including previous and ongoing medications, prior anticancer 
therapies, disease history. 
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Procedurea 
Screening  
Treatment 
Period  
(14 days) 
Surgeryc 
Post treatment safety 
follow-up period 
Notes 
up to 14 days before 
randomization 
D1b 
D7  
(±2) 
D14 
 
D15  
(+1) 
30 (±7) days after last IMP 
intake 
 
Laboratory assessments 
X 
(X) 
 
X 
 
 
Standard hematology, clinical chemistry and coagulation panels.  
These assessments will be repeated within 1 day prior to the 
first dosing of IMP if abnormal or if screening assessment >7 days 
of D1.  
See Section 10.2 for details. 
Viral serologies 
X 
 
 
 
 
 
Viral serologies include hepatitis A antigen or IgM hepatitis A 
antibody, HBs antigen or hepatitis B viral DNA, hepatitis C antibody 
or quantitative hepatitis C viral (HCV) ribonucleic acid (RNA). 
Single 12-lead ECG  
X 
 
 
 
 
 
See Section 8.2.3 for details. 
Triplicate ECG 
 
X 
 
X 
 
 
Electronic records of triplicate ECG are required at  
pre-dose on D1 and at pre-dose and 3h post-dose on D14. See 
Section 8.2.3 for details. 
Vital signs 
X 
(X) 
X 
X 
 
 
These assessments will be repeated within 1 day prior to the 
first dosing of IMP if abnormal or if screening assessment >7 days 
of D1. See Section 8.2.2 for details. 
Patient diary distribution 
 
X 
 
 
 
 
 
Patient diary review 
 
 
X 
X 
 
 
 
Amcenestrant administration 400 mg 
QD 
 
Continuous once a 
day (QD) 
 
 
Study treatment should be taken in the morning.  
Study treatment duration is planned for 14 days, and should not 
exceed 14 days. IMP will be dispensed at the study site visits on 
D1.  
On D1 and D14, IMP will be taken on-site after fasting tests and 
pre-dose assessment.  
See Section 6.1 for details. 
Amcenestrant administration 200 mg 
QD 
 
Continuous once a 
day (QD)  
 
 
Letrozole administration 
 
Continuous once a 
day (QD) 
 
 
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Procedurea 
Screening  
Treatment 
Period  
(14 days) 
Surgeryc 
Post treatment safety 
follow-up period 
Notes 
up to 14 days before 
randomization 
D1b 
D7  
(±2) 
D14 
 
D15  
(+1) 
30 (±7) days after last IMP 
intake 
 
Tumor Biopsyd 
X 
 
 
 
X 
 
Participant selection is based on the biopsy at diagnosis analyzed 
in a local lab. 
A new core-cut biopsy (baseline sample) should be performed prior 
to the first dosing of IMP, as well as a core-cut biopsy from surgery 
specimen or new core-cut biopsy after the last IMP intake for study 
purpose. Alternatively, tissue from the diagnostic biopsy may be 
used for the baseline sample if certain criteria are fulfilled. Baseline 
and post-treatment biopsy will be centrally examined.  
See Section 8.6.1 for details. 
Tumor size by ultrasound 
X 
 
 
X 
 
 
Measurement of tumor size using ultrasound at screening 
(baseline) and on D14. At screening, tumor size assessed by 
ultrasound will also be used for inclusion criteria. See Section 8.1.2 
for details. 
Pathological tumor (pT) stage, the 
pathological node (pN) stage, pCR 
and ECOG response assessment, 
Preoperative Endocrine Prognostic 
Index (PEPI) 
 
 
 
 
X 
 
Pathological tumor (pT) stage, the pathological node (pN) stage, 
and pCR results will be collected from the local pathologist’s report 
following examination of tissue (breast and nodes) removed at the 
time of surgery and reported in eCRF. ECOG response will be 
assessed by the investigator according to ECOG response criteria. 
See Section 8.1.1 and Section 8.1.3 for details. 
AE/SAE review 
====================================→ 
AEs of new onset as well as worsening of baseline signs and 
symptoms are to be reported from the signing of the informed 
consent to 30 (±7) days following the last IMP intake.  
All SAEs, and non-serious AEs of special interest, and non-serious 
AEs related to IMP still ongoing at the post treatment safety follow-
up visit, will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up.  
See Section 8.3 for details. 
Concomitant medication 
====================================→ 
The period of collection of concomitant medications extends from 
the signing of the informed consent to 30 (±7) days following the 
last IMP intake. See Section 6.5 for details.  
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Procedurea 
Screening  
Treatment 
Period  
(14 days) 
Surgeryc 
Post treatment safety 
follow-up period 
Notes 
up to 14 days before 
randomization 
D1b 
D7  
(±2) 
D14 
 
D15  
(+1) 
30 (±7) days after last IMP 
intake 
 
Genetic sample (plasma for cfDNA)  
 
X 
 
X 
 
 
cfDNA sample collected on D1 and D14. See Section 8.7 for 
details. 
Genetic sample (saliva for reference 
DNA) 
 
X 
 
 
 
 
Saliva will be collected on D1 to extract DNA which will be used as 
a normal reference for the mutation analysis. See Section 8.7 for 
details 
Genetic sample (blood for DMET 
genotyping) 
 
X 
 
 
 
 
Blood sample will be collected on Day 1 for amcenestrant treatment 
arms only. See Section 8.7 for details 
Amcenestrant PK 
 
 
 
X 
X 
 
PK sampling is planned only for amcenestrant treatment arms. 
D14: Pre-dose (P00), T3h post dose (P01) 
D15: T24h post dose (P02) after last administration of 
amcenestrant (D14) 
When PK and triplicate ECG are scheduled at the same time, PK 
sample will be taken just after ECG recording. Participants will take 
IMP on-site on days of PK sampling.  
See Section 8.5 for details. 
AE = adverse event, cfDNA = cell free DNA, DMET = Drug metabolizing enzymes and transporters, eCRF = electronic case report form, ECG = electrocardiogram, ECOG PS = Eastern Cooperative Oncology Group 
Performance Status, IMP = investigational medicinal product, IRT = Interactive response technology, pCR = pathological complete response, PEPI = Preoperative Endocrine Prognostic Index, PK = pharmacokinetic, 
pN = pathological node, pT = pathological tumor, QD = once daily, SAE = serious adverse event 
a Procedure: Assessments to be performed prior to study treatment administration unless otherwise indicated. Informed consent should be signed before any study specific procedures. It can be signed more than 
14 days prior to randomization. Screening time indicates in which timeframe exams used to support eligibility have to be done prior to randomization. All the tests or procedures scheduled on D1 should be done at 
predose time unless otherwise stated. 
b D1 refers to the day the participant receives the initial dose of study treatment which will be a single administration of amcenestrant 400 mg or 200 mg QD, or letrozole 2.5 mg QD. 
c Surgery: The date of surgery should be fixed before randomization takes place. The time between first IMP administration and surgery should be of 14 days and the last dose is planned to be taken the day before 
surgery. Surgery should be done 1 day after the last IMP administration; however this could exceptionally be extended to a maximum of 48h after last IMP administration. In case of a longer unexpected surgery 
delay (>48 hours from last IMP administration), all efforts should be done to perform a tumor biopsy no more than 48 hours of last IMP administration. 
d Tumor biopsy: Determination of tumor characteristics (HER2 status by IHC or FISH, ER and PgR by IHC, Ki67 by IHC, etc) on the diagnostic biopsy specimen based on local laboratory results serves for 
participant selection. For clinical sites reporting Ki67 expression by range rather than a single value, a local re-evaluation might be requested to confirm Ki67 expression ≥15%. A fresh core-cut biopsy (baseline 
sample) should be collected prior to the first dosing of IMP. Alternatively, tissue from the diagnostic biopsy may be used for the baseline sample if certain criteria are fulfilled (see Section 8.6.1 for details). The 
baseline biopsy is recommended to be performed after the eligibility is confirmed, if possible. The baseline biopsy may be performed any time prior to the initiation of study treatment. Post-treatment core-cut biopsy 
should be performed on the excised tissues during surgery provided the surgery is performed on D15 (+1). If surgery is delayed for any reason, every effort should be made to perform a new tumor core-cut biopsy 
within 48 hours maximum after last IMP intake. Baseline and post-treatment biopsy will be centrally examined for Ki67, DNA mutation analysis, RNA expression analysis, and protein analysis (eg, ER, PgR, BCL2, 
CyclinD1, etc). 
 
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2 
INTRODUCTION  
Amcenestrant is a potent, orally bioavailable, and selective ER inhibitor that belongs to the SERD 
class of compounds. Amcenestrant antagonizes the binding of estradiol to ER and also promotes 
the transition of ER to an inactive conformation that leads to up to 98% receptor degradation at 
nanomolar concentrations in cellular assays. Amcenestrant is a superior and broader ER degrader 
than all known SERD competitors. These dual properties of amcenestrant translate in a deeper 
inhibition of ER pathways and a more effective anti-proliferative activity in ER-dependent breast 
cancer cell lines driven by mutant or wild type ER compared to fulvestrant. 
Amcenestrant is currently in clinical development in metastatic breast cancer; first in human 
(TED14856; NCT03284957) study started in September 2017 and the dose escalation of 
amcenestrant single agent is completed, dose expansion is ongoing.  
A detailed description of the chemistry, pharmacology, efficacy and safety of amcenestrant is 
provided in the Investigator’s Brochure. 
2.1 
STUDY RATIONALE  
Short pre-surgical trials (also known as “window” trials) are non-therapeutic studies in which 
patients are treated for 2 to 3 weeks immediately after their diagnostic biopsy and before breast 
surgery (1). Biomarkers of cellular activity (Ki67) and/or drug target modulation are measured in 
intraoperative biopsies and/or the surgical specimen. Because these studies do not have a 
therapeutic intent, patient safety and reasonable knowledge of the optimal drug dose are major 
considerations for this approach so delays and/or complications from surgery are avoided. In a 
review of “window” trials in >4,000 patients and in all breast tumor types, there were only 
two deaths related to investigational drugs, and only 1% of patients could not undergo surgery due 
to adverse events (1, 2). 
These short-term preoperative ‘window’ studies are a validated strategy to provide rapid and  
cost-efficient proof-of-concept for novel treatment approaches by assessing the direct effects of 
the study treatment on the tumor tissue (1, 2). The principle is to have access to tumor tissue 
before, under and after treatment for pharmacodynamic assessment and correlative studies thus 
providing critical insight into the optimal patient population, differences in activity between 
agents, influence of the tumor biology on sensitivity, and molecular mechanisms of response or 
resistance. 
Detailed studies in the neoadjuvant setting in prospective randomized clinical trials have 
demonstrated the utility and validity of changes in Ki67 as a predictor of benefit from treatment 
and of long-term outcome (3, 4). In the neoadjuvant IMPACT study, suppression of Ki67 at 
2 weeks was greater with anastrozole than with either tamoxifen or the combination of 
anastrozole plus tamoxifen, and this correlated with recurrence-free survival (5, 6). 
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Although Ki67 measurements in preoperative trials cannot replace the need for adjuvant trials with 
clinical endpoints, they can be highly instructive in selecting or rejecting candidate approaches 
for Phase III studies and defining the most appropriate patient populations.  
The purpose of the proposed short-term preoperative study is to evaluate the pharmacodynamic 
activity of two doses of amcenestrant, a potent, orally bioavailable, and selective ER inhibitor that 
belongs to the SERD class of compounds in comparison with letrozole. Amcenestrant antagonizes 
the binding of estradiol to ER and promotes the transition of ER to an inactive conformation that 
leads to up to 98% receptor degradation at nanomolar concentrations in cellular assays. These 
dual properties of amcenestrant translate in a deeper inhibition of ER pathways and a more 
effective anti-proliferative activity in ER-dependent breast cancer cell lines driven by mutant or 
wild type ER compared to fulvestrant.  
2.2 
BACKGROUND  
Breast cancer is the most commonly diagnosed cancer and the second leading cause of death in 
women (7). In the United States (US) in 2019, it was estimated 268,600 new cases of invasive 
breast cancer as well as 62,930 additional cases of in situ breast cancer would be reported. 
Approximately 41,760 women were expected to die from breast cancer in 2019 (8). 
Based on data from 2008 to 2014, the 5-year relative survival of individuals with breast cancer of 
all stages is 89.9% (9). Although the survival of patients with early breast cancer (defined as 
cancers that may have spread to nearby lymph nodes but not to distant parts of the body, 
ie, Stages I, IIA, IIB, and IIIA) is favorable, the survival of patients with advanced metastatic 
breast cancer (mBC) is poor; the 5-year relative survival is 100% for Stage I, 93% for Stage II, 
72% for Stage III, and 22% for Stage IV (10, 11). Both endogenous and exogenous steroid 
hormones such as estrogen and progesterone have been implicated in the pathogenesis of breast 
cancer. Clinical treatment decisions are driven by the expression of estrogen receptors (ERs), 
progesterone receptors and human epidermal growth factor receptor (HER2) receptor status into 
HER2+, ER+/HER2- and triple negative clinical subtypes. About 75% of breast cancers express 
estrogen receptor alpha (ERα) which is a hormone regulator transcription factor (12). ER-positive 
breast cancers respond well to therapy targeting ER signaling either through competitive binding 
of ER antagonists such as tamoxifen or by blocking the production of estrogen by aromatase 
inhibitors (AIs) (13). 
2.3 
BENEFIT/RISK ASSESSMENT  
This study has no direct benefit to the breast cancer patient who is indicated for an immediate 
surgery with no need of neoadjuvant therapy. The aim of the study is to assess the magnitude of 
Ki67 decrease with amcenestrant compared to letrozole together with some other biomarkers that 
could be of importance for increasing our understanding of breast cancer, the selection of adjuvant 
therapy and potential targeted therapy in case of recurrence of the disease. More detailed 
information about the known and expected benefits and risks and reasonably expected adverse 
events (AEs) of amcenestrant may be found in the Investigator’s Brochure.  
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To determine whether amcenestrant given at 2 different 
doses improves the antiproliferative activity when compared 
to letrozole.  
Change in Ki67 (percentage of positive tumor cells tested by 
immunohistochemistry [IHC]) after a 14-day treatment period 
compared to baseline assessed by central reading.  
Secondary 
To assess the proportion of participants with a relative 
decrease from baseline in Ki67 ≥50% in the three treatment 
arms. 
The proportion of participants with relative decrease from 
baseline in the proliferation marker Ki67 (% positive tumor 
cells) ≥50% as tested by IHC after a 14-day treatment period 
compared to baseline.  
To assess ER degradation in biopsies in participants in the 
three treatment arms. 
Change in ER expression measured by H-Score after a 
14-day treatment period compared to baseline. 
To assess safety in the three treatment arms. 
AEs/SAEs and laboratory abnormalities. 
Tertiary/exploratory 
To assess the pharmacokinetics (PK) of amcenestrant 400 
mg QD and 200 mg QD.  
Amcenestrant plasma concentrations. 
To assess the complete cell cycle arrest (CCCA: Ki67 ≤2.7%) 
rate in the three treatment arms. 
The proportion of participants achieving CCCA (Ki67 ≤2.7%) 
after a 14-day treatment period. 
To determine the expression of additional tumor protein 
biomarkers (eg, BCL2, etc) and the RNA profile over time in 
the three treatment arms. 
Change in protein expression (as measured by H-score) and 
in RNA expression profile on tissue sample after a 14-day 
treatment period compared to baseline.  
To assess protein biomarkers in tumor tissues by using digital 
image-based methods and changes over time in the three 
treatment arms 
Protein expression at baseline and change over time 
compared to baseline, by means of digital image-based 
method, after a 14-day treatment period.  
To determine the DNA mutation profile in tumor and cell-free 
DNA (cfDNA) to assess a potential link with Ki67 effect. 
DNA mutation profile in tumor on tissue sample and cfDNA in 
blood sample at baseline and after a 14-day treatment period, 
and change in cfDNA mutation profile after a 14-day 
treatment period compared to baseline. 
To evaluate PK/PD relationship of amcenestrant with 
pharmacodynamics and/or safety. 
Amcenestrant PK, biomarker expression and 
electrocardiogram (ECG). 
To assess the Eastern Cooperative Oncology Group (ECOG) 
response rate in the three treatment arms. 
ECOG response according to ECOG response criteria (14) 
(based on breast tumor shrinkage, pCR and ECOG 
performance status) after a 14-day treatment period. 
To assess the Preoperative Endocrine Prognostic Index 
(PEPI) risk score of the three treatment arms. 
PEPI risk score assessed after a 14-day treatment period. 
To assess in participants the pathological complete response 
(pCR) of amcenestrant given at 2 different doses and 
letrozole. 
The proportion of participants achieving pCR after a 14-day 
treatment period. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the pharmacodynamic, PK, efficacy, safety assessments selected for this study are 
considered well established and relevant in an oncology Phase 2 study setting. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is an international, prospective, open-label, Phase 2 randomized study of 2-week 
preoperative treatment in post-menopausal patients with ER positive, HER2 negative invasive 
primary breast cancer.  
After confirmation of eligibility criteria and the date of breast conservative surgery is fixed, 
postmenopausal women with early breast cancer will be randomly (1:1:1) assigned to one of the 
following treatment arms: amcenestrant 400 mg QD, amcenestrant 200 mg QD or letrozole 
2.5 mg QD. Patients will be treated for 14 days, the last dose of study treatment being taken the 
day before surgery. Paired biopsies (before and after therapy) will be required for assessment of 
Ki67 and other biomarkers.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Amcenestrant is a potent, orally bioavailable, and selective ER inhibitor that belongs to the SERD 
class of compounds. It antagonizes the binding of estradiol to ER and promotes the transition of 
ER to an inactive conformation that leads to up to 98% receptor degradation at nanomolar 
concentrations in cellular assays. These dual properties of amcenestrant translate in a deeper 
inhibition of ER pathways and a more effective anti-proliferative activity in ER-dependent breast 
cancer cell lines driven by mutant or wild type ER compared to fulvestrant. The primary objective 
of this short-term preoperative study is to evaluate the pharmacodynamic activity of two doses of 
amcenestrant in comparison with letrozole. 
Detailed studies in the neoadjuvant setting in prospective randomized clinical trials have 
demonstrated the utility and validity of changes in Ki67 as a predictor of benefit from treatment 
and of long-term outcome (3, 4). In the neoadjuvant IMPACT study, suppression of Ki67 at 
2 weeks was greater with anastrozole than with either tamoxifen or the combination of 
anastrozole plus tamoxifen (5, 6). So Ki67 is selected as the primary endpoint of this study. 
Although Ki67 measurements in preoperative trials cannot replace the need for adjuvant trials with 
clinical endpoints, they can be highly instructive in selecting or rejecting candidate approaches 
for Phase 3 studies and defining the most appropriate patient populations.  
4.3 
JUSTIFICATION FOR DOSE  
The rationale for selecting amcenestrant 400 mg QD and 200 mg QD doses is based on the 
preliminary safety review of TED14856 Phase 1 study and pharmacokinetic/pharmacodynamic 
(PK/PD) data from advanced/metastatic breast cancer patients.  
As of 29 May 2019, 16 patients have been treated with amcenestrant single agent QD in 
Study TED14856 Part A. These patients were treated at 20 mg (3 patients), 150 mg (3 patients), 
200 mg (4 patients), 400 mg (3 patients), and 600 mg (3 patients). In this study, 
pharmacodynamics assessments included 18F-fluoroestradiol (18F-FES PET)/computerized 
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tomography which has been validated as an accurate method for localizing ER-expressing tumors 
and as a predictive assay for breast cancer endocrine therapy. The 18F-FES PET results indicated 
an inhibition of ER binding of 88-100% in the patients treated from 150 mg to 600 mg.  
No dose-limiting toxicity (DLT) has been reported at dose levels up to 600 mg QD during DLT 
observation period (first 28-day period). All 16 of 16 patients (100.0%) experienced at least 
1 TEAE regardless of relationship. The frequently reported TEAEs were hot flush, diarrhea, 
constipation, and nausea in each 6 patients (37.5%), decreased appetite in 5 patients (31.3%), 
asthenia and fatigue in each 4 patients (25.0%), hypoaesthesia, night sweat, and arthralgia in each 
3 patients (18.8%), nasopharyngitis, urinary tract infection, upper respiratory tract infection, 
dysgeusia, photophobia, dyspnea, cough, abdominal pain upper, vomiting, dry skin, rash, back 
pain, myalgia, musculoskeletal chest pain, and pain in 2 patients each (12.5%).  
A total of 3 serious TEAEs have been reported in 2 patients; one patient who received 
amcenestrant 150 mg QD experienced Grade 3 back pain, and fatal disease progression. Another 
patient who received amcenestrant 600 mg QD experienced Grade 3 failure to thrive. All of these 
events were considered to be not related to amcenestrant. 
At the time of the dose escalation analysis, a partial response (PR) was observed in 1 patient 
receiving 150 mg daily, stable disease (SD) in 8 patients (50%) and progressive disease in 
7 patients (43.8%). The clinical benefit rate (CBR) was observed in 8 patients (50%).  
Pharmacokinetic data were obtained from two Phase 1 studies: one study in healthy post-
menopausal women after a single dose of 100 to 400 mg and one study mentioned above in mBC 
patients after repeated QD administration from 20 to 600 mg. From a total of 16 patients dosed 
QD repeatedly with amcenestrant in Study TED14856, a high variability of exposures was 
observed after the first dose (average CV >60%) and a moderate variability after repeated 
administrations (average CV ~ 45%). The PK profile generally showed a rapid absorption 
(median time to achieve maximum concentration (tmax) ~ 3h) followed by a biphasic elimination 
profile. Overall across doses, apparent volume of distribution was large (~ 120 L), and apparent 
systemic clearance was low (~ 14-15 L/h). Preliminary data from the single ascending dose study 
in healthy population (100 to 300 mg in fasted state) showed a terminal half-life around 20 h. A 
moderate accumulation was observed on Day 21/22 after QD administrations up to 200 mg while 
no accumulation was observed at higher doses. Exposure (Cmax, AUC0-24h) increases with the dose 
after single dose, and up to 400 mg after repeated once daily administrations, slightly less at 
600 mg. When given with food, no major increase of exposure was observed (no change on Cmax 
and ~ 30 % increase on AUC0-24h) with a delay on tmax by 1 hour. 
At the time of the dose escalation analyzes, a partial response was observed in 1 patient receiving 
150 mg daily, stable disease in 8 patients (50%) and progressive disease in 7 patients (43.8%). In 
accordance to the results obtained from these three parameters, safety, 18F-FES-PET scans and 
pharmacokinetics, the recommended dose of amcenestrant was fixed at 400 mg QD. This 
recommended dose was established in mBC patients, however for patients with early breast 
cancer, a lower dose of 200 mg QD is thought to be of interest and is being explored with the 
assumption that adjuvant therapy is usually 5 years and this will allow selection of the most 
optimal exposure to therapy.  
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4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if she has completed all phases of the 
study including post treatment safety follow-up visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
 INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply (in 
case bilateral breast cancer is diagnosed at the same time, only one location as per Investigator 
judgment will be selected for all selection and assessment criteria): 
Age 
I 01. Participant must be older than 18 years of age inclusive, or country's legal age of majority 
if the legal adult age is >18 years old at the time of signing the informed consent 
Type of participant and disease characteristics 
I 02. Patients with histological or cytological proven diagnosis of invasive breast 
adenocarcinoma  
I 03. Localized breast cancer eligible for upfront breast conservative surgery or upfront 
mastectomy: Stage I, Stage II or operable Stage III (excludes T4) (AJCC Cancer Staging 
Manual 8th edition 2017; [15]) 
I 04. Participants must be postmenopausal women as defined by one of the following: 
a) With spontaneous cessation of menses >12 months prior to randomization. 
b) Or who have received hormonal replacement therapy but have discontinued this 
treatment AND have FSH level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L if institutional range is not available) prior to randomization. 
(Note: serial FSH measurements are required to confirm postmenopausal status in 
participants who are not using hormonal replacement therapy and in the absence of 
amenorrhea >12 months.) 
c) Or with status post bilateral surgical oophorectomy. 
d) Or post bilateral ovarian ablation through pelvic radiotherapy.  
I 05. A breast tumor size of at least 10 mm in greatest dimension measured by ultrasound 
I 06. Primary tumor must be positive: 
- 
ER (≥1% tumor cell staining by IHC) 
- 
HER2 non-overexpressing by IHC (0, 1+) or in situ hybridization-negative based on 
single-probe average HER2 copy number <4.0 signals/cell or dual-probe 
HER2/centromeric probe for chromosome 17 (CEP17) ratio <2 with an average HER2 
copy number <4.0 signals/cell (as per the American Society of Clinical Oncology 
guidelines). 
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I 07. Ki67 level of at least 15% at diagnosis from immunohistochemistry of the tumor based on 
local laboratory results 
I 08. ECOG performance status 0-1 
Weight 
I 09. Not Applicable 
Sex 
I 10. Female 
Informed Consent 
I 11. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of 
amcenestrant or letrozole. Participants unable to swallow normally and to take capsules or 
tablets. Predictable poor compliance to oral treatment. Participants with known active 
hepatitis A (positive HA antigen or positive IgM); B (either positive HBs antigen or 
positive hepatitis B viral DNA test above the lower limit of detection of the assay); C 
(positive hepatitis C antibody result or quantitative hepatitis C (HCV) ribonucleic acid 
(RNA) results greater than the lower limits of detection of the assay) infection; or hepatic 
cirrhosis. 
E 02. Participant with any other cancer. Adequately treated basal cell or squamous cell skin 
cancer or in situ cervical cancer or any other cancer from which the participant has been 
disease free for >3 years are allowed. 
E 03. Evidence of metastatic spread by standard assessment according to local practice. 
Prior/concomitant therapy 
E 04. Treatment with strong CYP3A inducers within 2 weeks before first study treatment 
administration or 5 elimination half-lives whichever is longest and cannot be replaced. 
E 05. Deleted in Protocol Amendment 02. 
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E 06. Treatment with drugs that are sensitive substrates of P-glycoprotein (P-gp) (dabigatran, 
digoxin, fexofenadine) or of breast cancer resistance protein (BCRP) (rosuvastatin, 
sulfasalazine) within 2 weeks before first study treatment administration or 5 elimination 
half-lives whichever is longer. 
E 07. Use of any investigational agent within 4 weeks prior to randomization.  
E 08. Recent use of hormone replacement therapy (last dose ≤30 days prior to randomization). 
E 09. Prior anti-cancer treatment is not allowed unless it was completed at least 1 year prior to 
inclusion into this trial. 
Prior/concurrent clinical study experience 
E 10. Previous systemic or local treatment for the new primary breast cancer currently under 
investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments). 
Diagnostic assessments 
E 11. Inadequate hematological function including neutrophils <1.5 × 109/L; platelet 
count <100 × 109/L, hemoglobin <8.0 g/dL. 
E 12. Prothrombin time/international normalized ratio (INR) >1.5 times the upper limit of 
normal (ULN) or outside therapeutic range if receiving anticoagulation that would affect 
the prothrombin time/INR.  
E 13. Inadequate renal function with serum creatinine ≥1.5 × ULN or between 1.0 and 
1.5 × ULN with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 as 
estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) formula 
(see Section 10.13 Appendix 13). 
E 14. Liver function parameters with one of the following:  
- 
Aspartate aminotransferase >1.5 × ULN 
- 
Alanine aminotransferase >1.5 × ULN  
- 
Total bilirubin >1.5 × ULN. 
Other exclusions 
E 15. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 16. Deleted in Protocol Amendment 01. 
E 17. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
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E 18. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the ICH-GCP Ordinance E6). 
E 19. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 20. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
Criteria added in Amended Protocol 
E 21. Treatment with drugs that have the potential to inhibit UGT (uridine 5'-diphospho-
glucuronosyltransferase), including but not limited to atazanavir and probenecid within 
2 weeks before first study treatment administration or 5 elimination half-lives whichever is 
longest and cannot be replaced 
5.3 
LIFESTYLE CONSIDERATIONS  
Amcenestrant toxicity studies indicate a potential risk for phototoxicity (described in the IB). For 
this reason, participants should avoid direct exposure to natural or artificial sunlight during study 
treatment and for at least 5 days after discontinuation of amcenestrant. It is recommended to 
advise to wear protective clothing, lip balm, and a broad-spectrum sunscreen with high sun 
protection factor (eg, ≥30) to cover UVA and UVB light exposure when outdoors with frequent 
re-application as necessary. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) should not 
be rescreened. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
Amcenestrant 400 mg QD 
Amcenestrant 200 mg QD 
Letrozole 2.5 mg QD 
Intervention name 
Amcenestrant 
Amcenestrant 
Letrozole (Femara®) 
Type 
Drug 
Drug 
Drug 
Dose formulation 
Capsules for oral use 
Capsules for oral use 
Tablets for oral use 
Unit dose strength(s) 
100 mg capsule 
100 mg capsule 
2.5 mg tablet 
Dosage level(s) 
4 capsules QD, given in the 
morning, either with or 
without meal. Capsules 
should be taken 
approximately at the same 
time every day. 
2 capsules QD, given in the 
morning, either with or 
without meal. Capsules 
should be taken 
approximately at the same 
time every day. 
1 tablet QD given in the 
morning, either with or 
without meal. Tablets 
should be taken 
approximately at the same 
time every day. 
Route of administration 
oral 
oral 
oral 
IMP or NIMP 
IMP 
IMP 
IMP 
Packaging and labeling 
Study intervention will be 
provided in blisters 
containing capsules. 
Two blisters will be sealed 
in 1 wallet. Each wallet will 
be labeled as required per 
mandatory regulatory 
requirements 
Study intervention will be 
provided in blisters 
containing capsules. 
Two blisters will be sealed 
in 1 wallet. Each wallet will 
be labeled as required per 
mandatory regulatory 
requirements 
Two blisters (each blister 
contains 10 tablets) will be 
removed from the 
commercial box and will be 
added in a new box. The 
box and the blisters will be 
labeled with all mandatory 
regulatory requirements 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
A complete description of the IMPs and their proper handling will be provided in a Pharmacy 
Manual available at the Investigational Site. 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study interventions. All study interventions must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
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3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).  
4.  A written authorization for destruction will be given by the Sponsor once the study 
intervention reconciliation is achieved. This destruction can be performed at site 
depending on study intervention specificities and local requirements or study 
interventions can be returned to the Sponsor for destruction. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.6). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allows the IMPs to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an Interactive 
Response Technology (IRT). The IRT generates the participant randomization list and allocates 
the intervention number and the corresponding intervention kits to the participants according to it. 
Before the study is initiated, the telephone number and call-in directions for the Interactive Voice 
Response System and/or the log in information and directions for the Interactive Web Response 
System will be provided to each site. The IRT centralized randomization system will be used to 
prevent the Investigators from knowing in advance the treatment assignment. 
Investigational medicinal product (IMP) will be dispensed at the study visit summarized in the 
Schedule of Activities (SoA). Participants will be randomized within 3 days prior to first IMP 
dosing (Day 1). 
Returned study intervention should not be re-dispensed to the participants. 
Participants cannot be randomized more than once. 
Methods of blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an IRT system. Potential bias will be reduced by the following steps. 
• Central randomization 
• The treatment will not be blinded to participants and investigators but will be blinded for 
the assessors of the primary endpoint Ki67 (ie, histopathologists in central lab) to avoid 
the potential for bias. 
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6.4 
STUDY INTERVENTION COMPLIANCE  
A patient diary will be provided to all participants during treatment.  
The person responsible for drug dispensing is required to maintain adequate records of the study 
treatment. These records (eg, product accountability and inventory forms at site level) include the 
date the study treatment is received from the Sponsor, dispensed to the participant and destroyed 
or returned to the Sponsor. The packaging batch number on the pack must be recorded on the drug 
accountability form. 
Participant compliance will be assessed at the Day 7 visit via the patient diary and at the Day 14 
visit by counting returned capsules/tablets. At the Day 14 visit, the Investigator/Clinical staff will 
count the number of capsules/tablets, remaining in the returned packs, and fill in the Intervention 
Log Form and record the dosing information on the appropriate page(s) of the eCRF. The monitor 
in charge of the study then checks the eCRF data by comparing them with the IMP which he/she 
has retrieved and intervention log forms. 
On Day 1, while the participant is in the clinic, patient diary will be dispensed and the study staff 
will demonstrate to the participant how to record information in the patient diary. Participants will 
note every day the hours of amcenestrant/letrozole given PO intake. If vomiting occurred after the 
intake of capsules/tablets, they need to report it in the same diary. In case of an early vomiting 
event, the administered dose of amcenestrant/letrozole given PO should not be repeated, and the 
participant should be instructed not to make it up the next day and resume the treatment the next 
day as prescribed. This information should be recorded in the diary. The diary will then be 
completed by the participant each day for each dose and will be returned to the study personnel on 
Day 7 and at the end of study treatment. Participants who inadvertently take 1 extra dose during a 
day must be instructed to skip the next day’s dose. 
Participants will be requested to return all unused amcenestrant/letrozole given PO to the study 
site at the end of the study treatment for a full compliance assessment. Clinic staff will record the 
study medication dosing information based on information from the patient diary and the 
compliance assessment.  
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or medicine) that the participant received within 30 days prior to 
randomization or receives during the study must be recorded in the eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) during 14-day treatment if the drug is a potential enzyme 
inducer or 5 half-lives (whichever is longer) before the start of study intervention until completion 
of the follow-up visit, unless, in the opinion of the Investigator and Sponsor, the medication will 
not interfere with the study. 
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Concomitant medication may be considered on a case-by-case basis by the Investigator.  
Any medication which is considered necessary for the participant’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator, except for those listed below.  
Any anti-cancer medications (other than the study treatment) and hormone replacement 
therapy/hormonal contraception are prohibited from the date of informed consent to the end of 
study treatment.  
The following therapies/medications are prohibited throughout the active treatment phase for the 
amcenestrant treatment arms: 
• The concomitant use of drugs that are strong inducers of CYP3A since they may decrease 
amcenestrant exposure (See Section 10.8).  
• Herbal medications and food supplements including St John’s Wort and genistein during 
treatment period since they could decrease amcenestrant exposure. 
• The concomitant use of drugs that are sensitive substrates of P-gp (dabigatran, digoxin, 
fexofenadine) or BCRP (rosuvastatin, sulfasalazine), since amcenestrant is a potential 
inhibitor of P-gp and BCRP and may increase their absorption.  
• The concomitant use of drugs that have UGT inhibition potential and are contraindicated 
with UGT substrates, including but not limited to atazanavir and probenecid, since 
amcenestrant is substrate of UGT1A1 and UGT1A4. 
Special caution should be taken with regards to the following therapies for the amcenestrant 
treatment arm: 
• Proton Pump Inhibitors (PPI) (ie, omeprazole): when prescribed, amcenestrant intake 
should be preferred with food. 
• Drugs that are sensitive substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 
since it may result in loss of efficacy of these agents (See Section 10.9). 
• Participants should avoid direct exposure to natural or artificial sunlight during study 
treatment and for at least 5 days after discontinuation of amcenestrant. It is recommended 
to advise to wear protective clothing, lip balm, and broad-spectrum sunscreen with a high 
sun protection factor (eg, ≥30) to cover both UVA and UVB light exposure when outdoors 
with frequent re-application as necessary. 
Regarding the control arm of letrozole: 
• Co-administration of letrozole with tamoxifen, other anti-estrogens or estrogen-containing 
therapies should be avoided as these substances may diminish the pharmacological action 
of letrozole. 
• In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, 
but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole 
concomitantly with medicinal products whose elimination is mainly dependent on these 
isoenzymes and whose therapeutic index is narrow. 
• For detailed information for contraindication and drug-drug interaction of letrozole, please 
refer to the approved letrozole label. 
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6.6 
DOSE MODIFICATION  
If a dose of IMP is vomited or omitted, the participant should not take the dose later or 2 doses at 
the next planned dose, and this information has to be recorded in the patient diary and eCRF.  
Investigational medicinal product dose omission is allowed in case of severe toxicity and the 
reason should be documented in the eCRF. Doses omitted for toxicity are not to be replaced after 
the 14-day treatment period or compensated at the next planned IMP intake during the 14-day 
treatment period. 
Conditions for dose modifications are aligned in Table 3. Please refer to letrozole label 
information on additional specific contraindications and events requiring use precaution, and 
instruction of dose modification.  
Table 3 - Dose modification for amcenestrant arms and letrozole arm  
NCI-CTCAE grade 
Dose modifications 
Grade 1 or 2 
No dose adjustment required except for Grade 2 alanine transferase defined as an AESI * 
Grade ≥3  
Amcenestrant and letrozole should be definitely discontinued. No reintroduction is allowed. 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.  
* See Section 8.3 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
There is no access to intervention after the end of the study. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
The IMP should be continued whenever possible. Any IMP discontinuation must be fully 
documented in the eCRF. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
The duration of study intervention is 14 days. Participants may withdraw from study treatment if 
they decide to do so, at any time and irrespective of the reason, or this may be done at the 
discretion of the Investigator. All efforts should be made to document the reason(s) for 
discontinuation and this should be documented in the eCRF. If study intervention is permanently 
discontinued, the participant will remain in the study to be evaluated for safety.  
Handling of participants after definitive intervention discontinuation 
If the participants withdraw from study treatment before completing 14-day period, they will be 
requested to get back to the study sites as per planned visit dates after discontinuation. As an 
example, a participant who discontinues treatment on Day 6 will come to site for planned visits on 
Day 7 and Day 14. All procedures pre-scheduled for these Day 7 and Day 14 visits will be 
performed except PK sampling and ECG. If the participants have received less than 70% of 
planned dose (ie, less than a total of 10 days of treatment), the breast ultrasound will not be 
performed either. The post-treatment core-cut biopsy sampling from surgery specimen or a new 
core-cut biopsy will be performed as scheduled. 
All participants will be requested to participate in the post-treatment safety follow-up visit 
(30 [±7] days after last IMP intake).  
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
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• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
Participants who withdraw from the study intervention before Day 14 should be explicitly asked 
about the contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the  
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-randomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1 (Section 10.1.9). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. If the participant fails to meet the exclusion criteria 
related to laboratory assessments at Screening, the laboratory assessments may be 
performed one more time to assess eligibility.  
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• Additional safety tests (eg, ECG, hematology, coagulation, and clinical chemistry) can be 
performed whenever clinically indicated.  
• The date of surgery should be fixed before randomization takes place. The time between 
first IMP administration and surgery should be of 14 days. Surgery should be done 1 day 
after the last IMP administration; however this could exceptionally be extended to a 
maximum of 48 hours after the last IMP administration. In case of a longer unexpected 
surgery delay (>48 hours from last IMP administration), all efforts should be done to 
perform a tumor biopsy no more than 48 hours of last IMP administration. 
• The IMP dose will be taken on-site after fasting tests and pre-dose assessment on Day 1 
and Day 14.  
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 14: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency. 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Pathological complete response  
Pathological Complete Response (pCR) results will be collected from the local pathologist’s 
report following examination of tissue (breast and nodes) removed at the time of surgery and 
reported in eCRF. 
pCR is defined as ypT0N0 or ypTisN0: No histologic evidence of invasive tumor cells in the 
surgical breast specimen and axillary nodes after neoadjuvant treatment. (Eighth Edition AJCC 
Cancer Staging Manual; [15]). 
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8.1.2 ECOG response  
Eastern Cooperative Oncology Group (ECOG) response is to be measured according to ECOG 
response criteria (14) (based on breast tumor shrinkage, pCR and ECOG performance status) by 
the investigator after a 14-day treatment period. 
Tumor size will be measured using breast ultrasound at screening and on Day 14. At screening, 
tumor size assessment will be used for inclusion criteria and baseline value.  
See Appendix 11 (Section 10.11) for details. 
8.1.3 Preoperative Endocrine Prognostic Index (PEPI)  
PEPI score will be assessed after a 14-day treatment period. The assessment includes relapse-free 
survival (RFS) risk score and breast cancer specific survival (BCSS) risk score. 
The total PEPI score is the sum of the risk points derived from the pathological tumor (pT) stage, 
the pathological node (pN) stage, Ki67 levels and ER status (Allred score) of the surgical 
specimen. The pT and pN will be assessed locally. The Ki67 and ER status will be assessed 
centrally.  
See Appendix 12 (Section 10.12) for details.  
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
(at screening only) and weight will also be measured and recorded. 
• Performance status as measured by the ECOG (Appendix 10 [Section 10.10). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• Temperature, pulse rate, and blood pressure will be assessed at the time points defined in 
the SoA (Section 1.3). 
8.2.3 Electrocardiograms  
• Standard 12-lead ECGs are recorded after at least 10 minutes in supine position using an 
electrocardiographic device.  
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• Single 12-lead ECGs (safety ECGs) will be recorded at screening (locally assessed).  
• Triplicates (3 12-lead ECGs) will be recorded within 5 minutes with at least 1 minute 
between 2 replicates on Day 1 and Day 14 in accordance with the SoA (Section 1.3), and 
can be repeated as clinically indicated.  
Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to: 
A single 12-lead ECG (25 mm/s, 10mm/mV) printout with heart rate, PR, QRS, QT, QTc 
automatic correction evaluation (by the ECG device), including date, time and number of 
the participants, signature of the research physician, and at least 3 complexes for each 
lead. The Investigator’s medical opinion will be recorded in the eCRF. This printout will 
be retained at the site. ECGs will also be digitally stored to enable further reading by an 
ECG Core laboratory. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 
• The Investigator must review the laboratory report, and document this review. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA. 
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management (eg, SAE 
or leading to dose modification), then the results must be recorded in the eCRF. 
- 
Liver function tests Grade ≥3 during participation in the study or within 30 days after 
the last dose of study intervention should be repeated until the values return to normal 
or baseline. If such values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified if it is not considered to be related to the underlying disease.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
• Pregnancy occurring in a female participant entered in the clinical trial. It will be qualified 
as an SAE only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant is mandatory until the outcome has 
been determined (See Appendix 4 [Section 10.4]). 
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• Symptomatic overdose (serious or nonserious) with IMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug. 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• Increase in alanine transaminase (ALT) ≥ Grade 2.  
- Liver function tests should be performed in patients with onset of otherwise 
unexplained nausea, jaundice, right upper abdominal pain, fever, or rash. LFTs include 
AST, ALT, ALP (isoenzymes if increase in ALP ≥ Grade 3), total bilirubin (direct 
bilirubin if total bilirubin >2 × ULN), GGT, and INR (if total bilirubin >2.5 × ULN). 
- Discontinue study intervention in case of increase in ALT ≥ Grade 2 if still on 
treatment, and repeat Liver function tests (LFTs) within 2-3 days. If not recovered, 
monitor LFTs weekly until recovery to Grade ≤1 (or baseline grade). Confounding 
factors such as, hepato-biliary disorders, concomitant medications, etc. should be 
excluded prior to study treatment discontinuation. 
- An ultrasound or other imaging in liver should be considered based on the clinical 
presentation. 
- A consultation with a hepatologist should be undertaken if there is,  
 unexplained or persistent increase in ALT ≥ Grade 3 despite study treatment 
discontinuation.  
 ALT >3 × ULN and concomitant jaundice (total bilirubin >2.5 × ULN), in patients 
with normal ALT and total bilirubin at baseline. 
 to exclude hepato-biliary disorders (eg, hepatotropic virus infections, autoimmune 
or alcoholic hepatitis, Non-Alcoholic Steatohepatitis, etc) or drug induced liver 
injury. 
- Further hepatic virology will be undertaken as per the site’s local guidelines for the 
treatment of cancer patients, taking into account the local and national 
recommendations.  
• Photosensitivity 
- 
If photosensitivity reaction is suspected in study participants, consider dermatologist 
consultation. Confounding factors such as other dermatological disorders, drug 
eruptions resulting from concomitant medication use, etc should be excluded prior to 
discontinuation of amcenestrant. In case of amcenestrant discontinuation because of 
photosensitivity reaction, study participant should be followed for possibility of 
development of other manifestations of phototoxicity such as photo-onycholysis, 
lichenoid reaction or actinic granuloma. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
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AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until the 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 8.3), and non-serious AEs related to IMP still ongoing at the pre-specified 
study end-date, will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
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• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5 Pregnancy  
• Details of all pregnancies in females will be collected after the signing the ICF until 
outcome of pregnancy (See Appendix 4 [Section 10.4]). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose (as defined in Section 8.3), the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until IMP 
can no longer be detected systemically (at least 7 days for amcenestrant and 5 times the 
half life time of letrozole from the date of overdose). 
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3. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document appropriately in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
• Pharmacokinetic sampling is planned only in participants randomized in amcenestrant 
treatment arms.  
• Blood samples of approximately 1 mL will be collected for measurement of plasma 
concentrations of amcenestrant as specified in the SoA (Section 1.3) using a validated 
liquid chromatography-mass spectrometry/mass spectrometry assay. Instructions for the 
collection and handling of PK samples will be provided by the Sponsor in the laboratory 
manual.  
• Samples will be used to evaluate the PK of amcenestrant. Samples collected for analyses 
of amcenestrant plasma concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
• It is of utmost importance to collect all blood samples at the specified time windows and 
according to the specifications (refer to the laboratory manual). 
• Samples missed or lost for any reason should be recorded. Actual dates and times (24-hour 
clock time) of blood collection should be recorded. Actual dates and times of previous 
drug administration should also be precisely recorded. 
For the comfort of the participants, some PK samplings may be deleted during the course of the 
study if they are no longer deemed necessary by the Sanofi PK team. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF.  
8.6 
PHARMACODYNAMICS  
Ki67 is a marker of cellular proliferation and has shown value as a predictor of benefit from 
treatment and of long-term outcome. Change in Ki67 is the primary endpoint. Ki67 will be 
evaluated in tumor tissue by IHC (See Section 8.6.1 for details). Ki67 index will be recorded 
independently by 2 histopathologists blinded to treatment allocation. 
For additional parameters, please see Section 8.7 and Section 8.8. 
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8.6.1 Tumor biopsy  
Determination of tumor characteristics (HER2 status by IHC or FISH, ER and PgR by IHC, Ki67 
by IHC, etc) on the diagnostic biopsy specimen based on local laboratory results serves for 
participant selection. For clinical sites reporting Ki67 expression by range rather than a single 
value, a local re-evaluation might be requested to confirm Ki67 expression ≥15%. 
During the study, tumor biopsy will be performed at the time points described in SoA 
(Section 1.3), and the assessment window is not impacted by dose omission. Biopsy samples will 
be examined for Ki67, DNA mutation analysis, RNA expression analysis, and protein analysis 
(eg, ER, PgR, BCL2, Cyclin D1) in central laboratory. Ki67 index will be recorded independently 
by 2 histopathologists blinded to treatment allocation. Complete Cell Cycle Arrest (CCCA: Ki67 
≤2.7%) will be evaluated. Additional protein expression assessments by digital method will be 
performed for some biomarkers (eg, Ki67). 
• A fresh core-cut biopsy sample will be collected prior to the first dosing of IMP serving as 
baseline value. It is recommended that the baseline biopsy should be performed after the 
eligibility is confirmed, if possible. The baseline biopsy may be performed any time prior 
to the initiation of study treatment. Alternatively, biopsy tissue from the diagnostic biopsy 
may be used as baseline sample if the following criteria are fulfilled: 
- 
There is sufficient material available for biomarker analysis (a minimum of 7 x 5-µm 
sectioned FFPE slices on slides are required); AND 
- 
Diagnostic biopsy performed within 4 weeks prior to randomization; AND 
- 
No hormone replacement therapy (HRT) administered from 30 days prior to diagnostic 
biopsy till screening; AND 
- 
No anticancer treatment administrated between diagnosis and screening. 
• Post-treatment core-cut biopsy samples will be collected on the excised tissues during 
surgery. The surgery should be performed on Day 15 (+1). If surgery is delayed for any 
reason, every effort should be made to perform a new tumor core-cut biopsy within 
48 hours maximum after last IMP dose. If a new tumor core-cut biopsy within 48 hours 
maximum after last IMP dose is not performed, nevertheless it is recommended to collect 
post-treatment core-cut biopsy samples on the excised tissues during the planned surgery. 
Post-treatment biopsy samples should be collected in the same area as for baseline biopsy 
as far as possible. 
For both the baseline pre-treatment and the post-treatment biopsy samples, a tissue block is 
preferred for the central analysis. If tissue sections are provided instead, it is preferred to have 
approximately at least 9 x 5-µm and 5 x 10-µm sections on slides, though a smaller number of 
slides for the baseline sample are acceptable, if necessary (see above for minimum requirement). 
Pre-treatment and post-treatment biopsy samples will be fixed in neutral-buffered formalin for  
24-72 hours prior to processing and embedding at local pathology centers. These biopsy samples 
will be sent for analyses to a central laboratory. 
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8.7 
GENETICS  
Genetic analysis of tumor biopsies and cell-free DNA (cfDNA) will be performed in this study. 
Cancer gene mutations present in the tumor prior to treatment might influence the response to 
amcenestrant. The presence of gene mutations in tumor DNA may be assessed through  
A) Mutation analysis of DNA isolated from a tumor biopsy, and  
B) Mutation analysis of cfDNA isolated from plasma. 
Both biopsies and cfDNA samples will be collected pre-treatment and post treatment. These 
analyses will focus on genes that may increase understanding of disease subtypes, the biology of 
cancer and related conditions, how the body handles amcenestrant, and drug response and 
toxicity, and possibly to identify new drug targets or biomarkers. 
In addition, saliva will be collected pre-treatment as a source of normal reference DNA for 
comparison with the tumor-derived DNA data. Sequencing may be performed on the DNA from 
the saliva sample. In the event of technical issues affecting the sample, a replacement genetic 
saliva DNA sample may be requested from the participant. 
At the study visit as specified in the SoA (Section 1.3), a blood sample will be collected only in 
amcenestrant treatment arms to investigate allelic variants of drug metabolizing enzymes  
(for example variants of UGT1A1 and UGT1A4), drug transporters and/or other ADME related 
genes as intrinsic factors associated with PK or PD variability of amcenestrant. This sample will 
be used for this specific analysis and not for other future research. 
Special procedures for collection, handling, storage, and shipment will be described in a separate 
laboratory manual which will be available at the investigational site. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable 
additional analysis of DNA biomarkers to increase understanding of amcenestrant and/or cancer 
or related diseases, and potentially to identify new drug targets or biomarkers. 
See Section 10.5 (Appendix 5) for Information regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in the laboratory manual. 
8.8 
BIOMARKERS  
Several tumor biomarkers are evaluated in this study. For more information on DNA biomarkers, 
see Section 8.7 of the protocol.  
8.8.1 Protein biomarkers  
The expression of several proteins in the tumor will be assessed by IHC of biopsy tissue collected 
pre-treatment and post-treatment. These proteins may include estrogen receptor (ER), the 
progesterone receptor (PgR), Ki-67, B-Cell Lymphoma 2 (BCL2), Cyclin D1, and potentially 
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other proteins related to cancer or the activity of amcenestrant. These studies will be conducted by 
a central IHC lab. 
These studies will increase the understanding of the activity of amcenestrant and may increase our 
knowledge of cancer or related conditions.  
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarkers related to amcenestrant or cancer, or to develop methods, assays, 
prognostics and/or companion diagnostics.  
8.8.2 RNA transcriptome research  
Genome-wide transcriptome studies of ribonucleic acid (RNA) isolated from tumor biopsies are 
planned in this study by measuring the relative abundances of the RNA transcripts. This will 
enable the evaluation of changes in transcriptome profiles that may increase understanding of the 
pathogenesis of cancer and related conditions, the participant’s response to amcenestrant, and 
disease subtypes, and possibly to identify new drug targets or biomarkers. 
The samples may be analyzed by RNAseq or similar technologies. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable 
additional analysis of RNA biomarkers to increase understanding of amcenestrant and/or cancer 
or related diseases, and potentially to identify new drug targets or biomarkers. 
8.8.3  Future use of samples  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For participants who have consented to it, the samples that are unused or left over 
after testing may be used for other research purposes related to oncology than those defined in the 
present protocol (excluding genetic analysis conducted primarily to provide information on the 
likelihood of developing diseases other than cancer or related conditions). 
These other research analyses will help to understand either the disease or IMP response, or to 
develop and/or validate a bioassay method, or to identify new drug targets or biomarkers. These 
samples will remain labeled with the same identifiers used during the study. They will be 
transferred to a Sanofi site (or a subcontractor site) which can be located outside of the country 
where the study is conducted. The Sponsor has included safeguards for protecting participant 
confidentiality and personal data. 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
This study is designed to test: 
• The null hypothesis that the true log-fold change in Ki67 after a 14-day treatment period 
for both amcenestrant arms and the control arm are the same.  
• The alternative hypothesis that the true log-fold change in Ki67 after 14-day treatment 
period is greater for either of amcenestrant arm compared to the control arm. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size is determined based on the following assumptions:  
• The geometric mean of percentage change in Ki67 after a 14-day treatment period for the 
control arm is assumed to be 70% (5, 16, 17). 
• The geometric mean of reduction in Ki67 after a 14-day treatment period is increased to 
85% for each amcenestrant arm. Therefore the geometric means of residual Ki67 (defined 
as one minus the geometric mean of reduction) are assumed to be 30% for the control arm 
and 15% for treatment arms, corresponding to a log fold difference of -0.693  
(log(0.15)-log(0.3)) under the alternative hypothesis.  
• The standard deviation of the log-fold change after a 14-day treatment period is assumed 
to be 1. 
A total of 40 evaluable participants (where evaluable are defined as participants who have 
both baseline and post treatment available biopsies with Ki67 values) per treatment arm will be 
needed, in order to achieve 85% marginal power at the overall one-sided Type I error rate of 2.5% 
controlled with an Hochberg procedure, based on a one-sided t-test on the log-transformed data. 
The disjunctive power, ie, the probability to reject at least one null hypothesis associated with the 
comparison amcenestrant and the control arm, is estimated at 91.5%. 
Allowing for a 5% non-evaluable participant rate, the total sample size for randomization is 
126 participants (42 per treatment arm).  
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 4): 
Table 4 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the informed consent form  
Intent-to-treat (ITT) population  
All participants from the enrolled population and for whom there is a confirmation of 
successful allocation of a randomization number by IRT. Participants will be 
analyzed according to the treatment arm assigned at randomization. This 
population will be used for analysis of baseline parameters. 
Modified ITT (mITT) population 
All participants from the ITT population who have taken at least one drug, and who 
have both baseline and post treatment available biopsies with Ki67 values. This is 
the primary analysis population for all pharmacodynamic and efficacy parameters 
Per-protocol (PP) population 
All participants from the mITT population without relevant deviation(s), which could 
affect the evaluation of the study drug on the primary endpoint. Details of relevant 
deviations would be further specified in the statistical analysis plan. PP population 
will be used for sensitivity analysis of the primary endpoint. 
Safety 
All participants randomly assigned to study intervention and who take at least 
1 dose of study intervention. Participants will be analyzed according to the 
treatment arm they actually received. This population is the primary population for 
the analysis of all safety parameters 
Pharmacokinetic-evaluable 
All participants from the safety population who receive at least one dose of 
amcenestrant and with at least 1 evaluable post-treatment plasma concentration. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
9.4.1 Efficacy/pharmacodynamics analyses  
All efficacy and pharmacodynamics analyses will be performed on the mITT population unless 
stated otherwise. Analysis for the primary endpoint, and the secondary endpoint of proportion of 
participants with a relative decrease from baseline in Ki67 ≥50%, will be repeated on the PP 
population as sensitivity analysis. 
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Table 5 - Efficacy/pharmacodynamics analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
Change in Ki67 after a 14-day 
treatment period compared to 
baseline 
 
Analysis of covariance (ANCOVA) model on the log transformed values for hypothesis 
testing using the Hochberg step-up procedure for multiplicity adjustment 
Secondary 
The proportion of participants 
with a relative decrease from 
baseline in Ki67 ≥50% 
Change from baseline in ER 
expression  
 
Descriptive statistics by treatment arm and Clopper-Pearson method for CI calculation 
 
 
Descriptive statistics by treatment arm 
Tertiary/Exploratory 
Will be described in the statistical analysis plan (SAP) 
9.4.1.1 Analysis of primary endpoint  
On the assumption of a log-normal distribution, the Ki67 values will be log-transformed before 
analysis. The change of log(Ki67) between baseline and after a 14-day treatment period will be 
compared between groups using an analysis of covariance (ANCOVA) model adjusting for 
baseline Ki67 expression. For each group, the geometric mean of Ki67 at baseline and after a 
14-day treatment period and the geometric mean of percentage reduction in Ki67 will be provided 
along with the 95% confidence interval. The geometric mean ratio of proportional change of Ki67 
between groups and associated 95% confidence interval will be provided. 
The assumption on normality of log transformed Ki67 values will be addressed before performing 
the proposed ANCOVA. In case this assumption is not fulfilled, alternative non-parametric 
(ie, Wilcoxon Mann-Whitney) test may be used. 
Due to the multiplicity of tests as each amcenestrant dose/regimen will be compared to the control 
arm, a Hochberg step-up procedure will be used to control the overall one-sided Type I error rate 
of 2.5%. 
9.4.1.2 Analysis of secondary endpoints  
Relative decrease from baseline in Ki67 ≥50% 
The proportion of participants with a relative decrease from baseline in Ki67 ≥50% between 
baseline and after a 14-day treatment will be provided for each treatment arm along with the 
95% CI computed using the Clopper-Pearson method. 
ER degradation 
Change from baseline in ER expression as measured by H-Score will be summarized for each 
arm.  
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9.4.2  Safety analyses  
All safety analyses will be performed on the Safety Population. 
Table 6 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
No primary endpoint is defined for safety analyses 
Secondary 
AEs/SAEs and laboratory abnormalities 
 
Descriptive statistics 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
9.4.2.1 Analysis of adverse events  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• The on-treatment period is defined as the time from the first dose of IMP up to last dose of 
IMP.  
• The post-treatment safety follow-up period is defined as the time from last administration 
of the IMP to the last administration of the IMP + 30 days. 
Pretreatment AEs are defined as any AE occurring during the pretreatment period. 
Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator’s 
opinion), or become serious during  
• on treatment period only, or 
• the period including both the on-treatment and post-treatment period 
All TEAE analyses will be produced for the two analysis periods as listed above. Pretreatment 
AEs will be described separately.  
Treatment-emergent AEs will be coded according to MedDRA. Adverse events will be graded 
according to the NCI-CTCAE v5.0. The grade will be taken into account in the summary. For 
participants with multiple occurrences of the same PT, the maximum grade will be used.  
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• Treatment-emergent AEs 
• Grade ≥3 TEAEs 
• Grade 5 TEAEs (any TEAE with a fatal outcome during the on-treatment period) 
• Serious TEAEs 
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• Treatment-emergent AEs leading to definitive treatment discontinuation 
• Treatment-related TEAEs 
• Treatment-related TEAEs Grade ≥3 
• Serious treatment-related TEAEs.  
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v5.0 grade (all grades and Grade ≥3) for the safety population. 
Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to definitive 
discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
AESIs, and AEs/SAEs occurring during the post-treatment period. 
9.4.2.2 Analyses of clinical laboratory evaluations  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the on-treatment period will be provided for the 
safety population. 
When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
9.4.3 Other analyses  
Data from other assessments (including ECGs and vital signs) will be summarized and listed, 
clinically significant values will be flagged, and any other information collected will be listed as 
appropriate. 
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. Pharmacokinetic/pharmacodynamic analyses will be 
described in the SAP or in a dedicated PK/PD SAP. 
9.5 
INTERIM ANALYSES  
There are no interim analyses planned for this study. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines,  
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
“Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on afro American population for the FDA or on Japanese population for 
the Pharmaceuticals and Medical Devices Agency in Japan)”. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
There are no study committees in this protocol. 
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
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10.1.7 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to  
peer-reviewed journals following internal company review for accuracy, fair balance and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
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• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results.  
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 7 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 7 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistry 
Blood urea nitrogen (BUN) or urea 
 
Creatinine 
 
Glucose fasting 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Total protein 
Coagulation 
Prothrombin time 
International normalized ratio (INR) 
Other screening tests 
Follicle-stimulating hormone (as needed to confirm postmenopausal status) 
Viral serologies including hepatitis A antigen or IgM hepatitis A antibody, HBs antigen or 
hepatitis B viral DNA, hepatitis C antibody or quantitative hepatitis C viral (HCV) 
ribonucleic acid (RNA) 
The results of each test must be entered into the CRF 
 
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
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immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it using NCI-CTCAE v5.0. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
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• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken  
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the medical monitor by telephone. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
Not applicable as this study enrolls postmenopausal women. 
COLLECTION OF PREGNANCY INFORMATION: 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Follow-up will be required 
until outcome of pregnancy. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
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10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, biopsy samples, plasma samples (for cfDNA) and 
blood sample (for DMET genotyping) will be collected for DNA analysis. 
• DNA samples will be used for research related to amcenestrant and related diseases. They 
may also be used to develop tests/assays including diagnostic tests related to amcenestrant 
and cancer. Genetic research may consist of the analysis of one or more candidate genes or 
the analysis of genetic markers throughout the genome (as appropriate). 
• DNA samples will be analyzed for mutations in genes related to cancer and/or the 
response to amcenestrant. Additional analyses may be conducted if it is hypothesized that 
this may help with interpretation of the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to amcenestrant or study interventions of this class to understand 
study cancer or related conditions. 
• In addition, saliva will be collected pre-treatment as a source of normal reference DNA for 
comparison with the tumor-derived DNA data. Sequencing may be performed on the DNA 
from the saliva sample. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained no longer than 15 years following the last participant’s last 
visit for the study, or other period as per local requirements. 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
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10.7 
APPENDIX 7: ABBREVIATIONS  
 
18F-FES-PET: 
fluoroestradiol positron emission tomography 
ADME: 
absorption distribution metabolism and excretion 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AI: 
aromatase inhibitor 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariences 
AST: 
aspartate aminotransferase 
BCRP: 
breast cancer resistance protein 
BCSS: 
breast cancer specific survival 
CBR: 
clinical benefit rate 
CCCA: 
complete cell cycle arrest 
cfDNA: 
cell free deoxyribonucleic acid 
CI: 
confidence interval  
CIOMS: 
council for international organizations of medical sciences 
CONSORT: 
consolidated standards of reporting trials 
CRF: 
case report form 
CTFG: 
clinical trial facilitation group 
CYP: 
cytochrome P 
DLT: 
dose limiting toxicity 
DMET: 
drug metabolizing enzymes and transporters 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eGFR: 
estimated glomerular filtration rate 
ER: 
estrogen receptor 
ERα: 
estrogen receptor alpha 
FFPE: 
formalin fixed paraffin embedded 
FISH: 
fluorescence in-situ hybridization 
GCP: 
good clinical practice 
GGT: 
gamma-glutamyl transferase 
HER2: 
human epidermal growth factor receptor 2 
HRT: 
hormone replacment therapy 
IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
international council for harmonization 
IEC: 
independent ethic committee 
IHC: 
immuno histochemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB: 
institutional review board 
IRT: 
Interactive Response Technology 
LFT: 
liver function test 
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mBC: 
metastatic breast cancer 
MDRD: 
modification of diet in renal disease 
mITT: 
modified intent-to-treat 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
pCR: 
pathological complete response 
PD: 
pharmacodynamics 
PEPI: 
preoperative endocrine prognostic index 
P-gp: 
P-glycoprotein 
PgR: 
progesterone receptors 
PK: 
pharmacokinetic 
pN: 
pathological node 
PO: 
oral dose 
PP: 
per protocol 
PPI: 
proton pump inhibitors 
PR: 
partial response 
pT: 
pathological tumor 
QD: 
once daily 
RFS: 
relapse-free survival 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
stable disease 
SERD: 
selective estrogen receptor degrader 
SoA: 
schedule of activties 
SUSAR: 
suspected unexpected serious adverse reactions 
TEAE: 
treatment emergent adverse events 
UGT: 
uridine 5'-phospho-glucoronosyltransferase 
ULN: 
upper limit of normal 
US: 
United States 
UV: 
ultraviolet 
 
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10.8 
APPENDIX 8: LIST OF STRONG CYP3A4 INDUCERS  
Concomitant administration of medications that are strong CYP3A inducers are not permitted 
throughout the active treatment phase in the amcenestrant treatment arms.  
The following tables were extracted in October 2020 from the Drug Interaction Database from the 
University of Washington (www.druginteractioninfo.org). 
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Table 8 - Strong CYP3A inducers  
Inducers 
Therapeutic Class 
Victim (oral unless 
otherwise specified) Max AUCR 
Precipitant dose (oral) 
Strong Inducers (AUCR ≤0.2 or CL Ratio ≥5) 
Rifampin 
Antibiotics 
Budesoinide 
0.003 
600 mg QD (7 days) 
Mitotane 
Other Antineoplastics 
Midazolam 
0.06 
Maximum of 3.5g TID (chronic 
therapy) 
Avasimibe 
Other Antilipemics 
Midazolam 
0.07 
750 mg/day (7 days) 
Rifapentine 
Antibiotics 
Midazolam 
0.07 
20 mg/kg QD (14days) 
Apalutamide 
Antiandrogens 
Midazolam 
0.08 
240 mg QD (29 days) 
Ivosidenib 
Cancer Treatments 
Midazolam 
0.10 (PBPK) 
1200 mg QD (19 days; PBPK 
modeling) 
Phenytoin 
Anticonvulsants 
Nisoldipine 
0.11 
200-450 mg/day (chronic 
treatment) 
Carbamazepine 
Anticonvulsants 
Quetiapine 
0.13 
200 mg TID (26 days) 
Enzalutamide 
Antiandrogens 
Midazolam 
0.14 
160 mg QD (85±3 days) 
St John’s Wort 
extract 
Herbal Medicines 
Midazolam 
0.20 
300 mg TID (14 days) 
Lumacaftor 
Cystic Fibrosis 
Treatments 
Ivacaftor 
0.20 
Not provided 
Phenobarbital 
Anticonvulsants 
Verapamil 
0.23 
100 mg QD (21 days) 
AUC = area under the curve; CL = clearance; QD = once daily; TID = three times a day. 
 
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10.9 
APPENDIX 9: LIST OF CYP SENSITIVE SUBSTRATES  
In vivo, amcenestrant is a moderate CYP3A inducer, and in vitro a potential inducer of CYP2B6 
and CYP2Cs family. Therefore, study participants receiving amcenestrant and treated or intended 
to be treated with the following drugs presented as CYP sensitive substrates should be carefully 
monitored since it may result in loss of efficacy of these agents. 
The tables for CYP sensitive substrates were extracted in October 2020 from the Drug- Drug 
Interaction Database from the University of Washington (www.druginteractioninfo.org). Some 
known substrates of the enzymes may not be listed because they do not have changes in exposure 
reaching sufficient level or may not have DDI studies with AUC/CL changes available. 
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Table 9 - In vivo CYP3A sensitive substrate  
Drug (oral) 
Therapeutic Class 
alfentanil 
Opioids 
alisporivir 
Antivirals 
almorexant 
Hypnotics - Sedatives 
alpha-dihydroergocryptine 
Dopaminergic Agonists 
aplaviroc 
CCR5 Receptor Antagonists  
aprepitant 
Neurokinin-1 Receptor Antagonists 
asunaprevir 
Antivirals 
atazanavir 
Protease Inhibitors 
atorvastatin 
HMG CoA Reductase Inhibitors (Statins) 
avanafil 
Erectile Dysfunction Treatments 
blonanserin 
Antipsychotics  
brecanavir 
Protease Inhibitors 
brotizolam 
Benzodiazepines 
budesonide 
Corticosteroids 
buspirone 
Anxiolytics  
capravirine 
Antivirals 
casopitant 
Neurokinin-1 Receptor Antagonists 
conivaptan 
Vasopressin Antagonists 
danoprevir 
Antivirals 
darifenacin 
Muscarinic Antagonists 
darunavir 
Protease Inhibitors  
dronedarone 
 Antiarrhythmics 
ebastine 
 H1 Receptor Antagonists 
eletriptan 
Triptans  
eliglustat (in subjects CYP2D6 PMs) 
Glucosylceramide Synthase Inhibitors 
elvitegravir 
HIV-Integrase Strand Transfer Inhibitors 
eplerenone 
Diuretics 
everolimus 
Immunosuppressants  
felodipine 
Calcium Channel Blockers  
indinavir 
Protease Inhibitors 
isavuconazole 
Antifungals 
itacitinib 
Kinase Inhibitors 
ivabradine 
Cardiovascular Drugs 
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Drug (oral) 
Therapeutic Class 
ivacaftor 
Miscellaneous Agents 
levomethadyl (LAAM) 
Drug Addiction Treatments 
lomitapide 
Other Antilipemics 
lopinavir 
Protease Inhibitors 
lovastatin 
HMG CoA Reductase Inhibitors (Statins) 
lumefantrine 
Antimalarials  
lurasidone  
Antipsychotics  
maraviroc 
CCR5 Receptor Antagonists 
midazolam 
Benzodiazepines 
morphothiadin 
Antivirals 
naloxegol 
Gastrointestinal Agents 
nisoldipine 
Calcium Channel Blockers  
paritaprevir 
Antivirals 
perospirone 
Antipsychotics  
quetiapine 
Antipsychotics  
saquinavir 
Protease Inhibitors 
sildenafil 
Erectile Dysfunction Treatments 
simeprevir 
Protease Inhibitors 
simvastatin 
HMG CoA Reductase Inhibitors (Statins) 
sirolimus 
Immunosuppressants  
tacrolimus 
Immunosuppressants 
terfenadine 
H1 Receptor Antagonists  
ticagrelor  
Anticoagulants and Antiplatelets 
tilidine 
Treatments of Pain and Inflammation 
tipranavir 
Protease Inhibitors  
tolvaptan 
Vasopressin Antagonists 
triazolam 
Benzodiazepines  
ubrogepant 
Migraine Treatments 
ulipristal 
Hormones 
vardenafil 
Erectile Dysfunction Treatments 
vicriviroc 
CCR5 Receptor Antagonists 
vilaprisan 
Progesterone Receptor Modulator 
voclosporin 
Immunosuppressants 
Note: The present list includes CYP3A substrates with AUC Ratio of at least 5 when co-administrated with strong CYP3 inhibitor. 
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Table 10 - In vivo CYP2B6 sensitive substrate  
Substrate (oral) 
Therapeutic Class 
bupropion 
Anticoagulants and Antiplatelets 
efavirenz  
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 
Note: There are no CYP2B6 substrates with AUC Ratio of at least 5, or decrease in oral CL of 80% or more. However, bupropion and efavirenz 
are considered the most sensitive substrates studied. 
Table 11 - In vivo CYP2C8 sensitive substrate  
Substrate (oral) 
Therapeutic Class 
daprodustat 
Other 
dasabuvir 
Antivirals 
repaglinide 
Meglitinides 
Note: The present list includes CYP2C8 substrates with AUC Ratios ≥5 or CL Ratios ≤0.20. 
Table 12 - In vivo CYP2C9 sensitive substrate  
Substrate (oral) 
Therapeutic Class 
tolbutamide 
Sulfonylureas 
(S)-warfarin  
Anticoagulants and Antiplatelets 
benzbromarone 
Anticoagulants and Antiplatelets 
celecoxib 
NSAIDS 
ibuprofen 
NSAIDS 
glimepiride 
Sulfonylureas 
glipizide 
Sulfonylureas 
lornoxicam 
NSAIDS 
meloxicam 
NSAIDS 
piroxicam 
NSAIDS 
Note: The present list includes CYP2C9 substrates with AUCR ≥5 or CL Ratio ≤0.20 
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Table 13 - In vivo CYP2C9 sensitive substrate  
Substrate (oral) 
Therapeutic Class 
lansoprazole (dexlansoprazol) 
Proton Pump Inhibitors 
(S)-mephenytoin 
Anticonvulsants 
omeprazole 
Proton Pump Inhibitors 
tilidine 
Treatments of Pain and Inflammation 
(R)-(-)-hexobarbital 
Hypnotics - Sedatives 
(R)-mephobarbital 
Anticonvulsants 
clobazam (parent drug) 
Benzodiazepines 
diazepam 
Benzodiazepines  
gliclazide 
Sulfonylureas 
pantoprazole 
Proton Pump Inhibitors 
proguanil (prodrug) 
Antimalarials 
rabeprazole 
Proton Pump Inhibitors 
Note: The present list includes CYP2C19 substrates with an AUCR ≥5, or CL ratio ≤0.20. 
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the 
clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly 
with medicinal products whose elimination is mainly dependent on these isoenzymes and whose 
therapeutic index is narrow. 
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10.10 APPENDIX 10: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS  
Table 14 - ECOG performance status scale  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
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10.11 APPENDIX 11: EASTERN COOPERATIVE ONCOLOGY GROUP RESPONSE 
CRITERIA  
Table 15 - ECOG response criteria  
Complete Response 
Clinical: Complete disappearance of all clinically detectable malignant disease 
Pathologic: Pathologic proof of a clinically complete response after repeat biopsy of areas of 
known malignant disease 
Partial Response 
≥50% decrease in tumor area (multiplication of longest diameter by the greatest perpendicular 
diameter), or ≥50% decrease in the sum of products of the perpendicular diameters of 
multiple lesions in the same organ site, or decrease in uni-dimensional measurable disease of 
≥30%, without increase in size of any area of known malignant disease of ≥25% or 
appearance of new areas of malignant disease 
Stable Disease 
No significant change in measurable or evaluable disease: 
• 
No increase in size of any known malignant disease 
• 
No appearance of new areas of malignant disease 
• 
This designation includes 
- 
Decrease in tumor area of in the sum of products of the individual lesions of <50% 
OR 
- 
Decrease in uni-dimensional measurable disease of <30% 
OR 
- 
Increase in size of any area of known malignant disease of <25% in any site 
• 
No deterioration in ECOG performance status of ≥1 level related to malignant disease 
Progressive Disease 
• 
Significant increase in size of lesions present at the start of therapy or after a response  
- 
≥25% in the area of any malignant lesions >2 cm2 or in the sum of products of the 
individual lesions, or 
- 
≥50% in the area if only one lesion is measurable and was ≤2 cm2 at the initiation 
of therapy 
OR 
• 
Appearance of new metastatic lesions known not to be present at the start of therapy 
OR 
• 
Stable objective disease associated with deterioration in ECOG performance status of 
≥1 level related to malignancy 
Repeat measurement should be performed at the same pre-therapy site(s) of malignant disease. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
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10.12 APPENDIX 12: PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX  
Table 16 - Preoperative endocrine prognostic index (PEPI)  
Pathology, biomarker status 
Relapse-Free Survival (RFS) 
Breast Cancer-Specific 
Survival (BCSS) 
Pathological tumor size 
 
 
T1/2 
0 
0 
T3/4 
3 
3 
Node status 
 
 
Negative  
0 
0 
Positive 
3 
3 
Ki67 
 
 
0%-2.7% (0-1*) 
0 
0 
>2.7%-7.3% (1-2*) 
1 
1 
>7.3%-19.7% (2-3*) 
1 
2 
>19.7%-53.1% (3-4*) 
2 
3 
>53.1% (>4*) 
3 
3 
ER status, Allred score 
 
 
0-2 
3 
3 
3-8 
0 
0 
* The natural logarithm interval corresponding to the percent Ki67 values on the original percentage scale 
Source: Matthew J. Ellis, Yu Tao, Jingqin Luo, et al. Outcome Prediction for Estrogen Receptor – Positive Breast Cancer Based on 
Postneoadjuvant Endocrine Therapy Tumor Characteristics. J Natl Cancer Inst. 2008;100:1380-8. 
10.13 APPENDIX 13: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA  
GFR (mL/min/1.73 m2) = 175 × (Scr) -1.154 × (Age)-0.203 × (0.742 if Female) × (1.212 if  
black race). 
GFR = Glomerular Filtration rate, Scr = Serum creatinine in mg/dL, Age in years 
Source: https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators/mdrd-adults-conventional-units. 
GFR calculator can be found via https://www.mdcalc.com/mdrd-gfr-equation.  
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10.14 APPENDIX 14: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by 
a governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials 
Guidance. Sponsor agreement MUST be obtained prior to the implementation of these procedures 
for the duration of the emergency. 
The decision for each individual participant to remain and/or start in the study should be made on 
a case by case basis based on best Investigator medical judgment. The clinical judgment of the 
treating physician should guide the management plan of each participant based on individual 
benefit/risk assessment and the evolving situation at the site. However, in case new participant 
eligible for the trial, the PI/site should assess the capacity to maintain these patients into the trial 
before any screening procedures will start. If the site cannot guarantee an accurate follow-up in 
the context of the trial, alternative treatment outside the clinical trial should be proposed. 
When participants are already randomized and/or treated, attempts should be made to perform all 
assessments in accordance with the protocol to the extent possible. 
When possible, the focus should be on Investigational Medicinal Product (IMP) administration 
and safety blood collection (eg, biochemistry and hematology). However, all efforts should be 
made to perform the measurements of key parameters for efficacy endpoints (eg, tumor 
assessments) (Section 8). The deviations from the study protocol (eg, treatment delay, omission, 
tests not performed…) should be documented in the source document and collected in the 
appropriate pages of the eCRF. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data (eg safety 
assessments, efficacy assessments especially the tumor assessment, PRO). 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed. 
Contingencies implemented due to emergency will be documented. 
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The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (Section 10.1.3). 
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10.15 Appendix 15: PROTOCOL AMENDMENT HISTORY  
Amendment 01 dated 20-Jan-2020  
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of activities 
Added details on information to be 
completed for demography and added the 
follicle stimulating hormone (FSH) test 
For completeness and consistency 
Section 1.3, schedule 
of activities, Section 
8.7 genetics and 
Section 10.5 genetics 
Added one blood sample for SAR439859 
treatment arms to investigate allelic 
variants of drug metabolizing enzymes 
and/or drug transporters 
To investigate drug metabolism enzyme variants  
(eg, UGT1A1 and UGT1A4) as intrinsic factors 
associated with PK of PK variability of SAR439859 
according to FDA’s comments 
Section 1.3 schedule 
of activities, Section 
7.1.1 definitive 
discontinuation and 
Section 8.6.1 tumor 
biopsy 
Revised “biopsy from surgery specimen” 
to “core-cut biopsy from surgery 
specimen” 
To clarify the requirement of surgical specimen 
handling 
Section 1.3 schedule 
of activities; Section 
8.6.1 tumor biopsy 
“For clinical sites reporting Ki67 
expression by range rather than a single 
value, a local re-evaluation might be 
requested to confirm Ki67 expression 
≥15%.” was added. 
To clarify that the precise value of Ki67 is needed to 
evaluate the patient’s eligibility, especially when ki67 is 
reported as 11-20% by the local lab.  
Section 4.3 
Justification for dose 
Revised safety data language according to 
new approved version of IB (3.0)  
To be in line with the new approved version of IB (3.0) 
of SAR439859. 
Section 5.1 Inclusion 
criteria 
Modified I03 to add Stage I patients and 
patients intended for upfront mastectomy 
Stage I patients could be included if the minimum 
tumor size is ≥10 mm, and patients intended for 
upfront mastectomy should not be excluded in this 
study. 
Section 5.1 Inclusion 
criteria and Section 
10.4 Contraception 
guidance 
Modified I04 to remove premenopausal 
women on GnRH analog and 
perimenopausal women (cessation of 
menses of duration ≤12 months), and 
modified text in Appendix 4 accordingly 
It’s not proper to compare post-therapy biopsy tissue 
versus baseline biopsy tissue in case GnRH analog is 
given in-between. It is also difficult to diagnose 
menopause for perimenopausal women by the FSH 
test. Hence premenopausal women on a GnRH and 
perimenopausal woman will not be included. 
Section 5.1 Inclusion 
criteria 
In I05, “A breast tumor size of at least 
10 mm in short axis measured by 
ultrasound” was replaced by “A breast 
tumor size of at least 10 mm in greatest 
dimension measured by ultrasound” 
According to AJCC Cancer Staging Manual 8th edition 
2017, the size of tumor refers to the greatest 
dimension. 
Section 5.2 Exclusion 
criteria 
E08, “Currently receiving (and unwilling to 
discontinue) hormone replacement 
therapy (last dose <14 days prior to 
randomization)” was replaced by “Recent 
use of hormone replacement therapy (last 
dose ≤30 days prior to randomization)” 
Discontinuing HRT could have impact on the tumor 
including analysis of key biomarkers such as Ki67. So 
the washout duration of HRT should be at least 
30 days prior to randomization.  
Section 5.2 exclusion 
criteria 
“E16 Men” was deleted. 
It’s a duplicated information with I10 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 exclusion 
criteria; Section 6.5 
Concomitant therapy 
New exclusion criteria E21 added. And 
drugs that are potential inhibitors of UGTs 
are moved to the list of prohibited 
therapies/medications 
To be in line with the IB of SAR439859, drugs that are 
potential inhibitors of UGTs are added to the exclusion 
criteria and the list of prohibited therapies/medications. 
Section 5.3 lifestyle 
consideration; 
Section 6.5 
concomitant therapy 
The duration of sun protection for patients 
taking SAR439859 was extended from 
“during study treatment” to “during study 
treatment and for at least 5 days after 
discontinuation of SAR439859” 
SAR439859 is expected to be eliminated from plasma 
after 5 times plasma half-life (approximately 24 hours). 
So, it is recommended that sun screen should be used 
during the treatment and at least 5 days after 
discontinuation of SAR439859. 
Section 6.6 Dose 
modification 
Dose modification criteria for SAR439859 
and letrozole was modified to not allow 
any dose modification or reintroduction of 
study treatment for NCI CTCAE Grade ≥3 
AEs. 
There is no justification to re-challenge SAR439859 or 
letrozole to a patient after the first occurrence of 
Grade ≥3 AE considering the short period of treatment  
(ie, 14 days) while in addition no direct benefit is 
intended to the patient in this study. 
Section 8.3 AE and 
SAE 
"symptomatic overdose has to be reported 
as a standard AE." replaced to 
"asymptomatic overdose has to be 
reported as a standard AE." 
Error correction 
Section 8.6.1 tumor 
biopsy 
Diagnostic biopsy baseline sample 
timelines changed from “within 3 months 
prior to randomization” To “within 4 weeks 
prior to randomization” 
“No hormone replacement treatment 
administrated from 30 days prior to 
diagnostic biopsy till screening” added. 
Clarification to be closer to the clinical practice. 
Discontinuing HRT could have impact on the tumor 
cell. If HRT is used within 30 days prior to diagnostic 
biopsy, the diagnostic biopsy should not be adopted as 
baseline sample. 
Section 8.6.1 tumor 
biopsy 
The fixing time for the tumor biopsy 
sample is revised from 24-48 hours to 
24-72 hours prior to processing and 
embedding at local pathology centers. 
To keep consistent with the updated requirements on 
tumor sample fixing in lab manual. 
Section 8.7 Genetics 
and Section 10.5 
Genetics 
“Genome-wide sequencing of DNA 
isolated from a tumor biopsy” is revised to 
“Mutation analysis of DNA isolated from a 
tumor biopsy”, and “or analysis of the 
entire genome” is deleted 
Genetic research will be proceeded with targeted 
panel, not Whole Exome Sequencing. 
Section 10.2 Clinical 
laboratory tests 
Estradiol is removed from screening tests 
Only FSH test is needed to confirm the 
postmenopausal status of the patients. Estradiol is not 
needed in this study. 
Throughout the 
amended protocol 
Performed administrative and editorial 
updates and corrections. 
To improve consistency and clarity. 
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11 
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2):951s-8s. 
6. Dowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, et al. Biomarker 
changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of 
hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 
2005;23(11):2477-92. 
7. Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, et al. Annual Report to 
the Nation on the Status of Cancer, Part I: National Cancer Statistics. Cancer. 
2018;124(13):2785-800. 
8. American Cancer Society. Cancer Facts & Figures 2019. Atlanta: American Cancer Society; 
2019. 
9. National Cancer Institute. SEER Stat Fact Sheets: Breast Cancer. [Online]. 2019. [cited 2019 
Mar 19] Available from URL:https://seer.cancer.gov/statfacts/html/breast.html. 
10. National Cancer Institute. NCI Dictionary of Cancer Terms. [Online]. 2016. [cited 2019 Mar 
19] Available from URL: http://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid5 446564. 
11. American Cancer Society. Breast Cancer Detailed Guide. [Online]. 2016. [cited 2016 Mar 7] 
Available from URL: http://www.cancer.org/acs/groups/cid/documents/webcontent/003090-
pdf. pdf. 
12. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and 
prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):R6. 
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13. Puhalla S, Bhattacharya S, Davidson NE. Hormonal therapy in breast cancer: a model disease 
for the personalization of cancer care. Mol Oncol. 2012;6(2):222-36. 
14. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
15. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al, editors. AJCC 
Cancer Staging Manual (8th edition). Springer International Publishing: American Joint 
Commission on Cancer; 2017. 
16. Schmid P, Pinder SE, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II Randomized 
Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole 
Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast 
Cancer. J Clin Oncol. 2016;34(17):1987-94. 
17. ClinicalTrials.gov. A Neoadjuvant Study of Abemaciclib (LY2835219) in Postmenopausal 
Women With Hormone Receptor Positive, HER2 Negative Breast Cancer (neoMONARCH). 
Available from URL: https://clinicaltrials.gov/ct2/show/NCT02441946.  
 
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According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Phase 2 window study of two dose levels of SAR439859 (SERD) versus letrozole 
in newly diagnosed pre-operative post-menopausal patients with ER positive, 
HER2 negative primary breast cancer 
SAR439859-ACT16106 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 09-Jun-2021 
Total number of pages: 
51 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objective .............................................................................................................................. 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.2.3 
Exploratory objectives ...................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy /pharmacodynamics endpoints......................................................................................... 12 
2.1.3.1 
Primary endpoint(s) ........................................................................................................................ 12 
2.1.3.2 
Secondary endpoint(s) ................................................................................................................... 13 
2.1.3.3 
Additional endpoint(s) .................................................................................................................... 13 
2.1.4 
Safety endpoints ............................................................................................................................ 13 
2.1.4.1 
Adverse events variables ............................................................................................................... 14 
2.1.4.2 
Deaths ............................................................................................................................................ 15 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 15 
2.1.4.4 
Vital signs variables ....................................................................................................................... 15 
2.1.4.5 
Electrocardiogram variable ............................................................................................................ 16 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 16 
2.1.6 
Pharmacodynamic variables .......................................................................................................... 16 
2.1.6.1 
Mutational profiling in circulating free DNA .................................................................................... 16 
2.1.6.2 
Tumor biopsy ................................................................................................................................. 17 
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2.1.7 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 17 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 18 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 19 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 19 
2.3.1 
Intent-to-treat (ITT) population ....................................................................................................... 20 
2.3.2 
Modified ITT (mITT) population ...................................................................................................... 20 
2.3.3 
Per-protocol (PP) population .......................................................................................................... 20 
2.3.4 
Safety population ........................................................................................................................... 21 
2.3.5 
Pharmacokinetic population ........................................................................................................... 21 
2.3.6 
Pharmacokinetic/pharmacodynamic population ............................................................................ 21 
2.4 
STATISTICAL METHODS ............................................................................................................. 21 
2.4.1 
Demographics and baseline characteristics .................................................................................. 22 
2.4.2 
Prior or concomitant medications ................................................................................................... 22 
2.4.3 
Anticancer therapies ...................................................................................................................... 22 
2.4.4 
Extent of investigational medicinal product exposure and compliance ......................................... 23 
2.4.5 
Analyses of efficacy/pharmacodynamics endpoints ...................................................................... 24 
2.4.5.1 
Analysis of primary endpoint(s) ...................................................................................................... 24 
2.4.5.2 
Analyses of secondary endpoints .................................................................................................. 26 
2.4.5.3 
Additional analyses ........................................................................................................................ 27 
2.4.6 
Analyses of safety data .................................................................................................................. 28 
2.4.6.1 
Analyses of adverse events ........................................................................................................... 28 
2.4.6.2 
Deaths ............................................................................................................................................ 30 
2.4.6.3 
Analyses of laboratory variables .................................................................................................... 30 
2.4.6.4 
Analyses of vital sign variables ...................................................................................................... 31 
2.4.6.5 
Analyses of electrocardiogram variables ....................................................................................... 31 
2.4.7 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 32 
2.4.7.1 
Analysis of Pharmacokinetic variables........................................................................................... 32 
2.4.7.2 
Pharmacodynamic variables .......................................................................................................... 32 
2.4.8 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 33 
2.4.9 
Pharmacokinetic/Pharmacodynamic analysis ............................................................................... 33 
2.4.9.1 
PK / PD analyses ........................................................................................................................... 33 
2.4.9.2 
Concentration-ECG analyses ........................................................................................................ 34 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 35 
2.5.1 
General conventions ...................................................................................................................... 35 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 35 
2.5.3 
Missing data ................................................................................................................................... 35 
2.5.4 
Unscheduled visits ......................................................................................................................... 37 
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2.5.5 
Pooling of centers for statistical analyses ...................................................................................... 37 
2.5.6 
Statistical technical issues ............................................................................................................. 37 
3 
INTERIM ANALYSIS ..................................................................................................................... 38 
4 
DATABASE LOCK ........................................................................................................................ 39 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 40 
6 
REFERENCES ............................................................................................................................... 41 
7 
LIST OF APPENDICES ................................................................................................................. 42 
APPENDIX A 
TNM ANATOMIC STAGE GROUPS ................................................................................... 43 
APPENDIX B 
EASTERN COOPERATIVE ONCOLOGY GROUP RESPONSE CRITERIA ..................... 44 
APPENDIX C 
PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX (PEPI) ......................................... 45 
APPENDIX D 
TECHNICAL DETAILS FOR PRIMARY ANALYSIS ........................................................... 46 
APPENDIX E 
TECHNICAL DETAILS FOR ICC CALCULATION .............................................................. 47 
APPENDIX F 
GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY 
PARAMETERS .............................................................................................................................. 48 
APPENDIX G 
INTERNATIONALLY AGREED SOC ORDER .................................................................... 49 
APPENDIX H 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 50 
APPENDIX I 
ECG CRITERIA FOR POTENTIALLY SIGNIFICANT ABNORMALITIES - FOR 
PHASE 2/3 STUDIES (ONCOLOGY ONLY) ................................................................................. 51 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomical, therapeutic and chemical 
BCL2: 
B-Cell Lymphoma 2 
BUN: 
blood urea nitrogen 
cfDNA: 
cell-free DNA 
CI: 
confidence interval 
CTCAE: 
Common Terminology Criteria for Adverse Events 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
ER: 
estrogen receptor 
HER2: 
human epidermal growth factor receptor 2 
INR: 
international normalized ratio 
ITT: 
intent-to-treat 
MedDRA: 
Medical Dictionary of Regulatory Activities 
mITT: 
modified ITT 
MRD: 
minimal residual rate 
NCI: 
National Cancer Institute 
PEPI: 
Preoperative Endocrine Prognostic Index 
PgR: 
progesterone receptor 
PP: 
per-protocol 
PT: 
prothrombin time 
QD: 
once daily 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN  
This is an international, prospective, open-label, Phase 2 randomized study of 2-week 
preoperative treatment in ER positive, HER2 negative invasive primary breast cancer.  
After a screening phase of up to 14 days, postmenopausal women with early breast cancer will be 
randomly (1:1:1) assigned to one of the following treatment arms: amcenestrant 400 mg QD, 
amcenestrant 200 mg QD or letrozole 2.5 mg QD. Patients will be treated for 14 days. The 
surgery date should be fixed before randomization. The surgery is to be performed 1 (+1) day 
after the last dose of study treatment. 
Approximately 126 patients will be randomized such that 120 evaluable participants are reached. 
A total of 40 evaluable participants per treatment arm are expected.  
1.2 
OBJECTIVES  
1.2.1 Primary objective  
The primary objective is to determine whether SAR439859 given at 2 different doses improves 
the antiproliferative activity when compared to letrozole. 
1.2.2 Secondary objectives  
The secondary objectives are: 
• To assess the proportion of participants with a relative decrease from baseline in Ki67 
≥50% in the three treatment arms. 
• To assess ER degradation in biopsies in participants in the three treatment arms. 
• To assess safety in the three treatment arms. 
1.2.3 Exploratory objectives  
The exploratory objectives are: 
• To assess the pharmacokinetics (PK) of SAR439859 400 mg QD and 200 mg QD. 
• To assess the complete cell cycle arrest (CCCA: Ki67 ≤2.7%) rate in the three treatment 
arms. 
• To determine the expression of additional tumor protein biomarkers (eg, BCL2) and the 
RNA profile over time in the three treatment arms. 
• To assess protein biomarkers in tumor tissues by using digital image-based methods and 
changes over time in the three treatment arms. 
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• To determine the DNA mutation profile in tumor and cell-free DNA (cfDNA) to assess a 
potential link with Ki67 effect 
• To evaluate PK/PD relationship of SAR439859 with pharmacodynamics and/or safety. 
• To assess the Eastern Cooperative Oncology Group (ECOG) clinical response rate in the 
three treatment arms. 
• To assess the Preoperative Endocrine Prognostic Index (PEPI) risk score of the three 
treatment arms 
• To assess in participants the pathological complete response (pCR) of SAR439859 given 
at 2 different doses and letrozole 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size is determined based on the following assumptions:  
• The geometric mean of percentage reduction in Ki67 after a 14-day treatment period for 
the control arm is assumed to be 70% (1, 2, 3). 
• The geometric mean of reduction in Ki67 after a 14-day treatment period is increased to 
85% for each SAR439859 arm. Therefore the geometric means of residual Ki67 (defined 
as one minus the geometric mean of reduction) are assumed to be 30% for the control arm 
and 15% for treatment arms, corresponding to a log fold difference of -0.693 (log(0.15)-
log(0.3) under the alternative hypothesis.  
• The standard deviation of the log-fold change after a 14-day treatment period is assumed 
to be 1. 
A total of 40 evaluable participants (where evaluable are defined as participants who have both 
baseline and post treatment available biopsies with Ki67 values) per treatment arm will be needed, 
in order to achieve 85% marginal power at the overall one-sided Type I error rate of 2.5% 
controlled with an Hochberg procedure, based on a one-sided t-test on the log-transformed data. 
The disjunctive power, ie, the probability to reject at least one null hypothesis, that the true log-
fold change in Ki67 after a 14-day treatment period for both SAR439859 arms and the control 
arm are the same, is estimated at 91.5%. 
Allowing for a 5% non-evaluable participant rate, the total sample size for randomization is 
126 participants (42 per treatment arm). 
1.4 
STUDY PLAN  
Graphical study design is presented in Figure 1. Details on efficacy and safety assessments are 
included in Section 1.3 of the protocol. 
 
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Figure 1 - Graphical study design  
 
 
 
IMP = investigational medicinal product, QD = once daily, R= randomization 
  
 
Screening period / 
baseline 
Treatment period 
(14 days)  
Post-treatment safety 
follow-up period 
(30 ±7 days)  
Surgery and 
tumor biopsy 
Up to 14 days 
before 
randomization 
D1 
1st IMP 
intake 
SAR439859 400 mg QD 
SAR439859 200 mg QD 
Letrozole 2.5 mg QD 
D7 (±2)  
D14 
Last IMP 
intake 
D15 (+1) 
30 (±7) days 
after last IMP 
intake 
Within 
3 days 
R 
Biopsy 
Baseline 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The protocol amendment history table below gives the timing, rational, and key details of major 
changes to the protocol statistical section. 
Table 1 - Protocol amendment statistical changes  
Amendment 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
26-Jan-2021 
To add baseline Ki67 as a covariate 
when comparing the Ki67 log-
proportional change after a 14-day 
treatment period between treatment 
groups. 
Changed statistical model from t-test to 
analysis of covariance (ANCOVA) model. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the amended statistical analysis plan. 
Table 2 - Statistical analysis plan statistical changes  
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
This version 
To remove hypothesis test for primary 
endpoint due to early enrollment 
termination. 
Removed p-value calculation by Hochberg 
procedure and multiplicity issue in 
Section 2.4.5.1. 
2 
This version 
To assess the impact of Ki67 from 
different resource on primary analysis. 
Performed primary analysis on Ki67 by each 
reader as sensitivity analysis in Section 2.4.5.1.3. 
2 
This version 
To keep consistent with ICC 
calculation. 
The derivation of the single Ki67 value used for 
primary analysis model has been clarified based 
on the average of the log transformed values 
instead of the average of two raw values in 
Section 2.1.3.1. 
2 
This version 
To add baseline Ki67 as a covariate 
when comparing the log proportional 
change after a 14-day treatment period 
between treatment groups. 
The statistical model has been changed from 
t-test to analysis of covariance (ANCOVA) model. 
2 
This version 
To align with Protocol Amendment 02 
Added Complete Cell Cycle Arrest (CCCA) as an 
exploratory endpoint in Section 2.1.3.3 and 
corresponding analyses in Section 2.4.5.4. 
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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
This version 
Based on the findings of the POETIC 
trial (4), patients with a high Ki67 at 
baseline (ie, ≥10%) and a low Ki67 
(ie, <10%) after 2 weeks of AI had a 
lower 5-years recurrence rate than 
patients with a high Ki67 at both 
baseline and after 2 weeks of AI. 
Added post-treatment Ki67 <10% as an 
exploratory endpoint in Section 2.1.3.3 and 
corresponding analyses in Section 2.4.5.4. 
2 
This version 
To align with Protocol Amendment 02. 
Added photosensitivity reaction in AESI in 
Section 2.1.4.1 
2 
This version 
To detail the analysis of additional 
tumor protein biomarkers. 
Specified the analysis for additional protein 
biomarkers (PgR, BCL2, Cyclin D1 etc) in 
Section 2.4.7.2.2 
2 
This version 
Additional analyses of ECG were added 
to further safety evaluation.  
The following analyses have been added: 
• 
Abnormalities analyses 
• 
Descriptive statistics and plots 
• 
Validation of the QT correction 
• 
Concentration-ECG analyses 
2 
This version 
To detail the model used in primary 
analysis. 
Added appendix of Technical details for primary 
analysis 
2 
This version 
To add ECG criteria for potentially 
significant abnormalities as reference. 
Added appendix of ECG criteria for potentially 
significant abnormalities - for Phase 2/3 studies 
(oncology only) 
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last value or measurement taken up to the date and time of the 
first dose of study treatment irrespective of the treatment. This definition applies for all variables 
unless otherwise specified.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with summary statistics in the safety and efficacy sections (Section 2.4.6 and Section 2.4.5). 
Demographic characteristics 
Demographic variables include race (White, Black or African American, Asian, American 
Indian/Alaska Native, Native Hawaiian/Other Pacific Islander, Not reported, Unknown), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), age in years (quantitative 
and qualitative variable: [18-64], [65-84], and  ≥85 years, height, weight (kg) and ECOG 
performance status (PS) at baseline.  
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at diagnosis 
The following disease characteristics at initial diagnosis will be described: 
• Time from initial diagnosis of breast cancer to first study treatment administration (in 
weeks), 
• Histology 
• Disease Location  
• Laterality 
• Histopathology type 
• Stage of the disease.  Stage I-IV for breast cancer will be derived from TNM information 
as collected in CRF based on the rules defined in Appendix A 
• HER2 status  
• ER status (local assessment as collected in CRF) 
• PgR status (local assessment as collected in CRF) 
• Ki67 level (%) (local assessment as collected in CRF, quantitative and qualitative variable: 
<15%, ≥15% to <20%, and ≥20%) 
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Disease characteristics at baseline (central assessment) 
• Ki67 level (%) (quantitative and qualitative variable: <15%, ≥15% to <20%, and ≥20%) 
• ER status  
• PgR status  
• BCL2 status  
• Cyclin D1 status  
Prior anti-cancer therapies 
• Prior anti-cancer treatment or radiotherapy 
Patients with prior anti-cancer treatment or radiotherapy are not allowed for study participation 
(unless the treatment was completed 1 year before study entry).  Listings of prior anti-cancer 
therapies, if any, will be provided for prior anti-cancer treatment as well as radiotherapy 
respectively.  
2.1.2 Prior or concomitant medications  
All medications taken from the signed informed consent date up to the first study treatment 
administration and until the end of the study (ie, 30 days after the end of treatment) are to be 
reported in the case report form pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD), 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the patient used prior (<) to first study treatment 
administration. Prior medications can be those discontinued before first administration or 
those ongoing during the treatment phase.   
• Concomitant medications are any treatments received by the patient concomitantly to the 
study treatment from first administration to the last administration +30 days. A given 
medication can be classified both as a prior medication and as a concomitant medication.   
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.3. 
2.1.3 Efficacy /pharmacodynamics endpoints  
2.1.3.1 Primary endpoint(s)  
The primary endpoint is the percentage reduction in Ki67 level after a 14-day treatment period 
compared to baseline. Ki67 level is expressed in terms of percentage of positive tumor cells tested 
by immunohistochemistry [IHC]) and will be recorded independently by 2 histopathologists. A 
single Ki67 result derived by the antilog transformation of the mean of the log of 2 reported 
values, will be used for calculation. The inter-reader variability in reporting Ki67 values will be 
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assessed during the trial, and a third adjudicator might be involved if the agreement between two 
Ki67 values does not meet the pre-specified criteria  (see Section 2.4.5.1.1).  
The primary endpoint is calculated as: 100 × (Ki67pre - Ki67post) / Ki67pre, where Ki67pre and 
Ki67 post are used to denote the pre-treatment and post-treatment Ki67 values respectively. Since 
both SAR439459 and letrozole treatments intend to reduce Ki67 levels, a positive result is 
expected with this formula and denoting Ki67 value reduction.  
2.1.3.2 Secondary endpoint(s)  
Secondary efficacy endpoints are defined below. 
• The proportion of participants with relative decrease from baseline in Ki67 ≥50% 
(ie, 100 ×(Ki67pre - Ki67post)/Ki67pre  ≥50%)  as tested by IHC after a 14-day treatment 
period compared to baseline.  
• Change in ER expression H-Score after a 14-day treatment period. This endpoint is 
calculated as H-scorepost –H-scorepre，where H-scorepost and H-scorepre are used the denote 
the post- and pre-treatment H-scores respectively.  
2.1.3.3 Additional endpoint(s)  
• ECOG response rate is defined as clinical complete response (cCR), pathological complete 
response (pCR) or partial response (PR), as measured by ultrasound according to ECOG 
response criteria (see Appendix B).  The ECOG response (except pCR) will be assessed by 
investigator and collected in CRF. 
• The proportion of participants achieving pCR after a 14-day treatment period.  The pCR 
will be assessed by investigator and collected in CRF.  
• PEPI risk score is the sum of the risk points derived from the pT stage, the pN stage, Ki67 
levels and ER status of the surgical regimen. It will be calculated with the rules as defined 
in Appendix C. PEPI score will be calculated for both RFS and BCSS based scale.  
• Complete cell cycle arrest (CCCA) is a marker of reduced cellular proliferation, is defined 
as a Ki67 ≤2.7% at D15 on central assessment. 
• The proportion of participants with post-treatment Ki67 <10%. 
• Additional protein expression assessments (eg, Ki67) by using digital image-based 
method. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, vital signs, weight, electrocardiogram (ECG) and 
ECOG PS. 
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Observation period  
The observation period starts from the time when the patient gives informed consent and is 
divided into 3 periods: 
• The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• The on-treatment period is defined as the time from the first dose of IMP up to last dose of 
IMP.  
• The post-treatment safety follow-up period is defined as the time from last administration 
of the IMP to the last administration of the IMP +30 day 
2.1.4.1 Adverse events variables  
AEs (including serious adverse events [SAEs] and AEs of special interest [AESI]) will be 
collected from the time of signed informed consent until the end of study. In addition, All SAEs,  
non-serious AEs of special interest (as defined in Section 2.1.4.1),  and non-serious AEs related to 
IMP still ongoing at time of study treatment discontinuation will be followed until resolution or 
stabilization. 
Adverse event observation period  
• Pretreatment AEs are defined as any AE occurring during the pretreatment period.  
• Treatment-emergent AEs (TEAEs) are defined as AEs that develop, worsen (according to 
the Investigator’s opinion), or become serious during  
- 
on treatment period (from first dose of IMP to last dose of IMP), or 
- 
on treatment and post-treatment period (from first dose of IMP to last dose of IMP 
+30 days) 
Analysis will be performed for both analysis periods (see Section 2.4.6.1) 
• All AEs (including SAEs and AESI) will be graded according to National cancer institute 
common terminology for adverse events (NCI-CTCAE) v5.0 and coded to a lower-level 
term (LLT), preferred term (PT), high-level term (HLT), high-level group term (HLGT), 
and associated primary system organ class (SOC) using the version of MedDRA currently 
in effect at Sanofi at the time of database lock. 
Adverse events of special interest 
Specific analyses will be performed for the following AEs (see Section 2.4.6.1): 
• Pregnancy occurring in a female participant entered in the clinical trial. 
• Symptomatic overdose (serious or nonserious) with IMP 
• Increase in alanine transaminase (ALT) ≥ Grade 2 
• Photosensitivity reaction  
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2.1.4.2 Deaths  
A listing of on-study deaths (if any) will be provided. 
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis including hematology and biochemistry. 
Clinical laboratory values will be converted into standard international units that will be used in 
all listings and tables. 
For laboratory safety variables, parameters measured on the day of the first study treatment intake 
will be considered as part of the baseline measurements. 
For laboratory safety variables, the treatment period will start at first study treatment intake 
+1 day. 
The laboratory safety parameters will be classified as follows:   
• Hematology  
- 
Red blood cells, platelets, and white blood cells: platelet count, red blood cell (RBC) 
count, hemoglobin, hematocrit, white blood cell with differential: neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils.  
- 
Coagulation: prothrombin time (PT) and international normalized ratio (INR). 
• Biochemistry 
- 
Metabolism: fasting glucose, total protein.  
- 
Electrolytes: potassium, sodium, calcium.  
- 
Renal function: creatinine, blood urea nitrogen (BUN), urea, eGFR 
- 
Liver parameters: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, total and direct bilirubin. 
• Hormone:  
- 
Follicle-stimulating hormone (for women with non-childbearing potential)  
2.1.4.4 Vital signs variables  
Vital signs include: pulse rate, systolic and diastolic blood pressure, weight, temperature and 
ECOG PS (0, 1, 2, 3, 4, 5). 
For vital signs, parameters measured on the day of the first study treatment intake will be 
considered as part of the baseline measurements. 
For vital signs, the treatment period will start at first study treatment intake +1 day. 
For a given parameter, a patient will be considered as evaluable if at least one measure of this 
parameter is available during the on-treatment period. 
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2.1.4.5 Electrocardiogram variable  
Triplicate electrocardiogram assessments will be described as normal or abnormal by central 
reading at pre-dose on Day 1 and at pre-dose and 3h post-dose on Day 14. 
Single 12-lead ECGs will be recorded at screening by local assessment and investigator’s opinion 
(normal/abnormal) will be reported.  
The following parameters will be assessed/derived and provided for statistical analysis: 
• PR (in ms)  
• QRS (in ms) 
• QT (in ms) 
• Mean RR (in ms) 
• QTcB (in ms) = QT.RR-0.50 
• QTcF (in ms)=QT.RR-0.33 
• Heart rate (in bpm) = 60/RR with RR in seconds 
In case of triplicates assessments, only the mean of the triplicate will be presented. All parameters 
will be analyzed as raw data and absolute change from baseline (raw value at visit X - baseline 
value). In addition, for the abnormalities analyses and descriptive statistics, PR and QRS will be 
also analyzed as percent change from baseline (100 x [raw value at visit X - baseline 
value]/baseline value). Semi-automatic reading from core lab of these quantitative parameters will 
be used for concentration-ECG analyses. 
2.1.5 Pharmacokinetic variables  
SAR439859 plasma concentrations will be determined at the predefined time point according to 
the SoA presented in Section 1.3 of the protocol.  
In addition, population PK approaches might be used to calculate individual PK parameters 
estimates. The population PK analysis, if any, will be described in a separate report.  
PK concentrations (and potentially PK parameter estimates) will be used to conduct an 
exploratory PK/PD relationship analysis of SAR439859 with pharmacodynamics (eg, Ki67) 
and/or safety (eg, triplicate ECG parameters, incidence of AEs). 
2.1.6 Pharmacodynamic variables  
2.1.6.1 Mutational profiling in circulating free DNA  
Genomic analyses on circulating cell-free DNA (cfDNA) isolated from plasma samples will be 
performed in this study at baseline. The mutational status of a panel of 77 cancer driver genes 
(Roche AVENIO panel) will be determined by next generation sequencing (NGS) technology. 
Different types of genomic aberrations will be investigated such as single nucleotide variants, 
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indels, abnormal copy number variants or fusion genes. For both single nucleotide variants and 
indels, the type of mutation (missense, frameshift, inframe, …), the mutant allele frequency (%) 
and the mutant concentration (ie, the number of mutant molecules per mL plasma) will be 
provided.  
In addition, saliva samples will be collected pre-treatment as a source of normal reference DNA 
for comparison with the cfDNA but also with the tumor-derived DNA (see Section 2.1.6.2) data. 
Sequencing may be performed on the DNA from the saliva sample. In the event of technical 
issues affecting the sample, a replacement genetic saliva DNA sample may be requested from the 
participant. 
2.1.6.2 Tumor biopsy  
Determination of tumor characteristics (HER2 status by IHC or FISH, ER by IHC, Ki67 by 
IHC, etc) on the diagnostic biopsy specimen based on local laboratory results serves for 
participant selection. 
Biopsy samples collected at screening and after a 14-day treatment period will be centrally 
examined for Ki67, DNA mutation analysis, RNA expression analysis, and protein analysis 
(eg, ER, PgR, BCL2, Cyclin D1) in central laboratory. Ki67 index will be recorded independently 
by 2 histopathologists blinded to treatment allocation. For the assessment of agreement in Ki67 
measurements, see Section 2.4.5.1.1. Ki67, ER, PgR, BCL-2 will also be collected by digital 
image-based method. 
Genome-wide transcriptome sequencing of ribonucleic acid (RNA) isolated from tumor biopsies 
will be performed at screening and after a 14-day treatment period by measuring the relative 
abundances of the RNA transcripts through RNA sequencing. The ER activation score related to 
ER degradation will be derived from these RNAseq data. Other gene signatures (such as PAM50), 
immune cell abundances or pathways may be also explored from these data.  
Finally, whole exome sequencing from tumor biopsies will be also performed at screening to 
highlight genomic aberrations directly from the tumor. A focus will be done on a predefined 
cancer research list containing around 1600 genes. As for mutational profiling from cfDNA, 
different types of genomic aberrations will be investigated such as single nucleotide variants, 
indels, abnormal copy number variants or fusion genes. For both single nucleotide variants and 
indels, the type of mutation (missense, frameshift, inframe, …) and the mutant allele frequency 
(%) will be provided. The saliva samples will be used to differentiate somatic from non-somatic 
mutations. The tumor mutational burden score and the microsatellite instability will be also 
obtained from these data. 
2.1.7 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
Further therapies after discontinuation of IMP include further anti-cancer therapy, surgery and 
radiotherapy. 
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2.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patients who signed the study informed consent. 
Randomized patient consists of all participants from the enrolled population and for whom there is 
a confirmation of successful allocation of a randomization number by IRT. This population is also 
referred as the intent-to-treat (ITT) population defined in Section 2.3.1.  
For patient study status, the total number of patients for each one of the following categories will 
be presented in the clinical study report (CSR) using a flow-chart diagram or a summary table: 
• Screened patients 
• Nonrandomized but treated patients 
• Randomized patients 
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who completed treatment 
• Patients who discontinued study treatment and reasons for permanent discontinuation 
• Patients who completed study. 
• Patients who did not complete the study period and reasons for study discontinuation 
• Patient still on treatment (interim analysis only) 
Number of screened patients, number of screen failure patients and reasons for screen failure will 
be summarized in a separated table. In addition, number and percentage of screened patients by 
country and sites will be presented. 
For all categories of patients (except for the screened and nonrandomized category) percentages 
will be calculated using the number of patients in randomized population as the denominator.  
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group.  
Additionally, the following analysis populations will be summarized in a table by number of 
patients on the randomized population: 
• Intent-to-treat population 
• Modified ITT (mITT) population 
• Per-protocol (PP) population 
• Safety population  
• Pharmacokinetic-evaluable population 
Definition of study populations are provided in Section 2.3. 
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2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
• A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized twice,  
OR 
• A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
• Kit dispensation without IRT transaction 
• Erroneous kit dispensation 
• Kit not available 
• Randomization by error 
• Patient randomized twice 
2.3 
ANALYSIS POPULATIONS  
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
The randomized population is defined in Section 2.2. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
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2.3.1 Intent-to-treat (ITT) population  
ITT population is defined as all participants from the enrolled population and for whom there is a 
confirmation of successful allocation of a randomization number by IRT. Participants will be 
analyzed according to the treatment arm assigned at randomization. This population will be used 
for analysis of baseline parameters. 
2.3.2 Modified ITT (mITT) population  
mITT population is defined as all participants from the ITT population who have taken at least 
one drug, and who have both baseline and post treatment available biopsies with Ki67 values. 
This is the primary analysis population for all efficacy and pharmacodynamic parameters. 
2.3.3 Per-protocol (PP) population  
PP population is defined as all participants from the mITT population without relevant 
deviation(s), which could affect the evaluation of the study drug on the primary endpoint. PP 
population will be used for sensitivity analysis of the primary endpoint. 
Major or critical deviations leading to exclusion from the per-protocol population is defined as 
follows:     
• Informed consent procedure:  
- 
Patient does not sign study informed consent or informed consent is signed after study 
procedure 
• Inclusion/exclusion criteria:  
- 
Patient without histological and cytological proven diagnosis of invasive breast 
adenocarcinoma  
- 
The localized breast cancer is not eligible for upfront breast conservative surgery or 
upfront mastectomy 
- 
Patient is not postmenopausal as per age and criteria defined in the protocol 
- 
The breast tumor size is less than 10 mm in short axis measured by ultrasound 
- 
Patient doesn't have a primary tumor positive in ER or non-overexpressing HER2 per 
protocol definition 
- 
Ki67 level is lower than 15% at diagnosis from immunohistochemistry of the tumor 
based on local laboratory results 
- 
Ki67 level is lower than 15% at baseline based on central laboratory results 
- 
Prior anti-cancer treatment was completed <1 year prior to inclusion into this trial 
- 
Patient is not female 
- 
Recent use of hormone replacement therapy (last dose ≤30 days prior to 
randomization) 
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• Concomitant medications/therapy 
- 
Protocol prohibited therapy/medication/vaccine administered 
• IMP management:  
- 
Patient receives ≤10 days or ≥16 days of the IMP treatment 
• Randomization procedure: 
- 
IMP dispensed without Randomization 
- 
IMP actually dispensed to the subject is different from the IMP allocated 
2.3.4 Safety population  
Safety population is defined as all participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be analyzed according to the treatment 
arm they actually received at Day 1.  
Randomized patients from whom it is unclear whether they took the IMP will be included in the 
safety population, and included in the treatment arms as randomized. 
Non-randomized but treated patients will not be part of the safety population; however, their 
safety data will be presented separately. 
This population is the primary population for the analysis of all safety parameters. 
2.3.5 Pharmacokinetic population  
Pharmacokinetic-evaluable population is defined as all participants from the safety population 
who receive at least one dose of SAR439859 and with at least 1 available post-treatment plasma 
concentration with adequate documentation of dosing and sampling dates and times. 
2.3.6 Pharmacokinetic/pharmacodynamic population  
PK/PD population is defined as all treated subjects as long as they had at least one 
pharmacodynamic assessment time-matched with pharmacokinetic parameters of interest. The 
specific population will be defined for each PK/PD analysis. 
2.4 
STATISTICAL METHODS  
Continuous data will be summarized using the number of available data, mean, standard 
deviation, median, minimum and maximum for each treatment group.  
Categorical and ordinal data will be summarized using the number and percentage of patients in 
each treatment group. 
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Due to early termination of enrollment, the planned sample size will not be achieved, therefore no 
hypothesis test will be performed on primary endpoint, confidence intervals will be estimated as 
two-sided and will used for descriptive purposes only. 
In summary tables, treatment arms will be presented as follows: 
• SAR439859 400 mg QD (SAR439859 400 mg) 
• SAR439859 200 mg QD (SAR439859 200 mg) 
• Letrozole 2.5 mg QD (Letrozole 2.5 mg) 
Parameters on demographics and baseline characteristics would be provided by treatment arms 
and overall.  
2.4.1 Demographics and baseline characteristics  
Parameters described in Section 2.1.1 will be summarized on the ITT population using descriptive 
statistics. Analyses for the safety population will be included in the appendices if the size of the 
safety population is different (>10%) from the size of that in the primary analysis population for 
any treatment group. 
The medical and surgical history will be summarized according to the SOC and PT (SOC will be 
sorted according to the internationally agreed order (see Appendix G) and PT by overall 
decreasing frequency). 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the ITT population. The anti-cancer 
therapy will be listed separately.  
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomic category (ATC) class and the first 3 digits of the ATC class (therapeutic 
category).  All ATC codes corresponding to a medication will be summarized, and the patients 
will be counted once in each ATC category (anatomic or therapeutic) linked to the medication. 
Therefore, the patients may be counted several times for the same medication.  
The tables for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on the incidence in SAR439859 400 mg QD 
column. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used.  
2.4.3 Anticancer therapies  
A listing of prior anti-cancer treatment, including intent, reason of discontinuation, 
relapse/progression date, best response, regimen/line number, drug name, start and end 
date/ongoing, will be provided by patient.  
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A similar listing will be provided for prior radiation therapy, including location, total dose, intent, 
start and end date/ongoing.   
2.4.4 Extent of investigational medicinal product exposure and compliance  
The extent of investigational medicinal product (IMP) exposure will be assessed and summarized 
on the safety population (Section 2.3.4), by treatment group. 
Following information will be summarized: 
• Duration of exposure (days) defined as (date of last dose – date of first dose +1). 
• Cumulative dose (mg): the cumulative dose is the sum of all doses during the study 
treatment exposure. 
• Actual dose intensity (mg/day): 
ADI=
Cumulative Dose (mg)
Duration of exposure in days 
• Planned dose intensity (mg/day) is the planned dose at Day 1 per protocol:  
- 
400 mg/day for the SAR439859 400 mg QD group 
- 
200 mg/day for the SAR439859 200 mg QD group 
- 
2.5 mg/day for the letrozole 2.5 mg QD group.  
• The relative dose intensity (RDI, in %) for SAR439859 or letrozole is defined as:  
Relative Dose Intensity= Actual Dose Intensity
Planned Dose Intensity ×100 
Summary statistics will be provided for cumulative dose, actual dose intensity and relative dose 
intensity (according to the following categories: 0-80%, 80-100%, >100%). 
Dose modifications 
• Dose reduction:  a dose is deemed to have been reduced if the dose taken by a patient is 
lower than the dose taken on the previous day or the day before dose(s) omitted. 
• Dose omission: one omission corresponds to a dose with a dose equal to 0 mg/day 
between two non-zero doses. Several consecutive dose omissions will be counted as one 
episode of omission. 
Dose information variables will be summarized descriptively (n, mean, standard deviation, 
median, minimum and maximum). Analyses will be performed based on the number of patients. 
The number of patients with at least one SAR439859 or letrozole dose modification with the 
following details will be provided: 
• Number (%) of patients with at least one dose modification (reduction or omission) 
• Number (%) of patients with at least one dose reduction 
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• Number (%) of patients with at least one dose omission 
• Number (%) of dose reductions by patient according to the following categories: 0, 1, >1 
• Number (%) of dose omissions by patient according to the following categories: 0, 1, >1 
• Number (%) of patients with at least 4 consecutive days of dose omission 
2.4.5 Analyses of efficacy/pharmacodynamics endpoints  
2.4.5.1 Analysis of primary endpoint(s)  
2.4.5.1.1 Primary analysis  
The primary analysis will be performed on the mITT population defined in Section 2.3.2. 
Ki67 at baseline (Ki67pre), after a 14-day treatment period (Ki67post) and the percentage reduction 
in Ki67 from baseline defined as 100 × (Ki67pre - Ki67post) / Ki67pre will be summarized by 
treatment groups using descriptive statistics (such as the number of observations, arithmetic mean, 
geometric mean, median, standard deviation (SD), minimum, and maximum).The geometric mean 
of percentage reduction in Ki67 will be calculated with 1 minus geometric mean of proportional 
change, where proportional change is Ki67post/ Ki67pre. 
The percentage reduction in Ki67 from baseline for each patient will be displayed in a waterfall 
plot. In the waterfall plot, patients with Ki67 level decreased after 14-day treatment will have 
negative percentage change. The patients will be ordered from highest positive change to smallest 
negative change. 
Assuming Ki67 value follows a log-normal distribution, log (Ki67post) and log (Ki67pre) will be 
used to denote the logs of the post-treatment and baseline values respectively. 0.1% will be added 
to untransformed Ki67 with 0 value to avoid the mathematical anomaly that arises because the log 
of zero is minus infinity. As a consequence of the assumption of a lognormal distribution, the log 
proportional changes ie, log(Ki67post/Ki67pre) is also normally distributed. The log proportional 
change will be compared between treatment arms using an analysis of covariance (ANCOVA) 
model adjusting for the log Ki67 at baseline. Geometric LS-means ratio of proportional change 
(and associated 95% CI) between treatment arms will be calculated from the estimate (and 
associated 95% CI) of the difference of least squared (LS)-means of the log-proportional change 
(and associated 95% CI) from the ANCOVA model and converted by antilog transformations. For 
each treatment arm, geometric LS-means of the proportional change from baseline (and associated 
95% CI) will be obtained from the ANCOVA model after conversion by antilog transformations. 
Geometric LS-means of percentage reduction in Ki67 (and associated 95% confidence intervals) 
will be calculated with 1 minus geometric LS-means of proportional change (and associated 95% 
confidence intervals). Hypothesis test will not be performed due to early enrollment termination. 
Details of primary analysis can be found in Appendix D. 
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Evaluation of inter-reader variability 
The reproducibility of Ki67 measurements among readers will be estimated by calculating an 
intraclass correlation coefficient (ICC). The definition along with the statistical model for ICC 
estimation are provided in Table 3. 
Table 3 - Estimation of ICC during the trial  
Notation 
Definition 
Model  
Consistency or 
absolute agreement 
ICC 
The inter-reader agreement on log 
proportional change from baseline in 
Ki67 measurement after 14-day 
treatment period. 
Mixed-effect model adjusted for 
baseline covariate, based on single 
rating 
Absolute agreement 
Mean estimations along with 95% confidence intervals will be reported for the ICC. Details of 
ICC estimation can be found in Appendix E. 
The ICC estimate will be checked at the following time-points: 
• The interim analysis when 20 patients in each arm evaluable for the primary endpoint 
(Section 3) 
• The analysis when at least 75% patients of the study completed treatment and Ki67 value 
available for analysis.  
• The analysis when all of the patients completed treatment and Ki67 value available for 
analysis.  
The ICC has a range of 0-1, with 1 denoting highest agreement.  The ICC estimate at each 
analysis will be reviewed with study team, and in case a high inter-reader variability is suspected 
(eg, ICC <0.8), team would evaluate the necessity of inviting a third adjudicator to provide a 
single Ki67 result based on the readings of two assessors.  
In any case, the decision as to whether adjudication will take place needs to be finalized before 
database lock.   
2.4.5.1.2 Subgroup analyses  
Evaluation of consistency 
The consistency of the results from the primary analysis will be evaluated across pre-defined 
subgroups in patients available in the subgroup of consideration. The subgroups included but not 
limited are defined in Table 4. Depending upon the study results, additional subgroups may be 
examined, and subgroups with small sample sizes may be pooled to create a larger meaningful 
subgroup. For each subgroup, geometric LS-mean of percentage reduction in Ki67 with their 
associated 95% CIs and geometric LS-mean ratio of proportional change between treatment arms 
with their associated 95% CIs will be provided for each treatment arm.  
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Evaluation of interactions 
For each pre-defined factor defined in Table 4, log-fold change in Ki67 will be analyzed using 
linear regression model with terms for the factor, treatment and their interaction, adjusted by log 
baseline Ki67. The p-value of the test of interaction will be provided. 
Other prognostic factors 
Since the results from the primary analysis could be impacted by confounding factors, any 
potential issues will be examined and, if confirmed, exploratory analysis of the primary endpoint 
will be done accordingly. A multiple linear regression model will be used to identify prognostic 
factors among the demographic and baseline characteristics factors described in the Table 4 using 
a stepwise selection procedure with a 15% significance level for removing effects. For significant 
prognostic factors identified in the multivariate model, the balance between treatment groups will 
be assessed.  
Table 4 - Subgroup analyses  
Prognostic factor 
Description 
Age 
<65 years or ≥65 years 
Race 
Asian or White or Other 
Tumor stage 
1 or 2 or ≥ 3 
Tumor size (greatest dimension) 
≥10 mm to < 20mm, ≥ 20mm 
Ki67 level at baseline (per central assessment) 
<20% or ≥20% 
ER H-score at baseline 
Low ER+. (H-score 1-100) or 
            moderate ER+ (H-score 101-200) or 
 high ER+ (H-score 201-300). 
Progesterone receptor 
< 20% vs ≥20% 
2.4.5.1.3 Sensitivity analyses  
The primary analysis will also be performed according to each reader, respectively.  
The primary analysis will be repeated in the PP population. 
2.4.5.2 Analyses of secondary endpoints  
Analysis of secondary endpoints will be performed primarily on the mITT population and may be 
performed on the PP population. 
Relative decrease from baseline in Ki67 ≥50% 
The proportion of participants with a relative decrease from baseline in Ki67 ≥50% (ie (Ki67pre - 
Ki67post)/Ki67pre ≥50%) will be provided for each treatment arm along with the 95% CI computed 
using the Clopper-Pearson method.  
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Logistic regression will be used with a 50% decrease in Ki67 as the response variable to 
determine potential factors (as defined in Table 4) that are predictive and/or prognostic for the 
disease.  A multivariable logistic regression model will be conducted using a stepwise selection 
procedure with a 15% significance level for removing effects.  
ER degradation by protein expression 
ER expression in H-score before and after treatment, the absolute change from baseline (defined 
as ER H-scorepost – ER H-scorepre) as well as the relative change from baseline (defined as 100 × 
(absolute change from baseline / ER H-scorepre)) will be summarized for each arm. In case 
differences on baseline ER H-score are observed, additional ANCOVA model on the absolute 
change from baseline adjusted for baseline may be performed. In that case, LS-means of the 
absolute change from baseline and associated 95% CI will be provided. 
2.4.5.3 Additional analyses  
Clinical response rate 
ECOG response rate on each arm will be estimated by dividing the number of participants with 
clinical response (defined as clinical complete response (cCR), pathological complete response 
(pCR) or partial response (PR) as measured by ultrasound according to ECOG response criteria) 
by the number of participants from analysis population of the respective treatment arm. In 
addition, 95% two-sided CIs will be computed using the Clopper-Pearson method.  
pCR rate 
Pathological complete response rate on each randomized arm will be estimated by dividing the 
number of participants with complete pathological response (ie, no histologic evidence of invasive 
tumor cells in the surgical breast specimen and axillary nodes identified after neoadjuvant 
treatment) by the number of participants from the analysis population of the respective treatment 
arm. In addition, 95% two-sided CIs will be computed using the Clopper-Pearson method.  
PEPI risk score 
The total PEPI score, as defined in Section 2.1.3.3, is the sum of the risk points derived from the 
pT stage, the pN stage, Ki67 levels and ER status of the surgical regimen.  The total score after 
treatment will be summarized (quantitatively and by 3 risk categories: 0 (low risk), 1-3 (medium 
risk) and >=4 (high risk)) for each treatment arm.   
Complete cell cycle arrest (CCCA) 
The proportion of participants with CCCA will be provided for each treatment arm along with the 
95% CI computed using the Clopper-Pearson method. 
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Post-treatment Ki67 <10%  
The proportion of participants with post-treatment Ki67 <10% will be provided for each treatment 
arm along with the 95% CI computed using the Clopper-Pearson method. 
Ki67 by digital image-based method 
The primary analysis defined in Section 2.4.5.1.1 (except for ICC) will be performed on Ki67 
results by digital image-based method. 
2.4.6 Analyses of safety data  
The summary of safety results will be presented by treatment group.  All safety analyses will be 
performed on the safety population as defined in Section 2.3.4. Safety data in patients who do not 
belong to the safety population (eg, exposed but not randomized) will be listed separately. 
2.4.6.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Treatment emergent AEs are defined as AEs that develop, worsen (according to the Investigator’s 
opinion), or become serious during the  
• on treatment period (from first dose of IMP to last dose of IMP), or 
• on treatment and post-treatment period (from first dose of IMP to last dose of 
IMP+30 days) 
TEAE analyses will be produced for both analysis periods and therefore two sets of TEAEs tables 
will be generated. Pre-treatment adverse events will be described separately.  
The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same adverse event, the maximum (worst) grade by period of observation is 
used. Summaries will be provided for all grades and for grade ≥3 (including Grade 5). Missing 
grades, if any, will be included in the “all grades” category.  
Sorting within tables ensures the same presentation for the set of all adverse events for each 
observation period (pre-treatment and treatment-emergent). For that purpose, the table of all 
treatment-emergent adverse events presented by SOC and PT sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs will define the presentation order for all 
other tables unless otherwise specified. Sorting will be based on the incidence of AEs of the 
SAR439859 400 mg QD arm. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• Overview of TEAEs, summarizing number (%) of patients with any 
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- 
Treatment emergent AEs 
- 
Grade ≥3 TEAEs 
- 
Grade 5 TEAE (any TEAE with a fatal outcome during the on-treatment period) 
- 
Serious TEAEs 
- 
Treatment emergent AEs leading to definitive treatment discontinuation 
- 
Treatment-related TEAE 
- 
Treatment-related TEAEs of grade ≥3 
- 
Serious treatment-related TEAEs 
• All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least 1 treatment-emergent adverse event sorted by the SOC internationally agreed 
order. The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 
1 TEAE. 
• Most frequent (5% of patients overall, on PT) TEAE by primary SOC and PT, 
• All treatment-related TEAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 related TEAE. 
Analysis of all treatment emergent serious adverse event(s) 
• All serious TEAEs by primary SOC, HLGT, HLT, and PT, showing the number (%) of 
patients with at least 1 serious TEAEs, sorted by the internationally agreed SOC order. 
The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• All serious TEAEs by primary SOC and PT, showing the number (%) of patients with at 
least 1 serious TEAE. 
• All serious treatment-related TEAEs, by primary SOC and PT, showing the number (%) of 
patients with at least 1 serious related TEAE.  
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAE leading to definitive treatment discontinuation by primary SOC and PT, 
showing the number (%) of patients with at least 1 TEAE leading to treatment 
discontinuation. 
A listing of patients with a TEAE leading to treatment discontinuation will be provided. This 
listing will include the TEAE, toxicity grade, relationship to study treatment and the day of 
occurrence. 
Analysis of all treatment-emergent adverse event(s) leading to dose reduction 
• All TEAEs leading to dose reduction by primary SOC and PT, showing the number (%) of 
patients with at least 1 TEAE leading to dose reduction. 
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Analysis of adverse events of special interest 
• A listing of patients with at least one AESI cited in Section 2.1.4.1 will be provided. This 
listing will include the category of AESI, the seriousness, the day of occurrence and the 
outcome. 
Analysis of pre-treatment adverse events  
• All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
2.4.6.2 Deaths  
A listing of all deaths during the study will be provided, including the period of occurrence 
(eg, pretreatment, on-treatment or post-treatment follow up) and the reason of death. A table 
summary for number (%) of patients who died by study period and reason of death might be 
generated as needed.  
2.4.6.3 Analyses of laboratory variables  
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters defined in Section 2.1.4.3. Each test result will be graded by NCI-CTCAE version 5.0 
whenever applicable. 
For hematological parameters and for some selected biochemistry parameters, Sanofi sponsor 
generic ranges (LLN, ULN) are defined and will be used for grading (see list of parameters in 
Appendix F). For other biochemistry parameters (eg, for hepatic enzymes ALT, AST, Alkaline 
phosphatase, total bilirubin), grading will be derived using local laboratory normal ranges. The 
number of patients with abnormal laboratory tests at baseline will be presented by grade and all 
grades together. The frequency of patients in each grade and all grades of laboratory abnormalities 
during treatment will be summarized. For patients with multiple occurrences of the same 
laboratory variable during the treatment, the maximum grade (worst) per patient will be used. The 
denominator used for percentage calculation is the number of patients with at least 1 evaluation of 
the laboratory test during the considered observation period. When appropriate, the summary table 
will present the frequency of patients with any grade of abnormal laboratory tests and with Grade 
3-4 abnormal laboratory tests. 
In addition, for hematology and biochemistry toxicities, shift tables showing the number of 
patients in each grade at baseline by grade during the on-treatment period will be provided.  
For laboratory tests for which NCI-CTCAE V5.0 scale is not applicable, potentially clinically 
significant abnormalities (PCSA) values are defined as abnormal values considered medically 
important by the Sponsor according to predefined criteria/thresholds based on literature review 
(Appendix H). 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment period, 
taking into account all evaluations performed during the on-treatment period, including 
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nonscheduled or repeated evaluations. The incidence of PCSA any time during the on-treatment 
period will be summarized by treatment group irrespective of the baseline level. 
Laboratory parameters for which both CTCAE grading or PCSA criteria are not applicable will be 
classified into low/normal/high group by means of laboratory normal ranges. For such parameters, 
a summary table which present the frequency of patients with any abnormal test will be provided.  
2.4.6.4 Analyses of vital sign variables  
Vital signs parameters are described in Section 2.1.4.4. 
• Summaries of baseline, Day 7 and Day 14 (or end of treatment) assessments will be 
provided for all parameters (except for weight which will be assessed at baseline and D14 
only). 
• For ECOG performance status, a shift table will be provided for post-treatment evaluation 
relative to baseline. 
For vital sign variables, potentially clinically significant abnormalities (PCSA) values are defined 
as abnormal values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review. PCSA criteria will determine which patients had at 
least 1 PCSA during the on-treatment period, taking into account all evaluations performed during 
the on-treatment period, including nonscheduled or repeated evaluations. The number of all such 
patients will be the numerator for the on-treatment PCSA percentage. The treatment-emergent 
PCSA denominator by group for a given parameter will be based on the number of patients 
assessed for that given parameter in the treatment-emergent adverse event period by treatment 
group on the safety population 
The incidence of PCSAs during the on-treatment period will be summarized by treatment group 
irrespective of the baseline and/or according to the following baseline categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
2.4.6.5 Analyses of electrocardiogram variables  
Abnormalities analyses 
For all parameters, an “on-treatment” analysis will be performed on the safety population, using 
all assessments during the TEAE period including any unplanned/rechecked values. 
The same definition of PCSAs (Appendix I) will be used for all parameters, whatever the source. 
For the PCSAs on change from baseline in corrected QT data, in case a subject experienced 
multiple abnormalities, she will be counted only once in the most severe category.  
Counts of subjects with PCSAs will be provided in summary tables regardless of the normal or 
abnormal status of the baseline. This table will be presented by treatment group. 
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Descriptive statistics and plots 
For each of the ECG parameters, descriptive statistics on baseline and changes from baseline at 
each post-baseline time point will be provided by treatment group. Summary plots (mean +/- 
SEM) will be provided by visit and treatment group. 
Validation of the QT correction 
In order to explore whether the QTcF interval seem to be independent from the RR intervals, the 
plots of the QTcF intervals versus RR (using all replicates) will be provided, separately for off-
drug and on-drug data, using ECGs send by core lab. The scatter plots, the regression line, and 
estimator of slope with 90% confidence interval (CI) will be provided, separately for off drug and 
on drug and in each treatment group. 
2.4.7 Analyses of pharmacokinetic and pharmacodynamic variables  
2.4.7.1 Analysis of Pharmacokinetic variables  
Plasma concentrations will be summarized for each SAR439859 treatment arm by time point 
using descriptive statistics (such as the number of observations, arithmetic and geometric mean, 
median, standard deviation (SD), standard error (SE), coefficient of variation (CV)%, minimum, 
and maximum). 
Plasma concentrations will be included in the descriptive statistics if actual sampling occurs in the 
following predefined time windows: within 2 hours before administration for predose sample on 
Day 7, Day 14, [2-4h] for samples at 3h post dose on Day 14 and Day 15;  
In addition, a listing of individual concentration data by time and day will be provided. 
Concentrations reported as below the limit of quantification (BLQ) will be replaced by 0 for 
descriptive statistics. 
In case PK parameters estimates are calculated and used as part of the PK/PD exploratory 
analysis, they will be summarized by SAR439859 treatment arm using descriptive statistics (such 
as the number of observations, arithmetic and geometric mean, median, standard deviation (SD), 
standard error (SE), coefficient of variation (CV)%, minimum, and maximum). 
2.4.7.2 Pharmacodynamic variables  
2.4.7.2.1 Mutational profiling in circulating free DNA  
Descriptive statistics of the type of genomic aberrations at baseline will be provided. The 
prevalence of patients with mutations for each gene and the overall genomic profile of patients 
(annotated with the treatment arm and possibly other patients’ characteristics) will be described. 
For some key genes of interest, additional analyses may be performed by treatment arm to better 
understand the circulating mutational profile of patients. To this end, the description of each 
aberration or the distribution of the mutant allele frequency, mutant concentration and abnormal 
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copy number variant will be also described through descriptive statistics. Some associations with 
baseline or pharmacodynamic variables (eg, the baseline or % change from baseline of Ki67, the 
change in ER expression H-Score) will be presented through descriptive statistics and graphical 
presentation. 
The genomic aberrations detected in the cfDNA will be compared to the ones identified from the 
tumor biopsies.  
2.4.7.2.2 Tumor biopsy analyses  
The additional protein biomarkers (PgR, BCL-2, Cyclin D1 and potentially other proteins) will be 
analyzed similarly to the ER protein (see Section 2.4.5.2).  
For tumor-related RNA data, the measurements at baseline and after a 14-day treatment in 
addition to the change from baseline will be described per treatment arm for each gene signature 
(eg, ER activation score) or immune scores by descriptive statistics and graphical visualization. 
For tumor-related DNA data, the prevalence of patients with mutations for each gene and the 
overall genomic profile of patients (annotated with the treatment arm and possibly other patients’ 
characteristics) will be described at baseline. For some key genes of interest, additional analyses 
may be performed by treatment arm to better understand the tumor mutational profile of patients. 
To this end, the description of each aberrattion at baseline or the evolution of the mutant allele 
frequency/copy number variation over time will be also described through descriptive statistics 
and graphical visualization. Some associations with baseline or pharmacodynamic variables 
(eg, the baseline or % change from baseline of Ki67, the change in ER expression H-Score) will 
be presented through descriptive statistics and graphical presentation. The tumor mutational 
burden score and the microsatellite instability will be also described with descriptive statistics per 
treatment arm. 
2.4.8 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
A summary table will be provided for further anti-cancer therapies based on WHO-DD coding. 
Similar analysis will be performed for further radiotherapy. 
A listing of surgery information, including the date and type of surgery, and the reason of surgery 
not performed (if any) will be provided.   
2.4.9 Pharmacokinetic/Pharmacodynamic analysis  
2.4.9.1 PK / PD analyses  
Graphical presentation of SAR439859 PK concentrations (and possibly PK parameters of interest) 
will be done in regards of efficacy/PD endpoints. Efficacy/PD endpoint would include but may 
not be limited to Ki67 expressed as % change from baseline, change in ER expression H-Score or 
ER activation score (degradation). Plasma concentrations below LLOQ will be replaced by 
LLOQ/2. 
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2.4.9.2 Concentration-ECG analyses  
Exploratory plots 
The relationship between change from baseline of ECG parameters and SAR439859 
concentrations will be first explored graphically, in order to investigate any potential delayed or 
sustained effects and the type of modeling to be done, using the following plots, by treatment 
group:  
• Plot of mean (± SEM) change from baseline in ECG data and mean SAR439859 
concentration versus time (hours post-dose) overlaid onto the same plot. 
• A scatterplot for PK plasma concentration versus change from baseline in ECG parameter, 
including trend lines (simple linear regression and loess line) 
Concentration - ECG analyses will be performed for the QTcF, heart rate, PR and QRS intervals. 
Time-matched pharmacokinetic concentrations will be used. 
Modeling 
In case of direct and linear relationship between concentrations and change from baseline in ECG 
parameters (QTcF, HR, PR, and QRS), a linear mixed effect model will be carried out, with 
population intercept, fixed terms for nominal time, with the concentration (slope) and the baseline 
ECG parameter (centered baseline values: subject’s baseline minus the mean of the overall 
population) as covariates, and with random terms for individual subject deviation from the 
population intercept and slope, using SAS Proc Mixed. The analysis model was the following:  
Change from Baseline in ECG parameterij = (+ Ai) +× Baseline ECGi + C×Timej +  × 
Concentrationij + eij 
with: 
• α and β are the fixed population intercept and concentration slope. 
• γ is the fixed effect for the baseline ECG slope 
• Ai is the random intercept for the ith subject, with Ai assumed to be normally distributed 
with null mean and an unstructured variance-covariance matrix per subject block. 
• C is the fixed effect associated with Timej (0 for pre-dose of D14 and 1 for 3h post-dose of 
D14) 
• eij represents i.i.d. standard normal errors. 
The estimates of each effect of the model, along with their 95% confidence interval, will be 
provided. In addition, prediction of change from baseline in ECG parameters at selected 
concentrations (geometric mean concentration at 3h of D14 for each dose) will be also calculated 
from the model (estimates and 90% confidence intervals). The scatter plot of individual ECG 
values versus PK concentrations with the regression line overlaid will be also provided. 
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Goodness-of-fit and residual plots will be provided. In case of lack of fit (ie, the linear model is 
not adequate), alternative models will be explored, like linear models using transformed 
concentration values (eg, logarithmic concentrations) or nonlinear models (Emax or sigmoid Emax 
models).  
The following goodness-of-fit plots were provided: 
• Model observed versus predicted change from baseline in ECG (delta ECG) 
• Quantile-Quantile plots of residuals 
• Distribution of residuals 
• Residual plots for concentration, centered baseline ECG and time 
• Quantiles of concentration and change from baseline ECG overlaid with slope of the final 
model 
Effect of SAR439859 on heart rate will be evaluated by plotting the time course of the mean 
change from baseline in heart rate by dose.  
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
Not applicable. Renal function parameter including eGFR will be collected directly via CRF.  
2.5.2 Data handling conventions for secondary efficacy variables  
Not applicable. 
2.5.3 Missing data  
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with non-
missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
Handling of disease characteristics missing/partial dates 
• If the day is missing, it will be imputed by 1. 
• If the month is missing, it will be imputed by 1 (only for medical history variables). 
• If the year is missing, no imputation will be performed. 
Incomplete date of cancer diagnosis: 
• 
 If the day of the cancer diagnosis is missing, the date will be imputed to the first day of 
the month. 
• 
 If day and month of the cancer diagnosis are missing, no imputation will be done. 
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Handling of medication missing/partial dates  
No imputation of medication (other than anti-cancer therapies) start/end dates or times will be 
performed.  If a medication date or time is missing or partially missing and it cannot be 
determined whether it was taken prior or concomitantly, it will be considered a prior and 
concomitant medication. 
Imputation of incomplete date for post anti-cancer treatment start date  
For post anti-cancer treatments, if the medication start date is missing, it will be imputed as 
follows: 
• If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date +1. 
• If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 
• If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start date will be set to the treatment end 
date +1. 
• If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
• If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
• If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set 
to 01. 
• If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date +1. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
• For the calculation of the treatment duration, the date of the last dose of IMP is equal to 
the date of last administration reported on the end-of-treatment case report form page.  If 
this date is missing, the exposure duration should be left as missing.  
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
• When the date and time of the first IMP administration is missing, all adverse events that 
occurred on or after the day of randomization should be considered as treatment-emergent 
adverse events.  The exposure duration should be kept as missing. 
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Missing grade 
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done and missing grades will be summarized in the 
“all grades” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to the regimen is missing, then the relationship to the regimen 
has to be assumed and the adverse event considered as such in the frequency tables of possibly 
related adverse events, but no imputation should be done at the data level. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or > ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
2.5.4 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. 
2.5.5 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
2.5.6 Statistical technical issues  
Not applicable. 
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3 
INTERIM ANALYSIS  
In order to support project strategic planning, an interim analysis may be conducted after the first 
20 patients in each arm evaluable for the primary endpoint. The analysis will have no impact on 
the trial itself.  
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4 
DATABASE LOCK  
The final database lock is planned 4 weeks after last patient last visit in the study. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
  
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6 
REFERENCES  
1. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, et al. Short-term changes in 
Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen 
alone or combined correlate with recurrence-free survival.  Clin Cancer Res. 2005;11(2 Pt 
2):951s-8s. 
2. Schmid P, Pinder S, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II Randomized 
Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole 
ComparedWith Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast 
Cancer. J Clin Oncol. 2016;34(17):1987-94. 
3. ClinicalTrials.gov. A Neoadjuvant Study of Abemaciclib (LY2835219) in Postmenopausal 
Women With Hormone Receptor Positive, HER2 Negative Breast Cancer (neoMONARCH) 
[Online]. 2020 [cited 2021 Jun 09]. Available from URL: 
https://clinicaltrials.gov/ct2/show/NCT02441946 
4. Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, et al. Long-term outcome 
and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women 
with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-
group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443-54. 
 
 
 
 
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7 
LIST OF APPENDICES  
 
Appendix A 
TNM anatomic stage groups 
Appendix B 
Eastern Cooperative Oncology Group Response Criteria 
Appendix C 
Preoperative Endocrine Prognostic Index (PEPI) 
Appendix D 
Technical details for primary analysis 
Appendix E 
Technical details for ICC calculation 
Appendix F 
Generic ranges for hematological and biochemistry parameters 
Appendix G 
Internationally agreed SOC order 
Appendix H 
Potentially clinically significant abnormalities criteria 
Appendix I 
ECG criteria for potentially significant abnormalities – for Phase 2/3 studies 
(oncology only) 
 
 
 
 
 
 
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Appendix A 
TNM anatomic stage groups  
 
When T is 
And N is 
And M is  
Then the stage group is 
Tis 
N0 
M0 
0 
T1 
N0 
M0 
1A 
T0 
N1mi 
M0 
1B 
11 
N1mi 
M0 
1B 
T0 
N1 
M0 
IIA 
T1 
N1 
M0 
IIA 
T2  
N0 
M0 
IIA 
T2  
N1 
M0 
IIB 
T3  
N0 
M0 
IIB 
T1  
N2  
M0 
IIIA 
T2 
N2 
M0 
IIIA 
T3  
N1 
M0 
IIIA 
T3 
N2 
M0 
IIIA 
T4 
N0 
M0 
IIIB 
T4 
N1 
M0 
IIIB 
T4 
N2 
M0 
IIIB 
Any T 
N3 
M0 
IIIC 
Any T 
Any N 
M1 
IV  
Source: Giuliano AE, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. 
CA Cancer J. Clin. 2017;67:290–303. doi: 10.3322/caac.21393 
Note to programmer:  
T0 corresponds to “No evidence of primary tumor” as collected in CRF 
N0 corresponds to “No regional lymph nodes metastasis” as collected in CRF.               
M0 corresponds to “No distant metastasis” as collected in CRF.  
If any of the following is checked, then the stage would be “Not evaluable”.  
• 
Primary tumor cannot be evaluated 
• 
No regional lymph node metastasis 
• 
No distant metastasis. 
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Appendix B 
Eastern Cooperative Oncology Group Response Criteria  
 
Complete Response 
Clinical: Complete disappearance of all clinically detectable malignant disease 
Pathologic: Pathologic proof of a clinically complete response after repeat biopsy of areas of 
known malignant disease 
Partial Response 
≥50% decrease in tumor area, without increase in size of any area of known malignant 
disease of >25% or appearance of new areas of malignant disease 
Stable Disease 
No significant change in measurable or evaluable disease: 
• 
No increase in size of any known malignant disease 
• 
No appearance of new areas of malignant disease 
• 
This designation includes 
- 
Decrease in tumor area in the sum of products of the individual lesions of 
<50% 
OR 
- 
Decrease in uni-dimensional measurable disease of <30% 
OR 
- 
Increase in malignant disease of <25% in any site 
• 
No deterioration in ECOG performance status of ≥1 level related to malignant 
disease 
Progressive Disease 
• 
Significant increase in size of lesions present at the start of therapy or after a 
response  
- 
≥25% in the area of any malignant lesions >2 cm2 or in the sum of products of the 
individual lesions, or 
- 
≥50% in the area if only one lesion is measurable and was ≤2 cm2 at the initiation 
of therapy 
OR 
• 
Appearance of new metastatic lesions known not to be present at the start of 
therapy 
OR 
• 
Stable objective disease associated with deterioration in ECOG performance status 
of ≥1 level related to malignancy 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55 
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Statistical Analysis Plan  
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 45 
Appendix C 
Preoperative Endocrine Prognostic Index (PEPI)  
 
Pathology, biomarker status 
Relapse-Free Survival (RFS) 
Breast Cancer-Specific 
Survival (BCSS) 
Pathological tumor size 
 
 
T1/2 
0 
0 
T3/4 
3 
3 
Node status 
 
 
Negative  
0 
0 
Positive 
3 
3 
Ki67 
 
 
0%-2.7% (0-1*) 
0 
0 
>2.7%-7.3% (1-2*) 
1 
1 
>7.3%-19.7% (2-3*) 
1 
2 
>19.7%-53.1% (3-4*) 
2 
3 
>53.1% (>4*) 
3 
3 
ER status, H-score score 
 
 
0-2 
3 
3 
3-8 
0 
0 
* The natural logarithm interval corresponding to the percent Ki67 values on the original percentage scale 
Source: Matthew J. Ellis, Yu Tao, Jingqin Luo, et al. Outcome Prediction for Estrogen Receptor – Positive Breast Cancer Based on 
Postneoadjuvant Endocrine Therapy Tumor Characteristics. J Natl Cancer Inst. 2008;100:1380-8. 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
09-Jun-2021 
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Version number: 2 
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Page 46 
Appendix D 
Technical Details for Primary Analysis  
For each treatment arm: 
• the geometric mean of Ki67 proportional change (and associated 95% CI) will be 
computed as  
exp (arithmetic mean of Ki67 log-proportional change) 
• the geometric mean of Ki67 percent reduction (and associated 95% CI) will be computed 
as 
1 - geometric mean of proportional change (and associated 95% CI) 
 
An analysis of covariance (ANCOVA) will be used to compare the Ki67 log-proportional changes 
between groups,  
 
Y = a + bX + cZ 
Where 
• Y is log-proportional change from baseline to D14, 
• X is the treatment group variable, 
• Z is the log baseline Ki67, ie, log(Ki67pre), 
Geometric LS-means ratio of proportional change (and associated 95% CI) between treatment arm 
will be calculated from the estimate (and associated 95% CI) of the difference of LS-means of the 
log-proportional change (and associated 95% CI) and converted by antilog transformations. 
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Statistical Analysis Plan  
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Page 47 
Appendix E 
Technical Details for ICC calculation  
A mixed effect model will be fitted to the log proportional change of Ki67 measurement after 
14-day treatment period:  
𝑦𝑖𝑗= µ + 𝑟𝑖+ 𝛿𝑋𝑖𝑗+ 𝜀𝑖𝑗      
Where 
• 𝑦𝑖𝑗 is the log proportional change from baseline to Day 14 in Ki67 measurement for the ith 
patient scored by the jth reader 
• 𝑟𝑖 is the random effect of the ith patient 
• 𝑋𝑖𝑗 is the log baseline Ki67 value for the ith patient scored by the jth reader 
• 𝜀𝑖𝑗 is the residual error term 
The random effects ri, and εij are assumed to be normally distributed with means of zero and 
variances of 𝜎1 and 𝜎2, respectively, and to be independent of each other. 
ICC is defined by 𝜎1/ (𝜎1 + 𝜎2) 
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Statistical Analysis Plan  
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Version number: 2 
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Page 48 
Appendix F 
Generic ranges for hematological and biochemistry parameters  
The current list of generic ranges for hematological parameters (for adults) is provided in the table 
below: 
Table 5 - Generic ranges for hematological parameters  
LBTEST 
GENDOR 
LBSTRESU 
LBGNNRLO - LBGNNRHI 
Hemoglobin 
M 
g/L 
135 - 175 
Hemoglobin 
F 
g/L 
120 - 160 
Lymphocyte 
 
10^9/L 
1 - 2 
Neutrophils 
 
10^9/L 
1.8 - 3.15 
Platelets 
 
10^9/L 
150 - 350 
Leukocytes 
 
10^9/L 
4.5 - 11 
Eosinophils 
 
10^9/L 
0 - 0.4 
Basophils 
 
10^9/L 
0 - 0.15 
Monocytes 
 
10^9/L 
0.18 - 0.5 
Hematocrit 
M 
v/v 
0.41 - 0.53 
Hematocrit 
F 
v/v 
0.36 - 0.46 
Erythrocytes 
M 
10^12/L 
4.5 - 5.9 
Erythrocytes 
F 
10^12/L 
4 - 5.2 
INR 
 
v/v 
0.8 - 1.2 
The current list of generic ranges for biochemistry parameters (for adults) is provided in the table 
below: 
Table 6 - Generic ranges for biochemistry parameters  
LBTEST 
LBSTRESU 
LBGNNRLO - LBGNNRHI 
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
3.6 - 7.1 
Calcium 
mmol/L 
2.2 - 2.6 
Chloride 
mmol/L 
80 - 115 
Glucose 
mmol/L 
3.900001 - 6.999999 
Bicarbonate (HC03) 
mmol/L 
22 - 29 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
Based on NEJM (N Engl J Med 2004;351:1548-63.): “Laboratory Reference Values”, Alexander Kratz, M.D., Ph.D., M.P.H., 
Maryjane Ferraro, Ph.D., M.P.H., Patrick M. Sluss, Ph.D., and Kent B. Lewandrowski, M.D. 
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Statistical Analysis Plan  
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Version number: 2 
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Page 49 
Appendix G 
Internationally agreed SOC order  
The internationally agreed order (Guideline on summary of product characteristics, 
December 1999, European commission) for SOC: 
1. Infections and infestations 
2. Neoplasms benign and malignant (including cysts and polyps) 
3. Blood and the lymphatic system disorders 
4. Immune system disorders 
5. Endocrine disorders 
6. Metabolism and nutrition disorders 
7. Psychiatric disorders 
8. Nervous system disorders 
9. Eye disorders 
10. Ear and labyrinth disorders 
11. Cardiac disorders 
12. Vascular disorders 
13. Respiratory, thoracic and mediastinal disorders 
14. Gastrointestinal disorders 
15. Hepato-biliary disorders 
16. Skin and subcutaneous tissue disorders 
17. Musculoskeletal, connective tissue and bone disorders 
18. Renal and urinary disorders 
19. Pregnancy, puerperium and perinatal conditions 
20. Reproductive system and breast disorders 
21. Congenital and familial/genetic disorders 
22. General disorders and administration site conditions 
23. Investigations 
24. Injury and poisoning 
25. Surgical and medical procedures 
26. Social circumstances 
27. Product Issues 
The other terms are sorted by dictionary code order. 
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Statistical Analysis Plan  
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Version number: 2 
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Page 50 
Appendix H 
Potentially clinically significant abnormalities criteria  
 
Parameter 
PCSA 
Comments 
Pulse rate  
(Heart rate) 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007 
Laboratory 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Basophils 
>0.1 Giga/L 
 
Monocytes 
>0.7 Giga/L 
 
RBC 
≥6 Tera/L 
 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
 
 
 
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Statistical Analysis Plan  
09-Jun-2021 
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 51 
Appendix I 
ECG criteria for potentially significant abnormalities - for Phase 2/3 
studies (oncology only)  
 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White 
Paper on PR and QRS (Nada et al. Am Heart J. 2013; 
165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
 
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