A Randomized, Multicenter, Double-blind, Phase 3 Study of Amcenestrant (SAR439859) Versus Tamoxifen for the Treatment of Patients With Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative or Positive, Stage IIB-III Breast Cancer Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Sanofi

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AMENDED CLINICAL TRIAL PROTOCOL 01 
Protocol title: 
A randomized, multicenter, double-blind, Phase 3 study of 
amcenestrant (SAR439859) versus tamoxifen for the 
treatment of patients with hormone receptor-positive, 
human epidermal growth factor receptor 2-negative or 
positive, stage IIB-III breast cancer who have discontinued 
adjuvant aromatase inhibitor therapy due to treatment-
related toxicity  
Protocol number: 
EFC16133/BIG 20-01/AFT-55/EORTC-2033 
Amendment number: 
01  
Compound number 
(INN/Trademark): 
SAR439859 
Amcenestrant/Not Applicable 
Brief title: 
Study of amcenestrant (SAR439859) versus tamoxifen for 
patients with hormone receptor-positive (HR+) early breast 
cancer, who have discontinued adjuvant aromatase 
inhibitor therapy due to treatment-related toxicity 
(AMEERA-6)  
Acronym: 
AMEERA-6 
Study phase: 
Phase 3 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address: 
1 Avenue Pierre Brossolette 
Chilly Mazarin, 91380 France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
133204 
EudraCT: 
2021-000398-10 
NCT: 
Not applicable 
WHO: 
Not applicable 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 
05-May-2022 
Total number of pages: 146 
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NCT05128773

Amended Clinical Trial Protocol 01 
SAR439859-EFC16133 - amcenestrant 
05-May-2022 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document  
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 01 
All 
05 May 2022, version 1 (electronic 1.0) 
Original Protocol 
All 
02 September 2021, version 1 (electronic 2.0) 
Amended protocol 01 (05-May-2022) 
This amended protocol 01 (Amendment 01) 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 because it either significantly impacts the safety or physical/mental integrity 
of participants or the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The objective of this first amended protocol is to modify the protocol:  
• Following ethical committees and health authorities’ requests. 
• Clarifications due to questions from sites of eligibility criteria related to disease 
characteristics, prior/concomitant therapy and disease assessment, biological samples and 
storage. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Entire document 
Regarding human epidermal growth factor receptor 2-
negative, the word was “receptor” added as missing in the 
original text. 
Correction of typographical errors and minor 
inconsistencies 
Clarifications across several 
sections 
 
Correction 
Section 1.1-Synopsis 
In the section Analysis of primary endpoint, the level of 
confidence “95% two-sided” for the confidence interval of 
the hazard ratio removed 
Clarification considering that the 
level of confidence will be 
adjusted for the Type 1 error 
spent at interim analysis and 
final analysis 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3-Schedule of 
activities 
 
1) assessments during the follow up period will be done 
Q12 months after last IMP dose;  
2) FSH and estradiol are collected at screening for eligibility 
and to confirm the menopausal status;  
3) to measure bone mineral densitometry other quantitative 
methods are allowed;  
4) for disease staging, PET-CT is permitted;  
5) at screening staging of disease is needed for patients at 
highest risk of recurrence as outlined in I08; 
6) PGIC, MMAS8 not performed during follow-up period; 
7) Plasma biomarkers-Central labs and Optional blood 
samples for future research at C2D1 are collected before 
IMP administration. 
Clarifications and cleaning of 
inconsistencies 
 
Section 1.3-Schedule of 
activities 
1) addition of gynaecological examination one year after 
randomization and annually until end of treatment. 
2) The frequency of pregnancy testing was increased to 
every 12 weeks from visit 11 until the end of the mandatory 
period of contraception as per Appendix 4: either onsite or 
at home. 
1) To monitor the risk of 
endometrial changes due to 
tamoxifen and to be compliant 
with Korean competent 
authorities. 
2) The end of the mandatory 
period of contraception is aligned 
with CMPH recommendation 
regarding fetal toxicity risk of 
tamoxifen to be compliant with 
French competent authorities. 
Section 2.3 
Eye disorder was added in the table as a potential risk of 
clinical significance of tamoxifen. 
For the purpose of tamoxifen risk 
mitigation on eye disorder and to 
be compliant with Belgian and 
French competent authorities. 
Section 5.1: Inclusion criteria 
I02: rephrased to clarify axillary lymph nodes testing for ER 
and/or PgR (if done, must be positive to be eligible). 
Clarification. 
Section 5.1: Inclusion criteria 
I03:  
- 
Addition of unknown HER2 status as eligible. 
- 
Enrollment replaced by randomization. 
To allow patients who may have 
unknown HER2 status to enroll. 
Section 5.1: Inclusion criteria 
I04: 
- 
Participants could have had adjuvant radiation if 
indicated.  
- 
TNM staging for participants with upfront surgery  
- 
In case of neoadjuvant systemic therapy, 
participants must have stage II-III disease based 
on clinical staging (cTNM) and residual nodal 
disease after definitive breast surgery (ypN1-3). 
- 
Participants with only residual micro-metastatic 
disease (N1mic) or isolated tumor cells (ITCs) in 
the axillary lymph nodes are not eligible 
Note: the One-Step Nucleic Acid Amplification 
(OSNA) method is acceptable for sentinel lymph-
node assessment. 
Clarification and detail about 
staging based on type of 
treatment patient received 
(neoadjuvant vs adjuvant). 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1: Inclusion criteria 
I05: Inclusion criterion regarding the AI(s) previously 
received rephrased. 
Clarification 
Section 5.1: Inclusion criteria 
I07:  
- 
The wash-out period after CDK4/6 is at least 
4 weeks between the last dose and randomization. 
- 
Prior treatment with PARP inhibitors or other oral 
anticancer agents is allowed but must have wash-
out period of at least 2 weeks between the last 
dose and randomization 
Clarification related to CDK 4/6 
washout prior to randomization 
to be compliant with the French 
Competent Authorities. 
Prior oral anticancer agents 
allowed with a washout of 
2 weeks, PARP inhibitors 
specifically mentioned given 
recent approval of adjuvant 
PARP inhibitors in high risk early 
breast cancer. 
Section 5.1: Inclusion criteria 
I08: rephrased  
Clarification 
Section 5.1: Inclusion criteria 
I11: 
- 
Recommendation to test FSH and estradiol for 
participants post bilateral ovarian ablation through 
pelvic radiotherapy  
- 
For contraception, inclusion of reference to 
Appendix 4 (contraception guidelines); 
 
Confirmation of postmenopausal 
status. 
 
Clarification to be compliant with 
the French Competent 
Authorities. 
Section 5.2: Exclusion criteria 
E01: rephrased 
Clarification (no change in 
content) 
Section 5.2: Exclusion criteria 
E02: specified “known” active hepatitis 
Clarification that if active 
hepatitis is “known” patient is 
excluded; hepatitis serologies 
are not required but may be 
obtained per PI discretion and 
clinical decision making (no 
change in content) 
Section 5.2: Exclusion criteria 
E03: criterion related to prior breast cancer history 
rephrased 
Clarification (no change in 
content) 
Section 5.2: Exclusion criteria 
E08: rephrased and enrollment replaced by randomization. 
Clarification 
Section 5.2: Exclusion criteria 
E09: prior treatment for bone health, risk reduction, or a 
prior breast cancer with raloxifene or tamoxifen (SERM) is 
permitted if discontinued at least 3 years before diagnosis 
of current breast cancer. 
Modification of prior treatment to 
allow inclusion of participants 
who received SERMs as long as 
there is a window of 3 years 
between completion of SERM 
and current breast cancer 
diagnosis 
Section 5.2: Exclusion criteria 
E12: Washout period of 2 weeks added for OATP1B1/1B3 
sensitive substrates drugs. 
Clarification 
Section 5.2: Exclusion criteria 
E13: Wash out period for strong CYP3A4 inducers modified 
for 3 weeks.  
E14 and E15: removal of 5 elimination half-lives. 
Clarification to delete 
5 elimination half-lives and have 
a period to simplify 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2: Exclusion criteria 
E17: restriction regarding blood transfusion not permitted 
within 2 weeks prior to randomization; 
To ensure blood counts are not 
within range for study due to 
blood transfusions, for example 
patients who may have residual 
toxicity from chemotherapy 
Section 5.2: Exclusion criteria 
E20: total bilirubin cut-off increased to >1.5 x ULN 
To align with current clinical 
pratice 
Section 6.1.4 
No specific water requirement (noncarbonated removed) 
Clarification (more water initially 
required for studies with 
significant PK monitoring; in this 
study sparse PK studies will be 
done and no specific water 
requirement is needed) 
Section 6.3 
The randomization will not be possible if study treatment 
and ER/PgR central results are not available at site. 
For unblinding, actions for emergency unblinding and 
unblinding after the first IBCFS event clarified 
Clarification 
Section 6.4 
IMPs omissions and NIMP delays/omissions will be 
recorded in the CRF. 
Clarification 
Section 6.8 
Any concurrent anti-cancer treatment (surgery, 
radiotherapy, systemic therapy) except for participants 
diagnosed during the study with a second primary 
malignancy not requiring systemic therapy 
(ie, chemotherapy, hormonal therapy, targeted therapy, etc) 
and for whom study treatment is temporarily suspended to 
allow local treatment (surgery and/or radiation) A list of 
strong CYP3A inducers was added. 
In this trial other anticancer 
treatment than the study 
treatment is not permitted 
 
Clarification 
Section 8.1 
This section is rephrased, restructured and revised for 
consistency with schedule of assessments. 
Clarifications and cleaning of 
inconsistencies 
Section 8.2.1 
Gynecological examination added 
Request from Korean competent 
authorities to add gynecologic 
exams based on endometrial 
risks from tamoxifen 
Section 8.2.2 
Body temperature added to vital signs 
Request from United Kingtom 
competent authority to ensure 
there are no signs of infection. 
Section 8.3.1 
All AEs and SAEs will be collected from the signature of 
ICF to 30 days after last IMP dose. 
After this period, all ongoing related AEs, all ongoing SAEs 
regardless of relationship with study treatment, and all new 
related AEs (serious or nonserious), are to be reported and 
followed up until resolution or stabilization. 
Clarification 
Section 8.4 
Approximately 300 plasma samples will be collected 
Increase the number of plasma 
samples in order to have 
100 samples from Chinese 
patients and 200 from other 
countries 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5 
The gDNA material will be only used for the elimination of 
the non-somatic variants of the tumor genetic studies and it 
will not be subject of any study by itself. 
The genetic findings will be reported to the sites. 
Clarifications 
Section 8.6.2 
The total number of blood s-monovette edta 1,2 mL tubes 
for plasma collected C2 and C7 will be 300. 
Increase the number of plasma 
samples in order to have 
100 samples from Chinese 
patients and 200 from other 
countries 
Section 8.9 and Section 10.5 
Appendix 5 
Biological samples will be stored for 15 years. Data related 
to future research will be stored for 25 years. 
Clarifications 
Section 9.2.1 
In Table 7 Timing of analyses, the word “approximately” 
has been added in the column “Number of events required” 
Clarification if the number of 
events required is not reached in 
a reasonable timeframe 
Section 9.2.2 
In the Table 8 and in the text, the level of confidence 
“95%”/”95 two-sided” for the confidence interval of the 
hazard ratio removed, respectively. 
Clarification considering that the 
level of confidence will be 
adjusted for the Type 1 error 
spent at interim analysis and 
final analysis 
Section 9.3 
Cumulative probability to stop for futility under IBCFS HR = 
0.76 (false negative rate) added in Table 11 - Summary of 
IBCFS summary 
Request from French competent 
authorities 
Section 10.2 Appendix 2 
Other blood tests will include FSH, estradiol, PT/INR and 
bone turnover markers. If local lab cannot measure bone 
tumor markers, samples will be shipped to a central lab 
Clarifications 
Section 10.4 Appendix 4 
This appendix includes information on contraception for 
pre/perimenopausal participants. Both male and female 
participants must agree to be on GnRH. Female patients 
must agree to use highly effective methods of contraception 
during the treatment period until the end of relevant 
systemic exposure (ie, 5 times of the longest IMP half-life 
(tamoxifen) plus 6 months period, which corresponds to 
~9 months for tamoxifen as per CMDh guidance. Male 
participants without prior orchiectomy must keep 
contraceptive measures until 160 days after last IMP dose. 
Collection of pregnancy information over a period of 6 to 
8 weeks however it may be longer if required by local 
regulations. 
Update for female contraception 
period requested by French 
ethics committee.  
Update for male contraception 
period requested by Belgium and 
United Kingdom competent 
authorities. 
Section 10.8 Appendix 8  
For CHINA: a total of100 plasma samples was added for 
PK analysis. Genetic analyses and biomarker research for 
FFPE at screening is not applicable. 
Clarifications 
Section 10.10.1 Appendix 10  
New information regarding Gr 4 toxicity 
Update of safety guidelines 
requested by French competent 
authorities. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 13 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 22 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 23 
2 
INTRODUCTION............................................................................................................................ 38 
2.1 
STUDY RATIONALE ..................................................................................................................... 39 
2.1.1 
Study rationale and purpose .......................................................................................................... 39 
2.1.2 
Rationale for dose and regimen selection ..................................................................................... 39 
2.1.2.1 
AMEERA-1 trial .............................................................................................................................. 39 
2.1.2.2 
Antitumor activity of amcenestrant compared to fulvestrant .......................................................... 40 
2.1.2.3 
AMEERA-4 trial .............................................................................................................................. 40 
2.1.2.4 
AMEERA-6 trial .............................................................................................................................. 41 
2.2 
BACKGROUND ............................................................................................................................. 42 
2.2.1 
Adjuvant hormonal therapy ............................................................................................................ 42 
2.2.2 
Early discontinuation and non-adherence to hormonal therapy .................................................... 43 
2.2.3 
Clinical benefit of aromatase inhibitors as adjuvant treatment ...................................................... 43 
2.2.4 
Rationale for the duration of prior anti-aromatase inhibitor therapy .............................................. 44 
2.2.5 
Rationale for the inclusion of participants with HER2+ disease .................................................... 45 
2.2.6 
Rationale for Hormone receptor positivity threshold ...................................................................... 45 
2.2.7 
Rationale for the primary endpoint ................................................................................................. 45 
2.2.8 
Rationale for the assumption in the tamoxifen arm ....................................................................... 46 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 48 
2.3.1 
Risk assessment ............................................................................................................................ 48 
2.3.2 
Benefit assessment ........................................................................................................................ 52 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 52 
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2.3.4 
COVID-19 risk and benefit assessment ......................................................................................... 52 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 54 
3.1 
APPROPRIATENESS OF MEASUREMENTS  ............................................................................. 57 
4 
STUDY DESIGN ............................................................................................................................ 58 
4.1 
OVERALL DESIGN ........................................................................................................................ 58 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 59 
4.2.1 
Participant input into design ........................................................................................................... 60 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 61 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 61 
5 
STUDY POPULATION .................................................................................................................. 62 
5.1 
INCLUSION CRITERIA .................................................................................................................. 62 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 66 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 69 
5.3.1 
Sun protection ................................................................................................................................ 69 
5.3.2 
Osteoporosis .................................................................................................................................. 69 
5.3.3 
Activity ............................................................................................................................................ 69 
5.4 
SCREEN FAILURES ..................................................................................................................... 69 
5.5 
CRITERIA FOR TEMPORARILY DELAYING  .............................................................................. 70 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 71 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 71 
6.1.1 
Treatment starts after randomization ............................................................................................. 72 
6.1.2 
Patient diaries ................................................................................................................................ 72 
6.1.3 
Drug dispensation .......................................................................................................................... 72 
6.1.4 
Amcenestrant/Amcenestrant-matching placebo ............................................................................ 72 
6.1.5 
Tamoxifen/Tamoxifen-matching placebo ....................................................................................... 73 
6.1.6 
Non-investigational medicinal products ......................................................................................... 73 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 73 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 74 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 76 
6.5 
DOSE MODIFICATION .................................................................................................................. 76 
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6.5.1 
Missed doses ................................................................................................................................. 77 
6.5.2 
Retreatment criteria in case of treatment-related toxicity .............................................................. 77 
6.5.3 
Restarting study medications following treatment interruption ...................................................... 77 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 78 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 78 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 78 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 80 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 80 
7.1.1 
Permanent discontinuation ............................................................................................................ 80 
7.1.2 
Handling of participants after definitive intervention discontinuation ............................................. 80 
7.1.3 
Extended adjuvant endocrine therapy ........................................................................................... 81 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 81 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 82 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 83 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 83 
8.1.1 
At Screening ................................................................................................................................... 83 
8.1.2 
Post baseline .................................................................................................................................. 84 
8.1.3 
Overall survival follow-up ............................................................................................................... 84 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 84 
8.2.1 
Physical examinations ................................................................................................................... 85 
8.2.2 
Vital signs ....................................................................................................................................... 85 
8.2.3 
Clinical safety laboratory assessments .......................................................................................... 85 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 86 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 86 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 87 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 87 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 87 
8.3.5 
Pregnancy ...................................................................................................................................... 87 
8.3.6 
Adverse event of special interest ................................................................................................... 88 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 89 
8.4 
PHARMACOKINETICS .................................................................................................................. 89 
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8.5 
GENETICS ..................................................................................................................................... 90 
8.6 
BIOMARKERS ............................................................................................................................... 91 
8.6.1 
Rationale ........................................................................................................................................ 91 
8.6.1.1 
Biomarker evaluations ................................................................................................................... 91 
8.6.1.2 
Endocrine sensitivity ...................................................................................................................... 91 
8.6.1.3 
Material and methods .................................................................................................................... 92 
8.6.1.4 
Objectives ...................................................................................................................................... 92 
8.6.2 
Sample table .................................................................................................................................. 93 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 94 
8.8 
HEALTH ECONOMICS .................................................................................................................. 94 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 94 
8.10 
PATIENT REPORTED OUTCOMES (PROS) ............................................................................... 95 
8.10.1 
FACT-GP5 ..................................................................................................................................... 96 
8.10.2 
EORTC QLQ-30 ............................................................................................................................. 96 
8.10.3 
EORTC QLQ-BR23 ........................................................................................................................ 97 
8.10.4 
EORTC QLQ-IL127 ........................................................................................................................ 97 
8.10.5 
PRO-CTCAE .................................................................................................................................. 97 
8.10.6 
MMAS-8 ......................................................................................................................................... 98 
8.10.7 
PGI-S and PGI-C ........................................................................................................................... 98 
8.10.8 
EUROQoL EQ-5D-5L ..................................................................................................................... 99 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 100 
9.1 
POPULATIONS FOR ANALYSES ............................................................................................... 100 
9.2 
STATISTICAL ANALYSES .......................................................................................................... 100 
9.2.1 
General considerations ................................................................................................................ 100 
9.2.2 
Primary endpoint .......................................................................................................................... 101 
9.2.3 
Secondary endpoint(s) ................................................................................................................. 103 
9.2.3.1 
Key secondary efficacy endpoint ................................................................................................. 103 
9.2.3.2 
Other secondary efficacy endpoints............................................................................................. 104 
9.2.3.3 
Other endpoints............................................................................................................................ 106 
9.2.4 
Tertiary/exploratory endpoint(s) ................................................................................................... 107 
9.2.5 
Safety analysis ............................................................................................................................. 107 
9.2.5.1 
Adverse events ............................................................................................................................ 107 
9.2.5.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ............................................... 108 
9.2.5.3 
Product complaints ...................................................................................................................... 109 
9.2.6 
Other analysis .............................................................................................................................. 109 
9.3 
INTERIM ANALYSES  ................................................................................................................. 109 
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9.3.1 
EORTC independent DMC .......................................................................................................... 110 
9.4 
SAMPLE SIZE DETERMINATION............................................................................................... 111 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 112 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 112 
10.1.1 
Trial organization.......................................................................................................................... 112 
10.1.2 
Regulatory and ethical considerations ......................................................................................... 112 
10.1.3 
Financial disclosure ..................................................................................................................... 113 
10.1.4 
Informed consent process ............................................................................................................ 114 
10.1.5 
Data protection ............................................................................................................................. 115 
10.1.6 
Committees structure ................................................................................................................... 117 
10.1.7 
Dissemination of clinical study data ............................................................................................. 117 
10.1.8 
Data quality assurance ................................................................................................................ 118 
10.1.9 
Source documents ....................................................................................................................... 119 
10.1.10 Study and site start and closure ................................................................................................... 119 
10.1.11 Publication policy ......................................................................................................................... 120 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 120 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ....................................................................... 122 
10.3.1 
Definition of AE ............................................................................................................................ 122 
10.3.2 
Definition of SAE .......................................................................................................................... 123 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 124 
10.3.4 
Reporting of SAEs ....................................................................................................................... 126 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 127 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 130 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 130 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................. 131 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 131 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 131 
10.10 
APPENDIX 10: ADDITIONAL APPENDICES .............................................................................. 133 
10.10.1 Recommended dose modification guidelines for study treatment-related adverse event ........... 133 
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10.10.2 Methods for selecting items from the pro-CTCAE item library .................................................... 134 
10.10.3 Eastern Cooperative Oncology Group performance status scale ............................................... 135 
10.10.4 Abbreviated modification of diet in renal disease formula ........................................................... 135 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 136 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 138 
11 
REFERENCES............................................................................................................................. 139 
 
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LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 49 
Table 2 - Objectives and endpoints ............................................................................................................... 54 
Table 3 - Study intervention(s) administered ................................................................................................ 71 
Table 4 - Study arm(s) ................................................................................................................................... 72 
Table 5 - Data collection of biological samples ............................................................................................. 93 
Table 6 - Populations for analyses .............................................................................................................. 100 
Table 7 - Timing of analyses ....................................................................................................................... 101 
Table 8 - Summary of primary estimand of the primary endpoint ............................................................... 102 
Table 9 - Summary of primary estimand of the key secondary endpoint .................................................... 104 
Table 10 - Efficacy analyses ....................................................................................................................... 106 
Table 11 - Summary of IBCFS analyses ..................................................................................................... 110 
Table 12 - Piecewise enrollment assumptions ............................................................................................ 111 
Table 13 - Protocol-required laboratory tests .............................................................................................. 121 
Table 14 - Recommended dose modification or discontinuation of study treatment-related toxicities ....... 133 
Table 15 - Symptomatic AEs and items selected from the PRO-CTCAE item library for inclusion in 
EFC16133 and inclusion criteria met by each symptomatic AE ................................................................. 134 
Table 16 - Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale ....................... 135 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 22 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A randomized, multicenter, double-blind, Phase 3 study of amcenestrant (SAR439859) versus 
tamoxifen for the treatment of patients with hormone receptor-positive, human epidermal growth 
factor receptor 2-negative or positive, stage IIB-III breast cancer who have discontinued adjuvant 
aromatase inhibitor therapy due to treatment-related toxicity  
Brief title: 
 
Study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive 
(HR+) early breast cancer, who have discontinued adjuvant aromatase inhibitor therapy due to 
treatment-related toxicity (AMEERA-6)  
Rationale: 
Selective estrogen receptor degraders (SERDs) are competitive estrogen receptor (ER) antagonists 
that also induce conformational ER changes which lead to the degradation of ER via a ubiquitin 
proteasome system. The unique dual function of SERDs (ER antagonism and depletion) may 
enable them to block ER signaling in cellular settings where other endocrine agents, such as 
tamoxifen or aromatase inhibitors (AIs) have failed. 
The purpose of the proposed study is to demonstrate the superiority of a new oral SERD, 
amcenestrant (SAR439859) versus tamoxifen on invasive breast cancer-free survival (IBCFS) in 
patients with hormone-receptor positive (HR+) early breast cancer who have discontinued 
adjuvant AI therapy due to treatment-related toxicity. For this population, there are currently 
limited treatment options after AI discontinuation, which include either switching to another AI 
which may have similar side effects, or to tamoxifen. It is estimated that about 30% of the patients 
treated with aromatase inhibitor discontinue their adjuvant therapy and that 22% discontinue 
during the first year (1, 2). 
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Objectives and endpoints: 
  
Objectives 
Endpoints 
Primary 
 
• 
To determine whether amcenestrant once a day 
(QD) improves the invasive breast cancer-free 
survival (IBCFS) when compared to tamoxifen QD 
in patients with early breast cancer as adjuvant 
treatment 
 
• 
IBCFS is defined according to Standardized 
Definitions for Efficacy End Points in Adjuvant Breast 
Cancer Trials (STEEP) criteria version 2.0 (3) as the 
time interval from the date of randomization to the 
date of the first occurrence of one of the following 
events:  
- 
Ipsilateral invasive breast tumor recurrence 
(IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original 
primary. 
- 
Local-Regional invasive breast cancer 
recurrence: invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of 
the ipsilateral breast.  
- 
Distant recurrence: metastatic disease-breast 
cancer that has either been biopsy confirmed or 
clinically diagnosed as recurrent invasive breast 
cancer.  
- 
Death attributable to any cause, including 
breast cancer, non-breast cancer, or unknown 
cause.  
- 
Invasive Contralateral breast cancer.  
Secondary 
 
Key secondary endpoints 
 
• 
To determine whether amcenestrant once a day 
(QD) improves the invasive disease-free survival 
(IDFS) when compared to tamoxifen QD in patients 
with early breast cancer as adjuvant treatment 
 
• 
IDFS is defined according to STEEP criteria (4) as 
the time interval from the date of randomization to 
the date of the first occurrence of one of the 
following events:  
- 
Ipsilateral invasive breast tumor recurrence 
(IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original 
primary.  
- 
Local-Regional invasive breast cancer 
recurrence: invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of 
the ipsilateral breast. 
- 
Distant recurrence: metastatic disease-breast 
cancer that has either been biopsy confirmed or 
clinically diagnosed as recurrent invasive breast 
cancer.  
- 
Death attributable to any cause, including 
breast cancer, nonbreast cancer, or unknown 
cause. 
- 
Invasive Contralateral breast cancer 
- 
Second nonbreast primary invasive cancer 
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Objectives 
Endpoints 
Other secondary endpoints 
 
• 
To evaluate the distant recurrence-free survival 
(DRFS) in both treatment arms 
 
• 
DRFS is defined according to STEEP criteria (4) as 
the time interval from the date of randomization to 
the date of the first occurrence of one of the 
following events: distant recurrence or death 
attributable to any cause (including breast cancer, 
nonbreast cancer, or unknown cause). 
• 
To evaluate the locoregional recurrences-free 
survival (LRRFS) in both treatment arms 
 
• 
LRRFS is defined as the time interval from the date 
of randomization to the date of the first occurrence of 
one of the following events: local/regional ipsilateral 
recurrence, invasive contralateral breast cancer or 
death attributable to any cause (including breast 
cancer, nonbreast cancer, or unknown cause). 
• 
To evaluate the overall survival (OS) in 
both treatment arms 
 
• 
OS is defined as the time interval from the date of 
randomization to the date of death due to any cause. 
• 
To evaluate the breast cancer-specific survival 
(BCSS) in both treatment arms 
 
• 
BCSS is defined as the time interval from the date of 
randomization to the date of death attributable to 
breast cancer cause 
• 
To evaluate patient-reported overall treatment-
related side effect bother, treatment-related 
symptoms, and quality of life in both treatment 
arms 
• 
This patient reported outcome (PRO) objective will 
be evaluated using the following endpoints:  
- 
Change from baseline in overall side effect 
bother as measured by the Functional 
Assessment of Cancer Therapy Item GP-5 
(FACT-GP5).  
- 
Change from baseline in systemic therapy side 
effects as measured by the EORTC Quality of 
Life Questionnaire Breast cancer module 
(EORTC-QLQ-BR23) systemic therapy side 
effects scale.  
- 
Change from baseline in global health 
status/quality of life as measured by the 
EORTC Core Quality of Life Questionnaire 
(EORTC QLQ-C30) global health status/quality 
of life (GHQ) scale 
• 
To evaluate safety in both treatment arms 
• 
Adverse events (AEs)/serious adverse events 
(SAEs), laboratory abnormalities and adverse events 
of special interest (AESIs). 
• 
To characterize the pharmacokinetics (PK) of 
amcenestrant 
• 
Amcenestrant predose concentrations  
 
 
 
 
 
 
For China please see Section 10.8 [Appendix 8] for details. 
Overall design: 
This is a prospective, randomized, international, multicenter, double-blind, double-dummy, 
Phase 3 study comparing the efficacy and evaluating the safety of amcenestrant versus tamoxifen. 
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The study will have 3 main periods: screening, active treatment, and follow up. 
Men, pre/peri-menopausal women (with GnRH analog approved for use in early breast cancer) 
and post-menopausal women with HR+ early breast cancer, who have discontinued adjuvant AI 
therapy due to treatment-related toxicity will enter the screening period to assess their eligibility.  
Participants still on AI treatment may enter the screening period for central confirmation of 
biomarkers and screening imaging assessments. The other assessments/questionnaires 
required before randomization will be performed/completed when patient is off the AI 
therapy. 
All eligible participants for whom ER and PgR status have been centrally confirmed will be 
randomly assigned using an IRT to either amcenestrant 200 mg daily (experimental) arm or 
tamoxifen 20 mg daily (control) arm in a 1:1 ratio.  
• Arm A: Amcenestrant 200 mg + tamoxifen-matching placebo  
• Arm B: Amcenestrant-matching placebo + tamoxifen 20 mg 
All randomized patients will also receive the matching placebo of the other treatment under 
evaluation. Both treatments are given orally. 
The study population will be stratified by the following factors, as reported at the time of 
randomization: 
• Prior exposure to (neo)adjuvant AI therapy: ≤12 months vs. >12 months 
• Prior exposure to (neo)adjuvant chemotherapy and HER2 status: HER2-negative breast 
cancer with NO prior (neo)adjuvant chemotherapy vs. HER2-negative breast cancer with 
prior (neo)adjuvant chemotherapy vs. HER2-positive breast cancer with prior 
(neo)adjuvant chemotherapy 
Note: Participants with unknown HER2 status will be classified as HER2-negative. 
• Prior exposure to CDK4/6 inhibitor (Yes or No) 
• Geographic regions (North America, Europe vs. Asia Pacific vs. Other) 
• Men or peri-/pre-menopausal women vs. post-menopausal women 
During the treatment period, men and pre/perimenopausal women will receive GnRH analogs as 
approved in the respective countries.  
Participants will receive their assigned treatment for the planned duration of 5 calendar years or 
until diagnosis of disease recurrence per IBCFS definition or any other withdrawal criterion 
whichever occurs first. 
Early discontinuation during the active study treatment period will be left at the investigator’s 
discretion.  
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Extended adjuvant endocrine therapy upon completion of study treatment is allowed, but 
treatment will not be provided by the sponsor. Treatment recommendation should be considered 
on an individual patient basis taking into consideration clinico-pathologic characteristics, patient’s 
preferences, and total duration of adjuvant endocrine therapy at the time of study treatment 
completion or discontinuation. When extended adjuvant endocrine therapy is considered, 
treatment options include adjuvant tamoxifen or adjuvant aromatase inhibitor.  
In case of diagnosis of second non-breast primary invasive cancers, the decision to keep the 
patient on protocol treatment is based on clinical judgement of the treating physician. Patients 
diagnosed with a second primary malignancy not requiring systemic therapy (ie, chemotherapy, 
hormonal therapy, targeted therapy, etc) and with no evidence of breast cancer recurrence may 
continue with study drug treatment according to the protocol and schedule of assessment, if 
considered by the investigator to be in the patient’s best interest, whenever possible. Study 
treatment may be temporarily suspended to allow for local treatment (surgery and/or radiation) of 
the second non-breast primary invasive cancer; in this situation, the maximally allowed period of 
protocol treatment discontinuation should not exceed a total of 3 months in any 12-month time 
period.  
Participants discontinuing or completing the active study treatment period will be followed up to 
10 years from randomization, except in case of premature study termination due to one of the 
following reasons: withdrawal of consent, loss to follow-up or death.  
An Independent Data Monitoring Committee (IDMC) will monitor the safety data on a periodic 
basis. The IDMC will make recommendations as to whether the trial should continue based on 
ongoing reviews of safety data. The IDMC will also evaluate efficacy at the interim analyses and 
make a recommendation regarding study continuation based on observed results of the current 
study and/or external study data generated with amcenestrant. The IDMC procedures will be 
described in the full protocol and detailed in the IDMC charter and will be approved by IDMC 
members. 
A Study Steering Committee will supervise the progress of the trial, review relevant information 
that may affect the study conduct as well as review and take decisions to act on the IDMC 
recommendations. 
Brief summary:  
This is a parallel treatment, Phase 3, Participant, Investigator and Outcomes Assessor masked, 
2 arms randomized study.  
Number of participants: 
It is anticipated that approximately 4670 participants will be screened to achieve 3738 randomly 
assigned to study intervention with a balanced randomization ratio (1869 participants per 
intervention group). 
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Intervention groups and duration: 
Participants will be randomly assigned (1:1) to either Arm A (experimental) or Arm B (control): 
• Arm A: Amcenestrant (SAR439859) 200 mg + tamoxifen-matching placebo  
• Arm B: Amcenestrant (SAR439859)-matching placebo + tamoxifen 20 mg 
Treatments in both arms are given orally.  
Participants will receive their assigned treatment for the planned duration of 5 calendar years or 
until the occurrence of any withdrawal criterion, whichever occurs first.  
During the treatment period, men and pre/perimenopausal women will receive GnRH analogs as 
approved in the respective countries.  
No dose reductions for amcenestrant and tamoxifen are permitted but dosing omissions are 
allowed in case of toxicity. Temporary study treatment interruption is also permitted in special 
circumstances as described in protocol Section 6.5.3. 
Study intervention(s) 
Investigational medicinal products (IMPs) 
Amcenestrant (SAR439859) and amcenestrant (SAR439859)-matching placebo 
• Amcenestrant formulation: 200 mg tablets 
• Route of administration: oral route 
• Dose regimen: the recommended dose is 200 mg once daily, to be taken approximately at 
the same time each day, with food. 
• Amcenestrant-matching placebo will be supplied as tablets identical to amcenestrant 
200 mg tablets in appearance. 
Tamoxifen and tamoxifen-matching placebo 
• Tamoxifen formulation: 20 mg tablets 
• Route of administration: oral route 
• Dose regimen: the recommended dose is 20 mg once daily, to be taken approximately at 
the same time each day, with food. 
• Tamoxifen-matching placebo will be supplied as tablets identical to tamoxifen 20 mg 
tablets in appearance. 
For IMPs, if a dose is vomited or omitted the participant should not take the dose later or 2 doses 
at the next planned dose. 
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Non-investigational medicinal products (NIMPs) 
• Goserelin or other GnRH analog approved for use in early breast cancer as per site/ 
country availability.  
Statistical considerations  
Sample size determination: 
For IBCFS primary endpoint, a total of 568 IBCFS events will be needed to reject the null 
hypothesis using a log-rank test at the one-sided level of 2.5% and 90% power under the 
assumption of a hazard ratio (HR) of 0.76. Assuming proportional hazards under an exponential 
model and based on an anticipated 4-year IBCFS rate of 82% in the tamoxifen arm, this is 
expected to correspond to a 4-year IBCFS rate of 86% in the amcenestrant arm. 
Based on piecewise enrollment assumption over 24-month period, an IBCFS cut-off date (COD) 
of 60 months after the first participant randomized and an annual dropout rate of 1%, a total of 
3738 participants are expected to be randomized in a 1:1 ratio into the amcenestrant and 
tamoxifen arms. 
The number of events/sample size calculation accounts for two interim analyses at 1/3 (non-
binding futility only) and 3/4 (efficacy and non-binding futility) of the planned total number of 
events. 
Main analysis population: 
• Intent-to-treat (ITT) population: All participants who signed the informed consent form 
(ICF) 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 is the primary population for all efficacy parameters. 
• Safety population: All participants who signed the ICF and for whom there is a 
confirmation of successful allocation of a randomization number by IRT and who took 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.  
Analysis of primary endpoint: 
Primary efficacy analysis will consist of IBCFS comparison between the amcenestrant arm and 
the tamoxifen arm through a logrank test procedure stratified by the stratification factors (except 
geographic region to minimize the risk of power loss due to large number of strata and potentially 
low number of events in some strata) as entered in the IRT. A one-sided Type I error rate of 2.5% 
will be used for statistical testing.  
The HR estimates and corresponding confidence intervals will be provided using the Cox 
proportional hazard model stratified by the same stratification factors as those used for the logrank 
test described above. The IBCFS quantiles and IBCFS rates at different time points (calculated 
using the Kaplan-Meier methods) as well as corresponding 95% CIs will be presented by 
treatment arm. The Kaplan-Meier IBCFS curves will also be provided. 
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Analysis of main secondary endpoints: 
Key secondary endpoint (IDFS) 
Same statistical methods as defined for the IBCFS will be used. To ensure a strong control of the 
overall Type I error rate at a one-sided 2.5%, a hierarchical testing strategy will be used. In other 
words, comparison between arms on the IDFS will be performed only if the primary analysis of 
the IBCFS is statistically significant.  
Other secondary efficacy endpoints 
For the following time to event secondary endpoints (DRFS, LRRFS, OS), same statistical 
methods as defined for the IBCFS and IDFS endpoints will be used, with the exception that no 
statistical testing will be performed. 
For the endpoint BCSS, the HR estimate and corresponding 95% two-sided confidence intervals 
(CIs) will be provided by using Fine and Gray model accounting for competing risks and stratified 
by the stratification factors (except geographic region) as entered in the IRT. The cumulative 
incidence of breast cancer-related deaths at different timepoints (calculated using the cumulative 
incidence function method) as well as 95%CIs will be presented by treatment arm. The 
corresponding BCSS rates and 95%CIs will be computed as “1 minus cumulative incidence 
function”. The cumulative incidence curves will also be provided. 
Analysis of safety endpoints 
Adverse events will be coded according to MedDRA and graded according to the NCI-CTCAE 
v5.0. Summaries will be provided for all grades combined and for Grade ≥3 (including Grade 5). 
Adverse event incidence table will be provided by treatment group for all types of treatment-
emergent adverse events (TEAEs): all TEAEs, all treatment emergent AESI (defined with a PT or 
a prespecified grouping), all treatment emergent SAEs, all TEAEs related to IMP, all TEAEs 
leading to permanent treatment discontinuation and all TEAEs leading to dose modification. 
Death will also be analyzed. 
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 (all grades 
and by grade) using the worst grade during the on-treatment period will be provided on the safety 
population. 
Data Monitoring/Other committee: Yes 
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
C1D1
-28 days
C58D1
EOT
(± 3)
Screening Period
….
C2D1
5-year Treatment Period (C1 – C65)
Follow-up Period
Survival / Disease Follow-up
AI = aromatase inhibitor; C = Cycle; CT = chemotherapy; D = day; EOT = End of Treatment; IMP = investigational medicinal product; PO = per os; QD = once a day; R = randomization
A cycle is defined as a 28-day period.
R
Stratification factors:
• Prior exposure to AI
• Prior exposure to CT and 
HER2 status
• Prior exposure to CDK4/6 
inhibitor
• Geographic region
• Men/Menopausal status 
(± 7)
C4D1
(± 7)
C7D1
(± 7)
30 days (± 7) 
after last IMP
1869 patients
1869 patients
Participants will receive their assigned treatment for the planned duration of 5 
calendar years or the occurrence of any withdrawal criterion, whichever occurs first. 
Amcenestrant  200 mg PO QD (D1-D28) +
Tamoxifen-matching placebo PO QD (D1-D28)
Amcenestrant-matching placebo PO QD (D1-D28) 
+  Tamoxifen 20 mg PO QD (D1-D28)
Yearly ( 45 days)
Arm A
Arm B
(up to 10 yearsfrom randomization
whateverthe treatmentduration)
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Inclusion exclusion 
criteria / Informed consent 
X 
 
 
 
 
 
 
 
Informed consent (including 
genetic sampling) may be signed 
prior to D-28.  
Recheck clinical status before 
randomization and/or first dose of 
study medication. 
For patients still on AI at screening, 
inclusion/exclusion criteria should 
be evaluated when AI has been 
discontinued  
Demography, 
medical/surgical and 
disease history, prior 
cancer therapies 
X 
 
 
 
 
 
 
 
At screening visit only.  
Prior AI treatments (duration of 
treatment, reason(s) for 
discontinuation) to be collected. 
For patients still on AI at screening, 
medical history should be 
evaluated when AI has been 
discontinued. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Vital signs, physical 
examination/ signs and 
symptoms 
X 
Xa 
 
Xb  
X 
X 
a. Visit 1 
b. At visit 3 and then at each visit 
during the treatment period. 
Vital signs will be collected at 
baseline and during the treatment 
period. 
ECOG performance 
status,  
body weight and height 
X 
X 
 
Height will be collected at 
screening only. 
At baseline after patient has 
discontinued AI 
Gynecological 
examination 
 
X 
 
From one year after randomization 
and annually until the end of 
treatment 
Follicle-stimulating 
hormone 
(pre/perimenopausal 
women only)- Local labs 
X 
 
 
 
 
 
  
 
At screening for eligibility and to 
confirm the menopausal status. As 
per local regulations, to 
demonstrate postmenopausal 
status, serial measurements of 
FSH may be required.  
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Estradiol 
(pre/perimenopausal 
women only) – Local labs 
Xa 
Xb 
 
a. At screening for eligibility and to 
confirm the menopausal status  
b. At each visit during the treatment 
period, and at EOT. 
Female participant will be 
categorized as premenopausal or 
postmenopausal at the time of 
study entry. This designation shall 
not change during the course of 
study participation; even if a 
premenopausal woman will 
become postmenopausal during 
the course of study participation, 
she will still be categorized as 
premenopausal for the purposes of 
the study. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Pregnancy test 
(pre/perimenopausal 
women only) – Local labs 
Xa 
 
 
Xb 
 
a. Serum pregnancy test (β-hCG) 
to be done within 14 days before 
starting study treatment. 
b. Urine pregnancy test (dipstick) to 
be done for WOCBP: 
- At each visit from visit 1 to visit 10 
- Every 12 weeks from visit 11 until 
the end of the mandatory period of 
contraception as per Appendix 4: 
either onsite or at home  
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Laboratory assessments 
– Local labs 
Xa 
Xb 
 
Hematology, biochemistry panels 
and coagulation: 
a. To be performed at screening 
within 7 days of Cycle 1 D1 after 
patient has discontinued AI. 
b. At each visit during the treatment 
period, at EOT, and as clinically 
indicated. 
  
Lipids assessments on Visit 1, 
Visit 3, Visit 4, and as clinically 
indicated. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Bone mineral 
densitometry ) / Dual-
energy X-ray 
absorptiometry (DXA)  
 
Xa 
Xb 
a. Screening: to be done if not 
already done in the past 12 months 
prior to randomization. 
b. Post baseline: every 2 years 
from randomization (+/-1 month) 
until end of follow -up period 
Other quantitative methods giving 
similar T-score values, including 
ultrasound bone densitometry and 
QCT (quantitative computerized 
tomodensitometry) are also 
accepted. 
Bone Turnover Markers 
(CTX, P1NP) – Local labs 
Xa 
Xb 
 
a. Screening: to be done if not 
already done in the past 12 months 
prior to randomization. 
b. During the treatment period: 
every 2 years from randomization 
(+/-1 month) 
12-lead ECG 
X 
 
 
 
 
 
X 
 
Screening (after patient has 
discontinued AI), EOT and as 
clinically indicated  
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Randomization 
X 
 
 
 
 
 
 
 
Eligibility criteria data collection 
and central confirmation of ER and 
PgR biomarkers to be completed 
prior to IRT randomization call  
Study Treatment Administration: 
IMP dispensation call 
 
X 
 
X 
X 
Xa 
 
 
a. Visit 16 (C58): IMP dispensation 
from C58 to C65, ie, 32 weeks 
amcenestrant +  
tamoxifen-matching 
placebo 
 
Once daily 
 → 
 
 
 
tamoxifen +  
amcenestrant-matching 
placebo 
 
Once daily 
 → 
 
 
 
NIMP: GnRH analog 
 
→ 
 
 
- Goserelin or other GnRH analog 
approved for use in early breast 
cancer as per site/ country 
availability 
- In men and pre/perimenopausal 
women 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
AE/SAE review 
=============================→ 
X 
(ongoing 
related AEs, 
AESI, 
ongoing 
SAEs at EOT 
and new 
related 
AE/SAEs) 
 
Concomitant medication 
review 
=============================→ 
X 
(related to 
AE/SAEs 
listed above) 
From the date of informed consent 
form up to 30 days after the last 
dose of study treatment 
Disease assessments: 
Disease recurrence 
assessment 
X 
At every visit and as clinically 
indicated until the detection of 
locoregional recurrence and distant 
recurrences (whichever comes 
last) or end of follow-up period, 
whichever comes first.  
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Mammogram 
Xa 
Xb 
a. Screening: to be done if not 
already done in the past 6 months 
prior to randomization.  
If local investigator plans to use 
MRIs instead of mammograms 
during the study, MRI will have to 
be performed at baseline 
b. Post baseline: yearly from 
randomization (±30 days), and as 
clinically indicated until the 
detection of locoregional 
recurrence and distant recurrences 
(whichever comes last) or end of 
follow-up period, whichever comes 
first.  
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Radionuclide Bone 
Scan Whole Body; CT 
Scan / MRI /PET-CT 
Ultrasound of Chest, 
Abdomen, Pelvis or any 
clinically indicated sites 
of disease; Clinical 
evaluation of superficial 
disease 
(Xa) 
(Xb) 
 
a. Screening: to be done for 
patients at highest clinical risk for 
disease recurrence as outlined in I 
08 (Section 5.1), for patients with 
stage IIIA or higher as clinically 
indicated. 
b. Post baseline: to be done as 
clinically indicated until the 
detection of locoregional 
recurrence and distant recurrences 
(whichever comes last) or end of 
follow-up period, whichever comes 
first. 
 
Biopsy (disease 
recurrence proof) 
 
(X) 
Disease recurrence should be 
confirmed histologically whenever 
possible. For the locoregional 
recurrence including skin 
recurrence it is strongly 
recommended to perform a biopsy 
unless clinically contra-indicated. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Overall Survival Follow-up 
 
 
 
 
 
 
X 
After discontinuation of study 
treatment, post-study survival 
status (including post-study 
anticancer therapies; disease 
recurrence for patients who 
complete or prematurely 
discontinue study treatment without 
disease recurrence) will be 
collected 
Electronic PRO measures: 
EORTC QLQ-C30, 
EORTC QLQ-BR23, 
EORTC-QLQ-IL127, 
EQ-5D-5L, PGIS  
 
Xa  
Xb 
a. Data collected prior to first IMP 
intake on device at site on D1 C1 
or earlier if patient has no 
unrecovered acute toxic effects of 
prior AI therapy (see exclusion 
criteria 6). 
b. At each visit after the 1st cycle 
(D1 C2-C58) during the treatment 
period, at EOT, and at the first two 
post-treatment follow up visits. 
Data collected on device at site. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
PGIC, MMAS-8 
 
 
X 
 
At each visit starting after the 1st 
cycle (D1 C2-C58) during the 
treatment period and at EOT. 
Data collected on device at site. 
FACT-GP5, PRO-
CTCAE items  
 
Xa  
Xb 
a. Data collected prior to first IMP 
intake on device at site on D1 C1 
or earlier if patient has no 
unrecovered acute toxic effects of 
prior AI therapy (see exclusion 
criteria 6). 
b. Data collected on device at 
home weekly in the first 6 weeks 
(+/-1 day) and every cycle on D1 
C3-C6 (+/-7 days). Data collected 
on device at site at each visit 
starting after the 6th cycle (D1 C7-
C58) during the treatment period, 
at EOT, and at the first two post-
treatment follow up visits. 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
Samples for Translational research: 
FFPE tumor tissue 
Xa 
 
 
 
 
 
Xb (optional) 
 
Refer to Section 8.6.2 for details 
a. Most recent archived FFPE 
biopsied tumor tissue samples 
b. Collected at EOT for patients 
who discontinued treatment due to 
disease recurrence 
Plasma biomarkers – 
Central labs 
 
Xa 
Xa 
 
 
 
Xb 
 
 
Refer to Section 8.6.2 for details 
a. Pre-dose 
b. Collected at EOT for patients 
who discontinued treatment due to 
disease recurrence 
Blood sample for 
genomic DNA – Central 
labs 
 
X 
 
 
 
 
 
 
Refer to Section 8.5 and 
Section 8.6.2 for details 
Pre-dose C1D1 after patient has 
discontinued AI 
Blood sample for 
pharmacokinetics – 
Centralized assay 
 
 
Xa 
 
Xb 
 
 
 
Refer to Section 8.4 and 
Section 8.6.2 for details 
a. At pre-dose 
b. Samples to be taken at pre-dose 
C7, C13 and C25 
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Procedure 
Screening 
Period 
Treatment Period  
[5 years – C1-C65] 
EOT 
Follow-
up 
Period 
Notes 
Patient Visit # 
0 
 1 
2 
 3 
 4-10  
Q12 weeks  
11-16  
Q24 weeks  
17 
≥18 
 
Patient Cycle Visit # 
Baseline 
C1  
D1 
C2  
D1  
C4  
D1  
C7, C10, 
C13, C16, 
C19, C22, 
C25  
D1 
C28, C34, 
C40, C46, 
C52, C58 
D1 
D30  
after last 
IMP dose 
Q12 
months 
after last 
IMP dose  
 
 
Time Window (day) 
Up to 28 days 
before 
randomization 
±3  
±3  
±7  
±7  
±7  
±7 
±45 
 
(Optional) Blood 
Samples for Future 
Research  
 
Xa 
Xa 
 
 
 
Xb 
 
Refer to Section 8.6.2 for details 
a. Pre-dose 
b. Collected at EOT for patients 
who discontinued treatment due to 
disease recurrence 
All study visits performed during treatment period and follow-up period are conducted on-site (in participants without disease recurrence). On-site visits could be substituted by remote visits in specific circumstances.  
Screening: Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening defined timeframe. Informed consent should be signed before any study specific 
procedures. It can be signed more than 28 days prior to randomization. Screening time indicates in which timeframe exams used to support eligibility have to be done prior to randomization.  
Randomization: To take place once the consented patient has completed all the necessary screening procedures and is deemed eligible for study entry by the Investigator or designee. All eligible patients must be 
randomized using IRT. Every effort should be made to start treatment within 3 working days of randomization.  
Treatment period: A cycle is defined as a 28-day period. Men and pre/perimenopausal women will receive GnRH analog on D1 of the cycle. 
Physical examination/ signs and symptoms evaluation: At a minimum, assessments of the cardiovascular system, pulmonary system, gastrointestinal system (including palpation of liver and spleen), examination 
of the skin, and breast exam (palpation of breast/chest wall, axillae, supra- and infraclavicular regions). Symptom-directed physical examinations should be performed at screening and at each subsequent visit.  
Cycle 1 D1 refers to the day the patient receives the initial dose of IMP. Repeated evaluation of body weight, signs and symptoms, physical examination and laboratory tests is not necessary if performed within 7 days 
prior to1st IMP administration. If evaluation performed during screening is abnormal, repeated evaluation is recommended within 2 days prior to 1st IMP administration. 
End of treatment (EOT): should be performed 30 days (±7 days) after the last IMP and prior to the initiation of any new anti-cancer therapy, whichever comes first. 
Follow-up period: each participant will be followed from EOT to up to 10 years from randomization except in case of premature study termination due to one of the following reasons: withdrawal of consent, loss to 
follow-up or death. 
PRO/HRQL assessments: EORTC-QLQ-C30, EORTC-QLQ-BR23, EORTC-QLQ-IL127, FACT GP5, EQ-5D-5L, PRO-CTCAE, PGIC, PGIS, and MMAS-8 to be administered to each study participant after informed 
consent. At each assessment time, PRO/HRQL to be administered prior to any treatment- or study- related activities, including administration of IMP, laboratory work, radiological assessments, discussion with the 
participant regarding their treatment or health status, and similar activities 
Mammogram: It shall not include patients with prior bilateral mastectomy. In case of unilateral mastectomy, unilateral mammogram will be performed. 
 
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Abbreviations: AE = adverse event; AESI = adverse event of special interest; AI = aromatase inhibitor; C = cycle; COA = clinical outcomes assessment; COD = cut-off date; CT scan = computed tomography scan; 
CTX = C-terminal telopeptide; DNA = deoxyribonucleic acid; D = day; DXA = Dual-energy X-ray absorptiometry; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
EORTC = European Organization for Research and Treatment of Cancer; EQ-5D-5L = EuroQoL questionnaire with 5 dimensions and 5 levels per dimension; ER= estrogen receptor;  
FACT GP5 = Functional Assessment of Cancer Therapy – Item GP5; FFPE = formalin fixed paraffin embedded; FSH = follicle-stimulating hormone; GnRH= gonadotropin-releasing hormone;  
HRQL = health-related quality of life; IL127 = ad-hoc item list constructed from the EORTC item library; IMP = investigational medicinal product; IRT= interactive response technology; MRI = magnetic resonance 
imaging; MMAS = Morisky Medication Adherence Scale; NIMP = non-investigational medicinal product; PGIC = Patient Global Impression of Change scale- Side effects of treatment; PGIS = Patient Global Impression 
of Severity scale- Side effects of treatment; P1NP = Procollagen type I N-terminal propeptide; QLQ BR23 = EORTC QLQ breast cancer specific module; QLQ C30 = EORTC core quality of life questionnaire version 3; 
PRO = patient-reported outcome; PRO-CTCAE = patient-reported outcomes version of the common terminology criteria for adverse events; SAE = serious adverse event. 
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2 
INTRODUCTION  
Both endogenous and exogenous steroid hormones such as estrogen and progesterone are known 
to contribute to the pathogenesis of breast cancer. Clinical treatment decisions of breast cancer are 
commonly driven by tumoral expression of hormone receptors (HRs), namely ER and 
progesterone receptors (PgR), as well as expression of HER2. While breast cancer can be 
subdivided by numerous systems, the most clinically relevant subtypes are HR-positive, HER2-
positive (HER2+), and triple-negative breast cancer. About 75% of breast cancers express 
estrogen ERα which is a hormone receptor that regulates gene transcription (5). 
As estrogens have a major impact in breast cancer development and progression, endocrine 
treatment (ET) is an increasingly and systematically used treatment option as adjuvant (after 
surgery) or neoadjuvant (before surgery) therapy (6, 7, 8). The current ETs that are used in the 
adjuvant setting are tamoxifen, a selective ER modulator (SERM) that acts by blocking the ER, 
and the AIs (letrozole, anastrozole, and exemestane), which reduce estrogen levels by inhibiting 
the peripheral synthesis of estrogen (9, 10). 
Amcenestrant is a potent, orally bioavailable, and selective ERα inhibitor that belongs to the 
SERD class of compounds. SERDs have the potential to block endocrine-dependent and 
endocrine-independent ERα signalling by ablation of ERα and have been recognized to offer a 
therapeutic approach to ERα positive breast cancer in both early-stage breast cancer and advanced 
breast cancer. Amcenestrant antagonizes the binding of estradiol to ER but also promotes the 
transition of ERα to an inactive conformation that leads to up to 98% receptor degradation at sub-
nanomolar concentrations in cellular assays. 
These dual properties of amcenestrant translate in a deeper inhibition of ERα pathways and a 
more effective anti-proliferative activity in ERα-dependent breast cancer cell lines driven by 
mutant or wild-type ERα compared to other ERα inhibitors. 
Amcenestrant has the potential to provide effective and well-tolerated therapy for patients with 
early and advanced breast cancer with a convenient route of administration, oral (PO) versus 
intramuscular (IM), better bioavailability, and long-term maintenance of ER receptor blockade 
combined with a strong antitumor activity as compared to fulvestrant. A detailed description of 
the chemistry, pharmacology, pharmacokinetics, preliminary efficacy, and safety of amcenestrant 
is provided in the IB. 
Fulvestrant is the only currently approved SERD for HR+, HER2- metastatic breast cancer. 
Fulvestrant is approved for the treatment of patients with advanced breast cancer (either as 
monotherapy or in combination with targeted anticancer drugs) but it is not indicated as adjuvant 
endocrine therapy for patients with early-stage breast cancer. Fulvestrant has shown clinical 
benefit in the treatment of breast cancer patients who have progressed during endocrine therapies 
such as tamoxifen or AIs. However, fulvestrant must be administered as a monthly IM injection of 
a 500 mg dose to each gluteus maximus. Although fulvestrant has served as an important proof of 
concept for the SERD approach, this therapy is limited by its poor pharmaceutical properties 
which necessitate intramuscular administration and limits the applied dose, exposure, and optimal 
receptor engagement. 
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2.1 
STUDY RATIONALE  
2.1.1 Study rationale and purpose  
The purpose of the proposed study is to demonstrate the superiority of amcenestrant versus 
tamoxifen with regards to IBCFS in patients with HR+ early breast cancer who have discontinued 
aromatase inhibitor as adjuvant treatment due to treatment-related toxicities. For this population, 
there are currently limited treatment options after AI discontinuation, including switching to 
another AI which may have similar side effects, or switching to tamoxifen. This paucity of 
effective and tolerable options may contribute to early discontinuation of adjuvant endocrine 
therapy. Poor adherence has been shown to be associated with worse outcomes (11, 12). It is 
estimated that about 30% of the patients treated with aromatase inhibitor discontinue their 
adjuvant therapy and that 22% discontinue during the first year (1, 11). The primary endpoint of 
this study will be IBCFS defined as occurrence of first recurrence of the disease: ipsilateral or 
regional invasive, distant recurrence, contralateral invasive breast cancer and death. 
2.1.2 Rationale for dose and regimen selection  
2.1.2.1 AMEERA-1 trial  
The Phase 1/2 first-in-human (FIH) dose escalation and expansion AMEERA-1 (TED14856) 
study with amcenestrant single agent, has been designed for women with heavily pretreated, 
postmenopausal advanced or metastatic HR+/HER2-, breast cancer.  
A strong pharmacokinetic/pharmacodynamic relationship was established between amcenestrant 
plasma concentrations and associated 18F-FES PET percent occupancy of the ER. Overall mean 
occupancy per patient was 95.6% and 94.0% with amcenestrant 400 mg QD and 150-600 mg QD, 
respectively. The recommended dose of amcenestrant was established at 400 mg once daily when 
used as monotherapy for the treatment of advanced breast cancer.  
In AMEERA-1, the antitumor activity of amcenestrant as monotherapy was assessed in 
59 evaluable patients (treated from 150 to 600 mg QD) as well as in a subset of patients naïve 
from targeted therapies and fulvestrant. In the overall study population, the best overall responses 
(BOR) based on RECIST 1.1 criteria were 5 confirmed partial responses (PR; 8.5%), 24 stable 
disease (SD; 40.7%) and 30 progressive disease (PD; 50.8%). The antitumor activity observed in 
this population of heavily pretreated patients showed durable control of the disease with a high 
rate of clinical benefit [CBR (CR + PR + SD ≥24 weeks) = 33.9%] (13). 
Amcenestrant demonstrates a favorable safety profile. Limited treatment-emergent adverse events 
(TEAEs) related to amcenestrant as monotherapy were observed on AMEERA-1, all Grade 1 and 
2, the most frequent being: hot flush, arthralgia, and constipation. 
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2.1.2.2 Antitumor activity of amcenestrant compared to fulvestrant  
A comparison of the AMEERA-1 results with those of fulvestrant in the medical literature was 
undertaken in order to place the amcenestrant data in the context of historical data. A total of 
4 comparative studies were selected wherein fulvestrant was given as monotherapy and in which 
study eligibility criteria excluded patients with prior targeted therapies (mTOR and CDK 
4/6 inhibitors) and prior use of fulvestrant (14, 15, 16, 17). The objective response rate (ORR) and 
the CBR were indirectly compared with the recommended 500 mg dose of fulvestrant 
monotherapy in the second or third line setting among postmenopausal women with 
advanced/metastatic ER+/HER2− breast cancer and whose tumor responses were confirmed as 
per RECIST v1.1 in populations with measurable disease. The PALOMA-3 (13) and FAKTION 
(14) studies recruited women who had received up to 3 prior lines of endocrine therapy and the 
SOLAR-1 (15) and SANDPIPER (16) studies with up to 2 prior lines. The PALOMA-3 study 
excluded women who had received prior fulvestrant and CDK4/6, PI3K, and/or mTOR inhibitors. 
The FAKTION, SOLAR-1 and SANDPIPER studies excluded women who had received prior 
fulvestrant and PI3K inhibitors, and the SOLAR-1 and SANDPIPER studies also excluded 
women who had received prior mTOR inhibitors. All four comparator studies investigated less 
heavily pre-treated patients than in AMEERA-1. In these studies, the fulvestrant monotherapy 
ORR ranged from 10.9–16.2% and CBR ranged from 36.0-44.1% (18, 19, 20, 21). Meanwhile, 
the ORR and CBR in AMEERA-1 study in a similar subset population (14 patients who had not 
received prior therapy with fulvestrant, an mTOR inhibitor, or a CDK 4/6 inhibitor) compared 
favorably to these historical data with ORR of 21.4% and CBR of 64.3%.  
Given the demonstrated antitumor activity and safety of amcenestrant in the treatment of 
advanced breast cancer, there is interest in whether amcenestrant may also offer an effective and 
safe treatment option in the adjuvant setting. In order to address the early-stage breast cancer 
population, short-term preoperative studies are considered as 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 (22, 23). 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 (24, 25). For example, in 
the preoperative 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 was 
correlated with recurrence-free survival (26, 27). 
2.1.2.3 AMEERA-4 trial  
AMEERA-4 (ACT16106) is a dedicated window-of-opportunity study with amcenestrant in pre-
operative ER+/HER2- postmenopausal breast cancer patients. Data are not yet published.  
AMEERA-4 study assessed two dose levels of amcenestrant (200 mg and 400 mg daily) as 
compared to letrozole 2.5 mg daily among participants with newly diagnosed ER+/HER2- breast 
cancer with highly proliferative tumors (Ki67 ≥15% at diagnosis by local assessment). 
Participants were equally randomized to the three study arms above and treated with 14 days of 
endocrine therapy immediately prior to breast surgery with a primary endpoint of change in Ki67 
from baseline to Day 15. Central assessment of Ki67 was performed by two independent 
reviewers and the average value of these two reviewers at each timepoint was used for the primary 
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analysis. Ki67 change from baseline to Day 15 was analyzed based on an ANCOVA model of the 
log-proportional change from baseline (ie, 𝑙𝑜𝑔(
𝐷15
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒)), with treatment arm and log-Ki67 at 
baseline as fixed effect. Geometric LS-means and associated 95% confidence interval (CI) of the 
Ki67 relative reduction from baseline were obtained by back-transformation on the original scale. 
An administrative interim analysis was undertaken in April 2021 following the randomization of 
the first 63 patients. Regarding baseline characteristics of the study patients, there were no major 
imbalances noted between the study arms.  
Regarding safety, among 62 patients exposed to the study treatment, no safety issues were 
observed: there were few low-grade events observed in each treatment arm and no participants 
discontinued treatment due to adverse events. The most frequent TEAEs during the on-treatment 
and post-treatment periods of 10% or greater frequency in any treatment arm, all low-grade 
(grades 1 and 2), were: hot flush (19.0%), diarrhea (14.3%), arthralgia (14.3%) and breast pain 
(14.3%) for letrozole 2.5 mg (N = 21); asthenia (10.0%) and hot flush (5.0%) for amcenestrant 
200 mg (N=20); insomnia (14.3%), hot flush (9.5%) and arthralgia (4.8%) for amcenestrant 
400 mg (N=21). Regarding the primary endpoint, among 55 patients with evaluable paired tumor 
biopsies, the geometric LS-means [95% CI] were: 72.04% [59.73%;80.59%] for letrozole 2.5 mg 
(N=18); 68.17% [54.13%;77.92%] for amcenestrant 200mg (N=18); 74.99% [64.30%;82.48%] 
for amcenestrant 400 mg (N=19). The specific amcenestrant target ER protein was scored by IHC 
(H-score). ER expression decreased on average (SD) by 67.1% (±32.6%) and 47.8% (±68.7%) in 
amcenestrant 200mg and 400mg, respectively. As expected, letrozole had limited impact on ER 
expression (4.8% (±11%)).  
2.1.2.4 AMEERA-6 trial  
While the pharmacodynamic activity and safety results from AMEERA-4 could support use of 
either amcenestrant 200 mg or 400 mg in the AMEERA-6 study (EFC16133), the lower dose of 
200 mg is preferred given the proposed long-term exposure (5 years) in early breast cancer, in 
particular for these study participants who discontinued prior adjuvant AI due to treatment-related 
toxicities. 
As letrozole was found to be significantly more active than tamoxifen in a neoadjuvant study 
including postmenopausal patients with ER+ and/or PgR+ ineligible for breast-conserving surgery 
(28) and amcenestrant preliminary results were comparable to letrozole in AMEERA-4, the 
proposed treatment with amcenestrant in AMEERA-6 is considered as appropriate. 
In AMEERA-6 study, it is recommended to take amcenestrant with food in order to ensure 
favorable exposure for all patients, including those who may have lower absorption. This 
recommendation is supported by several food effect studies conducted during Phase 1 program on 
capsule or tablet formulations. The highest magnitude of food effect was 1.67-fold increase of 
Cmax and 1.77-fold increase of AUC with a moderate fat meal (400-500 Kcal containing 
approximately 9% protein, 27% lipids, and 64% carbohydrate) regardless of amcenestrant dose 
(200 to 600 mg) or formulation (capsule or tablet). In addition, recent data showed that a high fat 
meal (800 – 1000 Kcal containing approximately 15-19% protein, 60-63% lipids, and 25-31% 
carbohydrate) would increase Cmax by 1.25-fold and AUC by 1.71-fold for a single 400 mg dose. 
In repeated administration conditions, using a population model analysis, food effect accounted 
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for about 20% increase of the exposure. Using maximum food effect reported at higher dose in 
single dose studies, increase of exposure for a 200 mg dose remains within the range of highest 
exposure documented with 1200 mg single dose in healthy subjects and 600 mg QD or 300 mg 
BID in advanced cancer patients and is considered as safe. 
2.2 
BACKGROUND  
Breast cancer is the most commonly diagnosed cancer and the second leading cause of death in 
women (29). In 2020, there were 2.3 million women diagnosed with breast cancer and 
685 000 deaths globally. As of the end of 2020, there were 7.8 million women alive who were 
diagnosed with breast cancer in the past 5 years, making it the world’s most prevalent cancer. 
There are more lost disability-adjusted life years (DALYs) by women to breast cancer globally 
than any other type of cancer. Breast cancer occurs in every country of the world in women at any 
age after puberty but with increasing rates in later life (30). In the United States (US) in 2020, a 
total of 276 480 new cases of invasive breast cancer diagnosed in women and 2620 cases in men, 
are estimated (31). In Europe, breast cancer remains the most common cancer in females 
accounting for 28.8% of the total number of cancer diagnosis. The incidence of breast cancer in 
Europe is more than two times higher than new breast cancer cases in any other region (31, 32). 
Estimates suggest that approximately 6% of newly diagnosed breast cancer cases present with 
metastatic disease and that recurrence from early stage to distant sites occurs in 20%-50% of cases 
(33, 34). The median age of women at the time of breast cancer diagnosis is 62 years; 95% of new 
cases occur in women aged 40 years or older (35, 36, 18, 19). Recent scientific advances have 
established hormone-receptor (HR) status and HER2 status as important predictive markers for 
disease progression and treatment effectiveness. In a registry that included 57 483 case patients, a 
total of 72.7% of patients were HR(+)/HER2(-), 14.9% were HER2(+) and 12.4% were triple-
negative, meaning negative for three receptor types: ER, PgR, and HER2 (19). 
2.2.1 Adjuvant hormonal therapy  
Adjuvant endocrine therapy significantly improves long-term survival of HR+/HER2- breast 
cancer patients (20, 37). Patients with invasive breast cancers that are ER and/or PR + should be 
considered for adjuvant hormonal therapy (HT) regardless of patient age, lymph node status, or 
whether adjuvant chemotherapy is to be administered (20, 37) and regardless of HER2 status, 
unless clinically contraindicated. Despite the proven clinical efficacy of tamoxifen or AIs, many 
breast cancer survivors have recurrence either because of resistance to therapy, non-adherence to 
treatment, or premature discontinuation of therapy. 
In addition, many breast cancer survivors either fail to take the correct dosage at the prescribed 
frequency or discontinue therapy for tolerance (21). 
The adjuvant endocrine treatments are usually given for the standard duration of 5 years. 
Nevertheless, the high number of recurrences occurring after 5 years suggested that extending 
adjuvant endocrine therapy beyond 5 years could further improve outcomes, leading to the 
conduct of several randomized clinical trials. The extended duration of tamoxifen therapy has 
been shown to improve DFS and overall survival in the ATLAS (38) and aTTom trials (39). 
Meanwhile, in postmenopausal women, AIs have been shown to be more effective when 
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compared with tamoxifen. Recently, the DATA (40), IDEAL (41), and NSABP B42 (42) trials 
showed that extended adjuvant endocrine therapy with AIs beyond 5 years in postmenopausal 
women with early breast cancer may reduce the occurrence of second breast tumors. However, 
data from some of these studies (DATA, IDEAL) and others (ABCSG-16) (43) failed to 
demonstrate a significant benefit of 10 as compared to 7 years of adjuvant endocrine therapy. 
Furthermore, acute toxicities associated with adjuvant AIs are known to contribute to decreased 
compliance and also maybe associated with long-term toxicities. Therefore, it is suggested to 
extend adjuvant treatment only in women with high-risk early breast cancer who tolerate 
treatment well (44, 45). 
2.2.2 Early discontinuation and non-adherence to hormonal therapy  
Despite the benefit of adjuvant hormonal therapy (HT) on mortality among women with breast 
cancer, many women are non-adherent with its use. Hershman et al. investigated the effects of 
early discontinuation and nonadherence to HT on mortality in women enrolled in Kaiser 
Permanente of Northern California (KPNC) (1, 11). They identified women diagnosed with 
hormone-sensitive Stage I–III breast cancer between 1996–2007 and used automated pharmacy 
records to identify prescriptions and dates of refill. They categorized patients as having 
discontinued HT early if 180 days elapsed from the prior prescription. For those who continued, 
they categorized patients as adherent if the medication possession ratio was ≥80%. They used Cox 
proportional hazards models to estimate the association between discontinuation and non-
adherence with all-cause mortality. Among 8769 women who filled at least one prescription, 
3802 (43%) received only tamoxifen, while 2313 (29%) received only an AI, and 2654 (30%) 
received both types of medication. A total of 2761 (32%) discontinued therapy during a median 
follow-up of 4.5 years: 22% discontinued after AI therapy the first year of treatment. Estimated 
survival at 10 years was 80.7% for women who continued HT versus 73.6% for those who 
discontinued (p= <0.001). Both early discontinuation and non-adherence to HT were common and 
associated with increased mortality (1, 11). Currently, the predictors of treatment discontinuation 
are not clearly defined. Data from the open label, multicenter, randomized ELPh trial showed that 
32.4% of the patients treated with AI discontinued the treatment within 2 years because of adverse 
effects; 24.3% discontinued specifically because of musculoskeletal symptoms. The median time 
to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 
months) and the rate of discontinuation within the first year (excluding relapses) was 
approximately 20%. 
The remaining therapeutic options after early discontinuation of an adjuvant AI due to treatment-
related toxicities, are either treatment with another AI or tamoxifen. Many patients do not tolerate 
transition to a different AI and the last option is therefore either tamoxifen or absence of adjuvant 
therapy. 
2.2.3 Clinical benefit of aromatase inhibitors as adjuvant treatment  
As this particular population, patients who have discontinued adjuvant AI prematurely due to 
treatment-related toxicity, has never been explored in a prospective clinical trial, the BIG 1-98 
study conducted in the adjuvant setting using tamoxifen as a comparative arm was selected as a 
reference to the present study. The BIG 1-98 study (46) was a randomized, Phase 3, double blind 
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trial that compared 5 years of treatment with various adjuvant endocrine therapy regimens in 
postmenopausal women with hormone-receptor–positive breast cancer: letrozole, letrozole 
followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. Of note, patients were 
enrolled regardless of the HER2 status of the primary tumor. The primary analysis compares the 
two groups assigned to receive letrozole initially with the two groups assigned to receive 
tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to 
the time that treatments were switched.  
A total of 8010 women were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen 
group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group 
and 428 events in the tamoxifen group, with five-year DFS estimates of 84.0% and 81.4%, 
respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event 
ending a period of disease free survival (DFS) ([HR] 0.81; 95 % CI, 0.70 to 0.93; P = 0.003), 
especially the risk of distant recurrence (HR=0.73; 95 % CI 0.60 to 0.88; P = 0.001) (46). In 
addition, at a median follow-up of 71 months after randomization, analyses of sequential 
treatment arms, letrozole followed by tamoxifen (1540 patients) and tamoxifen followed by 
letrozole (1548 patients) were performed and compared to letrozole monotherapy arm 
(1546 patients). The primary endpoint, DFS, was not significantly superior for patients 
randomized to either sequential treatment as compared with letrozole alone (HR for tamoxifen 
followed by letrozole, 1.05 (99% [CI], 0.84 to 1.32) and HR for letrozole followed by tamoxifen, 
0.96 (99% CI, 0.76 to 1.2). However, there were more early relapses among women who were 
assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole 
alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in 
overall survival between women assigned to treatment with letrozole and those assigned to 
treatment with tamoxifen (HR for letrozole, 0.87; 95% CI, 0.75 to 1.02; p = 0.08). The rate of AEs 
was as expected on the basis of previous reports of letrozole and tamoxifen therapy (47). 
Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the 
tamoxifen group whilst women in the letrozole group had higher incidences of skeletal events, 
cardiac events and hypercholesterolemia. 
2.2.4 Rationale for the duration of prior anti-aromatase inhibitor therapy  
Data from the Oxford individual patient meta-analysis on 31920 postmenopausal women enrolled 
in nine randomized trials of AIs versus tamoxifen were published in 2015 and showed that the 
benefit of AIs over tamoxifen is accrued in the first two years of the randomized comparison (44).  
• In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen 
(9885 patients), most of the benefit of aromatase inhibitor over tamoxifen was accrued 
over the first 2 years of treatment with a 36% relative risk (RR) of any disease recurrence 
during years 0-1 after surgery (RR = 0.64, 0.52-0.78), dropping to 20% during years 2-4 
(RR = 0.80, 0.68-0.93). No further significant effect was observed after both treatments 
are stopped.  
• In the other comparison including 11798 patients who were disease-free after 2 years of 
tamoxifen and then randomized to either continue tamoxifen or to switch to an aromatase 
inhibitor, allocation to an aromatase inhibitor reduced the recurrence rate during years 2-4 
(RR = 0.56, 0.46-0.67) with no significant further effect on recurrence after the treatment 
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period. These results suggest that most of the benefit of aromatase inhibitor is delivered 
over the first 2 years of treatment.  
Based on the above-mentioned findings, the treatment with AI up to 2.5 years followed by 
tamoxifen is an effective treatment for patients who have discontinued adjuvant AI therapy due to 
treatment-related toxicities. 
2.2.5 Rationale for the inclusion of participants with HER2+ disease  
In the last two decades, improved clinical outcomes were registered for most trials in comparison 
with older studies as a result of mammography screening and progresses in the management of 
early-stage breast cancer. This is evident particularly for HER2+ tumors following the 
introduction of trastuzumab into the therapeutic armamentarium of the metastatic disease starting 
from early 2000 and then as adjuvant therapy for early-stage disease a few years later.  
BIG1-98 study enrolled participants with HR+ disease irrespective of HER2 status between 
March 1998 and May 2003. At that time trastuzumab was not yet approved for the treatment of 
HER2+ early-stage breast cancer. Hence, BIG1-98 population is characterized by higher risk 
profile due to the absence of anti-HER2 treatment in comparison with subsequent trials for 
HER2+ disease (48). 
Participants with histologically confirmed HR+ breast adenocarcinoma are eligible for the 
AMEERA-6 study, regardless of HER2 status. Those with HER2+ disease can be enrolled 
provided that they have been treated with chemotherapy and are no longer receiving anti-HER2 
systemic adjuvant therapy.  
Despite completion of anti-HER2- systemic adjuvant therapy, patients with HR+/HER2+ disease 
unfortunately remain at risk for disease recurrence. These patients should be treated with 
endocrine therapy for at least 5 years, and, similar to the participants on AMEERA-6 with 
HR+/HER2- disease, may also benefit from further adjuvant endocrine therapy in the context of 
early discontinuation of AI due to treatment-related toxicity.  
2.2.6 Rationale for Hormone receptor positivity threshold  
Hormone receptor positivity ≥10% is proposed, as per American Society of Clinical Oncology 
(ASCO)/College of American Pathologist guidelines (49). There are limited data on the overall 
benefit of endocrine therapies for patients with low level (1-10%) ER expression. Data suggest 
that invasive cancers with these results are heterogeneous in both behavior and biology and often 
have gene expression profiles more like ER-negative cancers. 
2.2.7 Rationale for the primary endpoint  
IDFS as per STEEP criteria, defined as the time from the date of randomization to the date of the 
first event of ipsilateral invasive breast tumor recurrence, regional invasive recurrence, distant 
recurrence, death, contralateral invasive breast cancer, or second non-breast primary invasive 
cancer, has been widely used as primary endpoint in recent adjuvant breast cancer studies 
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[monarchE (50), PALLAS (51), EarLEE-2 (52). However, the inclusion of the event of second 
primary cancer in the IDFS definition was a subject of considerable discussion:  
• As noted in Hudis et al, (4) it may be difficult to distinguish a second primary cancer in a 
nonbreast site (which may or may not be related to the primary cancer) from a distant 
recurrence of the primary breast cancer especially when the tumor site is not easily 
accessible for biopsy.  
• There is a well-known association between treatment and some second primary cancers. 
This is the case, for instance, of tamoxifen-induced endometrial cancer. Including events 
not related to the primary breast cancer or to the administered treatment might eventually 
dilute the treatment effect. Thus, including most types of second primaries of non-breast 
origin, except endometrial cancer, may be less relevant to the assessment of the treatment 
benefit of amcenestrant over tamoxifen in terms of improving breast cancer outcomes.  
• In addition, it has been shown in independent cohorts that the rate of second primary 
invasive cancers of nonbreast origin is increasing with age (53, 54). Considering that 
recent clinical trials enrolled older patients, the risk of second primary invasive cancers 
that might not be related to the primary breast cancer or to the treatment of the study 
population is not negligible.  
Based on these considerations, we have opted for IBCFS as the primary endpoint, excluding the 
second non-breast primary invasive cancers as event of interest. Our primary endpoint selection 
was also based: 
• on the use of IBCFS as the primary endpoint in other Phase 3 trials conducted in patients 
diagnosed with HER2-positive early breast cancer (54, 55).  
• on the recent revision of the STEEP criteria in adjuvant breast cancer by an international 
group of academic breast oncologists, as well as representatives from ASCO, the US 
National Cancer Institute (NCI), and the US Food and Drug Administration (FDA) (3). In 
this second version of the STEEP criteria, authors ultimately recommend the use of an 
additional endpoint, invasive breast cancer-free survival (IBCFS) which includes all IDFS 
events except second non-breast primary invasive cancers. 
2.2.8 Rationale for the assumption in the tamoxifen arm  
The intention of AMEERA-6 trial is to determine whether amcenestrant compared with tamoxifen 
improves IBCFS in patients who discontinued prior AI due to treatment-related toxicities. For the 
purpose of this study, patients diagnosed with early-stage breast cancer who are at high risk of 
disease recurrence will be selected.  
Regarding justification and rationale for the statistical assumption of the performance of 
participants treated on the tamoxifen arm in AMEERA-6, namely 4-year IBCFS of 82%, data 
from historical as well as more contemporaneous studies is informative.  
In the BIG 1-98 study (46), wherein the high-risk population represented 41% of the global trial 
population, the 5-year DFS among patients with node positive cancer was 77.9% in the letrozole-
only group in comparison with 71.4% in the tamoxifen-only group. 
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Meanwhile, more recent adjuvant trials in patients with ER+/HER2- early breast cancer evaluated 
the combination of CDK4/6-inhibitors with endocrine therapy as compared to standard endocrine 
therapies.  
In the PALLAS study, eligible patients were randomly assigned to receive palbociclib for 2 years 
plus endocrine therapy or standard endocrine therapy with or without an LHRH agonist. Primary 
endpoint was IDFS using STEEP definition and IBCFS was defined as a correlative and 
exploratory endpoint. Adjuvant endocrine therapy selection included 3872 (67.2%) of 
5760 patients initiating an AI, 1872 (32.5%) patients initiating tamoxifen, and 1136 (19.7%) 
patients receiving a concurrent LHRH agonist, similarly in both treatment arms. Among the 
5760 randomized patients, 3382 (58.7%) had high clinical risk, defined as more than 4 positive 
nodes, or one to three positive nodes either T3 or T4, or Grade 3 disease, or both. Results of the 
second interim analyses were reported recently. Invasive DFS did not statistically differ between 
the two groups, with a 3-year IDFS of 88.2% (95% CI 85.2-90.6) in the palbociclib plus endocrine 
therapy group, and 88.5% (85.8-90.7) in the endocrine therapy alone group (HR 0.93 [95% CI 
0.76-1.15]; logrank p = 0.51). When considering the exploratory endpoint of IBCFS, the 3-year 
IBCFS rate was 89.5% (95% CI 86.9-91.7) in the endocrine therapy alone group. In the high-risk 
clinical group, the 3-year IDFS rate was 83.6% (95% CI 78.7-87.7) in the endocrine therapy alone 
group (51). 
In the monarchE study, eligible patients were randomly assigned to receive abemaciclib for 
2 years plus endocrine therapy or standard endocrine therapy. Patients were eligible if they were 
at high risk of recurrence, defined as more than 4 positive nodes or one to three positive lymph 
nodes and at least one of the following features: tumor size ≥5 cm, histologic Grade 3, or centrally 
assessed Ki-67 ≥20%. Primary endpoint was IDFS using STEEP definition. The second interim 
analysis was reported at a median follow-up of 15.5 months. Anti-aromatase inhibitor was 
prescribed as the first endocrine therapy in 68.3% and tamoxifen in 31.4% patients randomized to 
the control arm. At the time of analysis, abemaciclib plus endocrine therapy demonstrated a 
statistically significant improvement in IDFS versus ET alone (HR, 0.75; 95% CI, 0.60 to 0.93), 
with 2-year IDFS rates of 92.2% in the abemaciclib arm versus 88.7% in the control arm (50). 
Other relevant historical studies have reported results in patients treated with a switch strategy 
with sequential adjuvant endocrine therapy after a period of being disease-free. 
The Intergroup Exemestane Study (IES) randomized postmenopausal women with ER+/unknown 
primary invasive breast cancer who remained disease free after 2 to 3 years of tamoxifen to either 
tamoxifen or exemestane for the remainder of the 5-year endocrine therapy period. Although this 
study assessed the other sequence of endocrine therapies as compared to the AMEERA-6 study 
(tamoxifen then anti-aromatase inhibitor versus continued tamoxifen) and the patient population 
which will be enrolled in AMEERA-6 is at higher risk of recurrence, these results can provide 
useful insights on clinical outcomes achieved after a period of being disease-free. At a median 
follow-up of 120 months, the cumulative incidence of breast cancer events remains constant for 
many years (56). A similar pattern of recurrence risk has been observed in a comparison from the 
Oxford meta-analysis including 11798 patients who were disease-free after 2 years of tamoxifen 
and then randomized to either continue tamoxifen or to switch to an aromatase inhibitor (53). 
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In this patient population, risk of disease recurrence is expected to remain similar over time as 
suggested by the Oxford meta-analysis and individual clinical trials evaluating adjuvant endocrine 
therapies, around 4 to 5% per year considering events qualifying for IBCFS endpoint.  
In summary, data from these studies is considered supportive for the reference value of 4-year 
IBCFS of 82% is considered for the control arm of AMEERA-6. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of amcenestrant may be found in the IB. 
Based on amcenestrant experience and the observed safety profile in the ongoing studies, as well 
as on safety precautions that have been established to safeguard the wellbeing of the participants, 
the benefit-to-risk assessment is deemed acceptable within the context of the planned AMEERA-6 
study. 
Moreover, the clinical benefit is expected to be relevant in patients, as preclinical findings and 
clinical pharmacodynamic results show a very high saturation of the ER at the tumor level. This 
current comparative study aims to show a relevant improvement of the efficacy of amcenestrant 
versus tamoxifen. 
2.3.1 Risk assessment  
To date, the efficacy and safety data from ongoing studies of amcenestrant support continued 
clinical development of amcenestrant. Based on non-clinical toxicity study results, completed or 
ongoing clinical studies in patients and in healthy post-menopausal participants, there have been 
no important identified risks confirmed so far. The important potential risks as per non-clinical 
toxicity and in vitro assessments include the following: gastrointestinal (GI) toxicity and 
complications; hepatotoxicity; photosensitivity; drug-drug Interaction; rash; osteoporosis and 
fertility impairment. Routine Pharmacovigilance (PV) activities are being conducted to monitor 
these potential risks associated with amcenestrant. Potential risks are summarized in Table 1.  
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Table 1 - Risk assessment  
Potential risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
Study intervention Amcenestrant (SAR439859) 
Gastrointestinal toxicity 
AMEERA-1 Arm#1 (Parts A and B): A total of 22 out 
of 62 patients who received amcenestrant 
monotherapy (>20 mg QD) developed various GI 
toxicities considered to be related to amcenestrant, 
none of them were of Grade ≥3. 
AMEERA-1 Arm#2 (Parts C and D): A total of 19 out 
of 39 patients who received 200 mg amcenestrant 
and palbociclib developed GI toxicities considered to 
be associated to amcenestrant, none of them were of 
Grade ≥3. 
In studies conducted in healthy subjects, there were 
few single occurrences of GI events considered 
related to amcenestrant. None of them were of 
Grade ≥3 
Events ≥ Grade 3 are to be closely 
monitored. 
Preventive or corrective treatment(s): 
antiemetics, antidiarrheal. 
Hepatotoxicity 
Preclinical safety data have shown evidence of 
hepatotoxicity in repeat dose toxicity study at 
100 mg/kg/day in dogs. 
AMEERA-1 Arm#1 (Parts A and B) / Arm#2 (Parts C 
and D): No event of hepatotoxicity considered to be 
related to amcenestrant has been reported. 
Studies in healthy subjects: In completed or ongoing 
studies in healthy subjects, 3 subjects developed 
asymptomatic transient ALT increase ≥ 2 × ULN with 
amcenestrant 300 mg SD alone or in combination 
with rifampicin. All occurrences were Grade 1. All 
events of ALT increase were non serious and 
spontaneously resolutive. 
Monitor LFT in cases of increase of 
Grade≥3 ALT, listed as AESI in the 
study. 
Monitor patients with symptoms/signs 
suggestive of hepatotoxicity: jaundice, 
increase of liver function tests (LFT) 
(ALT, AST, GGT, ALP and bilirubin). 
Patients with impaired liver function 
should not be included in the study 
(exclusion criterion E 20). 
Phototoxicity 
A phototoxicity risk for amcenestrant was identified 
based on the absorption spectrum of the compound 
and in an in vitro phototoxicity study in 3T3 cells 
which was confirmed in a repeat dose in vivo mouse 
phototoxicity study. 
Within the amcenestrant development program which 
includes the sun protection measures, cumulatively 
Grade 1 sunburns were observed only in 2 patients out 
of an estimated 700 participants exposed so far to 
amcenestrant doses (from 20 to 1200 mg). The first 
patient received amcenestrant 150 mg QD and 
experienced G1 sunburn while being exposed to sun 
without sun protection and the second patient 
developed G1 sunburn after amcenestrant 400 mg QD. 
Limitation of exposure to sunlight or 
artificial sunlight is recommended along 
with the requirement for sun protection 
measures (wear protective clothing, use 
a broad-spectrum sunscreen to cover 
ultra-violet A (UVA) and ultra-violet B 
(UVB) light exposure when outdoors with 
frequent re-application as 
necessary, along with lip balm (sun 
protection factor [SPF] ≥30). 
 
Rash 
In Ameera 2, 1 Grade 2 rash and 1 serious Grade 3 
rash maculo-papular were reported in Japanese 
patients (respectively at 400 mg QD and 300 mg 
BID). The last event was declared as a DLT. 
Grade 1 rashes have been reported in global 
population. 
Closely monitor if further risk 
mitigation/management is required 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
Osteoporosis 
Due to mechanism of action of amcenestrant, there is 
a theoretical risk of osteoporosis when patients are 
exposed long-term to amcenestrant. 
No case of osteoporosis has been reported in 
amcenestrant program. 
No long-term observation has been performed. 
Monitor DEXA at baseline and follow up 
every 2 years.  
Monitor bone markers CTX and P1NP at 
baseline and every 2 years. 
DDI 
Amcenestrant effect on other drugs: Amcenestrant is  
• 
A moderate inducer of CYP3A based on a 
midazolam clinical study. 
• 
A potential CYP2B6, CYP2Cs and UGTs 
inducer 
• 
A potential inhibitor of OATP1B1/1B3 
transporters 
 
 
 
 
Effect of other drugs on amcenestrant:  
• 
In vitro amcenestrant biotransformation occurs 
mainly through non-CYP enzymes (around 80% 
of hepatic clearance) involving UGT1A1 and 
1A4. CYP2C8 and CYP3A are involved to less 
than 20%. CYP3A clearance was confirmed to 
be minimal based on an itraconazole interaction 
clinical study. 
• 
Strong metabolism enzyme inducers 
(Rifampicin) decrease amcenestrant exposure 
by 30% 
 
No adverse event related to DDI has been reported 
in clinical studies as of 29 May 2021. 
Drugs which are sensitive substrates of 
CYP3A, CYP2B6, CYP2Cs, and/or UGT 
should be closely monitored for efficacy. 
 
Treatment with drugs that are sensitive 
substrates of OATP1B1/1B3 
(asunaprevir, batorvastatin, bosentan, 
danoprevir, fexofenadine, glyburide, 
nateglinide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin and simvastatin 
acid) should not be administered with 
amcenestrant.  
 
Drugs that are UGT inhibitors (ie, 
probenecid, atazanavir) should not be 
administered with amcenestrant. 
Drugs that are strong inducers of CYP3A 
should not be administered with 
amcenestrant. 
Patients with concomitant medications 
that are considered to interact with 
amcenestrant should be excluded 
(exclusion criteria: E 12, E 13, E 14, E 15 
and E 16). 
Study procedures 
Mammography 
Mammography to be performed annually with the risk 
of irradiation inducing potential cancers. However, 
this risk is considered minimal due to the low level of 
radiation. In addition, this procedure is standard for 
monitoring patients in the adjuvant setting. 
None 
Biopsies 
It is normal practice to biopsy possible recurrence of 
breast cancer to (a) confirm diagnosis and (b) check 
for change of subtype. 
When required, biopsies should be done 
only when tumor is accessible, limiting 
the risk of Infection or bleeding at the 
biopsy site. 
Special caution is needed for patients on 
anticoagulants, with INR increased, or 
with thrombocytopenia. 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
Other: Study intervention Tamoxifen 
Uterine malignancies 
An increased incidence of uterine malignancies 
(endometrial adenocarcinoma and uterine sarcoma), 
including fatal cases, has been reported with 
tamoxifen treatment. 
Promptly evaluate abnormal vaginal 
bleeding in woman with current or past 
tamoxifen use. 
Patients receiving or who have 
previously received tamoxifen should 
have annual gynecological examinations. 
Advise patients to promptly inform 
healthcare providers if they experience 
any abnormal gynecological symptoms 
(eg, menstrual irregularities, abnormal 
vaginal bleeding, changes in vaginal 
discharge, or pelvic pain or pressure). 
Thromboembolic events 
There is an increased incidence of thromboembolic 
events, including DVT and pulmonary embolism, 
during tamoxifen therapy. 
Carefully consider the risks and benefits 
of tamoxifen in women with a history of 
thromboembolic events. 
Advise patients to seek medical attention 
immediately if signs or symptoms of a 
thromboembolic event occur. 
Participants with abnormal coagulation 
profiles, or any history of coagulopathy 
within 6 months prior to the first dose of 
IMP including history of DVT or 
pulmonary embolism should be excluded 
(exclusion criterion: E 07. 
Hepatotoxicity 
Tamoxifen has been associated with changes in liver 
enzyme levels, and on rare occasions, a spectrum of 
more severe liver abnormalities including fatty liver, 
cholestasis, hepatitis, and hepatic necrosis. Some of 
these serious cases included fatalities. In most 
reported cases, the relationship to tamoxifen is 
uncertain. However, some positive rechallenges and 
dechallenges have been reported. 
Liver cancer and liver abnormalities, some fatal, have 
occurred. 
Perform periodic liver function testing as 
indicated in the protocol (as mentioned 
above for amcenestrant). 
Eye disorder 
There is a risk of ocular disorders with the use of 
Tamoxifen. Adverse drug reactions (ADR) have been 
reported in large Phase III clinical studies. 
The study treatment should 
be permanently discontinued in case 
of first recurrence of the same Grade 4 event 
considered related to the IMPs even though few 
Grade ≥3 adverse event are expected.  
Monitor ocular disorders as part of side 
effects related to Tamoxifen.  
Ensure appropriate surveillance and 
prompt evaluation of visual complaints. 
Embryo-fetal toxicity 
Can cause fetal harm. 
Advise females of reproductive potential 
and male with partner of reproductive 
potential of the potential risk to a fetus 
and to use effective contraception as 
indicated in the protocol. 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
DDI 
Concomitant medications with drugs that inhibit 
CYP2D6 may lead to reduced concentrations of the 
active metabolite endoxifen, one of the most 
important active metabolites of tamoxifen. This could 
lead to reduced efficacy of tamoxifen. 
A marked increase in anticoagulant effect may occur 
when tamoxifen is used in combination with warfarin. 
Strong CYP3A inducers (eg, rifampin) reduce 
tamoxifen exposure. 
Strong inhibitors of CYP2D6 
(eg, paroxetine, fluoxetine, quinidine, 
cinacalcet or bupropion) should be 
avoided during the study. 
When warfarin is prescribed, closely 
monitor coagulation indices for increased 
anticoagulant effect in patients.  
Strong CYP3A inducers should not be 
used with tamoxifen (as mentioned 
above for amcenestrant). 
2.3.2 Benefit assessment  
This new generation SERD, with an expected almost full inhibition of the ER target may represent 
a new therapeutic option with a better benefit/risk ratio than approved endocrine monotherapies, 
such as AIs, tamoxifen, and fulvestrant. 
Amcenestrant could provide meaningful benefit to participants who have a high-risk breast cancer 
disease and limited options after early discontinuation of AI adjuvant due to treatment-related 
toxicities. Moreover, preclinical findings and clinical pharmacodynamics show a very high 
saturation of the ER at the tumor level. This current comparative study aims to show a relevant 
improvement of the efficacy of amcenestrant versus tamoxifen. 
2.3.3 Overall benefit: risk conclusion  
Based on amcenestrant experience and the observed safety profile in the ongoing AMEERA-1 
study, as well as on safety precautions that have been established to safeguard the wellbeing of the 
participants, the benefit-to-risk assessment is deemed acceptable within the context of the planned 
AMEERA-6 study. 
Considering the measures taken to minimize risk to participants, the potential risks identified in 
association with amcenestrant are justified by the anticipated benefits that may be afforded to the 
study participants who have a high-risk breast cancer disease and limited options after AI adjuvant 
treatment discontinuation due to treatment-related toxicities. 
2.3.4 COVID-19 risk and benefit assessment  
Cancer patients are at increased risk of contracting SARS-CoV-2 infection and running more 
severe disease course (57). Cancer encompasses a heterogeneous group of subtypes and stages 
and the patient’s risk profile should therefore be individualized taking into consideration primary 
tumor type and stage as well as age and sex. The benefit and risk balance of anti-tumor treatments 
should be also tailored considering the overall treatment goal. For cancer in the curative setting, 
this risk/benefit balance favors maintaining systemic treatments. Based on a recently published 
consensus statement, some systemic therapies for the adjuvant treatment of early breast cancer, 
ie, endocrine therapy, are in principle not associated with risk of complications of COVID-19 and 
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should therefore be used as recommended by the guidelines (58). In the context of the AMEERA-
6 trial, no study-related risk minimization measures are recommended based on the favorable risk/ 
benefit balance of study population and anti-cancer treatment. The investigators should always 
exercise their medical judgement to individualize clinical decisions and adhere to local and 
institutional guidelines for SARS-CoV-2 infection prevention and vaccine administration. 
Refer to the contingency measures for a regional or national emergency that is declared by a 
governmental agency detailed in Section 10.9, (Appendix 9).  
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To determine whether amcenestrant once a day 
(QD) improves the invasive breast cancer-free 
survival (IBCFS) when compared to tamoxifen QD 
in patients with early breast cancer as adjuvant 
treatment  
 
• 
IBCFS is defined according to Standardized 
Definitions for Efficacy End Points in Adjuvant 
Breast Cancer Trials (STEEP) criteria version 2.0 
(3) as the time interval from the date of 
randomization to the date of the first occurrence of 
one of the following events:  
- 
Ipsilateral invasive breast tumor recurrence 
(IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original 
primary. 
- 
Local-Regional invasive breast cancer 
recurrence: invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of 
the ipsilateral breast.  
- 
Distant recurrence: metastatic disease-breast 
cancer that has either been biopsy confirmed 
or clinically diagnosed as recurrent invasive 
breast cancer.  
- 
Death attributable to any cause, including 
breast cancer, non-breast cancer, or unknown 
cause.  
- 
Invasive Contralateral breast cancer.  
Secondary 
 
Key secondary endpoint 
 
• 
To determine whether amcenestrant once a day 
(QD) improves the invasive disease-free survival 
(IDFS) when compared to tamoxifen QD in patients 
with early breast cancer as adjuvant treatment 
 
• 
IDFS is defined according to STEEP criteria (4) as 
the time interval from the date of randomization to 
the date of the first occurrence of one of the 
following events:  
- 
Ipsilateral invasive breast tumor recurrence 
(IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original 
primary.  
- 
Local-Regional invasive breast cancer 
recurrence: invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of 
the ipsilateral breast. 
- 
Distant recurrence: metastatic disease-breast 
cancer that has either been biopsy confirmed 
or clinically diagnosed as recurrent invasive 
breast cancer.  
- 
Death attributable to any cause, including 
breast cancer, nonbreast cancer, or unknown 
cause. 
- 
Invasive Contralateral breast cancer 
- 
Second nonbreast primary invasive cancer 
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Objectives 
Endpoints 
Other secondary endpoints 
 
• 
To evaluate the distant recurrence-free survival 
(DRFS) in both treatment arms 
 
• 
DRFS is defined according to STEEP criteria (4) as 
the time interval from the date of randomization to 
the date of the first occurrence of one of the 
following events: distant recurrence or death 
attributable to any cause (including breast cancer, 
nonbreast cancer, or unknown cause). 
 
• 
To evaluate the locoregional recurrences-free 
survival (LRRFS) in both treatment arms 
 
• 
LRRFS is defined as the time interval from the date 
of randomization to the date of the first occurrence 
of one of the following events: local/regional 
ipsilateral recurrence, invasive contralateral breast 
cancer or death attributable to any cause (including 
breast cancer, nonbreast cancer, or unknown 
cause). 
 
• 
To evaluate the overall survival (OS) in both 
treatment arms  
 
• 
OS is defined as the time interval from the date of 
randomization to the date of death due to any 
cause. 
 
• 
To evaluate the breast cancer-specific survival 
(BCSS) in both treatment arms 
 
• 
BCSS is defined as the time interval from the date 
of randomization to the date of death attributable to 
breast cancer cause 
 
• 
To evaluate patient-reported overall treatment-
related side effect bother, treatment-related 
symptoms, and quality of life in both treatment arms 
 
 
• 
This patient reported outcome (PRO) objective will 
be evaluated using the following endpoints:  
- 
Change from baseline in overall side effect 
bother as measured by the Functional 
Assessment of Cancer Therapy Item GP-5 
(FACT-GP5).  
- 
Change from baseline in systemic therapy side 
effects as measured by the EORTC Quality of 
Life Questionnaire Breast cancer module 
(EORTC-QLQ-BR23) systemic therapy side 
effects scale.  
- 
Change from baseline in global health 
status/quality of life as measured by the 
EORTC Core Quality of Life Questionnaire 
(EORTC QLQ-C30) global health status/quality 
of life (GHQ) scale 
• 
To evaluate safety in both treatment arms  
• 
Adverse events (AEs)/serious adverse events 
(SAEs), laboratory abnormalities and adverse 
events of special interest (AESIs). 
• 
To characterize the pharmacokinetics (PK) of 
amcenestrant 
• 
Amcenestrant predose concentrations 
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Objectives 
Endpoints 
Tertiary 
 
• 
To perform exploratory analyses of tumor tissue 
samples to investigate the predictive and prognostic 
value of sensitivity to endocrine therapy assessed 
by SET2,3 index measurement 
• 
Relationship between SETER/PR and SET2,3 index 
measurements assessed using FFPE slides and 
efficacy endpoints 
• 
To perform exploratory analyses of tumor tissue, 
serum, and plasma samples before treatment 
initiation to investigate the predictive and prognostic 
value of novel biomarkers related to safety and 
efficacy endpoints 
• 
Relationship between tumor derived tumor makers 
(DNA- or RNA-based and protein markers) before 
treatment initiation and safety / efficacy endpoint 
• 
To perform exploratory analyses of tumor tissue, 
serum, and plasma samples before treatment 
initiation to investigate the predictive and prognostic 
value of novel biomarkers related to safety and 
efficacy endpoints 
• 
Relationship between the changes from baseline 
and corresponding distribution of tumor derived 
tumor makers (DNA- or RNA-based and protein 
markers) upon disease recurrence and efficacy 
endpoints 
• 
To perform exploratory analyses of circulating tumor 
DNA to investigate the predictive and prognostic 
value of ESR1 mutation 
• 
Relationship between ESR1 mutations assessed in 
the ctDNA from plasma samples collected 
throughout the study and efficacy endpoints 
• 
To perform exploratory analyses of tumor tissue 
samples to investigate the predictive and prognostic 
value of breast cancer molecular subtypes (eg, 
Luminal A, Luminal B, non-Luminal) 
• 
Relationship between genomic signatures assessed 
using RNA sequencing data and efficacy endpoints 
• 
To perform exploratory analyses of tumor tissue 
samples to investigate the predictive and prognostic 
value of histological type (ductal, lobular, others) 
• 
Relationship between histological type and efficacy 
endpoints 
• 
To perform exploratory analyses aimed at 
identifying biomarkers are associated with 
resistance to endocrine therapy 
• 
Relationship between biomarkers collected 
throughout the study and efficacy endpoints. 
Biomarkers include tests performed in blood and 
tumor tissue, including, but not limited to the 
following: 
- 
ctDNA mutations analysis. 
- 
breast cancer molecular subtypes assessed 
using RNA sequencing. 
- 
ER activation score by RNA sequencing.  
- 
ER, PgR, Ki67, and Bcl-2 protein expression 
assessed using immunohistochemistry (IHC). 
• 
To evaluate patient-reported functional impact, 
treatment- related symptoms, health state utilities, 
and adherence in both treatment arms  
• 
This PRO objective will be assessed by the 
following endpoints:  
- 
Change from baseline in physical functioning 
as measured by the 5-item physical functioning 
scale of the EORTC-QLQ-C30.  
- 
Change from baseline in physical functioning 
as measured by the 8-item EORTC short form 
physical functioning scale (which includes 
physical function items from the EORTC QLQ-
C30 and EORTC IL127).  
- 
Patient-reported treatment-related symptoms 
will be measured using PRO-CTCAE items. 
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Objectives 
Endpoints 
- 
Health state utilities will be measured with the 
EQ-5D-5L.  
- 
Patient-reported medication adherence will be 
measured with the 8-item Morisky Medication 
Adherence Scale (MMAS-8). 
- 
Patient global impression of change (PGIC) in 
side effects of treatment and patient global 
impression of severity (PGIS) in side effects of 
treatment will be measured by PGIC and PGIS 
items. 
 
 
 
 
 
For China, please see Section 10.8 for details. 
3.1 
APPROPRIATENESS OF MEASUREMENTS   
The rationale for the choice of IBCFS as the primary endpoint has been extensively discussed in 
the Section 2.2.7 to be a more precise breast-cancer specific outcomes in this setting. IDFS has 
been widely used in other studies in the adjuvant setting and is considered as a key secondary 
endpoint in this study. Its formal testing will be performed if the primary test on IBCFS is 
significant and a particular care will be given to the description of the event contributing to this 
endpoint. Efficacy endpoints were defined as per the STEEP standardized definitions for efficacy 
endpoints in adjuvant breast cancer clinical trials (4) and its recent update STEEP Version 2.0 (3). 
The secondary efficacy endpoint LRRFS was defined using the definition in the recent previous 
trial conducted in this setting (50, 51), including the invasive contralateral breast cancers in the 
event definition.  
The current study will enroll a patient population who did not tolerate aromatase inhibitors; 
therefore, the evaluation of patient-reported outcomes is of importance including overall-
treatment related side effect both, treatment-related symptoms, and functional impact on quality of 
life. Self-reported treatment adherence is also of interest. All PRO questionnaires used in this 
study are validated questionnaires as described in Section 8.10.  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a prospective, randomized, international, multicenter, double-blind, double-dummy, 
Phase 3 study comparing the efficacy and evaluating the safety of amcenestrant versus tamoxifen. 
The study will have 3 main periods: screening, active treatment, and follow up. 
Men, pre/peri-menopausal women (with GnRH analog approved for use in early breast cancer) 
and post-menopausal women with HR+ early breast cancer, who have discontinued adjuvant AI 
therapy due to treatment-related toxicity will enter the screening period to assess their eligibility.  
Participants still on AI treatment may enter the screening period for central confirmation of 
biomarkers and screening imaging assessments. The other assessments/questionnaires 
required before randomization will be performed/completed when patient is off the AI 
therapy. 
All eligible participants for whom ER and PgR status have been centrally confirmed will be 
randomly assigned using an IRT to either amcenestrant 200 mg daily (experimental) arm or 
tamoxifen 20 mg daily (control) arm in a 1:1 ratio.  
• Arm A: Amcenestrant 200 mg + tamoxifen-matching placebo  
• Arm B: Amcenestrant-matching placebo + tamoxifen 20 mg 
All randomized patients will also receive the matching placebo of the other treatment under 
evaluation. Both treatments are given orally. 
The study population will be stratified by the following factors, as reported at the time of 
randomization: 
• Prior exposure to (neo)adjuvant AI therapy: ≤12 months vs. >12 months 
• Prior exposure to (neo)adjuvant chemotherapy and HER2 status: HER2-negative breast 
cancer with NO prior (neo)adjuvant chemotherapy vs. HER2-negative breast cancer with 
prior (neo)adjuvant chemotherapy vs. HER2-positive breast cancer with prior 
(neo)adjuvant chemotherapy 
Note: Participants with unknown HER2 status will be classified as HER2-negative. 
• Prior exposure to CDK4/6 inhibitor (Yes or No) 
• Geographic regions (North America, Europe vs. Asia Pacific vs. Other) 
• Men or peri-/pre-menopausal women vs. post-menopausal women 
During the treatment period, men and pre/perimenopausal women will receive GnRH analogs as 
approved in the respective countries.  
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Participants will receive their assigned treatment for the planned duration of 5 calendar years or 
until diagnosis of disease recurrence per IBCFS definition or any other withdrawal criterion 
whichever occurs first. 
Early discontinuation during the active study treatment period will be left at the investigator’s 
discretion.  
Extended adjuvant endocrine therapy upon completion of study treatment is allowed, but 
treatment will not be provided by the sponsor. Treatment recommendation should be considered 
on an individual patient basis taking into consideration clinico-pathologic characteristics, patient’s 
preferences, and total duration of adjuvant endocrine therapy at the time of study treatment 
completion or discontinuation. When extended adjuvant endocrine therapy is considered, 
treatment options include adjuvant tamoxifen or adjuvant aromatase inhibitor.  
In case of diagnosis of second non-breast primary invasive cancers, the decision to keep the patient 
on protocol treatment is based on clinical judgement of the treating physician. Patients diagnosed 
with a second primary malignancy not requiring systemic therapy (ie, chemotherapy, hormonal 
therapy, targeted therapy, etc) and with no evidence of breast cancer recurrence may continue with 
study drug treatment according to the protocol and schedule of assessment, if considered by the 
investigator to be in the patient’s best interest, whenever possible. Study treatment may be 
temporarily suspended to allow for local treatment (surgery and/or radiation) of the second non-
breast primary invasive cancer; in this situation, the maximally allowed period of protocol treatment 
discontinuation should not exceed a total of 3 months in any 12-month time period.  
Participants discontinuing or completing the active study treatment period will be followed up to 
10 years from randomization, except in case of premature study termination due to one of the 
following reasons: withdrawal of consent, loss to follow-up or death.  
An IDMC will monitor the safety data on a periodic basis. The IDMC will make 
recommendations as to whether the trial should continue based on ongoing reviews of safety data. 
The IDMC will also evaluate efficacy at the interim analyses and make a recommendation 
regarding study continuation based on observed results of the current study and/or external study 
data generated with amcenestrant. The IDMC procedures will be described in the full protocol and 
detailed in the IDMC charter and will be approved by IDMC members. 
A Study Steering Committee will supervise the progress of the trial, review relevant information 
that may affect the study conduct as well as review and take decisions to act on the IDMC 
recommendations. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The purpose of the proposed study is to demonstrate the superiority of amcenestrant versus 
tamoxifen with regard to IBCFS in patients with HR+ early breast cancer who have discontinued 
AI as adjuvant treatment due to treatment-related toxicities. For this population, there are 
currently limited treatment options after AI discontinuation, including switching to another AI 
which may have similar side effects, or switching to tamoxifen.  
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This is a randomized double-blinded placebo-controlled clinical trial, which is a gold standard to 
be able to change the current treatment guidelines. 
The scientific rationale for key aspects of the study design including patient population, choice of 
the primary endpoint have been detailed in the Section 2.1 and Section 2.2 . 
4.2.1 Participant input into design  
During the development of the study concept, the sponsor conducted patient panels and interviews 
with 40 participants (representing 5 countries in 3 regions) in April and May 2020. The patients 
supported the development of an adjuvant endocrine therapy with an improved safety profile and 
less side effects as well as innovative methods using technology to reduce the burden of clinical 
trial participation. 
During the development of the AMEERA-6 study, 9 patient representatives from the BIG’s 
Patient Partnership Initiative (PPI) were involved in the assessment of the PRO scales and 
adherence questionnaires to be implemented in the study.  
In particular, after having familiarized with the rationale behind the study and its proposed design, 
the patient partners were asked to provide their feedback on the 8 health-related quality of life 
(HRQL) scales and 2 adherence questionnaires that were proposed by a group of experts in the 
field, in particular on the following aspects: 
1. Burden and frequency of the questionnaires 
2. Satisfaction on the way the selected tools capture the discomfort that can occur with 
endocrine treatment 
3. Intrusiveness of the questions and scales 
4. Non-adherence scale 
5. Format of the questionnaires (digital versus paper-based) 
Based upon the feedback received from the patient representatives, three major changes were 
implemented in the protocol: 
• The breast version of the MIS-A questionnaire assessing adherence to treatment was 
removed. This topic will be assessed by the Morisky Medication Adherence Scale 
(MMAS-8) questionnaire. 
• Baseline PRO assessment: Originally, two baseline assessments were foreseen, one before 
randomization (ie, screening period) and at treatment start (D1C1). Given the remark of 
the PPI group that the intensity of the assessment was too high, it was decided to perform 
only one PRO assessment on D1C1 or earlier if patient has no unrecovered acute toxic 
effects of prior AI therapy. 
• Late follow-up: The patient representatives’ review indicated there was interest in a long-
term follow-up, given the good prognosis of these patients. Therefore, the protocol was 
updated with an additional post-treatment follow-up visit at two years after treatment. 
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4.3 
JUSTIFICATION FOR DOSE  
The term “dose” refers to 200 mg orally once daily for amcenestrant and to 20 mg orally 
once daily for tamoxifen. 
A dedicated window-of-opportunity AMEERA-4 (ACT16106) study with amcenestrant in pre-
operative ER+/HER2- postmenopausal breast cancer patients is currently ongoing. Findings from 
the administrative interim analysis of AMEERA-4 undertaken in April 2021 following the 
randomization of the first 63 patients have been used to support the dose of amcenestrant used in 
this study (Section 2.1.2). While the pharmacodynamic activity and safety results from 
AMEERA-4 could support use of either amcenestrant 200 mg or 400 mg in the AMEERA-6 
study, the lower dose of 200 mg is preferred given the proposed long-term exposure (5 years) in 
early breast cancer, in particular for these study participants who discontinued prior adjuvant AI 
due to treatment-related toxicities. 
The regulatory approved and administered schedule of tamoxifen 20 mg orally daily in adjuvant 
breast cancer will be used in this study. 
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study. 
Participants completing the active 5-year study treatment period or discontinuing prematurely will 
be followed up for 10 years from randomization. A participant is considered to have completed 
the study if he/she has completed all phases of the study including 5 years of treatment period and 
5 years of post-treatment period for the follow-up, except in case of premature study termination 
due to one of the following reasons: withdrawal of consent, loss to follow-up or death. 
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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: 
Age 
I 01. Participant must be 18 years of age inclusive or older, 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. Participants with histologically confirmed diagnosis of adenocarcinoma of the breast with 
documentation of ER+ (≥10% positive stained cells) and/or PgR+ (≥10% positive stained 
cells) based on invasive breast tumor cell staining by immunohistochemistry (IHC) assay 
consistent with central assessment. If axillary lymph nodes are tested, ER and/or PgR must 
also be positive. 
- 
Participants with bilateral invasive disease are allowed only if the contralateral breast 
tumor meet the criteria regarding ER and PgR-status described above. 
- 
In case of multicentric or multifocal or synchronous bilateral breast cancer, the lesion 
considered at highest risk for recurrence based on the investigators’ discretion will be 
used for central pathology review and stratification.  
I 03. Participants irrespective of HER-2 status (HER2-positive, HER2-negative, unknown) as 
assessed per ASCO/College of American Pathologist guidelines (59), are eligible provided 
in each case they meet the ER and PgR criteria in I 02. 
- 
HER2-negative is defined as a score of 0, 1+ by IHC or a negative in situ hybridization 
(ISH) based on single-probe average HER2 copy number  
- 
HER2-positive is defined as a score of 3+ by IHC or a positive ISH based on single-
probe average HER2 copy number. All adjuvant anti-HER2 treatment and 
chemotherapy must be completed prior to randomization. 
I 04. Participants with Stage IIB or Stage III invasive breast cancer per the AJCC Cancer 
Anatomic Staging 8th edition who have undergone adequate (definitive) breast surgery and 
adjuvant radiation (if indicated) for the current malignancy. Participants with inflammatory 
breast cancer are not eligible. 
- 
In participants having received upfront surgery with or without adjuvant systemic 
therapy, eligibility is based on pathological staging (pTNM) rather than clinical staging 
(cTNM), in case there is a discordancy between these. 
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- 
If neoadjuvant systemic therapy was administered, participants must have Stage IIB or 
Stage III invasive breast cancer based on clinical staging (cTNM) and have residual 
nodal disease after definitive breast surgery (ypN1-3).  
- 
Participants with only residual micrometastatic disease (N1mic) or isolated tumor 
cells (ITCs) in the axillary lymph nodes are not eligible. 
NOTE: the One-Step Nucleic Acid Amplification (OSNA) method is acceptable for 
sentinel lymph-node assessment. 
I 05. Participants who have received prior AIs (letrozole, anastrozole or exemestane or any 
sequence thereof) per the following: 
- 
Adjuvant AI therapy was discontinued due to treatment-related toxicity. 
- 
Minimum of 6 months duration of AI therapy is required 
- 
Maximum of 30 months duration of AI therapy is required (from initiation of first AI if 
there was a switch between AIs) 
- 
AIs are permitted in neoadjuvant setting and count toward the 30-month maximum 
duration. However, a minimum of 3 months of AI therapy are required in the adjuvant 
setting. 
NOTE: 
- 
A patient will not be eligible if he/she received AIs in only the neoadjuvant setting 
(at least 3 months of adjuvant AI therapy is required),  
- 
Switch between different adjuvant AIs before discontinuation is allowed.  
I 06. Participants for who the last AI adjuvant therapy was discontinued less than 3 months prior 
to randomization but stopped at least 1 week prior to patient randomization onto the trial. 
NOTE: In this case, the tumor material and imaging work up can be performed while 
participants are still treated with AIs. The other assessments/questionnaires required 
before randomization will be performed/completed when patient is off the AI therapy. 
I 07. Prior systemic therapies other than AI(s): 
- 
Participants who received prior treatment with cyclin-dependent kinase 4 and 6 
(CDK4/6) inhibitors are allowed but treatment must have a wash-out period of at least 
4 weeks between the last dose of the CDK4/6 inhibitor and randomization onto the 
trial.  
- 
Participants who received prior treatment with Poly ADP ribose polymerase (PARP) 
inhibitors or other oral anticancer agents (including oral fluoropyrimidines such as S-1 
and capecitabine) are allowed but must have a wash-out period of at least 2 weeks 
between the last dose of the anticancer agent and randomization. 
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I 08. Participants with absence of locoregional and/or advanced/metastatic disease with 
following imaging test(s): 
- 
A negative bilateral mammogram at study entry is required (exam does not need to be 
repeated if performed within 6 months prior to randomization). In participants with 
prior mastectomy, unilateral mammogram will be performed. In participants with prior 
bilateral mastectomy, mammogram is not indicated. 
NOTE: if local investigator plans to use MRIs instead of mammograms during the study, 
MRI will have to be performed at baseline. 
- 
Baseline staging must be performed prior to study enrollment for the following 
participants:  
- 
Participants with symptoms suggestive of metastatic disease indicated per 
investigator’s judgment (for example, if patient is symptomatic for bone pain 
and/or if alkaline phosphatase is significantly elevated ≥ 3×ULN).  
- 
Participants diagnosed with stage IIIA or higher and no staging evaluation was 
performed prior to study enrollment. Staging must include chest, abdominal ± 
pelvic, and bone imaging and clinical evaluation of superficial disease. 
Examination type for staging can include sonography, bone scan, CT, MRI and/or 
PET-CT as per investigator’s choice. 
I 09. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. 
I 10. Willingness and ability to provide tumor tissues (ie, archived formalin fixed paraffin 
embedded [FFPE] tissues). 
Weight 
Not applicable. 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 11. All 
For the contraceptive and barrier guidance, please refer to Appendix 4 Section 10.4. Contraceptive 
use by men with a partner of childbearing potential or women should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical studies. 
a) Male participants 
- 
Male with no prior bilateral orchiectomy can be enrolled if amenable to be treated with 
goserelin or other GnRH analog approved for use in early breast cancer in the 
respective countries. 
b) Female participants 
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• Postmenopausal women as defined by one of the following: 
- 
Age ≥60 years 
- 
Age <60 years: 
a) With spontaneous cessation of menses >12 months prior to randomization in the 
absence of chemotherapy, tamoxifen and toremifene. 
b) Or with cessation of menses of duration ≤12 months or secondary to hysterectomy 
AND have follicle stimulating hormone (FSH) and estradiol level in the 
postmenopausal range according to institutional standards (or >34.4 IU/L for FSH 
and <10 pg/mL for estradiol if institutional range is not available) prior to 
randomization, 
c) Or who have received hormonal replacement therapy but have discontinued this 
treatment AND have FSH and estradiol level in the postmenopausal range 
according to institutional standards (or >34.4 IU/L for FSH and <10 pg/mL for 
estradiol if institutional range is not available) prior to randomization, 
d) Or with status post bilateral surgical oophorectomy, 
e) Or post bilateral ovarian ablation through pelvic radiotherapy: recommended to 
have FSH and estradiol level in the postmenopausal range according to 
institutional standards (or >34.4 IU/L for FSH and <10 pg/mL for estradiol if 
institutional range is not available) prior to randomization.  
NOTE: As per local regulations, to demonstrate postmenopausal status, serial 
measurements of FSH may be required in patients who are not using hormonal 
contraception or hormonal replacement therapy, and in the absence of amenorrhea for 
at least 12 months. 
• Pre/perimenopausal women, ie, not meeting the criteria for being postmenopausal. 
- 
Pre/perimenopausal women can be enrolled if amenable to be treated with goserelin or 
other GnRH analog approved for use in early breast cancer in the respective countries. 
Informed Consent 
I 12. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.  
Other inclusions 
I 13. Participants with HIV are eligible if the disease is well-controlled with a viral load 
<200 copies of HIV per mL of blood.  
NOTE: antiretroviral medicines may interfere with IMP, refer to Section 6.8. 
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5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Multicentric, multifocal and/or bilateral breast cancer of which any histopathological 
examined lesion is both ER and PgR negative. 
E 02. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of 
amcenestrant and/or tamoxifen. Participants unable to swallow normally or unable to take 
tablets and capsules. Predictable poor compliance to oral treatment. Active inflammatory 
bowel disease or chronic diarrhea, known active hepatitis A/B/C*, hepatic cirrhosis, short 
bowel syndrome, or any upper gastrointestinal surgery including gastric resection or 
banding procedures. 
NOTE: * Active hepatitis, defined as: 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 and quantitative hepatitis C 
(HCV) ribonucleic acid (RNA) results greater than the lower limits of detection of the 
assay). 
E 03. Participants with a prior breast cancer history treated with AI  
E 04. Any other solid tumor or lymphoma diagnosis is not allowed except if the participant has 
been free from disease for ≥5 years. Adequately treated basal cell or squamous cell skin 
cancer or in situ cervical cancer are allowed. 
E 05. Pregnant or nursing women, or women of child-bearing potential without a negative 
pregnancy test prior to randomization. 
E 06. Participants with unrecovered acute toxic effects of prior AI therapy or surgical procedures 
of National Cancer Institute- Common Terminology Criteria of Adverse Events (NCI-
CTCAE) Version 5.0 Grade >1 (except alopecia or other toxicities not considered a safety 
risk for the participant at investigator’s discretion). 
E 07. Uncontrolled intercurrent illness, including psychiatric conditions that would limit 
compliance with study requirements. 
E 08. Participants with abnormal coagulation profiles, or any history of coagulopathy within 
6 months prior to the first dose of IMP including history of deep venous thrombosis (DVT) 
or pulmonary embolism. However, participants with the following conditions will be 
allowed to participate: 
- 
Participants with adequately treated catheter-related venous thrombosis occurring more 
than 1 month prior to the first dose of IMP. 
- 
Participants being treated with an anticoagulant, eg, warfarin, heparin, or direct oral 
anticoagulants (DOAC; eg, dabigatran, rivaroxaban) for a thrombotic event occurring 
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more than 6 months before randomization, or for an otherwise stable and allowed 
medical condition (eg, well-controlled atrial fibrillation) provided dose and 
coagulation parameters (as defined by local standard of care) are stable for at least 
1 month prior to the first dose of IMP. 
Prior/concomitant therapy 
E 09. Treatment with any SERD, tamoxifen or toremifene are not allowed as prior adjuvant 
therapy but could have been used as neoadjuvant therapy up to a maximum duration of 
3 months. Participants who were treated with a SERD, tamoxifen or toremifene in the 
neoadjuvant setting and who experienced disease progression are not allowed. Prior 
treatment with raloxifene or tamoxifen for bone health, risk reduction, or a prior breast 
cancer is allowed provided this was discontinued at least 3 years before diagnosis of 
current breast cancer. 
E 10. Ongoing treatment with HER2-directed therapy. Appropriate wash out between the last 
dose of HER2-directed therapy and randomization should be at least 4 weeks. 
E 11. Major surgery within 4 weeks before randomization. 
E 12. Treatment with drugs that are sensitive substrates of OATP1B1/1B3 (asunaprevir, 
atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, 
pravastatin, repaglinide, rosuvastatin and simvastatin acid) within 2 weeks before first IMP 
administration. 
NOTE: Refer to FDA website: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table5-1 
E 13. Treatment with strong CYP3A inducers within 3 weeks before first IMP administration. 
NOTE: List of strong CYP3A drugs can be found in section 6.8 concomitant therapy  
E 14. Treatment with drugs that have potential to inhibit UGT, including but not limited, to 
atazanavir and probenecid, within 2 weeks before IMP administration. 
E 15. Treatment with strong inhibitors of CYP2D6 within 2 weeks before first IMP 
administration NOTE: List of potential drugs interacting with CYP450 can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
Prior/concurrent clinical study experience 
E 16. Participation within 4 weeks before randomization in any other clinical study involving 
an investigational study treatment including anti-cancer agents. 
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Diagnostic assessments 
E 17. Inadequate hematological function including: 
- 
Hemoglobin <9 g/dL or blood transfusion support within 2 weeks prior to 
randomization 
- 
Neutrophils <1.5 x 109/L or growth factor support within 2 weeks prior to 
randomization 
- 
Platelet count <100 x 109/L or platelet transfusion support within 2 weeks prior to 
randomization 
E 18. Inadequate renal function with estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2 as estimated using the Modification of Diet in Renal Disease 
(MDRD) formula. 
E 19. 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 20. Inadequate liver function as defined as: 
- 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 x ULN 
- 
Alkaline phosphatase (ALP) >1.5 x ULN 
- 
Total bilirubin >1.5 x ULN (>3.0 x ULN with direct bilirubin within normal range in 
patients with Gilbert’s disease) 
Other exclusions 
E 21. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 22. Any country-related specific regulation that would prevent the participant from entering 
the study – see Section 10.8 (Appendix 8) of the protocol (country-specific requirements). 
E 23. 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 24. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 25. 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.  
All eligibility criteria must be adhered to. Protocol waivers or exemptions are not allowed. 
 
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5.3 
LIFESTYLE CONSIDERATIONS  
Compliance with the study protocol: Absence of any condition hampering compliance with the 
study protocol and follow-up schedule; those conditions should be discussed with the patient 
before randomization in the trial.  
5.3.1 Sun protection  
A phototoxicity risk for amcenestrant was identified based on the absorption spectrum of the 
compound in in vitro and in vivo preclinical studies. Within the amcenestrant development 
program which includes the below recommendations, cumulatively Grade 1 sunburns were 
observed only in 2 patients out of an approximately 700 participants exposed so far to 
amcenestrant doses (from 20 to 1200 mg).  
Participants should avoid direct exposure to natural or artificial sunlight during study treatment 
and for at least 5 days after last amcenestrant/amcenestrant-matching placebo dose. 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 UVA and UVB light exposure when outdoors with 
frequent re-application as necessary. 
5.3.2 Osteoporosis  
Lifestyle changes that preserve bone mineral density [eg, stopping or reducing smoking and 
drinking, and increasing physical activity, especially weight-bearing exercises), and adequate 
nutrition (protein, calcium, and supplementary vitamin D3)] are recommended. 
5.3.3 Activity  
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests.  
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). Only SAEs related to study 
procedures will be collected from signing of the informed consent form through the time the 
screen failure is declared.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Participants who are rescreened are required to sign a new informed consent 
form, and should be assigned a new study participant number, and all the screening procedures 
should be repeated and entered in the screening visit pages. In case the participant is a temporary 
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screen failure, there is no need to have participant reconsent (ie, new ICF signed) if the participant 
finally participates in the trial. However, if the reason for temporary screen failure is a reason that 
might have altered the initial given agreement of the participant to participate, the Investigator 
should ensure the willingness of the participant to continue or redo some screening procedures 
and his/her participation to the trial. This oral agreement should be documented in the 
participant’s chart. All the tests out of protocol window should be repeated and entered to the 
additional pages. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING   
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Section 10.9 (Appendix 9) should be considered. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention, marketed product and placebo 
intended to be administered to a study participant according to the study protocol. 
The study interventions, Amcenestrant/Amcenestrant-matching placebo and 
Tamoxifen/Tamoxifen-matching placebo, will be administered as a flat-fixed dose, and not by 
body weight or body surface area.  
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 3 - Study intervention(s) administered  
Intervention label 
Amcenestrant  
200 mg (SAR439859) 
Amcenestrant 
matching placebo 
Tamoxifen 20 mg 
Tamoxifen matching 
placebo 
Intervention 
name 
Amcenestrant 200 mg 
(SAR439859) 
Amcenestrant 
matching placebo 
Tamoxifen 20 mg 
Tamoxifen matching 
placebo 
Intervention 
description 
QD-tablet 
QD-tablet 
QD-tablet 
QD-tablet 
Type 
Drug 
Drug 
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Unit dose 
strength(s) 
 
 
 
 
Dosage level(s) 
1 tablet once a day 
with food, at 
approximately the 
same time every day 
(±3 hours) 
1 tablet once a day 
with food, at 
approximately the 
same time every day 
(±3 hours) 
1 tablet once a day 
with food, at 
approximately the 
same time every day 
(±3 hours) 
1 tablet once a day 
with food, at 
approximately the 
same time every day 
(±3 hours) 
Route of 
administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental active 
Experimental placebo 
Comparator 
Comparator placebo 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
Packaging and 
labeling 
Amcenestrant 200 mg 
will be provided in 
child resistant bottles 
(32 tablets per bottle). 
Labelling will be as 
required per country 
requirement 
Amcenestrant 
matching placebo will 
be provided in child 
resistant bottles 
(32 tablets per bottle). 
Labelling will be as 
required per country 
requirement 
Tamoxifen 20 mg will 
be provided in child 
resistant wallets 
(32 tablets per wallet). 
Labelling will be as 
required per country 
requirement 
Tamoxifen matching 
placebo will be 
provided in child 
resistant wallets 
(32 tablets per wallet). 
Labelling will be as 
required per country 
requirement 
[Current/former 
name(s) or 
alias(es)] 
Amcenestrant 200 mg 
(SAR439859) 
Amcenestrant 
matching placebo 
Tamoxifen 20 mg 
Tamoxifen matching 
placebo 
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Table 4 - Study arm(s)  
Arm title 
A 
B 
Arm type 
Experimental 
Active comparator 
Arm description 
Amcenestrant (SAR439859) 200 mg 
+ Tamoxifen Placebo 
Amcenestrant Placebo + Tamoxifen 
20 mg 
Associated intervention labels 
None 
None 
6.1.1 Treatment starts after randomization  
All participants entered into the study will be treated within 3 working days of randomization. 
A participant may receive additional study interventions if he/she meets retreatment criteria as 
determined by the Investigator and agrees to be retreated. Throughout the study, study 
intervention will be blinded. 
6.1.2 Patient diaries  
Participants will receive study drug diaries for Amcenestrant/Amcenestrant-matching placebo and 
Tamoxifen/Tamoxifen-matching placebo to document study intervention intake, and the 
completed study drug diaries should be returned to the study site at the subsequent study visit.  
6.1.3 Drug dispensation  
IMPs are dispensed at each protocol-scheduled on-site visit as defined in the SoA (Section 1.3 
“IMP dispensation call” raw). Between the protocol-scheduled on-site visits, interim visits may be 
required for IMP dispensing. As an alternative to these visits, IMPs may be supplied from the 
PI/site to the participant via a Sponsor-approved courier company where it was allowed by local 
regulations and agreed up on by the participant. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Section 10.9 (Appendix 9): Contingency measures for a regional or national emergency that is 
declared by a governmental agency. 
6.1.4 Amcenestrant/Amcenestrant-matching placebo  
Amcenestrant/Amcenestrant-matching placebo will be administered orally at a dose of 200 mg 
once daily in fed condition and at approximately the same time each day (±3 hours), together with 
Tamoxifen/Tamoxifen-matching placebo. The daily dose of amcenestrant (SAR439859) tablets is 
to be swallowed whole with water. The two tablets should be taken within 5 minutes. Study 
participants should be instructed not to bite or chew on the tablets. 
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6.1.5 Tamoxifen/Tamoxifen-matching placebo  
Tamoxifen/Tamoxifen-matching placebo will be administered orally at a dose of 20 mg once 
daily and at approximately the same time each day (±3 hours), together with 
Amcenestrant/Amcenestrant-matching placebo. The two tablets should be taken within 5 minutes. 
Study participants should be instructed not to bite or chew on the tablets. 
Refer to the Tamoxifen Summary of Product Characteristics for additional administration 
instructions. 
6.1.6 Non-investigational medicinal products  
Goserelin or other GnRH analog, approved for use in early breast cancer as per site/country 
availability, will be administered in male participants without prior orchiectomy and in 
pre/perimenopausal women.  
Refer to the corresponding Summary of Product Characteristics for additional administration 
instructions. 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
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.  
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention 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. The 
investigator, institution, or the head of the medical institution is responsible for study intervention 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records).  
Partially used and used study intervention will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
intervention will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the Monitoring Team.  
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization. 
Further guidance and information for the final disposition of used and unused study medications 
are provided in the pharmacy manual and/or monitoring plan.  
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 8.3.7).  
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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, allow the IMP 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  
Two systems requiring log in by the investigator will be used: 
• Medidata Rave EDC system, to be used to complete the eCRF 
• The IRT system for registration, randomization and drug supply information 
Both systems are accessible 24 hours a day, 7 days a week.  
The log in instructions for Rave EDC system and IRT system will be provided to each 
investigator prior to site authorization. 
Screening and randomization will be performed in three steps: 
• Step 1: Screening 
Participants will be recorded directly in the IRT system. At this stage, date of signature of 
informed consent and questions related to stratification factors (see Section 4.1) should be 
completed. Patient identifier will be created. In parallel, tumor sample has to be sent for 
central pathology assessment to confirm ER and PgR status. 
• Step 2: Eligibility criteria data collection and central confirmation of ER and PgR 
biomarkers 
Once a patient is registered in the IRT system, the investigator should log in on the 
Medidata Rave EDC system, to complete the eligibility related baseline information.  
Note that the tumor material shipment and imaging work up can be performed while 
patient is still treated with AI. The other assessments/questionnaires required before 
randomization should be performed/completed when the participant is off the prior AI 
therapy.  
• Step 3: Randomization 
Once eligibility criteria, ER / PgR status and discontinuation of prior AI therapy due to 
treatment-related toxicity have been confirmed, the participant could be randomized in the 
IRT system. During this step, stratification factors should be confirmed in the IRT system. 
- 
The randomized intervention kit number list is generated centrally by Sanofi. 
- 
The IMPs are packaged in accordance with this list. 
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The randomization and intervention allocation are performed centrally by an IRT. The 
IRT generates the participant randomization list and allocates the intervention number 
and the corresponding intervention kits to the participants according to it. Details of 
the IRT procedure will be provided in the IRT Site Manual. 
- 
Participant cannot be randomized more than once in the study. 
- 
Warning: the randomization will not be possible if study treatment and ER/PgR central 
results are not available at site. Please consider adequate timeframe. 
Methods of blinding 
• As per the double blind and double-dummy design, all randomized patients will also 
receive the matching-placebo corresponding to the other treatment arm. Amcenestrant-
matching placebo will be supplied as tablets identical to amcenestrant 200 mg tablets in 
appearance. Tamoxifen-matching placebo will be supplied as tablets identical to tamoxifen 
20 mg tablets in appearance. IMPs (amcenestrant, tamoxifen) and their matching-placebo 
will be supplied in indistinguishable boxes 
• The EORTC and the SANOFI study teams will be blinded to treatment allocation until the 
database lock for the primary analysis of the primary endpoint IBCFS. An independent 
unblinded statistician will be appointed by the EORTC HQ in order to prepare confidential 
reports for the IDMC reviews. Other intermediate reports (safety reports, data surveillance 
report, newsletters) issued before the primary analysis of IBCFS endpoint will be prepared 
by the blinded study teams. Medical review will be conducted blinded to treatment 
allocation. 
Unblinding 
The investigator and the site staff may be unblinded in one of the following cases: 
• Emergency unblinding: In case of emergency, the investigator has the sole responsibility 
to decide if unblinding of the participant’s treatment allocation is warranted. The 
Investigator should make every effort to contact the Sponsor and/or Sponsor’s 
representatives prior to unblinding a participant’s intervention assignment unless this 
could delay emergency treatment of the participant. The unblinding requests should be 
made by the investigator through the IRT system. The date and reason that the blind was 
broken must be recorded in the source documentation and case report form, as applicable. 
If the code is broken, the participant must withdraw from the IMP administration. 
• Unblinding after the first IBCFS event: Blinding codes may also be broken after a patient 
discontinues treatment due to disease recurrence, as determined by the treating 
investigator, but only if deemed essential to allow the investigator to select the patient's 
next treatment regimen and after discussion and agreement with the Sponsor.  
• Code should not be broken in the absence of emergency situations or disease recurrence. 
• The blinded EORTC statistician and the Sponsor’s statistician will receive the treatment 
allocations after the database lock for the primary analysis of the primary endpoint IBCFS.  
• Sponsor’s safety team may unblind the treatment allocation assignment for any participant 
with an SAE. 
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6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP will be supervised by the Investigator or Sub-investigator. 
IMP accountability: 
Intervention units are returned by the participant at each visit. In case of DTP process, the 
intervention units can be returned by the carrier (if defined in the contract). 
The Investigator counts the number of tablets, remaining in the returned packs, and fills in the 
Intervention Log Form. 
The Investigator records the dosing information on the appropriate page(s) of the CRF. 
The monitor in charge of the study then checks the CRF data by comparing them with the IMP 
which he/she has retrieved and intervention log forms. 
At each dispensation visit, when participants are dispensed with study intervention at the site, they 
will receive study intervention directly from the Investigator or designee, under medical 
supervision. On days when there are no on-site visits, study participants will take the study 
intervention at home. The study staff will demonstrate to the patient how to record information on 
study intervention intake in study medication diary. Study participants will have to complete the 
study medication diary and the completed study medication diary should be returned to study site 
at subsequent site visit. In case of an early vomiting event, the administered dose of study 
intervention should not be repeated.  
When participants take study intervention at home, compliance with study intervention will be 
assessed at each visit, using study medication diaries and study medical record (study source 
documentation). Compliance will be assessed by direct questioning, counting returned tablets 
during the site visits and documented in the source documents and CRF. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF. 
A record of the number of amcenestrant/amcenestrant-matching placebo, tamoxifen/tamoxifen-
matching placebo tablets and goserelin or other GnRH analog, dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for IMP omissions and NIMP delays/omissions 
will also be recorded in the CRF. 
6.5 
DOSE MODIFICATION  
No dose reduction of study intervention is permitted. Dose adjustment in case of treatment-related 
toxicity is managed by dose omission.  
Dose adjustment guidelines for study intervention (amcenestrant/amcenestrant-matching placebo 
and tamoxifen/tamoxifen-placebo) in case of treatment-related toxicity could be found in 
Section 10.10.1 (Appendix 10). 
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6.5.1 Missed doses  
• Any doses of study intervention that are not taken within 6 hours of the intended time 
should be considered as missed dose.  
• If the participant misses a dose of study intervention, a double dose should not be taken 
the next day to compensate the missed dose.  
• If the participant vomits a dose of study intervention, an additional dose should not be 
taken, and this information must be recorded in the study medication diary. The next 
prescribed dose should be taken at the usual time.  
• Doses omitted for toxicity are not to be replaced within the same cycle.  
6.5.2 Retreatment criteria in case of treatment-related toxicity  
Study treatment may be held up to 28 days to permit sufficient time for recovery from the toxicity. 
For patients not recovering from toxicity within 28 days, a delay >28 days is permitted if the 
patient benefits from the study intervention; the investigator will contact the Sponsor or Sponsor’s 
representatives for the retreatment. In absence of clinical benefit, permanent discontinuation of the 
study intervention should be considered. 
6.5.3 Restarting study medications following treatment interruption  
The criteria for restarting study medication following an interruption that was unrelated to toxicity 
from study intervention, examples including: 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Section 10.9 (Appendix 9): Contingency measures for a regional 
or national emergency that is declared by a governmental agency. 
• Patients with diagnosis of second non-breast primary invasive cancers may be considered 
for temporary discontinuation (treatment temporarily suspended to allow for local 
treatment of the second non-breast primary cancer).  
- 
If the interruption does not exceed 3 months in any 12-month time period with 
systemic therapy not required and no evidence of breast cancer recurrence, study 
treatment can be re-started.  
- 
If the interruption >3 months and the patient benefits from the study intervention, the 
investigator will contact the Sponsor or Sponsor’s representatives for the retreatment. 
In absence of clinical benefit, permanent discontinuation of the study intervention 
should be considered. 
• If Sponsor or Sponsor-representative’s approval to restart/rechallenge participant with 
study intervention is not granted, then participant must permanently discontinue study 
intervention and may continue in the study for protocol-specified follow up assessments. 
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6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
After normal completion of the IMP, patient will not receive additional doses. 
6.7 
TREATMENT OF OVERDOSE  
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor or Sponsor representatives immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
recovery to Grade ≤1  
3. Document appropriately in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor or Sponsor representatives based on the clinical evaluation of the 
participant. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) or other specific categories of interest) that the participant is receiving at the 
time of enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
The Sponsor or Sponsor representatives should be contacted if there are any questions regarding 
concomitant or prior therapy. The following therapies/medications are prohibited throughout the 
active treatment phase in relation to amcenestrant and/or tamoxifen treatment: 
• Any concurrent anti-cancer treatment (surgery, radiotherapy, systemic therapy) except 
for participants diagnosed during the study with a second primary malignancy not 
requiring systemic therapy (ie, chemotherapy, hormonal therapy, targeted therapy, etc) and 
for whom study treatment is temporarily suspended to allow local treatment (surgery 
and/or radiation). 
• Drugs that are strong inducers of CYP3A (including St John’s Wort and genistein used as 
herbal medicine or food supplement, rifampin, avasimibe, rifapentine, phenytoin, 
carbamazepine, lumacaftor, phenobarbital) since they may decrease amcenestrant 
exposure.  
• Drugs that are sensitive substrates of OATP1B1/1B3 including asunaprevir, atorvastatin, 
bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin and simvastatin acid, since amcenestrant is a potential inhibitor 
and may decrease their elimination. 
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• Drugs that are UGT inhibitors, including but not limited to atazanavir and probenecid, 
since amcenestrant is substrate of UGT1A1 and UGT1A4 and they may increase 
amcenestrant exposure. 
• Drugs that have an influence on the status of sex hormones, ie, additional hormonal 
treatments (either oral or transdermal) including estrogen, progesterone hormone 
replacement therapy, oral or other types of hormonal contraceptives (including implants 
and depot injections). 
• Strong and moderate inhibitors of CYP2D6 (eg, paroxetine, fluoxetine, quinidine, 
cinacalcet, bupropion, duloxetine, sertraline, trazodone, thioridazine, perphenazine, 
pimozide, clomipramine, terbinafine, diphenhydramine, amiodarone, cimetidine, 
chlorpromazine) since they could lead to reduced efficacy of tamoxifen. 
Special caution should be taken with regards to the following therapies in relation to amcenestrant 
treatment: 
• Drugs that are sensitive substrates of CYP3A, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGTs since it may result in loss of efficacy of these agents. Monitor patients for loss of 
efficacy if use of these medications, or substitute. 
• Note refer to the list of potential drugs interacting with CYP450 can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
• Warfarin: a marked increase in anticoagulant effect may occur when tamoxifen is used in 
combination with warfarin. Closely monitor coagulation indices in patients who require 
concomitant use of warfarin. 
The following concomitant treatments are permitted during this study: 
• Bisphosphonates may be used in post-menopausal patients (including pre/peri menopausal 
participants treated with GnRH analogs) as per local protocols. 
• Vaccines for COVID-19 infection:  
If investigators decide to administer SARS-CoV-2 vaccines in patients enrolled in the 
study, decisions should be individualized based on the risk of SARS-CoV-2 
complications and potential benefit from the vaccine, general condition of the patient and 
the severity of COVID-19 outbreak in a given area or region and in accordance with the 
vaccine label. Furthermore, the Country guidelines and/or institutional guidelines, must 
be followed. 
The available SARS-CoV-2 vaccines, that are not live attenuated vaccines, are not contra-
indicated in patients on anticancer treatment. 
Treatment schedule should not be altered because of the COVID-19 vaccination. 
The administration of a SARS-CoV-2 vaccine (including brand name) shall be added in 
the concomitant medication form in the eCRFs and noted in the patient’s Medical file. 
Any vaccine related AE(s) should be captured in the AE forms in the eCRFs. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
Study Intervention will be continued until the occurrence of one of the following criteria: 
• Normal completion of the study intervention (5 years) 
• Recurrence as defined in Section 9.2.2.  
- 
After the recurrence, the study intervention may be unblinded upon request of the 
investigator  
• In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
discontinued, the participant will remain in the study to be evaluated for the study 
endpoints unless she/he withdraws consent.  
- 
The investigator has the right to remove any participant (eg, poor compliance to the 
protocol, intercurrent illness that prevents further administration of study intervention) 
from study. 
• Participant’s request  
• Administration of the study intervention will be discontinued in the event of a TEAE that 
persists despite appropriate measures or any other AE that, in the opinion of the 
Investigator, warrants discontinuation (Section 6.5.2, Section 8.3.5). 
• Study intervention interruption exceeding 3 months, in absence of clinical benefit and 
approval from the Sponsor or Sponsor’s representatives as per Section 6.5.3 
• In case of unblinding, the participant must discontinue study intervention as per 
Section 6.4. 
7.1.2 Handling of participants after definitive intervention discontinuation  
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. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP. See the SoA 
(Section 1.3) for data to be collected at the time of discontinuation of study treatment and follow-
up and for any further evaluations that need to be completed. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
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7.1.3 Extended adjuvant endocrine therapy  
Extended adjuvant endocrine therapy upon completion of study treatment is allowed. Treatment 
recommendation should be considered on an individual patient basis taking into consideration 
clinico-pathologic characteristics, patients’ preferences, and total duration of adjuvant endocrine 
therapy at the time of study treatment completion or discontinuation. When extended adjuvant 
endocrine therapy is considered, treatment options include adjuvant tamoxifen or adjuvant 
aromatase inhibitor. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/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. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted. See SoA (Section 1.3) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• The participant who withdraws from the study will be permanently discontinued both from 
the study intervention and from the study at that time.  
• 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. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study for 
the follow up visits. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be 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 
eCRF 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 rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
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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 directly or indirectly 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 Section 10.1.10 
(Appendix 1). 
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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. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• Participants still on AI treatment may enter the screening period for central confirmation 
of biomarkers and screening imaging assessments. The other assessments and 
questionnaires required before randomization will be performed and completed when 
patient is off the AI therapy. 
• For each participant, the follow-up period is defined from EOT to up to 10 years from 
randomization except in case of premature study termination due to one of the following 
reasons: withdrawal of consent, loss to follow-up or death. 
8.1 
EFFICACY ASSESSMENTS   
8.1.1 At Screening  
• Mammogram 
At screening (within 28 days prior to randomization), mammogram* is required if not already 
done in the past 6 months prior to randomization. 
* If local investigator plans to use breast MRIs instead of mammograms during the study, breast 
MRI will have to be performed at screening 
Note: women with prior bilateral mastectomy should not get mammograms (or breast MRIs). 
• Baseline staging 
Baseline staging to document the absence of metastatic disease must be performed within 28 days 
prior to randomization for patients at highest clinical risk for disease recurrence: 
- 
Participants with symptoms suggestive of metastatic disease indicated per 
investigator’s judgment  
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Participants diagnosed with stage IIIA or higher and no staging evaluation prior to 
study enrollment.  
Staging must include chest, abdominal ± pelvic and bone imaging and clinical evaluation of 
superficial disease. Examination type for imaging staging can include sonography, bone scan, CT, 
MRI and/or PET-CT as per investigator’s choice.  
8.1.2 Post baseline  
• Mammogram/breast MRI 
Mammogram (or breast MRI) will be performed on yearly basis from randomization (± 30 days), 
and as clinically indicated until the detection of locoregional recurrence and distant recurrences 
(whichever comes last) or end of follow-up period, whichever comes first. 
• CT Scan/MRI/Other imaging 
The post baseline imaging work-up will be done as clinically indicated until the detection of 
locoregional recurrence and distant recurrences (whichever comes last) or end of follow-up 
period. 
The imaging work-up can include: Radionuclide Bone Scan Whole Body, CT Scan, MRI, PET-
CT, Ultrasound of Chest, Abdomen, Pelvis or any clinically indicated sites of disease and clinical 
evaluation of superficial disease. 
• Biopsy  
Disease recurrence should be confirmed histologically whenever possible.  
Note: for the locoregional recurrence including skin recurrence it is recommended to perform a 
biopsy unless clinically contra-indicated.  
8.1.3 Overall survival follow-up  
After discontinuation of study treatment, follow-up visits will be performed every 12 months  
(±45 days) from the last dose of study treatment for survival status and collection of data on post-
study anticancer therapies, and disease recurrence for patients who complete or prematurely 
discontinue study treatment without disease recurrence. 
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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8.2.1 Physical examinations  
• A physical examination should include, at a minimum, assessments of the cardiovascular 
system, pulmonary system, gastrointestinal system (including palpation of liver and 
spleen), examination of the skin, and breast exam (palpation of breast/chest wall, axillae, 
supra- and infraclavicular regions). Height (at baseline only) and weight will also be 
measured and recorded. Investigators should pay special attention to clinical signs related 
to previous serious illnesses. 
• A gynecological examination should be performed at least on a yearly basis according to 
the schedule provided in the SoA (see Section 1.3), or more frequently in case of sign or 
symptoms of endometrial abnormality (eg, abnormal bleeding). The examination should 
be performed as per the site’s local guidelines and the result should be reported as either 
normal or abnormal. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event. 
8.2.2 Vital signs  
• Body temperature, blood pressure and pulse measurements will be assessed with a 
completely automated device. Manual techniques will be used only if an automated device 
is not available. 
• Systolic and diastolic blood pressure, and pulse rate will be measured in a semi-supine 
position after 5 minutes rest. 
• Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.  
• Vital signs and ECG abnormalities are to be recorded as adverse events only if they are 
symptomatic and/or requiring corrective treatment and/or leading to treatment 
discontinuation and/or dose modification and/or fulfilling a seriousness criterion 
(see Section 10.3 [Appendix 3]). 
8.2.3 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the Investigator to 
be more severe than expected for the participant's condition. Laboratory abnormalities are 
to be recorded as adverse events only if they lead to treatment discontinuation and/or dose 
modification and/or fulfill a seriousness criterion and/or are defined as an AESI 
(see Section 10.3, [Appendix 3]). 
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• All laboratory tests with values considered clinically significantly abnormal 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 or are no longer considered 
clinically significant by the Investigator or medical monitor. 
- 
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 or 
Sponsor’s representatives notified. 
- 
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 
(Section 1.3).  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.  
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
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 8.2). 
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 ICF at the time points specified in the 
SoA (Section 1.3 and until at least 30 days after administration of the last study intervention. After 
this period, all ongoing related AEs, all ongoing SAEs regardless of relationship with study 
treatment, and all new related AEs (serious or nonserious), are to be reported and followed up 
until resolution or stabilization. All SAEs and AESI will be recorded and reported to the Sponsor 
or Sponsor’s representatives 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. 
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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. At the pre-specified study end-date, all SAEs, and AEs of 
special interest (as defined in Section 8.3.6) 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 provided 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. 
• 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. 
• Adverse events that are considered expected will be specified in the reference safety 
information (IB for Amcenestrant and SmPC or package insert for other IMP)  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.  
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB or state other documents and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.3.5 Pregnancy  
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until:  
• The 30 days after the last study treatment administration for female participants. 
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• The 30 days after the last study treatment administration for female partners of male 
participants. 
• 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).  
• Pregnancy of female participant will lead to definitive discontinuation of study 
intervention. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Adverse event of special interest  
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 of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP.  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male 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 or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• 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 should be reported as a standard AE. 
• Increase in alanine transaminase (ALT) ≥ Grade 3.  
- 
Omit study-treatment study-intervention administration and repeat LFTs within  
2-3 days. If not recovered, monitor LFTs weekly until recovery to Grade ≤1 
(or baseline grade). Confounding factors such as, liver metastasis, hepato-biliary 
disorders, concomitant medications, etc. should be excluded prior to dose 
modifications. Please refer to the dose modification guidelines for management of 
increase of ALT. [Appendix 10 (Section 10.10.1)].  
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- 
Close monitoring of study participants is recommended in cases of increase of 
Grade ≥3 ALT. LFTs 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 Grade >2), direct bilirubin, indirect 
bilirubin, GGT, and INR (if total bilirubin >2.5 ULN).  
- 
An ultrasound, or other imaging of liver, should be considered based on the clinical 
presentation.  
- 
A consultation with a hepatologist should be undertaken if there is,  
- 
Unexplained or persistent Grade ≥3 ALT despite dose omissions.  
- 
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, considering the local and national recommendations. 
• Photosensitivity  
- 
If photosensitivity 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 any dose modification (refer to Section 10.10.1 [Appendix 10] for treatment-
related dose modification for non-hematological toxicities). In case of study 
intervention discontinuation because of photosensitivity reaction, study participant 
should be followed for possibility of development of other manifestations of 
photosensitivity such as photo-onycholysis, lichenoid reaction or actinic 
granuloma. 
8.3.7 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 
PHARMACOKINETICS  
Whole blood samples will be collected from all participants for measurement of blood 
concentrations of amcenestrant using Dried Blood Spot (DBS) at time points specified in the SoA 
(Section 1.3) and additional information is provided in the sample Table 5 (Section 8.6.2). An 
aliquot of plasma will be prepared on C2 and C7 in a subset of patients to determine the 
Blood/Plasma ratio. Approximately 300 plasma samples (of which, approximately 100 samples 
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from Chinese patients) will be collected for the determination of Blood/Plasma ratio for 
amcenestrant. Plasma aliquot prepared and available in the Lab after the cutoff date for 
amcenestrant assay in plasma may not be assayed and may be discarded.  
The timing of sampling may be altered during the course of the study based on newly available 
data to ensure appropriate monitoring.  
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
or Sponsor’s representatives in a separate document (Central Laboratory Services Manual). The 
actual date and time (24-hour clock time) of each sample will be recorded. Pharmacokinetic 
samples will be tested by the Sponsor or Sponsor's representatives. 
Samples collected for analyses of amcenestrant concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study. 
Pharmacokinetic samples could also be used for testing analytical method performance such as 
comparability and incurred sample reproducibility, and for possible exploratory analysis of drug 
metabolites. The exploratory data may not be included in the study report but will be kept on file. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. The bioanalysts responsible for the 
sample analysis will be unblinded. They will, however, agree not to disclose the randomization 
schedule or the individual unblinded analytical results before the official opening of the 
randomization schedule. 
A population PK approach may be used to determine amcenestrant PK parameters. The 
determined Blood/Plasma ratio could be used to convert blood concentrations to plasmatic 
concentrations to compare AMEERA-6 PK parameters to plasmatic exposures obtained in others 
amcenestrant studies. 
8.5 
GENETICS  
The genomic DNA (gDNA) for the translational research studies will be extracted from a blood 
sample collected from participants (see sample Table 5 (Section 8.6.2) for the sample 
specifications). The gDNA material will be only used for the elimination of the non-somatic 
variants of the tumor genetic studies and it will not be subject of any study by itself. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent (see sample Table 5 below for the sample 
specifications). 
The tumor genomic material will be extracted from the FFPE tumor tissue collected at baseline 
and EOT for patients that discontinued the treatment due to disease progression, and will be 
collected for DNA and RNA isolation from all participants [see sample Table 5 (Section 8.6.2) for 
the sample specifications]. Participation is mandatory for the baseline analysis. [See Appendix 5, 
Section 10.5) for information regarding genetic research]. Details on processes for collection, 
shipment and destruction of these samples can be found in the laboratory manual. 
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The genetic findings will be reported to the sites. 
8.6 
BIOMARKERS  
8.6.1 Rationale  
8.6.1.1 Biomarker evaluations  
The overarching goal of the AMEERA-6 correlative science objectives is to investigate whether 
tumor-derived biomarkers assessed using tumor tissue and blood specimens predict benefit from 
amcenestrant compared to tamoxifen.  
The comprehensive collection of biospecimens will enable next generation sequencing 
technologies, protein, or metabolite-based assays aiming to identify predictors of treatment benefit 
and/or markers of resistance.  
The tumor tissue specimens will be profiled using DNA and RNA sequencing to generate a 
comprehensive “in silico” platform allowing the investigation of correlative science questions in 
an unbiased manner. Residual tumor specimens stored in the study biorepositories will enable 
validation of correlative science findings and additional research following the endorsement from 
the study Steering committee.  
The molecular classification of breast cancer (60, 61) has allowed us to understand the natural 
history of different subtypes of this disease including Luminal A, Luminal B basal-like and 
HER2-enriched. The RNA sequencing data will allow us to evaluate the benefit of amcenestrant 
compared to tamoxifen across its major molecular subtypes. 
8.6.1.2 Endocrine sensitivity  
Of importance, AMEERA-6 includes a comprehensive plan dedicated to evaluate the relative 
effectiveness of amcenestrant versus tamoxifen according to measurements of endocrine 
sensitivity through SET2,3 and/or other measurements of endocrine sensitivity.  
SET2,3 is a CLIA-compliant test that is applied to FFPE tissue sections and accurately measures 
endocrine-related transcriptional activity (SETER/PR index) that is then adjusted for baseline 
prognosis (T, N, RNA4) (62). The test measures 31 transcripts and has already demonstrated pre-
analytical and analytical validity, including inter-laboratory reproducibility.  
The SETER/PR index measures endocrine hormone receptor related transcriptional activity. The 
signature was designed to represent genes with strong correlation to both ER and progesterone 
receptor transcription, with exclusion of genes known to have a principal role in proliferation. 
Therefore, the design of the SETER/PR signature was intended to represent endocrine related 
transcription exclusive of the obviously prognostic effect of proliferation. Since estrogen 
activation of estrogen receptor has a profound effect on overall transcriptional profile, we can 
reasonably infer that the SETER/PR provides a measure of endocrine dependent activity in the 
cancer cells. The exclusion of the few obviously proliferative genes from the SETER/PR signature 
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(eg, cyclin D1) was specifically to avoid confounding influences of baseline molecular prognosis. 
The extent of endocrine related activity in a breast cancer has a relationship to prognosis, but its 
endocrine predictive information is expected to be stronger due to the biological rationale that 
greater endocrine-dependent cellular activity predicts greater susceptibility to targeted inhibition 
by endocrine therapy. 
The SET2,3 index was developed to represent the endocrine related transcription activity in the 
cancer sample (SETER/PR) adjusted for its baseline prognostic index. Thus, SET2,3 assay measures 
the weighted sum of SETER/PR and a baseline prognostic index that is derived from tumor stage, 
nodal metastases, and molecular subtype. Essentially, SET2,3 assay measures endocrine activity in 
the context of the natural baseline prognostic biology. In its simplest form, molecular subtype has 
been meaningfully represented using immunohistochemistry for just four proteins per (IHC4), 
namely estrogen receptor, progesterone receptor, HER2 receptor, and the proliferation marker 
Ki67. A baseline prognostic index used on SET2,3 recapitulates this by using RNA4 that is derived 
from the following four transcripts: estrogen receptor, progesterone receptor, HER2 receptor, and 
delete the proliferation gene after aurora kinase A. 
8.6.1.3 Material and methods  
Collection of samples for the defined and other biomarker research is also part of this study. The 
following samples for biomarker research are required and will be collected from all participants 
in this study as specified in the SoA (Section 1.3, and see sample Table 5 [Section 8.6.2] for the 
sample specifications): 
• Blood 
• Tumor FFPE tissue block at baseline (the most recent archived tumor FFPE sample) 
Optional samples for biomarker research that should be collected from participants in the study 
where possible are the following: 
• Tumor FFPE tissue at end of treatment (for patients who discontinue treatment due to 
disease recurrence) 
8.6.1.4 Objectives  
• Tumor protein biomarkers, such as ER, PgR, Ki67, and Bcl-2 protein expression by 
immunohistochemistry, endocrine sensitivity transcriptome evaluation (eg, SET index), 
ER activation score, artificial intelligence-based image analysis, gene expression/genomic 
aberration profile (in RNA and DNA including WES) and in archival and optional FFPE 
biopsy for participants who discontinued treatment due to disease recurrence to evaluate 
their association with the observed clinical responses to endocrine sensitivity.  
• To study the histological type studies (ductal, lobular, others) of the samples to investigate 
the predictive and prognostic value. 
• To retrospectively study tumor specimen gene expression profile (in RNA) including, but 
not limiting to with different scores (such as PAM50) in archival to evaluate recurrence 
risk and breast cancer molecular subtypes, as well as endocrine sensitivity/resistance by 
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RNA-based multigene assays. Extensive genomic landscape profiling, including whole 
transcriptome and mutational profiling by whole exome sequencing will also performed to 
characterize tumors and their characteristics. 
• To retrospectively study the ctDNA in blood at pre-treatment, on treatment, and upon 
disease recurrence to evaluate recurrence risk by ctDNA status and to evaluate genomic 
landscape and tumor burden, at baseline and changes over time by ctDNA analysis.  
For future/non-defined research: 
• Blood samples will be collected for proteomics studies in plasma. 
In addition, the samples will be stored, and analysis will be performed: 
• On other biomarker variants for the understanding of disease subtypes, disease biology, 
related conditions, drug response and toxicity. 
• For the identification of new drug targets or biomarkers that predict participant response to 
the treatment including new genes/genome candidates, serum analytes, or tissue 
biomarkers to evaluate their association with observed clinical responses to amcenestrant 
(SAR439859) versus tamoxifen. 
The samples may be used for non-defined research to possibly further study the disease biology, 
to develop methods, assays, prognostics studies and/or companion diagnostics related to the 
biology of the disease, pathways associated with the disease state, and/or the mechanisms of 
action of the drug. 
8.6.2 Sample table  
The collection of all samples is mandatory for the sites. 
Table 5 - Data collection of biological samples  
Patient's 
choice 
yesa/nob? 
Specimen 
type(s) 
Size/type of 
sample 
Collection time point(s) 
Purpose of use 
Estimated/ 
expected 
sample 
size 
No 
FFPE 
1xblock 
(preferred) or 25 
slides 
Baseline (most recent archived FFPE 
biopsied tumor tissue samples) 
Central review and 
Biomarker research 
1x3738 
Yes 
FFPE 
1xblock or 
25 slides 
Biopsy collected at EOT for patients 
who discontinue treatment due to 
disease recurrence 
Biomarker research 
and endocrine 
sensitivity study 
1x3738 
maximum of 
samples 
No 
Blood 
1x s-monovette 
edta 1,2 mL 
tube (DBS and 
plasma) 
Predose sample on C2, C7, C13 and 
C25 
DBS for the PK study 
4x3738 
(blood) 
Plasma aliquot on C2 
and C7 only, to 
determine 
Blood/Plasma ratio  
approx. 300 
plasma 
samples 
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Patient's 
choice 
yesa/nob? 
Specimen 
type(s) 
Size/type of 
sample 
Collection time point(s) 
Purpose of use 
Estimated/ 
expected 
sample 
size 
Yes 
Blood 
1xSTRECK 
10 mL tube 
(proteomics 
studies) 
Pre-dose sample on C1D1, C2D1 and 
upon disease recurrence 
Proteomic studies for 
future research 
3x3738 
maximum of 
samples 
No 
Blood 
1xEDTA 2 mL 
tube (for gDNA) 
Pre-dose (C1D1) 
Biomarker and 
genomic research 
1x3738 
2xStreck 10 mL 
tubes (plasma 
for ctDNA) 
Pre-dose (C1D1), pre-dose C2D1 and 
upon disease recurrence. 
6x3738 
maximum of 
samples 
a ”yes” means that the collection of this material is optional, as patients are given the choice in the Informed Consent Form (ICF). EORTC will 
not collect this type of material from patients not having specifically consented to this. 
b ”no” means that the collection of this material is mandatory for the study and patients are not given the choice in the ICF. If patients do not 
agree with sample collection, they cannot participate in the study 
Abbreviation: gDNA = genomic DNA; DBS= dried blood spot 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity is not evaluated in this study. 
8.8 
HEALTH ECONOMICS  
Not Applicable for this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.4) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to endocrine breast cancer treatment, and the disease and its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
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Remaining leftover samples will be used only after the study ends, ie end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. Data and 
samples will be used in alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These coded data 
and samples may be transferred to a Sponsor site (or a subcontractor site), which may be located 
outside of the country where the study is conducted. The Sponsor adopts safeguards for protecting 
participant confidentiality and personal data (see Section 10.1.5). 
Biological samples for future research will be stored for up to 15 years after the end of the study. 
Any samples remaining at the end of retention period will be destroyed. If a participant requests 
destruction of his/her samples before the end of the retention period, the Investigator must notify 
the Sponsor (or its contract organization) in writing. In such case, samples will be destroyed, and 
related coded data will be anonymized unless otherwise required by applicable laws. Relating data 
for future research will be stored for 25 years after the end of the study. 
Participant’s coded datasets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
8.10 
PATIENT REPORTED OUTCOMES (PROS)  
There are no PRO-specific eligibility criteria. All patients enrolled in the trial are expected to fill 
out the PRO questionnaires according to the pre-defined schedule in the SoA (Section 1.3), unless 
the required language translation is not available. If no validated translation exists for part of the 
questionnaires, then the validated portion of the questionnaire set will be administered to the 
patient. 
As stated in the SoA (Section 1.3), PRO measures are to be administered to each study participant 
after informed consent and prior to any treatment- or study- related activities, including 
administration of IMP, laboratory work, radiological assessments, discussion with the participant 
regarding their treatment or health status, and similar activities. The administration schedule for 
PRO assessments must be adhered to as much as possible, regardless of protocol deviations. As 
applicable in the SoA (Section 1.3), the PRO instruments will always be administered in the 
following standardized order: FACT-GP5, EORTC QLQ-C30, EORTC QLQ-BR23, EORTC 
QLQ-IL127, PRO-CTCAE™, EQ-5D-5L, PGIS, PGIC and MMAS-8. The PRO assessment 
schedule was designed to correspond with: clinical expectations regarding the onset and duration 
of symptomatic AEs; expectations regarding the timeframe in which observed changes in the 
concepts of interest are likely to occur; trial research objectives; trial duration; the dosage level 
and route of IMP administration; and other prespecified trial endpoints. 
All PRO questionnaires are designed for self-completion.  
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The primary mode of administration is via electronic clinical outcome assessment (eCOA) using 
an application on participants’ own devices. If the eCOA application fails, a web-based eCOA 
platform will be used as a back-up option. Provisioned back-up devices will be available at each 
site for participants without their own devices. Training for site staff and patients will occur 
according to the standards of the eCOA provider. Where participants completed their PRO 
assessment (ie, home versus site) will be documented. The clinical report forms will include a 
question whether the PRO assessments have been filled in, and if not, the reason why. It is 
recommended that a key person (eg, research nurse) not directly involved in the participant’s 
clinical care at each institution should be responsible for questionnaire data collection in order to 
optimize the participant compliance and to ensure the completeness of the data.  
In case, patients are not be able to physically attend hospital visits due to unforeseen restrictions 
(eg, COVID-19 pandemic restrictions), the PRO data can be collected by electronic assessment at 
home. Patients should be instructed to complete the questionnaires within the intended timepoint 
(according to protocol SoA). 
Nine PRO questionnaires will be used in this trial: FACT-GP5, EORTC QLQ-C30, EORTC 
QLQ-BR23, EORTC QLQ-IL127, PRO-CTCAE™, EQ-5D-5L, PGIS, PGIC and MMAS-8. 
Together, these questionnaires present up to 97 questions to the patients which can be completed 
in 30-45 minutes. 
8.10.1 FACT-GP5  
The FACT-GP5 (“I am bothered by side effects of treatment”) is a single-item from the 
Functional Assessment of Cancer Therapy-General (FACT-G) scale (63). Responses are given on 
a 5- point Likert-type scale recalling the past 7 days. Higher scores indicate a higher degree of 
side effect bother (64). The FACT-GP5 has been translated in over 50 languages according to a 
standardized translation procedure (65). 
8.10.2 EORTC QLQ-30  
The EORTC Quality of Life Questionnaire (QLQ-C30) version 3 (66) is valid for any cancer 
population and is composed of thirty distinct questions that are scored into fifteen multi-item and 
single-item scales (67). These include a global health status/QoL scale (2 items), five functional 
scales (physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), 
cognitive functioning (2 items), and social functioning (2 items)); eight symptom scales (fatigue 
(3 items), nausea and vomiting (2 items), pain (2 items), dyspnoea (1 item), insomnia (1item), 
appetite loss (1 item), constipation (1 item), diarrhoea (1 item)); and a financial difficulties scale 
(1 item). The questionnaire employs 28 4-point Likert-type scales with responses from “not at all” 
to “very much” and two 7-point Likert-type scales for global health and overall QOL. For 
functional and global QOL scales, higher scores represent a better level of functioning and are 
converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represents more severe 
symptoms. The reliability and validity of the questionnaire is highly consistent across different 
language-cultural groups (68, 69). The average time to complete the questionnaire is 
approximately 10 minutes. The EORTC QLQ-C30 version 3 has been translated in over 
50 languages according to a standardized translation procedure (70).  
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8.10.3 EORTC QLQ-BR23  
The EORTC QLQ breast cancer module (QLQ-BR23) is a 23-item disease-specific patient-
reported outcome measure of disease-related symptoms, treatment-related symptoms, and 
functioning relevant to patients with breast cancer. The QLQ-BR23 has been validated for use in 
conjunction with the QLQC30 (68, 71). The QLQ-BR23 consists of 23 4-point Likert scales with 
responses from “not at all” to “very much” which are scored into both multi-item scales and 
single-item scales, including: four functional scales (body image (4 items), sexual functioning 
(2 items), sexual enjoyment (1 item), and future perspective (1 item)); and four symptom scales 
(systemic therapy side effects (7 items), breast symptoms (4 items), arm symptoms (3 items), 
upset by hair loss (1 item)). The scoring principle is similar to the QLQ-C30 (67) with higher 
scores on the functional scales indicating higher levels of functioning and higher scores on the 
symptom scales indicating higher symptom levels. The average time to complete the 
questionnaire is approximately 10 minutes. The EORTC QLQ-BR23 has been translated in over 
50 languages according to a standardized translation procedure (70). 
8.10.4 EORTC QLQ-IL127  
In addition to the QLQ-C30, the EORTC Item Library (72) was used to construct an ad-hoc item 
list specific to this study. The aim was to add items from the EORTC CAT physical functioning 
questionnaire (68) in order to obtain an extended, more precise physical functioning scale. A total 
of 3 items were selected to include self-assessment on physical functioning:  
1. Do you have any trouble carrying a heavy bag upstairs? 
2. Do you have any trouble taking a long walk carrying a heavy pack on your back 
(eg, a filled rucksack)? 
3. Do you have any trouble hiking 3 km/2 miles on uneven surfaces? 
These questions are taken from the validated QLQ-CAT physical functioning questionnaire. 
Although this Item List is not a validated instrument, it is an ad-hoc instrument optimized for this 
specific setting and composed of integral parts of validated HRQL questionnaires. All three 
questions follow the same structure using a 4-point Likert scales with responses from “not at all” 
to “very much” and are translated according to a standardized translation procedure (72). These 
three questions will be scored together with the 5 physical functioning items of the QLQ-C30 
according to the CAT scoring procedure into an extended physical functioning scale. 
8.10.5 PRO-CTCAE  
The National Cancer Institute PRO-CTCAE™ was developed to evaluate symptomatic adverse 
events (AEs) by self-report among patients participating in cancer clinical trials (73, 74). The 
PRO-CTCAE item library includes 124 items that represent 78 symptomatic AEs in the clinician 
reported CTCAE. PRO-CTCAE items chosen for this study were systematically selected from the 
PRO-CTCAE item library to measure 14 symptomatic AEs (representing 24 items) known to be 
associated with amcenestrant and/or tamoxifen. PRO-CTCAE items included in this study assess 
the frequency, severity, interference, and/or presence/absence of the following 14 symptomatic 
AEs: hot flashes (2 items; frequency and severity); increased sweating (2 items; frequency and 
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severity); joint pain (3 items; frequency, severity, interference), muscle pain (3 items; frequency, 
severity, interference); fatigue (2 items; severity, interference); vaginal dryness (1 item; severity); 
vaginal discharge (1 item; presence/absence); irregular periods/vaginal bleeding (1 item; 
presence/absence); nausea (2 items; frequency, severity); vomiting (2 items; frequency, severity); 
diarrhea (1 item; frequency); constipation (1 item; severity); decreased appetite (2 items; severity, 
interference); rash (1 item; presence/absence). PRO-CTCAE frequency, severity, and interference 
items use a 5-point Likert-type response scale respectively ranging from "never" to "almost 
constantly", "none" to "very severe", and "not at all" to "very much" (each scored from 0 to 4, 
with higher scores indicating a higher frequency, severity, or interference of the given 
symptomatic AE) (75). PRO-CTCAE presence/absence items use a dichotomous "no"/"yes" 
response scale (scored 0 and 1, respectively) (75).  
In accordance with scale developer recommendations (76), conditional branching will be 
employed for the electronic administration of PRO-CTCAE symptom terms that have two or more 
items to reduce respondent burden. The logic branches from frequency, then to severity, then to 
interference. Using the joint pain items as an example: if a given respondent reports the frequency 
of joint pain is greater than "Never", the respondent will be administered the severity item; if the 
respondent reports severity of joint pain is greater than "None", the respondent will be 
administered the interference item. Using conditional branching in electronic PRO-CTCAE item 
administration, participants will be administered a minimum of 14 items and a maximum of 
24 items, depending upon their responses. 
Items from the PRO-CTCAE item library were selected in accordance with recommendations by 
the FDA (77, 78) and using methods informed by the published literature (79, 80). 
See Section 10.10.2 (Appendix 10) for detailed item selection methods.  
8.10.6 MMAS-8  
The Morisky Medication Adherence Scale (MMAS-8) is a validated assessment tool used to 
measure non-adherence in a variety of patient populations (81). It has proved to be a valuable 
resource to address adherence concerns, such as forgetting to take medications or discontinuing 
medications without guidance. If a patient scores higher on the scale, they are evaluated as more 
adherent. If they score lower on the scale, they are presumed to be struggling with nonadherence. 
By understanding how the patient scored on the scale, clinicians and health organizations can 
identify underlying issues that prevent patients from taking their medications correctly, if at all. 
8.10.7 PGI-S and PGI-C  
The Patient Global Impression scale (PGI), also known as Subject Global Impression (SGI), is the 
PRO counterpart to the Clinical Global Impressions scale, (CGI), which was published in 1976 by 
the US National Institute of Mental Health (82). Over the years, PGI scales were used in a broad 
range of diseases and were modified for the purpose of clinical settings. In this study, the PGI-S 
and PGI-C each consist of one item based on the CGI and adapted to the current setting. The PGI-
C measures change in side effects of treatment over time; while the PGI-S measures severity in 
side effects of treatment at the time of assessment.  
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8.10.8 EUROQoL EQ-5D-5L  
The EQ-5D-5L is a standardized, self-rated measure of health status developed by the EuroQoL 
Group (83) that is designed to provide a utility score suitable for use in health economic 
evaluations. It provides a descriptive classification based on self-assessment of 5 domains (84): 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a 5-level rating 
scale of no problems, slight problems, moderate problems, severe problems and extreme 
problems. These scores are combined to obtain discrete health states which can be assigned index 
values reflecting how good or bad a health state is according to the preferences of the general 
population of a country/region. In addition, it contains a self-rating of health on a vertical visual 
analogue scale from ‘the best health you can imagine’ to ‘the worst health you can imagine’ 
scored on a 0-100 scale. The EQ-5D-5L is available in more than 150 languages with all 
translations produced using a standardized translation protocol that conforms to internationally 
recognized guidelines (85). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 6): 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All participants from screened population who have been allocated to a randomized intervention 
by IRT regardless of whether the intervention was received. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention allocated 
by randomization. 
Safety 
All randomized participants who took at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received. 
PK population 
All randomized and treated participants (safety population) with at least one post-baseline PK 
concentration with adequate documentation of dosing and sampling dates and times. Participants 
will be analyzed according to the intervention they actually received. 
 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
9.2 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be finalized before the first database lock and will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints including 
primary and secondary endpoints. 
9.2.1 General considerations  
The baseline value is defined as the last available value before randomization, unless otherwise 
specified. 
Unless otherwise specified, analyses will be performed by intervention group (and overall for 
baseline and demographics characteristics). 
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
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• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days.  
• The post-treatment period is defined as the period from the end of the on-treatment 
period.  
Timing of the analyses: 
For each analysis, actual COD will be based on the actual date at which the minimum 
requirements in terms of number of events and follow-up are both met as described in the Table 7 
below. Per FDA request, the second interim analysis and the final analysis should be performed 
when at least 2 years and at least 3 years of follow-up have been observed for all patients, 
respectively. 
Table 7 - Timing of analyses  
Analysis 
Number of events 
required 
Minimum 
follow-up 
required 
Expected COD 
Interim analysis 1 IBCFS 
Approximately 189 
- 
28 months after first patient is 
randomized 
Interim analysis 2 IBCFS 
Approximately 426 
2 years 
48 months after first patient is 
randomized 
Final analysis IBCFS 
Approximately 568 
3 years 
60 months after first patient is 
randomized 
Long-term follow-up analysis 1 
- 
5 years 
5 years after last patient is 
randomized 
Long-term follow-up analysis 2 
- 
10 years 
10 years after last patient is 
randomized 
IBCFS = Invasive breast cancer-free survival; COD = Cut-off date 
 
9.2.2 Primary endpoint  
Invasive breast cancer-free survival (IBCFS) is defined as the time from the date of randomization 
to the date of the first occurrence of one of the following events: 
• Ipsilateral invasive breast tumor recurrence (IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original primary. 
• Local-regional invasive breast cancer recurrence: Invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of the ipsilateral breast. 
• Distant recurrence: Metastatic disease-breast cancer that has either been biopsy confirmed 
or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, non-breast cancer, or unknown 
cause. 
• Invasive contralateral breast cancer. 
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A summary of the primary estimand associated with the primary endpoint is provided in Table 8. 
Table 8 - Summary of primary estimand of the primary endpoint  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level 
summary 
(Analysis and missing 
data handling) 
Primary objective: to determine whether amcenestrant once a day (QD) improves the IDFS excluding second primary 
invasive cancers of non-breast origin (IBCFS) when compared to tamoxifen QD in patients with early breast cancer as 
adjuvant treatment 
Primary 
endpoint 
(Estimand 1) 
IBCFS 
ITT 
Interruption/discontinuation of study 
intervention: IBCFS will be analyzed 
based on disease assessments 
irrespective of study intervention 
interruption/discontinuation (treatment 
policy strategy). 
Start of new therapy prior to IBCFS event: 
IBCFS will be analyzed based on disease 
assessments regardless of whether new 
therapy is initiated prior to event of 
interest (treatment policy strategy). 
IBCFS event documented more than 
12m+90days after previous disease 
assessment: IBCFS will be censored at 
the last disease assessment prior to the 
event (hypothetical strategy). 
One-sided log-rank test 
stratified by randomization 
stratification factors (except 
geographical regions), as 
entered in the IRT system. 
Hazard ratio (HR) and 
corresponding CI estimated 
using stratified Cox proportional 
hazard model 
The Kaplan Meier estimate of 
event free probabilities at 
specified time points, quartiles 
and corresponding 95% CI from 
Kaplan Meier method 
Primary efficacy analysis will consist of IBCFS comparison between the amcenestrant arm and 
the tamoxifen arm through a logrank test procedure stratified by the stratification factors (except 
geographic region to minimize the risk of power loss due to large number of strata and potentially 
low number of events in some strata) as entered in the IRT. A one-sided Type I error rate of 2.5% 
will be used for statistical testing. 
The primary analysis of IBCFS will be based on the following censoring rules: 
• If none of the IBCFS event is observed before the IBCFS analysis COD, participants will 
be censored at the date of the last disease assessment documenting no IBCFS event before 
the COD. 
• A participant without an IBCFS event and without any valid postbaseline disease 
assessments will be censored at the day of randomization (Day 1). 
• An IBCFS event documented after more than 12 months + 90 days following 
randomization or the previous disease assessment, whichever is later, will be censored at 
the date of the last disease assessment documenting no IBCFS event prior to the 
documented IBCFS event or the date of randomization, whichever is later.  
Twelve months + 90 days is the longest allowed interval between visits in this trial as 
defined in the schedule of activities. 
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The HR estimates and corresponding confidence intervals will be provided using the Cox 
proportional hazard model stratified by the same stratification factors as those used for the logrank 
test described above. The IBCFS quantiles and IBCFS rates at different time points (calculated 
using the Kaplan-Meier methods) as well as corresponding 95% CIs will be presented by 
treatment arm. The Kaplan-Meier IBCFS curves will also be provided. 
Sensitivity, supportive and subgroup analyses of IBCFS will be performed as specified in the 
SAP. 
Two interim analyses at 1/3 (approximately 189 IBCFS events, non-binding futility only) and  
3/4 (approximately 426 IBCFS events, efficacy and non-binding futility) of the target number of 
events (approximately 568 IBCFS events) are planned. The primary IBCFS analysis corresponds 
either to a positive interim IBCFS analysis or the final IBCFS analysis. Detail of the interim 
analyses are provided in Section 9.3. 
9.2.3 Secondary endpoint(s)  
9.2.3.1 Key secondary efficacy endpoint  
IDFS  
IDFS (STEEP criteria) is defined as in the primary endpoint but including second non-breast 
primary invasive cancer. 
A summary of the primary estimated associated with the key secondary endpoint is provided in 
Table 9.  
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Table 9 - Summary of primary estimand of the key secondary endpoint  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level 
summary 
(Analysis and missing 
data handling) 
Key secondary objective: to determine whether amcenestrant once a day (QD) improves the invasive disease-free 
survival (IDFS) when compared to tamoxifen QD in patients with early breast cancer as adjuvant treatment 
Key 
secondary 
endpoint 
(Estimand 2) 
IDFS 
ITT 
Interruption/discontinuation of study 
intervention: IDFS will be analyzed based 
on disease assessments irrespective of 
study intervention 
interruption/discontinuation (treatment 
policy strategy). 
Start of new therapy prior to IDFS event: 
IDFS will be analyzed based on disease 
assessments regardless of whether new 
therapy is initiated prior to event of 
interest (treatment policy strategy). 
IDFS event documented more than 
12m+90days after previous disease 
assessment: IDFS will be censored at the 
last disease assessment prior to the event 
(hypothetical strategy). 
One-sided log-rank test 
stratified by randomization 
stratification factors (except 
geographical regions), as 
entered in the IRT system. 
Hazard ratio (HR) and 
corresponding 95% CI 
estimated using stratified Cox 
proportional hazard model 
The Kaplan Meier estimate of 
event free probabilities at 
specified time points, quartiles 
and corresponding 95% CI from 
Kaplan Meier method 
Analysis of the key secondary endpoint analysis will consist of IDFS comparison between the 
amcenestrant arm and the tamoxifen arm through a logrank test procedure stratified by the 
stratification factors (except geographic region to minimize the risk of power loss due to large 
number of strata and potentially low number of events in some strata) as entered in the IRT. 
In order to ensure a strong control of the overall Type I error rate at a one-sided 2.5%, 
a hierarchical testing strategy will be used. In other words, comparison between arms on the IDFS 
will be performed only if the primary analysis of the IBCFS is statistically significant. Therefore, 
a maximum of one formal statistical comparison is planned for IDFS. Otherwise, IDFS will be 
analyzed descriptively as for other secondary efficacy endpoints.  
Same statistical methods and censoring rules as defined for the IBCFS will be used. Sensitivity, 
supportive and subgroup analyses will be performed as specified in the SAP. 
9.2.3.2 Other secondary efficacy endpoints  
For all time to event secondary endpoints (DRFS, LRRFS, OS), the HR estimates and 
corresponding 95% two-sided CIs will be provided using the Cox proportional hazard model 
stratified by the stratification factors (except geographic region) as entered in the IRT. The time-
to-event and quantiles and probabilities of being event-free at different time points (calculated 
using the Kaplan-Meier methods) as well as corresponding 95% CIs will be presented by 
treatment arm. The Kaplan-Meier curves will also be provided. 
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For the endpoint BCSS, the HR estimate and corresponding 95% two-sided CIs will be provided 
by using Fine and Gray model accounting for competing risks and stratified by the stratification 
factors (except geographic region) as entered in the IRT. The cumulative incidence of breast 
cancer-related deaths at different timepoints (calculated using the cumulative incidence function 
method) as well as 95%CIs will be presented by treatment arm. The corresponding BCSS rates 
and 95%CIs will be computed as “1 minus cumulative incidence function”. The cumulative 
incidence curves will also be provided. 
Sensitivity, supportive and subgroup analyses will be performed as specified in the SAP. 
DRFS 
DRFS is defined as the time from date of randomization to the date of the first occurrence of one 
of the following events:  
• Distant recurrence: Metastatic disease-breast cancer that has either been biopsy confirmed 
or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or unknown 
cause. 
Same censoring rules as defined for the IBCFS will be used. 
LRRFS 
LRRFS is defined as the time from date of randomization to the date of the first occurrence of one 
of the following events:  
• Ipsilateral invasive breast tumor recurrence (IIBTR): invasive breast cancer involving the 
same breast parenchyma as the original primary. 
• Loco-regional invasive breast cancer recurrence: Invasive breast cancer in the axilla, 
regional lymph nodes, chest wall, and skin of the ipsilateral breast. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or unknown 
cause. 
• Invasive contralateral breast cancer. 
Same censoring rules as defined for the IBCFS will be used. 
Overall Survival 
Overall survival is defined as the time from date of randomization to the date of death due to any 
cause. In the absence of observation of death, survival time will be censored at the last date the 
participant is known to be alive or at the analysis cut-off date, whichever occurs first.  
A summary of the efficacy endpoints analyses is provided in Table 10. 
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Breast Cancer-Specific Survival 
Breast Cancer-Specific survival is defined as the time from randomization to the date of death 
attributable to breast cancer cause. Deaths attributable to nonbreast cancer cause or to unknown 
cause are considered competing risks at the date of death. In the absence of observation of death, 
survival time will be censored at the last date the participant is known to be alive or at the analysis 
cut-off date, whichever occurs first. 
Table 10 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
IBCFS 
 
Stratified logrank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for quantiles and probabilities of being event free at different time points. 
Secondary 
Key secondary 
IDFS 
 
 
 
Other secondary 
DRFS, LRRFS, 
OS 
 
BCSS 
 
 
Stratified logrank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for quantiles and probabilities of being event free at different time points. 
 
 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for quantiles and probabilities of being event free at different time points. 
 
Stratified Fine and Gray model for HR. 
Cumulative incidence function method for quantiles and probabilities of the event of interest at different 
time points. 
1 - Cumulative incidence function method for quantiles and probabilities of being event free at different 
time points. 
Exploratory 
Will be described in the SAP. 
IBCFS = invasive Breast Cancer-Free Survival; IDFS = invasive Disease-Free Survival; DRFS = Disease Recurrence Free Survival;  
LRRFS = locoregional recurrences-free survival; HR = hazard ratio; OS = overall survival; BCSS = Breast Cancer-Specific Survival; 
SAP = statistical analysis plan; 
9.2.3.3 Other endpoints  
Patient reported outcomes 
Patient reported outcome (PRO) endpoints for the PRO objective will be analyzed in participants 
from the safety population. These three endpoints are:  
• Change from baseline in overall side effect bother as measured by the Functional 
Assessment of Cancer Therapy Item GP-5 (FACT-GP5).  
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• Change from baseline in systemic therapy side effects as measured by the EORTC Quality 
of Life Questionnaire Breast cancer module (EORTC-QLQ-BR23) systemic therapy side 
effects scale.  
• Change from baseline in global health status/quality of life as measured by the EORTC 
Core Quality of Life Questionnaire (EORTC QLQ-C30) global health status/quality of life 
(GHQ) scale.  
For each questionnaire the compliance profile over time will be summarized on the safety 
population (number and percentage of forms received versus expected, and number and 
percentage of forms evaluable versus expected) per treatment arm. Reasons for non-completion 
will be summarized. 
Descriptive statistics on the absolute value and changes from baseline will be done for each 
treatment arm at each timepoint during treatment period, at EOT, and at the two post-treatment 
follow up visits will be summarized on the safety population. Between treatment comparisons of 
the change from baseline over time will be provided for these selected PRO endpoints based on 
the safety population who have completed the baseline and at least one post-baseline PRO 
assessment. No formal statistical hypothesis will be tested. 
Pharmacokinetics 
Pharmacokinetics analyses will be described in the SAP. 
9.2.4 Tertiary/exploratory endpoint(s)  
Analysis of tertiary and exploratory endpoints will be described in the SAP. 
9.2.5 Safety analysis  
9.2.5.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period.  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
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TEAEs 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 preferred term (PT), the maximum grade will be used. 
Summaries will be provided for all grades combined and for Grade ≥3 (including Grade 5). 
Missing grades, if any, will be included in the “all grades” category.  
Analysis of all adverse events 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), all treatment 
emergent SAEs, all TEAEs related to IMP, all TEAEs leading to permanent treatment 
discontinuation and all TEAEs leading to dose modification. 
The AE summaries will be generated with number (%) of participants experiencing at least 
one event.  
Deaths will also be analyzed. 
9.2.5.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Analyses according to PCSA and NCI grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version 5.0. In addition, for laboratory variables for which NCI-CTCAE scale is not applicable, 
vital signs and ECG variables, PCSA analyses will be performed based on the PCSA list currently 
in effect at Sanofi at the time of the database lock. 
Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For laboratory variables graded by NCI-CTCAE. 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.  
• The number (%) of participants with abnormal laboratory tests during the treatment-
emergent period will be summarized by grade. When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided.  
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For ECG, the incidence of participants with at least one abnormal ECG during the treatment-
emergent period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
• Normal/missing 
• Abnormal 
9.2.5.3 Product complaints  
Product complaints will be summarized in the safety population.  
9.2.6 Other analysis  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 (Appendix 9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
9.3 
INTERIM ANALYSES   
Two interim analyses are planned based on the primary IBCFS endpoint at 1/3 (non-binding 
futility only) and 3/4 (efficacy and non-binding futility) of the planned total number of events 
expected. The stopping boundaries for non-binding futility are based on the observed HR based 
on the stratified Cox proportional hazard model, ie, an HR>1.2 for the first interim analysis and an 
HR>1.1 for the second interim analysis. The stopping boundaries for efficacy will be derived 
based on the O’Brien and Fleming α-spending function and depend on the actual number of 
IBCFS events observed at the time of the second interim analysis relative to the planned total 
number of events (568). Per FDA request, the second interim analysis and the final analysis 
should be performed when at least 2 years and at least 3 years of follow-up have been observed 
for all patients, respectively. Therefore, the second interim analysis and the final analysis will be 
performed when both the minimum required number of events and the minimum follow-up 
criteria have been met. If the actual number of IBCFS events observed at the final analysis is 
greater than the planned total number of events (568), the Type I error rate spent at the second 
interim analysis will not be recalculated based on the actual number of IBCFS events to avoid the 
inflation of the overall Type I error rate. 
A summary of the IBCFS analyses is provided in Table 11. 
 
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Table 11 - Summary of IBCFS analyses  
Analysis 
Months 
after FPI 
(approx., 
under 
IBCFS 
HR=0.76) 
Planned 
accrual  
Number 
of 
events 
(under 
IBCFS 
HR=0.76) 
Information 
fraction 
Cumulative 
Probability 
to stop for 
futility 
under 
IBCFS 
HR=0.76 
(false 
negative 
rate) 
Cumulative 
Power 
(under 
IBCFS 
HR=0.76) 
Futility 
boundary 
Efficacy 
boundary 
IBCFS IA 
1 (non-
binding 
futility 
only) 
28 
3738 
189 
1/3 
0.1% 
 
HR > 1.2 
NA 
IBCFS IA 
2 
(non-
binding 
futility 
and 
efficacy) 
47.5 
3738 
426 
3/4 
0.1% 
69% 
HR > 1.1 
p ≤0.0096 
HRa ≤0.7971) 
IBCFS 
Final 
analysis 
60 
3738 
568 
1 
10% 
90% 
p >0.0221 
HRa >0.8447) 
p ≤0.0221 
HRa ≤0.8447) 
a HR is provided only for information purposes. The interim and final decisions will be based on p-values. 
FPI: First patient in; IA: interim analysis; HR: Hazard ratio; IBCFS: invasive breast cancer-free survival 
Note: numbers have been rounded. Calculations were made using East 6.5 software. 
In case of release of positive results at interim analysis, disease assessments data will continue to 
be collected for each patient according to the protocol (See Section 1.3) and IBCFS results will be 
updated at each subsequent planned analysis (non-inferential analysis only). 
The statistical analysis plan will describe the planned interim analyses in greater detail. 
9.3.1 EORTC independent DMC  
This study will use the EORTC IDMC. The first IDMC meeting will be set up to review early 
safety results (eg, after approximately 100 participants have completed at least 2 cycles, or after 
6 months after first participant randomized, whichever occurs first), and then periodically 
(eg, every 6 months) to examine the cumulative safety data, accrual and treatment exposure. 
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In addition to review of safety results, the IDMC will also evaluate efficacy at the two interim 
analyses and make a recommendation to the Study Steering Committee regarding study 
continuation based on observed results of the study. 
Ad hoc IDMC meetings may also be held if a significant safety issue or an issue deemed 
important for discussion arises on this or other amcenestrant studies. 
Following each meeting, the IDMC will make recommendations to the Study Steering Committee 
regarding the continued safety of treating ongoing and future study participants, as well as the 
course of action regarding the conduct of the study in compliance with the IDMC Charter.  
9.4 
SAMPLE SIZE DETERMINATION  
For IBCFS, a total of 568 IBCFS events will be needed to reject the null hypothesis using a log-
rank test at the one-sided level of 2.5% and 90% power under the assumption of an HR of 0.76. 
Assuming proportional hazards under an exponential model and based on an anticipated 4-year 
IBCFS rate of 82% in the tamoxifen arm, this is expected to correspond to a 4-year IBCFS rate of 
86% in the amcenestrant arm. 
Based on a piecewise enrollment assumption over 24 months as described in Table 12, an IBCFS 
cut-off date (COD) 60 months after the first participant randomized and an annual dropout rate of 
1%, a total of 3738 participants are expected to be randomized in a 1:1 ratio into the amcenestrant 
and tamoxifen arms. 
Table 12 - Piecewise enrollment assumptions  
Month 
Cumulative enrollment (%) 
3 
5% 
6 
15% 
12 
40% 
24 
100% 
The number of events/sample size calculation accounts for two interim analyses at 1/3 (non-
binding futility only) and 3/4 (efficacy and non-binding futility) of the planned total number of 
events (Section 9.3). 
Comparison between treatment arms on IDFS will be performed only if statistical significance has 
been achieved for IBCFS. Therefore, formal comparison on IDFS will be performed either at the 
second interim analysis or at the final analysis of IBCFS. Therefore, the number of IDFS events 
observed will depend on the occurrence of second non-breast primary invasive cancer and will 
therefore be at least equal to the number of IBCFS events. 
Calculations were made using East 6.5 software. 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
 
10.1.1 Trial organization  
AMEERA-6 is an industry sponsored trial, conducted in partnership between SANOFI, the Breast 
International Group (BIG), the European Organization for Research and Treatment of Cancer 
(EORTC) and Alliance Foundation Trials (AFT), and academic research groups from the BIG and 
the US networks.  
SANOFI is the Sponsor of the trial, and will provide funding, the investigational drug 
(amcenestrant) and the placebos for the trial. 
BIG is responsible of the conduct of the study within the BIG network, with EORTC leading the 
protocol development, the study management, and data analysis activities, as well as the medical 
monitoring, and AFT managing the study in the United States. Sanofi conducts the study in 
selected countries outside the geographical scope of the academic networks and oversees the 
global conduct of the trial. 
The protocol has been developed in collaboration between all four study partners, and subject to 
the approval by the Study Steering Committee. 
10.1.2 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 (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator’s Brochure (IB), 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. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
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• 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. 
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her 
designated healthcare professional, if so designated by the participant) is 
consistent with all applicable national, state, or regional laws and regulations in 
the country where the study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical 
validity.  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other 
individuals, eg, the finding relates to a communicable disease, Investigators 
should seek independent ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in 
the site medical files that she/he does not want to know about such findings. 
- 
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. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.3 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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10.1.4 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants, and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Privacy and Data Protection requirements including 
those of the Global Data Protection Regulation (GDPR) and of the French law, 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. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, Sponsor must define if those participants must or not re-consent or be 
informed of the amendment (eg, if the processing of personal data is modified, if the 
Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF (see Section 5.4). However, in 
case the participant is a temporary screen failure, there is no need to have participant reconsent 
(ie, new ICF signed) if the participant finally participates in the trial. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future 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. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 (Appendix 9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
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10.1.5 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
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 African American population for the FDA or on Japanese population 
for the Pharmaceuticals)”. They will not be collected in the countries where this is prohibited by 
local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• 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. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
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• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies’ 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
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10.1.6 Committees structure  
The study will be governed by the Steering Committee (SC), which will be the ultimate decision-
making body of the Study. The SC charter shall stipulate the composition as well as the working 
rules of the SC. The SC will be composed of representatives from the Sponsor (SANOFI) as well 
as representatives from the academic research groups (BIG, EORTC, AFT). 
The Executive Committee (EC) which is a subset of the SC, will serve to facilitate the work of the 
SC, to respond to questions of the JSMT and the IDMC, and report to the SC.  
The Joint Study Management Team (JSMT) will be responsible for the daily conduct of the Study, 
shall report to the Steering Committee and the Executive Committee and shall execute the 
decisions of both these committees. 
The Translational Advisory Committee (TAC) shall be the expert body which functions under the 
governance of the SC. It provides guidance to the SC on optimal use of study data and/or 
biological samples outside the protocol, and recommends to the SC for final approval, according 
to the Policy for Access to Study Data and Biological Samples. 
The SC, EC, JSMT and TAC composition, responsibilities and working procedures, will be 
described in the specific charters developed for the study. 
The independent data monitoring committee (IDMC) will be in charge of the independent 
oversight of this study. The composition of the IDMC is described in EORTC Policy 
"Independent Data Monitoring Committees for EORTC studies" (EORTC POL004, accessible on 
EORTC website) and its functioning is ruled by the charter annexed to the Policy. The IDMC 
membership, data to be reviewed, timing of the planned reviews as well as the operating 
procedures will be described in the IDMC charter. 
10.1.7 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly 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 patients are required to be submitted to peer-reviewed 
journals following the mutually agreed by the Study partners specific Publications and 
Presentations Policy developed for the study to ensure accuracy, fair balance in authorship 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 according to 
the study-specific Policy for Access to Study Data and Biological Samples.  
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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 will be described in the specific dedicated Policy for Access to Study Data and 
Biological Samples developed for the study.  
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organizations”. 
10.1.8 Data quality assurance  
• All participant data relating to the study will be recorded on electronic CRF unless 
transmitted to the Sponsor or Sponsor’s representatives electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in CRF Completion Guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined in the relevant study plans to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These pre-defined parameters will be monitored during the study and important deviations 
from the QTLs and remedial actions taken will be summarized in the clinical study report. 
• 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. 
• The Sponsor or Sponsor’s representatives 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). 
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• 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. 
10.1.9 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. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 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. 
10.1.10 
Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site termination 
The Steering Committee reserves the right to close the study site or terminate the study at any 
time for any reason. 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 Steering Committee, as well as reasons for the early closure 
of a study site by the Steering Committee or Investigator may include but are not limited to: 
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• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• 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 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should ensure 
appropriate participant therapy and/or follow-up. 
10.1.11 
Publication policy  
• Publications and oral presentations of any aspects from the study including study design 
and study results shall be in accordance with accepted scientific practice, academic 
standards and customs and in accordance with the specific dedicated Publications and 
Presentations Policy developed for the study. This policy will be made available to all 
investigators/sites and groups participating in the study. 
• The publications of the main trial results and any other related study publications will be 
written by the Study SC Chairs or others as applicable on the basis of the analysis reports 
performed at the EORTC Headquarters and will be sent to a major scientific journal. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 13 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. 
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Table 13 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) or Urea 
 
Creatinine 
 
Glucose non-fasting 
 
Potassium 
 
Sodium 
 
Calcium (total calcium) 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphataseb 
 
Total and direct bilirubin 
 
Lipids 
Total protein 
 
Total cholesterol 
LDL-cholesterol 
HDL-cholesterol 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c 
Other blood tests 
• 
Follicle-stimulating hormone and estradiol (pre/perimenopausal women only) 
• 
Coagulation: PT/INR  
• 
Bone turn over markers (CTX, P1NP)d 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 8.2.3 and Section 10.10.1 
(Appendix 10). All events of Grade ≥3 ALT increase should be reported as adverse events of special interest (AESI). 
b If alkaline phosphatase is elevated, consider fractionating.  
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
d β-CTX and tP1NP(total P1NP) are not acceptable. If the local lab cannot perform CTX and P1NP then serum should be sent to a central 
lab. 
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
 
10.3.1 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. 
Definition of unsolicited and solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a participant 
diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalisation, or emergency room visit, or visit to/by a health care provider). The 
participantswill be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participant and by review of available medical 
records at the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 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. 
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• 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 fulfill 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. 
• 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. 
10.3.2 Definition of SAE  
An SAE is defined as any adverse event 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 admitted (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. 
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Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent or significant 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 by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that 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. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse  
- 
Suicide attempt or any event suggestive of suicidality  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling)  
- 
Bullous cutaneous eruptions  
- 
Cancers diagnosed during the study or aggravated during the study 
10.3.3 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 e-CRF. 
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• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representatives in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representatives. 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’s representatives. 
• 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 to 1 of the following categories, using NCI-CTCAE v 5.0. 
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 that 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. 
• 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 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 Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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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’s 
representatives 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. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representatives will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) 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 Sponsor’s representatives by telephone. 
• Contacts for SAE reporting can be found in Investigator Study File. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representatives. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in Investigator Study File. 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
i. 
Premenarchal 
ii. 
Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
iii. 
Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, or in in participants who are not using hormonal 
contraception or hormonal replacement therapy (HRT), confirmation with more 
than one FSH measurement (>34.4 IU/L for FSH and <10 pg/mL for estradiol if 
institutional range is not available) is required, as per local regulations. HRT must 
be discontinued to allow confirmation of postmenopausal status before study 
enrollment. 
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CONTRACEPTION GUIDANCE: 
In addition to inclusion criteria I. 11 
• Female participants of child-bearing potential:  
- 
Must agree to be on a gonadotropin-releasing hormone analog (to be continued while 
receiving the study intervention) as per label  
- 
Must have negative serum ß-HCG test at screening 
- 
Must agree to use highly effective methods of contraception during the treatment 
period until the end of relevant systemic exposure (ie, 5 times of the longest IMP 
half-life (tamoxifen) plus 6 months period, which corresponds to ~9 months for 
tamoxifen as per CMDh guidance (86). 
- 
Must not donate ova from screening until the end of the contraception period as 
defined above 
• Male participants without prior orchiectomy: 
- 
Agree to be on a gonadotropin-releasing hormone analog (to be continued while 
receiving the study intervention) as per label and use a male condom during 
intercourse during study intervention until 160 days after the end of treatment period 
(corresponding to the end of relevant systemic exposure (ie, 5 times of the longest IMP 
half-life (tamoxifen) plus a further 90-day period) as per CMDh guidance (86) and 
should not father a child in this period. A condom is required to be used also by 
vasectomized men, as well as during intercourse with a male partner, in order to 
prevent delivery of the drug via seminal fluid. 
- 
Must not donate sperm from screening until the end of the contraception period as 
defined above. 
- 
Male participants should consider sperm preservation prior to beginning therapy with 
study IMPs, because exposure to IMP has the potential risk of testicular injury with 
partial or permanent infertility. 
- 
Male participants and male partners of female participants must wear a male condom 
with spermicide, in combination with a highly effective method of contraception. 
Note: In case of acceptable birth control method, partner WOCBP of a male participant should 
use a highly effective contraception during treatment of their partner and until the end of the 
contraception period as defined above.  
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly are considered as highly effective birth control methods*. 
Such methods include: 
• Intrauterine device. 
• Bilateral tubal occlusion. 
• Vasectomized partner. 
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• Sexual abstinence (Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant). 
Note: Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for those participating in clinical studies. 
* Failure rate of <1% per year when used consistently and correctly.  
The following birth control methods result in a failure rate of more than 1% per year and are not 
considered acceptable birth control methods when used alone in the current trial: 
• Male or female condom with or without spermicide. 
• Cap, diaphragm or sponge with spermicide. 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date, but may last longer according to local regulations. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial 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. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date but may last longer 
according to local regulations. Any termination of pregnancy will be reported, regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
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• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) 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. 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. 
10.5 
APPENDIX 5: GENETICS  
• A 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, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis from consenting 
participants. 
• DNA samples will be used for research related to germline mutations linked to the 
treatment outcome. The genetic research will consist on the analysis of the entire exome of 
the patient’s genome. 
• DNA samples will be analyzed for the germline mutations study by whole exome 
sequencing. 
• The samples will be analyzed to study the genetic factors involved in the response to the 
study intervention to understand the related conditions to the patient’s outcome. 
• 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 but no longer than 15 years after the end of the study or other 
period as per local requirements. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Not Applicable for this study. 
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10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable for this study. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
CHINA 
For study participants enrolled from clinical sites in China, central confirmation of ER and PgR 
for screening eligibility will be performed (collection of the most recent archived FFPE biopsied 
tumor tissue samples at screening) as well as PK analysis (collection of blood sample on pre-dose 
D1 Cycle 2, Cycle 7, Cycle 13 and Cycle 25 using DBS and approximately 100 plasma samples 
aliquots kept from on C2 and/or C7 blood collection, to determine Blood/Plasma ratio). 
Biological samples related to tertiary/exploratory (genetic analyses and biomarkers) endpoints 
will not be collected or analyzed. The impacted biological samples are: 
• Collection of plasma sample for Molecular profiling in ctDNA in all study participants on 
predose D1 Cycle 1 and Cycle 2, and EOT in case of disease recurrence. 
• Collection of blood sample for genomic DNA in all study participants on predose D1 
Cycle 1. 
• Collection of blood sample for future research on predose D1 Cycle 1 and Cycle 2, and 
EOT in case of disease recurrence. 
• Collection of FFPE tissue sample at EOT in case of disease recurrence. 
• Genetic analyses and biomarker research for FFPE tissue samples at screening (except that 
central confirmation of ER and PgR for screening eligibility will be performed). 
10.9 
APPENDIX 9: 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. 
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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 (Section 5.5). However, in case new 
participant is 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. 
Study assessments and procedures 
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). 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, 
mobile applications, 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. 
• The Direct-to-Patient (DTP) supply of the IMP from the PI/site where allowed by local 
regulations and agreed upon by participant. (Section 1). 
Contingencies implemented due to emergency will be documented. 
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 10.1.9). 
 
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10.10 APPENDIX 10: ADDITIONAL APPENDICES  
10.10.1 
Recommended dose modification guidelines for study treatment-related 
adverse event  
Recommended dose modifications of study intervention (Amcenestrant/Amcenestrant-
matching placebo, Tamoxifen/Tamoxifen-matching placebo) are presented in Table 14. 
Table 14 - Recommended dose modification or discontinuation of study treatment-related toxicities  
NCI CTCAE v5 grade 
Management of endocrine therapy 
(Amcenestrant/amcenestrant-matching placebo, Tamoxifen/tamoxifen-
matching (placebo) 
Toxicities 
Grade 1 or 2 
No dose adjustment is required. 
Grade 3 (if persisting 
despite optimal medical 
treatment) 
Administer endocrine therapy if toxicity is not attributed to the IMP. If attributable, omit endocrine 
therapy until symptoms resolve to Grade ≤1, or Grade ≤2 (if not considered a safety risk for the 
patient). 
If resolved to Grade ≤1, or Grade ≤2 (if not considered a safety risk for the patient), resume the 
omitted endocrine therapy at the same dose. 
In case of first recurrence of the same Grade 3 event: administer at the same dose if restart is 
possible. 
In case of second recurrence of the same Grade 3 event: permanently discontinue IMP.  
Grade 4 
Administer endocrine therapy if toxicity is not attributed to the IMP. If attributable, omit endocrine 
therapy until symptoms resolve to Grade ≤1, or Grade ≤2 (if not considered a safety risk for the 
patient). 
If resolved to Grade ≤1, or Grade ≤2 (if not considered a safety risk for the patient), resume the 
omitted endocrine therapy at the same dose. 
If resolved to Grade 3: refer to Grade 3 instructions above. 
In case of first recurrence of the same Grade 4 event attributed to the IMP: permanently 
discontinue IMP. 
Increase of ALT 
confounding factors such as, liver metastasis, hepato-biliary disorders, concomitant medications, etc. should be excluded prior 
to dose modifications 
Grade 0 or 1 
No dose adjustment is required 
Grade 2 
Omit endocrine therapies administration until recovery to Grade ≤1, and then restart endocrine 
therapies at the same dose.  
In case of recurrence of the same Grade 2 event: administer at the same dose if restart is possible. 
Grade 3 
Omit endocrine therapies administration. Repeat LFTs within 2-3 days. If ALT levels not 
recovered, monitor LFTs weekly (or more frequently, if clinically indicated) until recovery to 
Grade ≤1 ALT increased (or baseline grade). On recovery, restart endocrine therapies at the 
same dose.  
In case of first recurrence of the same Grade 3 event: administer at the same dose if restart is 
possible. 
In case of second recurrence of the same Grade 3 event: permanently discontinue endocrine 
therapies. 
Grade 4 
Permanently discontinue study treatment  
Liver function tests (LFTs) include AST, ALT, ALP (isoenzymes if Grade >2), total bilirubin (fractionated if >2 x ULN direct), GGT, and INR (if total 
bilirubin >2.5 ULN).  
Grading according to CTCAE v5.0. 
NCI CTCAE v5 = National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; LLN = lower limit of normal. 
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10.10.2 
Methods for selecting items from the pro-CTCAE item library  
PRO-CTCAE items chosen for this study were systematically selected from the PRO-CTCAE 
item library to measure 14 symptomatic AEs (representing 24 items) known to be associated with 
amcenestrant (as seen in the AMEERA-1 Phase 1/2 study) and/or tamoxifen (based on the USPI, 
EU SmPC, and/or clinician input). Items from the PRO-CTCAE item library were selected in 
accordance in the PRO-CTCAE with recommendations by the FDA (73, 74) and using methods 
informed by the published literature (75, 76). Items were eligible for inclusion if they assessed 
one or more attribute (frequency, severity, interference, presence/absence) of a symptomatic 
adverse event (AE) that:  
1.) was a related TEAE that occurred in ≥ 5% of the pooled population treated with 
amcenestrant ≥ 150 mg QD as monotherapy in Parts A and B of the AMEERA-1 
Phase 1/2 study (TED14856) (85);  
2.) occurred in ≥ 10% of patients on tamoxifen for adjuvant therapy in at least study listed 
in the tamoxifen USPI (86);  
3.) are very common (incidence of ≥1/10) in patients on tamoxifen per the tamoxifen EU 
SmPC (87); and/or  
4.) did not meet inclusion criteria 1, 2, or 3, but were considered clinically relevant in 
patients on tamoxifen based on clinician input and a retrospective cohort study of the 
clinician- and patient-reported toxicities experienced among early breast cancer 
patients on AIs and tamoxifen using data from the Unicancer CANcer TOxicities 
(CANTO) cohort. If a symptomatic AE was eligible for inclusion based on the criteria 
above and the PRO-CTCAE included multiple items associated with the symptomatic 
AE, all items available items were included. 
Table 15 presents the 14 symptomatic AEs (representing 24 items) selected for assessment from 
the PRO-CTCAE item library, the attributes assessed by the PRO-CTCAE items, the number of 
items assessed for each symptomatic AE, and the inclusion criteria met by each symptomatic AE.  
Table 15 - Symptomatic AEs and items selected from the PRO-CTCAE item library for inclusion in 
EFC16133 and inclusion criteria met by each symptomatic AE  
Symptomatic AE from PRO-
CTCAE Item Library 
Attributes assessed (number 
of items) 
Inclusion criteria met 
Hot flashes 
Frequency, severity (2) 
1, 2, and 3 
Increased sweating 
Frequency, severity (2) 
4 
Joint pain 
Frequency, severity, interference (3) 
1 and 2 
Muscle pain 
Frequency, severity, interference (3) 
4 
Fatigue 
Severity, interference (2) 
1, 2, and 3 
Vaginal dryness 
Severity (1) 
4 
Vaginal discharge 
Presence/absence (1) 
2 and 3 
Irregular periods/vaginal bleeding 
Presence/absence (1) 
2 and 3 
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Symptomatic AE from PRO-
CTCAE Item Library 
Attributes assessed (number 
of items) 
Inclusion criteria met 
Nausea 
Frequency, severity (2) 
1, 2, and 3 
Vomiting 
Frequency, severity (2) 
1 and 2 
Diarrhea 
Frequency (1) 
1 
Constipation 
Severity (1) 
1 
Decreased appetite 
Severity, interference (2) 
1 
Rash 
Presence/absence (1) 
3 
10.10.3 
Eastern Cooperative Oncology Group performance status scale  
Assessment of ECOG/WHO PS will be assessed at the time points specified in SoA (Section 1.3). 
ECOG PS (performance status) should be obtained on the scheduled day, even if study intervention 
is being held. 
Table 16 - Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale  
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 self-care but unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
10.10.4 
Abbreviated modification of diet in renal disease formula  
Glomerular Filtration Rate (GFR) (mL/min/1.73 m2) = 175 × (SCr) -1.154 × (Age)-0.203 × (0.742 if 
Female) × (1.212 if African-American). 
Abbreviation: SCr = Serum creatinine in mg/dL; Age in years 
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10.11 APPENDIX 11: ABBREVIATIONS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AI: 
aromatase inhibitor 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
BCSS: 
breast cancer-specific survival 
BID: 
twice daily 
BMD: 
bone mineral densitometry 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CDK4/6: 
cyclin-dependent kinase 4 and 6 
CI: 
confidence interval 
COA: 
clinical outcomes assessment 
CONSORT: 
Consolidated Standards of Reporting Trials 
CYP: 
cytrochrome P450 enzymes 
DBS: 
dried blood spot 
DDI: 
drug-drug interaction 
DFS: 
disease free survival 
DNA: 
deoxyribonucleic acid 
DRFS: 
distant recurrence-free survival 
DTP: 
direct to patient 
DVT: 
deep vein thrombosis 
DXA: 
dual-energy X-ray absorptiometry 
ECG: 
electrocardiogram 
eCOA: 
electronic clinical outcomes assessment 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EDC: 
electronic data capture 
eGFR: 
estimated glomerular filtration rate 
EORTC: 
European Organization for Reasecrh And Treatment of Cancer 
EOT: 
end of treatment 
EQ-5D-5L: 
EuroQoL Questionnaire with 5 Dimensions and 5 Levels per Dimension 
ER: 
estrogen receptor 
ESR1: 
Estrogen receptor gene 
EU: 
European Union 
FACT GP5: 
Functional Assesssment of Cancer Therapy - Item GP5 
FDA: 
Food and Drug Administration 
FFPE: 
formalin fixed paraffin embedded 
FIH: 
first-in-human 
FPI: 
first patient in 
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FSH: 
follicle stimulating hormone 
gDNA: 
genomic deoxyribonucleic acid 
GGT: 
gamma-glutamyl transferase 
GHQ: 
global health status/quality of life 
HCV: 
hepatitis C 
HER2: 
human epidermal growth factor receptor 2 
HR: 
hazard ratio 
HR+: 
hormone receptor positive 
HRQL: 
health-related quality of life 
HT: 
hormonal therapy 
IA: 
interim analysis 
IB: 
investigator brochure 
IBCFS: 
invasive breast cancer-free survival 
ICF: 
informed consent form 
IDFS: 
invasive disease-free survival 
IEC: 
Independent Ethics Committee 
IES: 
intergroup exemestane study 
IHC: 
immunohistochemistry 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
ITT: 
intent-to-treat 
LFT: 
liver function test 
LHRH: 
luteinising hormone releasing hormone 
LRRFS: 
loco-regional relapse-free survival 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMAS: 
Morisky medication adherence scale 
MRI: 
magnetic resonance imaging 
NCI-CTCAE: 
National Cancer Institute-Common Terminology Criteria for Adverse Event 
NMPA: 
National Medical Products Administration 
ORR: 
objective response rate 
OS: 
overall survival 
P1NP: 
Procollagen type I N-terminal propeptide 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PO: 
oral 
PR: 
partial response 
PRO: 
patient-reported outcome 
PRO-CTCAE: 
patient-reported outcomes version of the common terminology criteria for 
adverse events 
PT: 
preferred term 
QD: 
once a day 
QLQ BR23: 
EORTC quality of life questionnaire - Breast cancer specific module 
QLQ C30: 
EORTC core quality of life questionnaire version 3 
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RNA: 
ribonucleic acid 
RR: 
relative risk 
SAP: 
statistical analysis plan 
SARS-CoV-2: 
severe acute respiratory syndrome coronavirus 2 
SERD: 
selective estrogen receptor degrader 
SERM: 
selective estrogen receptor modulator 
SmPC: 
summary of product characteristics 
SoA: 
schedule of activities 
STEEP: 
standardized definitions for efficacy endpoints in adjuvant breast cancer trials 
SUSAR: 
suspected unexpected serious adverse reaction 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
UGT: 
uridine 5'-diphospho-glucoronosyltransferase 
ULN: 
upper limit of normal 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.  
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11 
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