Conditions: Breast Cancer Metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 367
Healthy volunteers: no

Brief summary:
Primary Objective:

To determine whether amcenestrant per overall survival (os) improves progression free survival (PFS) when compared with an endocrine monotherapy of the choice of the physician, in participants with metastatic or locally advanced breast cancer

Secondary Objectives:

* To compare the overall survival in the 2 treatment arms
* To assess the objective response rate in the 2 treatment arms
* To evaluate the disease control rate in the 2 treatment arms
* To evaluate the clinical benefit rate in the 2 treatment arms
* To evaluate the duration of response in the 2 treatment arms
* To evaluate the PFS according to the estrogen receptor 1 gene (ESR1) mutation status in the 2 treatment arms
* To evaluate the pharmacokinetics of amcenestrant as single agent
* To evaluate health-related quality of life in the 2 treatment arms
* To compare the overall safety profile in the 2 treatment arms

Detailed description:
The duration of the study for an individual participant will include a period to assess eligibility (screening period) of up to 4 weeks (28 days), a treatment period of at least 1 cycle (28 days of study treatment), and an end of treatment (EOT) visit at least 30 days (or until the participant receive another anticancer therapy, whichever is earlier) following the last administration of study treatment. Study treatment may continue until precluded by unacceptable toxicity, disease progression, death or upon participant's request to stop treatment, or Investigator decision, whichever occurs first.

An extension of recruitment for Chinese participants is planned in this study: After completion of randomization in the global part of the study, randomization will continue in China until approximately 90 Chinese participants are randomized.

Arms:
arm 1: Daily amcenestrant dose administered orally under fed or fast condition arm 2: Control treatment of the choice of the physician depending on each participant's medical condition and in accordance with the approved label may include 1 of the following treatments used as monotherapy.

Fulvestrant

Aromatase inhibitors (anastrozole, letrozole, exemestane)

Selective estrogen receptor modulator (Tamoxifen)

Interventions: intervention 1: Amcenestrant intervention 2: Fulvestrant intervention 3: Anastrozole intervention 4: Letrozole intervention 5: Exemestane intervention 6: Tamoxifen
Intervention descriptions: intervention 1: Pharmaceutical form: Capsule

Route of administration: Oral intervention 2: Pharmaceutical form: Solution for injection

Route of administration: Intramuscular intervention 3: Pharmaceutical form:Tablets or capsules

Route of administration: Oral intervention 4: Pharmaceutical form: Tablets or capsules

Route of administration: Oral intervention 5: Pharmaceutical form: Tablets or capsules

Route of administration: Oral intervention 6: Pharmaceutical form: Tablets or capsules

Route of administration: Oral

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 1.0 (02-MAY-2018) based on TransCelerate CPT version 4 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 06 
Protocol title: 
An open-label randomized Phase 2 trial of 
amcenestrant (SAR439859), versus endocrine 
monotherapy as per physician’s choice in patients with 
estrogen receptor-positive, HER2-negative locally 
advanced or metastatic breast cancer with prior 
exposure to hormonal therapies  
Protocol number: 
ACT16105 
Amendment number: 
06 
Compound number 
(INN/Trademark): 
SAR439859 
(Amcenestrant/Not Applicable) 
Brief title: 
Phase 2 study of amcenestrant (SAR439859) versus 
physician’s choice in patients with locally advanced or 
metastatic ER-positive breast cancer (AMEERA-3) 
Acronym: 
AMEERA-3 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 Avenue Pierre Brossolette 
91380 Chilly-Mazarin 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifying number(s): 
EudraCT number: 
2018-004593-98 
IND number: 
133204 
WHO number: 
U1111-1217-2774 
NCT number: 
NCT04059484 
EUDAMED 
Not applicable 
Other 
Not applicable 
 Date: 
10-Dec-2021
Total number of pages: 158 
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NCT04059484
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Amended Clinical Trial Protocol 06 
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 06 
All 
10 December 2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
All 
23 September 2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
17 December 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
30 June 2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
13 February 2020, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
08 August 2019, version 1 (electronic 1.0) 
Original Protocol 
 
11 December 2018, version 1 (electronic 1.0) 
Amended protocol 06 (10 December 2021) 
This amended protocol 06 (Amendment 06) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
Overall rationale for the amendment 
The objective of the amendment is to update the protocol with the following key changes: 
• 
To update the cut of date (COD) definition for the final progression free survival (PFS) 
analysis. 
• 
To update the censoring and event scheme of the PFS primary analysis. 
Protocol amendment summary of changes table 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 9.2 
Sample size 
determination and 
9.5.2 Interim analysis 
for overall survival  
The definition of the COD for the final PFS and OS analysis 
has been changed  
To allow more flexibility for the COD 
definition for final PFS and OS 
analyses. 
1.1 Synopsis and 
9.4.1.1 Analysis of the 
primary efficacy 
endpoint 
The definition of the censoring and event scheme for the PFS 
analysis has been changed. 
To align AMEERA-3 with the general 
FDA recommendation to censor 
patients after initiation of further anti-
cancer therapy or if the documented 
progression or death occurred after 
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Section # and 
Name 
Description of Change 
Brief Rationale 
two or more non-evaluable tumor 
assessments. 
1.1 Synopsis and 4.1 
Overall design 
The sections indicating the safety data to be collected after 
the COD for the final PFS analysis have been updated: 
“(…) and all new serious or related AEs (serious or not) 
occurring post-COD (…)” 
To clarify that SAEs are in scope of 
data to be collected post-COD, even if 
not related to IMP. 
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
2 
INTRODUCTION ............................................................................................................................ 25 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 30 
2.3.1 
Benefits .......................................................................................................................................... 30 
2.3.1.1 
Amcenestrant ................................................................................................................................. 30 
2.3.1.2 
Fulvestrant ..................................................................................................................................... 30 
2.3.1.3 
Aromatase inhibitors ...................................................................................................................... 31 
2.3.1.4 
Selective estrogen receptor modulators ........................................................................................ 32 
2.3.2 
Potential and identified risks .......................................................................................................... 32 
2.3.2.1 
amcenestrant ................................................................................................................................. 32 
2.3.2.2 
Fulvestrant ..................................................................................................................................... 33 
2.3.2.3 
Aromatase inhibitors ...................................................................................................................... 33 
2.3.2.4 
Selective estrogen receptor modulators ........................................................................................ 34 
2.3.3 
Conclusion ..................................................................................................................................... 35 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 36 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 37 
4 
STUDY DESIGN ............................................................................................................................ 38 
4.1 
OVERALL DESIGN ........................................................................................................................ 38 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 39 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 39 
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4.4 
END OF STUDY DEFINITION ....................................................................................................... 40 
5 
STUDY POPULATION .................................................................................................................. 41 
5.1 
INCLUSION CRITERIA .................................................................................................................. 41 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 43 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 45 
5.3.1 
Activity (Sun protection) ................................................................................................................. 45 
5.3.2 
Osteoporosis .................................................................................................................................. 46 
5.4 
SCREEN FAILURES...................................................................................................................... 46 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION ............................................................................................................................ 46 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 47 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 47 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 48 
6.2.1 
General rules .................................................................................................................................. 48 
6.2.2 
Storage conditions ......................................................................................................................... 48 
6.2.2.1 
Amcenestrant ................................................................................................................................. 49 
6.2.2.2 
Control products ............................................................................................................................. 49 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 49 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 50 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 50 
6.5.1 
Rescue medicine ............................................................................................................................ 52 
6.6 
DOSE MODIFICATION .................................................................................................................. 52 
6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 53 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 54 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 54 
7.1.1 
Permanent discontinuation ............................................................................................................ 54 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 55 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 56 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 57 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 58 
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8.1.1 
Criteria for response (antitumor activity) ........................................................................................ 58 
8.1.2 
Bone scans .................................................................................................................................... 58 
8.1.3 
Patient reported outcomes ............................................................................................................. 59 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 60 
8.2.1 
Physical examinations ................................................................................................................... 60 
8.2.2 
Vital signs ....................................................................................................................................... 61 
8.2.3 
Electrocardiograms ........................................................................................................................ 61 
8.2.4 
Clinical safety laboratory tests ....................................................................................................... 61 
8.2.5 
Suicidal risk monitoring .................................................................................................................. 61 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 62 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 63 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 64 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 64 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 64 
8.3.5 
Pregnancy ...................................................................................................................................... 64 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 65 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 65 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 65 
8.5 
PHARMACOKINETICS .................................................................................................................. 66 
8.6 
PHARMACODYNAMICS ............................................................................................................... 66 
8.6.1 
Tumor biopsy to assess estrogen receptor degradation (optional procedures) ............................ 66 
8.6.2 
Estradiol ......................................................................................................................................... 67 
8.7 
GENETICS ..................................................................................................................................... 67 
8.7.1 
Estrogen receptor 1 gene mutation status in cell-free DNA .......................................................... 67 
8.7.2 
Mutation profiling in cell-free DNA ................................................................................................. 68 
8.7.3 
RNA transcriptome analysis ........................................................................................................... 68 
8.7.4 
Drug metabolizing enzymes and transporters DNA sample .......................................................... 68 
8.8 
BIOMARKERS ............................................................................................................................... 68 
8.8.1 
Future use of samples ................................................................................................................... 69 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 69 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 70 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 70 
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9.2 
SAMPLE SIZE DETERMINATION  ................................................................................................ 70 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 71 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 72 
9.4.1 
Efficacy analyses ........................................................................................................................... 72 
9.4.1.1 
Analysis of primary efficacy endpoint............................................................................................. 73 
9.4.1.2 
Analysis of secondary efficacy endpoints ...................................................................................... 73 
9.4.2 
Safety analyses .............................................................................................................................. 75 
9.4.2.1 
Analyses of adverse events ........................................................................................................... 75 
9.4.2.2 
Analyses of clinical laboratory evaluations .................................................................................... 76 
9.4.3 
Other analyses ............................................................................................................................... 77 
9.4.3.1 
Analyses of patient reported outcome endpoints ........................................................................... 77 
9.4.3.2 
Analyses of other endpoints ........................................................................................................... 77 
9.5 
INTERIM ANALYSES  ................................................................................................................... 77 
9.5.1 
Interim analysis for progression-free survival ................................................................................ 77 
9.5.2 
Interim analysis for overall survival ................................................................................................ 78 
9.5.3 
Data Monitoring Committee ........................................................................................................... 79 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 80 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 80 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 80 
10.1.2 
Informed consent process .............................................................................................................. 80 
10.1.3 
Data protection ............................................................................................................................... 81 
10.1.4 
Committees structure ..................................................................................................................... 82 
10.1.5 
Dissemination of clinical study data ............................................................................................... 82 
10.1.6 
Data quality assurance .................................................................................................................. 83 
10.1.7 
Source documents ......................................................................................................................... 83 
10.1.8 
Study and site closure .................................................................................................................... 84 
10.1.9 
Publication policy ........................................................................................................................... 84 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 84 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 86 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 90 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 92 
10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 92 
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10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  ............................................... 92 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 93 
10.9 
APPENDIX 9: ABBREVIATIONS ................................................................................................. 100 
10.10 
APPENDIX 10: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ....................................................................................................................................... 102 
10.11 
APPENDIX 11: LIST OF STRONG CYP3A4 INDUCERS ........................................................... 102 
10.12 
APPENDIX 12: LIST OF CYP SENSITIVE SUBSTRATES ......................................................... 103 
10.13 
APPENDIX 13: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA .................................................................................................................................... 106 
10.14 
APPENDIX 14: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1) ...... 106 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 111 
10.15.1 Amended protocol 01: 08 August 2019........................................................................................ 111 
10.15.2 Amended protocol 02: 13 February 2020 .................................................................................... 117 
10.15.3 Amended protocol 03: 30 June 2020 ........................................................................................... 132 
10.15.4 Amended protocol 04: 17 December 2020 .................................................................................. 139 
10.15.5 Amended protocol 05: 23 September 2021 ................................................................................. 144 
10.16 
APPENDIX 16: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 146 
10.17 
APPENDIX 17: PATIENT REPORTED OUTCOMES .................................................................. 148 
10.17.1 EORTC QLQ-C30 ........................................................................................................................ 148 
10.17.2 EORTC QLQ-B23 ........................................................................................................................ 150 
10.17.3 EQ-5D-5L ..................................................................................................................................... 154 
11 
REFERENCES ............................................................................................................................. 155 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 36 
Table 2 - Overview of study interventions administered ............................................................................... 47 
Table 3 - Recommended dose modification and management of amcenestrant related toxicities............... 53 
Table 4 - Marginal power for overall survival................................................................................................. 71 
Table 5 - Populations for analyses ................................................................................................................ 71 
Table 6 - Efficacy analyses ........................................................................................................................... 72 
Table 7 - Safety analyses .............................................................................................................................. 75 
Table 8 - Progression-free survival analyses ................................................................................................ 78 
Table 9 - Overall survival analyses ............................................................................................................... 78 
Table 10 - Protocol-required safety laboratory assessments ........................................................................ 85 
Table 11 - China extension additional objectives and endpoints .................................................................. 93 
Table 12 - Pharmacokinetic flowchart for full pharmacokinetic sampling ..................................................... 95 
Table 13 - Blood sample volume collected per participant during extension part ......................................... 97 
Table 14 - List of pharmacokinetic parameters and definitions ..................................................................... 97 
Table 15 - Populations for analyses .............................................................................................................. 98 
Table 16 - Eastern Cooperative Oncology Group performance status scale .............................................. 102 
Table 17 - Response criteria, evaluation of target lesions .......................................................................... 109 
Table 18 - Response criteria, evaluation of nontarget lesions .................................................................... 109 
Table 19 - A summary of overall response status ....................................................................................... 109 
Table 20 - A summary of overall response status for non-measurable disease ......................................... 110 
Table 21 - Evaluation of best overall response ........................................................................................... 110 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 18 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
An open-label randomized Phase 2 trial of amcenestrant (SAR439859), versus endocrine 
monotherapy as per physician’s choice in patients with estrogen receptor-positive, HER2-negative 
locally advanced or metastatic breast cancer with prior exposure to hormonal therapies  
Brief title: 
 
Phase 2 study of amcenestrant (SAR439859) versus physician’s choice in patients with locally 
advanced or metastatic ER-positive breast cancer (AMEERA-3) 
Rationale: 
The treatment of metastatic/advanced breast cancer without visceral crisis is based on hormonal 
therapies given as monotherapy (tamoxifen, aromatase inhibitors [AI], fulvestrant) and in 
combination with targeted agents such as everolimus + exemestane and AI or 
fulvestrant + CDK4/6 inhibitors. These treatments were more often assessed in clinical studies in 
first and second lines, but few studies explore the efficacy in later lines. The purpose of this study 
is to evaluate the activity of amcenestrant, a potent, orally bioavailable, and selective estrogen 
receptor (ER) inhibitor that belongs to the selective estrogen receptor degrader (SERD) class of 
compounds in comparison with other endocrine treatments approved for the treatment of breast 
cancer, including fulvestrant, selective ER modulators (tamoxifen), and AIs (anastrozole, 
exemestane, and letrozole). Amcenestrant antagonizes the binding of estradiol to ER and 
promotes the transition of ER to an inactive conformation that leads to up to 98% receptor 
degradation at nanomolar concentrations in cellular assays. These dual properties of amcenestrant 
translate in a deeper inhibition of ER pathways and a more effective antiproliferative activity in 
ER-dependent breast cancer cell lines driven by mutant or wild type ER compared to fulvestrant. 
Fulvestrant is the only SERD currently marketed and is administered by intramuscular (IM) route. 
The other endocrine treatments listed above are given per os (PO).  
Amcenestrant recommended dose was established at 400 mg once daily (QD), based on the safety, 
pharmacokinetic and pharmacodynamic data review of the ongoing first in human study 
TED14856, from advanced breast cancer participants.  
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Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To determine whether amcenestrant 400 mg per os improves 
progression-free survival (PFS) when compared with an 
endocrine monotherapy of the choice of the physician, in 
participants with metastatic or locally advanced breast cancer.  
Progression-free survival is defined as the time interval from 
the date of randomization to the date of first documented 
tumor progression as per Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) assessed by independent central 
review (ICR) or death (due to any cause), whichever comes 
first. 
Secondary 
To compare the overall survival in the 2 treatment arms.  
Overall survival is defined as the time interval from the date of 
randomization to the date of documented death (due to any 
cause). 
To assess the objective response rate in the 2 treatment 
arms.  
Objective response rate is defined as the proportion of 
participants who have a confirmed complete response (CR) 
or partial response (PR), as best overall response (BOR) 
derived from overall response determined by ICR as per 
RECIST 1.1, from the date of randomization to the date of 
end of treatment.  
To evaluate the disease control rate in the 2 treatment arms.  
Disease control rate is defined as the proportion of 
participants who have a confirmed CR, PR, stable disease 
(SD), or Non-CR/ Non-PD as BOR determined by ICR as per 
RECIST 1.1 from the date of randomization to the date of end 
of treatment.  
To evaluate the clinical benefit rate in the 2 treatment arms.  
Clinical benefit rate is defined as the proportion of participants 
who have a confirmed CR, PR, SD, or Non-CR/ Non-PD for at 
least 24 weeks determined by ICR as per RECIST 1.1, from 
the date of randomization to the date of end of treatment.  
To evaluate the duration of response in the 2 treatment arms.  
Duration of response is defined as the time from 
first documented evidence of CR or PR until progressive 
disease (PD) as determined by ICR as per RECIST 1.1 or 
death from any cause, whichever occurs first.  
To evaluate the PFS according to the estrogen receptor 1 
gene (ESR1) mutation status in the 2 treatment arms.  
Progression-free survival as per ESR1 status determined at 
Cycle 1 Day 1.   
To evaluate the pharmacokinetics of amcenestrant as single 
agent. 
Amcenestrant plasma concentrations during the treatment 
period.  
To evaluate health-related quality of life in the 2 treatment 
arms.  
Disease-specific and generic health-related quality of life, 
disease and treatment-related symptoms, health state utility, 
and health status will be evaluated using the European 
Organisation for Research and Treatment of Cancer 
(EORTC) core quality of life questionnaire (QLQ-C30), the 
EORTC QLQ breast cancer specific module (BR23) and the 
EuroQoL questionnaire with 5◦dimensions and 5 levels per 
dimension (EQ-5D-5L), from Cycle 1 Day 1 until 90 days after 
last dose of the study treatment.  
To evaluate the overall safety profile in the 2 treatment arms.  
Adverse events/serious adverse events and laboratory 
abnormalities.  
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For China, please see Section 10.8 for details. 
Overall design: 
This is an international, prospective, open-label, Phase 2 randomized study. Men, postmenopausal 
women and premenopausal women on a gonadotropin-releasing hormone analog with locally 
advanced or metastatic breast cancer will be randomly (1:1) assigned to one of the following 
treatment arms: amcenestrant or an endocrine monotherapy of the choice of the physician.  
The population will be stratified according to the presence of visceral metastasis (defined by at 
least 1 liver or lung metastasis) (Yes or No), prior treatment with CDK4/6 inhibitors (Yes or No), 
and Eastern Cooperative Oncology Group status (0 or 1). 
Number of participants: 
Overall, 282 participants will be randomly assigned to study intervention with a balanced 
randomization ratio (141 participants randomized per treatment arm) in the global part of the 
study. The number of participants naïve to CDK4/6 inhibitors should not be higher than 20% of 
the overall sample size. 
After completion of randomization in the global part of the study (ie, all countries/sites including 
China), randomization will continue in China only until approximately 90 Chinese participants 
(including Chinese participants from the global part) are randomized.  
Intervention groups and duration: 
Participants will be treated (starting at a maximum of 3 days after randomization) with either 
amcenestrant or a single endocrine therapy of choice of the physician, depending on the 
randomization allocation. The potential control treatment should be selected in accordance with 
the Investigator’s best clinical judgment before randomization. Study treatment may continue 
until precluded by unacceptable toxicity, disease progression, upon participant’s request to stop 
treatment, or Investigator decision whichever occurs first.  
Study intervention(s) 
Investigational medicinal products (IMP) 
Amcenestrant: 
• 
Formulation: 100 mg capsules 
• 
Route(s) of administration: PO 
• 
Dose regimen: 4 capsules QD, given in the morning, regardless of food status. Capsules 
should be taken approximately at the same time every day (±3 hours). A cycle is 
artificially defined as a 4-week period. 
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Control: 
Only 1 of the following single agent control treatments is allowed per participant randomized to 
the control arm. The treatment will be selected before randomization in accordance with the 
Investigator’s best clinical judgment: 
• 
Fulvestrant (Faslodex®): 
- 
Formulation: 50 mg/mL injection for IM administration 
- 
Route(s) of administration: IM 
- 
Dose regimen: 500 mg IM as two 250-mg (5 mL) injections, 1 injection in each 
buttock (gluteal area), on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day cycle 
thereafter. 
• 
Or AIs (a cycle is artificially defined as 4-week period): 
- 
Formulation: in accordance with the approved label 
- 
Route of administration: PO 
- 
Dose Regimen:  
- 
Anastrozole 1 mg QD, to be taken approximately at the same time every day, 
regardless of food status 
- 
Letrozole 2.5 mg QD, to be taken approximately at the same time every day, 
regardless of food status 
- 
Exemestane 25 mg QD to be taken approximately at the same time every day after 
a meal. 
• 
Or Selective estrogen receptor modulator (a cycle is artificially defined as 4-week period): 
Tamoxifen: 
- 
Formulation: in accordance with the approved label 
- 
Route of administration: PO 
- 
Dose regimen: 20 mg/day to be taken QD or twice a day, approximately at the same 
time every day, regardless of food status. 
Statistical considerations: 
Sample size determination 
Global population 
In the global part of the study, a total of 201 progression-free survival (PFS) events assessed by 
independent central review (ICR) will be needed to detect a hazard ratio (HR) of 0.65 using a 
logrank test at the one-sided level of 2.5% and approximately 85% power. Assuming proportional 
hazards under exponential model and based on an anticipated median PFS time of 4.5 months in 
the control arm, this is expected to correspond to a median PFS of 6.9 months in the amcenestrant 
arm. In the global part of the study, based on an expected accrual rate 23.5 participants per month, 
accomplished over a period of about 12 months, and an annual dropout rate of 10%, a total of 
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282 participants are expected to be randomized in a 1:1 ratio into the amcenestrant arm and the 
control arm. The sample size calculation considers 1 futility interim analysis at 50% of the 
planned number of events. Under this current assumption, the cut-off date (COD) for final PFS is 
approximately 18 months after first participant randomized. 
Chinese population 
Chinese participants from the global part of the study and from the China extension part will be 
pooled for the purpose of the analysis of the Chinese population. Approximately 90 Chinese 
participants would need to be enrolled to reach 65 PFS events. 
Analysis populations: 
Enrolled population: All participants who sign the informed consent form.  
Intent-to-treat (ITT) population: All participants from the enrolled population and for whom there 
is a confirmation of successful allocation of a randomization number by Interactive Response 
Technology (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 randomly assigned to study intervention 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.  
Pharmacokinetic-evaluable population: All participants from the safety population who receive at 
least 1 dose of amcenestrant and with at least 1 evaluable plasma concentration post-treatment. 
Chinese participant populations will be defined for the efficacy and safety analyses in the China 
extension study.  
Primary analysis 
Primary analysis will consist of PFS comparison between the amcenestrant arm and the control 
arm through a logrank test procedure stratified by the stratification factors as entered in the IRT. 
A one-sided Type I error rate of 2.5% will be used for statistical testing. 
The analysis of PFS will be based on the following censoring rules: 
• 
If progression and death are not observed before the COD for final PFS, PFS will be 
censored at the date of the last valid disease assessment with no evidence of a disease 
progression prior to the initiation of a further anticancer therapy (if any). 
• 
A participant without an event (death or disease progression) and without any valid 
postbaseline disease assessments will be censored at the day of randomization (Day 1). 
• 
A participant with an event documented after two or more non-evaluable tumor 
assessments will be censored at the date of the last evaluable tumor assessment 
documenting no progression prior to the initiation of a further anticancer therapy. 
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The COD for final PFS analysis will be the date when approximately 201 PFS events assessed by 
ICR have been observed or when all participants from the global cohort have been followed-up 
for at least 10 months (or discontinued treatment), whichever is earlier. 
The HR estimates and corresponding 95% two-sided 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 median PFS and probabilities of being progression-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 PFS curves will also be provided. 
Sensitivity analyses of PFS will be performed (eg, different censoring rules and PFS assessed by 
the Investigator). Subgroup analyses of PFS will also be conducted as specified in the statistical 
analysis plan finalized before database lock. 
Analysis of key secondary efficacy endpoint 
Overall survival (OS) will be evaluated as a key secondary efficacy endpoint. In the absence of 
observation of death, survival time will be censored to the last date the participant is known to be 
alive. 
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 OS 
will be performed only if the primary analysis of the PFS is statistically significant.  
In case of statistically significant PFS, OS will be compared between treatment arms through a 
logrank test procedure stratified by the stratification factors as entered in the IRT. Otherwise, 
descriptive statistics of OS will be provided at the time of final PFS analysis. 
The COD for final OS analysis will be the date when approximately 196 death events have been 
observed (approximately 70% of the participants have died).  
Analysis of secondary efficacy endpoints 
Except for overall survival (OS), secondary endpoints will be analyzed at the time of the PFS 
analysis only. For these secondary endpoints, no formal statistical testing will be performed. The 
primary analysis will be based on ICR assessment and a sensitivity assessment will be based on 
the Investigator assessment. 
Objective response rate (ORR) will be summarized for the ITT population based on ICR 
assessment with descriptive statistics by treatment arm. The 95% two-sided CIs will be computed 
using the Clopper-Pearson method. 
The disease control rate and clinical benefit rate will be summarized for the ITT population with 
descriptive statistics by treatment arm. The 95% two-sided CIs will be computed using the 
Clopper-Pearson method. Similar analyses will be performed for the ITT population with 
measurable disease at study entry. Of note, the best overall response for each participant will also 
be summarized by treatment arm. 
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For the following time-to-event endpoints, similar methods to those described for the PFS will be 
used with the exception that no statistical test will be performed: 
• 
Duration of response will be summarized for the ITT population for participants who have 
achieved a confirmed partial response or complete response as best overall response with 
descriptive statistics by treatment arm. For participants with ongoing response at the time 
of the analysis, duration of response will be censored at the date of the last valid disease 
assessment not showing disease progression performed before the initiation of a new 
anticancer treatment (if any). Similar analyses will be performed for the ITT with 
measurable disease at study entry. 
• 
Progression-free survival by estrogen receptor 1 gene mutation status will be analyzed 
with similar methods to the PFS, with the exception that no statistical test will be 
performed. 
Description and analysis of patient reported outcomes (PRO) endpoints 
Analysis of the PRO endpoints will be based on participants from the safety population who have 
completed the baseline and at least 1 postbaseline assessment. 
The PRO analysis will be conducted on the European Organisation for Research and Treatment of 
Cancer (EORTC) core quality of life questionnaire (QLQ-C30), the breast cancer specific module 
(QLQ-BR23), and the EuroQoL questionnaire with 5 dimensions and 5 levels per dimension 
(EQ-5D-5L). For each treatment group and at each time point, the number and percentage of 
participants who completed these instruments will be summarized, as well as the reasons for 
non-completion of these measures. 
For the QLQ-C30 (15 total scales), QLQ-BR23 (8 scales), and EQ-5D-5L (health index and visual 
analogue scale) instruments, descriptive statistics on the absolute value and changes from baseline 
will be done for each treatment arm at each time point, at end of treatment (EOT) and 90 days 
after the last study administration (follow-up). Between treatment comparisons of the change from 
baseline over time will be provided for the QLQ-C30 (15 total scales), QLQ-BR23 (8 scales), and 
EQ-5D-5L (health index and visual analogue scale).  
Analysis of safety endpoints 
The observation period will be divided into 3 segments:  
• 
The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• 
The on-treatment period is defined as the time from the first dose of IMP up to 30 days 
after the last dose of IMP.  
• 
The post-treatment period is defined as the time starting 31 days after the last dose of IMP 
to study closure.  
Number and percentage of participants experiencing treatment-emergent adverse events (TEAEs) 
by Medical Dictionary for Regulatory Activities primary system organ class and preferred term 
will be summarized by National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) v5.0 grade (all grades and Grade ≥3) for the safety population. Similar 
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summaries will be prepared for treatment-related TEAEs, TEAEs leading to definitive 
discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
adverse events (AEs) of special interest, and AEs/serious AEs (SAEs) occurring during the 
post-treatment period. For participants with multiple occurrences of the same AE within the 
treatment period, the worst grade will be used.  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the treatment period will be provided for the 
safety population. 
Interim analysis 
An interim analysis is planned based on the primary PFS endpoint at 50% of the planned total 
number of PFS events (ie, approximately 101 PFS events). The interim analysis of PFS will be 
performed for futility without possible claim for overwhelming evidence of efficacy (therefore, no 
Type I error rate adjustment will be performed). The stopping boundary for futility is based on the 
observed HR based on Cox proportional hazard model, ie, an HR>1.1.   
Comparison between treatment arms on the OS will be performed only if the primary analysis of 
the PFS is statistically significant. Therefore, a maximum of 2 analyses are planned for OS: at the 
time of the primary analysis of PFS and at the final OS analysis. A gamma error spending 
function (γ = -8) will be used along with the hierarchical testing strategy to strongly control the 
Family Wise Error Rate (overall Type I error rate). If the value of the test statistic exceeds the 
efficacy boundary (z ≤-3.716, p ≤0.0001), superiority of OS will be claimed but survival data will 
continue to be collected until the end of study when approximately 196 death events have been 
observed. 
Planned cutoff date for the global study 
Estimated COD will be approximately 18 months after first randomized participant for the PFS 
analysis. No pharmacokinetic sample will be taken after Cycle 6 or COD for final PFS, whichever 
comes first. After COD for final PFS analysis, no more efficacy assessments will be performed 
except collection of survival status (not applicable to Chinese participants for whom the efficacy 
assessment would continue until the planned COD for China). The COD for the final analysis of 
OS will be approximately 46 months after the PFS analysis, when approximately 196 death events 
have been observed. If a participant treated continues to benefit from the treatment after the COD 
for OS analysis, the participant may continue until treatment is precluded by toxicity, progression, 
upon participant’s request to stop treatment, or Investigator decision. For cycles completed after 
the COD for final PFS analysis for the main cohort, only all ongoing SAEs (related or not), all 
related nonserious AEs ongoing at the COD, and all new serious or related AEs occurring 
post-COD and associated concomitant medication, as well as IMP administrations and reason for 
EOT will continue to be collected. 
Planned cutoff date for the Chinese participants 
Assuming that the first Chinese participant is planned to be enrolled 11 months after the first 
randomized participant of the global part and a 17-month enrollment period for Chinese 
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participants, the estimated China COD will be approximately 5 months after last Chinese 
participant enrolled.  
Data Monitoring Committee: Yes 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Note: For the China extension study, refer to Section 10.8. 
C = Cycle; D = day; IM = intramuscular; IMP = investigational medicinal product; OS = overall survival; PD = progressive disease; 
PFS = progression-free survival; R = randomization. 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Inclusion/exclusion 
criteria/informed 
consent 
X 
 
 
 
 
 
Section 5.1 
Section 5.2 
Section 8 
Randomization 
X 
 
 
 
 
 
Participants will be randomized within 
3 days prior to first dosing (C1D1) 
Section 6.3  
Demography, 
medical/surgical 
and disease history 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Section 8.2.1 
ECOG performance 
status/body weight 
X 
X 
X 
X 
X 
 
Section 8.2.1 
Vital signs, physical 
examination/signs 
and symptoms 
X 
Xa 
X 
X 
X 
 
a In C1D1, vital signs will also be 
assessed approximately 2 hours after 
dosing 
Section 8.2.1 
Hematology 
X 
 
X 
X 
X 
 
Section 8 
Section 10.2 (Appendix 2) 
Coagulation  
X 
 
 
 
 
 
Section 8 
Section 10.2 (Appendix 2) 
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Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Follicle-stimulating 
hormone and 
estradiol 
(premenopausal 
women only) 
X 
 
 
Xa 
Xa 
 
a For patients receiving Fulvestrant as 
IMP, the local estradiol sample will not 
be required 
Section 10.2 (Appendix 2) 
Pregnancy test 
(WOCBP only) - 
Local labs 
xa 
 
 
xb 
xb 
 
a Serum pregnancy test (β-hCG) to be 
done before starting study treatment. 
b Urine pregnancy test (dipstick) to be 
done on D1 of each cycle, and at EOT 
Section 10.2 (Appendix 2) 
Urine pregnancy test must have a 
sensitivity of at least 25 mIU/mL 
Clinical chemistry 
X 
 
X 
X 
X 
 
Section 8 
Section 10.2 (Appendix 2) 
12-lead ECG 
X 
 
 
Xa 
X 
 
a Cycle 2 Day 1 only. On C2D1, ECG 
will be measured at least 1 hour after 
study treatment administration. 
Section 8.2.3 
Urinalysis (dipstick) 
X 
 
 
 
X 
 
Section 8 
Section 10.2 (Appendix 2) 
Control arm 
physician’s choice: 
fulvestrant 
administration  
 
X 
X 
X 
 
 
Section 6.1 
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Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Control arm 
Physician’s choice: 
oral endocrine 
therapy  
 
Continuous once daily 
 
 
Section 6.1 
Amcenestrant 
administration 
 
Continuous once daily 
 
 
Section 6.1 
Concomitant 
medications 
Continuous throughout study period  
Section 6.5 
AE review 
Continuous throughout study period  
Section 8.3 
Tumor assessments 
X 
 
 
Xa 
 Xb 
Xc 
a Every 8 weeks after randomization, 
±7 days or when clinically indicated  
b If not done at the immediate previous 
cycle  
c If no radiological PD at last tumor 
assessment during the treatment 
period, disease assessment will 
continue to be performed every 
8 weeks ±7 days (projected from last 
tumor assessment) up to PD  
Section 8.1.1 
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Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Bone scans 
X 
 
 
Xa 
 
 
a If at screening, lesions are detected in 
the bone scan but not in the CT/MRI 
(RECIST 1.1) scan, further bone 
scans should be conducted every 
8 weeks ±7 days after randomization. 
If the lesions seen in the bone scan 
are no longer visible, these 
assessments should be conducted 
every 16 weeks ±7 days after 
randomization. 
If lesions are detected in the bone 
scan and CT/MRI (RECIST 1.1) scan, 
further bone scan assessments will be 
conducted every 16 weeks ±7 days 
after randomization. 
Section 8.1.2 
Further anticancer 
therapy 
 
 
 
 
 
X 
Section 6.7 
Survival 
assessment 
 
 
 
 
 
X 
 
QLQ-C30, 
QLQ-BR23, and 
EQ-5D-5L 
 
X 
 
Xa 
X 
Xb 
a Every cycle from Cycle 1 to Cycle 4 
and every 2 cycles thereafter 
b First follow-up visit only 
Section 8.1.3 
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Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Amcenestrant PK 
assessment 
 
Xa 
Xb 
Xc 
 
 
a Postdose time windows: 1.5 h ±0.5 h; 
4 h ±1 h 
b Predose 
c Cycle 2 Day 1:  
Predose 
Postdose time windows: 1.5 h ±0.5 h; 
4 h ±1 h; 8 h ±1 h  
Cycles 3, 4, and 6:  
Day 1: predose 
No PK sample will be taken after Cycle 6 
or PFS cut-off date, whichever comes 
first 
Section 8.5 
Tumor specimen/ 
biopsy (optional 
procedures)  
Xa 
 
Xb 
 
 
a Most recent archived biopsied tumor 
within past 3 months prior to initiation 
of study treatment, or fresh tumor 
biopsy collected from time of inclusion 
to C1D1 pre-treatment (optional) 
b Cycle 3 Day 1 (allowed up to Cycle 3 
Day 15 or within 14 days after first 
radiological tumor assessment after 
baseline). Tumor biopsy should be 
performed only after radiological 
assessment (optional) 
Section 8.6 
ESR1 analysis of 
cfDNA (plasma)  
 
X 
 
Xa 
 
 
a Cycle 3 Day 1 
Section 8.7.1 
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Procedure 
Screening  
(up to 28 days 
before 
randomization) 
Treatment Cycle 1 
Subsequent 
cycles 
EOT 
Follow-up (±5)  
(every 2 months) 
Notes 
D1 
D15 (±2) 
D1 (±2) 
D30 (±5)  
(after last study 
treatment 
administration) 
Mutation profiling in 
cfDNA (plasma)  
 
X 
 
 
X 
 
Section 8.7.2 
Normal tissue 
reference DNA 
(saliva)  
 
X 
 
 
 
 
Section 8.7.2 and Section 10.15.5 
Estradiol (serum) 
 
Xa 
 
Xb 
 
 
a Predose Cycle 1 Day 1 
b Cycle 3 Day 1 
Section 8.6.2 
Genetic sample 
(DMET genotyping) 
 
 
 
 
X 
 
 
 
 
Sample collected in amcenestrant 
treatment arm only  
Section 8.7.4 
C = cycle; cfDNA = cell-free deoxyribonucleic acid; CT = computed tomography; DMET = drug metabolizing enzymes and transporters; DNA = deoxyribonucleic acid; D = day; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; EQ-5D-5L = EuroQoL questionnaire with 5 dimensions and 5 levels per dimension; ESR1 = estrogen receptor 1 gene; MRI = magnetic 
resonance imaging; PFS = progression-free survival; PK = pharmacokinetics; QLQ-BR23 = EORTC QLQ breast cancer specific module; QLQ-C30 = EORTC core quality of life questionnaire; WOCBP = women of 
childbearing potential
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2 
INTRODUCTION  
Amcenestrant is a potent, orally bioavailable, and selective estrogen receptor (ER) inhibitor that 
belongs to the selective ER degrader (SERD) class of compounds. amcenestrant antagonizes the 
binding of estradiol to ER and promotes the transition of ER to an inactive conformation that 
leads to up to 98% receptor degradation at nanomolar concentrations in cellular assays (1). These 
dual properties of amcenestrant translate in a deeper inhibition of ER pathways and a more 
effective antiproliferative activity in ER-dependent breast cancer cell lines driven by mutant or 
wild type ER compared to fulvestrant. 
In locally advanced/metastatic breast cancer patients who progress after 1 or more lines of 
hormonal therapy, the current choice of further single agent treatment is mainly represented by 
3 classes of compounds: 
• 
Selective ER degraders: Fulvestrant (Faslodex®) is a potent approved SERD that binds 
and degrades ER. Recent data with fulvestrant administered 500 mg monthly to 
participants with recurrent hormone receptor-positive/human epidermal growth factor 
receptor 2 (HER2) negative breast cancer indicate significant antitumor activity in first 
line therapy, as well as after both antiestrogen and aromatase inhibitor (AI) failure. 
Fulvestrant is currently indicated for the treatment of postmenopausal women with 
metastatic hormone receptor-positive breast cancer: 
- 
Who have not previously been treated with endocrine therapy as monotherapy 
- 
Following the failure of endocrine therapy, as monotherapy and in combination with 
palbociclib or abemaciclib  
- 
For the first line treatment in combination with anastrozole. 
• 
Selective ER modulators (SERM) (tamoxifen): SERMs are cytostatic agents that 
competitively bind to ER in tumor cells and breast tissue, producing receptor dimerization 
and a nuclear complex that decreases deoxyribonucleic acid (DNA) synthesis and inhibits 
estrogenic effects. There are multiple approved indications for tamoxifen in breast cancer: 
- 
Adjuvant treatment of early stage ER-positive breast cancer 
- 
Treatment of ER-positive metastatic breast cancer 
- 
Treatment of women with ductal carcinoma in situ following breast surgery and 
radiation, to reduce the risk of invasive breast cancer 
- 
Treatment of hormone receptor-positive, HER2-negative metastatic breast cancer in 
postmenopausal women with secondary AI resistance, in combination with everolimus 
- 
Adjuvant treatment of breast cancer, to reduce the occurrence of contralateral breast 
cancer 
- 
Breast cancer prophylaxis in women who are at high risk for developing breast cancer. 
• 
Aromatase inhibitors (exemestane, anastrozole, and letrozole): Aromatase is a cytochrome 
P450 (CYP) enzyme involved in the synthesis of estrogen. Therefore, AIs function as 
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antiestrogens by decreasing the biosynthesis of estrogen from androgens, the primary 
estrogen biosynthesis pathway in postmenopausal women. There are 2 categories of AIs: 
the steroidal inhibitor exemestane and nonsteroidal inhibitors such as anastrozole and 
letrozole. Exemestane, a type 1 steroidal AI, binds irreversibly to aromatase, causing 
permanent inactivation of the enzyme even after the drug is cleared from circulation. 
Nonsteroidal (type 2) AIs, such as anastrozole and letrozole, bind reversibly to aromatase, 
thereby inhibiting the synthesis of estrogen. 
Exemestane is approved for the following indications:  
- 
Treatment of advanced breast cancer in postmenopausal women whose disease has 
progressed following tamoxifen therapy 
- 
Adjuvant treatment of ER-positive early breast cancer in postmenopausal women who 
have already received 2 to 3 years of tamoxifen therapy, and who are switched to 
exemestane for completion of a total of 5 consecutive years of adjuvant hormonal 
therapy 
- 
Treatment of ER-positive, HER2-negative, locally advanced or metastatic breast 
cancer in postmenopausal women refractory to letrozole or anastrozole, in combination 
with everolimus. 
Letrozole is approved for the following indications: 
- 
Adjuvant treatment of postmenopausal women with hormone receptor-positive early 
breast cancer 
- 
Extended adjuvant treatment of early breast cancer in postmenopausal women who 
have received 5 years of adjuvant tamoxifen therapy 
- 
First line treatment of postmenopausal women with hormone receptor-positive or 
hormone receptor status unknown, locally advanced or metastatic breast cancer 
- 
Treatment of advanced breast cancer in postmenopausal women with disease 
progression following antiestrogen therapy. 
- 
Neoadjuvant treatment of postmenopausal women with hormone receptor-positive, 
HER2-negative breast cancer where chemotherapy is not suitable and immediate 
surgery not indicated (European Union only). 
Anastrozole is approved for the following indications: 
- 
Adjuvant treatment of postmenopausal women with hormone receptor-positive early 
breast cancer 
- 
Adjuvant treatment of ER-positive early breast cancer in postmenopausal women who 
have received 2 to 3 years of tamoxifen therapy to complete a total of 5 consecutive 
years of adjuvant hormonal therapy 
- 
First line treatment of hormone receptor-positive or hormone receptor status unknown, 
locally advanced or metastatic breast cancer in postmenopausal women 
- 
In postmenopausal women with disease progression following tamoxifen therapy 
- 
First line treatment of hormone receptor-positive metastatic breast cancer in 
postmenopausal women, in combination with fulvestrant. 
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In prospective comparative studies conducted with fulvestrant monotherapy in postmenopausal 
women with breast cancer after progression to hormonal therapy and/or chemotherapy, time to 
progression (TTP)/progression-free survival (PFS) was between 3.5 and 5 months in the 
fulvestrant single agent arm. In a recent study comparing fulvestrant 500 mg combined with 
palbociclib with fulvestrant 500 mg alone in 521 participants, median PFS was 9.5 months (95% 
confidence interval [CI)]9.2 to 11.0) in the fulvestrant plus palbociclib group and 4.6 months (3.5 
to 5.6) in the fulvestrant plus placebo group (hazard ratio [HR] = 0.46, 95% CI 0.36-0.59, 
p<0.0001) (2). In a Phase 2 study conducted in 131 participants of fulvestrant 500 mg combined 
with everolimus versus fulvestrant, the PFS was 5.1 months for fulvestrant single agent (3). In a 
Phase 3 study, fulvestrant given at 500 mg intramuscularly (IM) on Day 0, 250 mg on Days 14, 
28, and 250 mg every 28 days thereafter was compared to exemestane 25 mg per os (PO) in 
693 women; median TTP was 3.7 months in both groups (4). 
In prospective comparative studies conducted with AIs in postmenopausal women with breast 
cancer after progression to hormonal therapy and/or chemotherapy, TTP/ PFS was about 
4.1 months in the exemestane single agent arm (5, 6). A comparative study including 3 arms 
(fulvestrant, fulvestrant combined with anastrozole, and exemestane) was conducted in 723 breast 
cancer patients who failed after prior hormonal therapy. The median PFS was of 3.4 months, 
4.8 months and 4.4 months, respectively (7). 
Finally, in metastatic breast cancer patients who progressed after 1 or 2 lines of hormonal therapy 
and who received a further hormonal single agent therapy, the efficacy results indicate a PFS of 
3.4 to 5.1 months and this result is consistent across studies. 
2.1 
STUDY RATIONALE  
The objective of this study is to compare the efficacy, safety, and pharmacodynamic (PDy) 
characteristics of amcenestrant and an endocrine monotherapy of the choice of the physician (AIs, 
tamoxifen, or fulvestrant) in participants with locally advanced/metastatic breast cancer who have 
failed to other hormonal therapies/chemotherapy. This condition represents an unmet need in this 
patient population and amcenestrant may represent a new therapeutic option expected to have a 
better risk/benefit ratio than approved endocrine monotherapy. 
The first in human (FIH) study with amcenestrant, TED14856, started in November 2017. This 
study was designed in several parts and includes ER-positive, HER2-negative, postmenopausal 
women presenting with measurable locally advanced/metastatic breast cancer who progressed 
after several therapies including hormonal as well as chemotherapies.  
Part A is a dose escalation phase evaluating several dose levels from 20 mg to 600 mg in a once 
daily (QD) regimen, with 3 evaluable participants planned per dose, with the aim of assessing 
safety (including dose-limiting toxicities), pharmacokinetics (PK), and PDy, and defining the 
recommended dose as single agent. Part B is an expansion phase of amcenestrant single agent in 
the same population. Part C is a dose escalation of amcenestrant in combination with palbociclib 
followed by Part D, an expansion phase with this combination. 
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As of 29 May 2019, a total of 16 postmenopausal participants presenting with locally 
advanced/metastatic breast cancer participated in the dose escalation (Part A) of the study. 
Participants were enrolled at 20 mg (3 participants), 150 mg (3 participants), 200 mg 
(4 participants), 400 mg (3 participants), and 600 mg (3 participants). In addition, 48 participants 
started the treatment in the expansion cohort (Part B). Dose escalation of amcenestrant QD in 
combination with palbociclib (Part C) started in January 2019 and is ongoing with amcenestrant 
200 mg and 400 mg QD, with 6 participants recruited so far. A total of 8 participants discontinued 
the study treatment due to progressive disease (PD) and 8 are currently in the treatment.  
From the TED14856 FIH study, analyses of heavily pretreated postmenopausal women presenting 
with metastatic breast cancers showed promising activity. A total of 16 participants treated with 
amcenestrant from 20 to 600 mg daily dose were part of the dose escalation phase. No 
dose-limiting toxicity was observed at all dose levels. amcenestrant was considered well tolerated 
with adverse events (AEs) generally of low grade. The results of 18fluoroestradiol 
(18FES)-positron emission tomography (PET) scans indicate an almost 90% or more occupancy of 
ER receptors by amcenestrant was reached from 150 mg. Pharmacokinetics of amcenestrant 
indicated limited accumulation and dose proportional increase of exposure up to 400 mg after 
repeated administration while limited gain at 600 mg. The impact of food is minimal, and the 
compound can be administered with or without food. The average plasma concentration observed 
before treatment administration (Ctrough) reached after repeated 400 mg QD was around 4 times 
above threshold concentration allowing 90% of signal inhibition at 18FES-PET scans. Taking into 
account all these parameters, the 400 mg dose level is considered as the recommended dose for 
the expansion cohort and will be explored in dose escalation combination with palbociclib of 
TED14856. 
Inhibition and down-regulation of ER are considered as pre-requisites for SERD compounds to be 
effective as well as to maintain the control of the disease. Amcenestrant and fulvestrant share the 
same mechanism of action. However, to optimize the beneficial effect, a 24-hour saturation of the 
receptor is expected for almost all participants, and significant residual ER availability has been 
observed during fulvestrant therapy in 38% of patients only, using 18FES-PET (8). Available PDy 
data indicate that with amcenestrant, high levels of inhibition of the signal were observed starting 
from the 150 mg dose level and up: 100% inhibition at this dose level and more than 87% in all 
other patients treated at further dose levels. Another point of differentiation of amcenestrant 
versus fulvestrant is its ability to be given PO compared to IM injection. This may have a 
substantial impact on the quality of life of the participants: the participants will be prescribed 
capsules and have a daily intake at home, not needing to go to their hospital/physicians to get their 
monthly injection. Another advantage of the PO route is its suitability for a subgroup of 
participants receiving anticoagulant therapy for whom IM injections are a risk, even if fulvestrant 
is carefully administered. 
2.2 
BACKGROUND  
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer 
death in women (9). In the United States, in 2019, a total of 268 600 new cases of invasive breast 
cancer as well as 62 930 additional cases of in situ breast cancer are estimated. From 2006 to 
2015, invasive female breast cancer incidence rates increased slightly, by 0.4% per year. 
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Approximately 41 760 women are expected to die from breast cancer in 2019. In men, 2670 new 
cases of invasive breast and 500 deaths were estimated in the United States, in 2019 (10).  
Both endogenous and exogenous steroid hormones such as estrogen and progesterone have been 
implicated in the pathogenesis of breast cancer. Clinical treatment decisions are driven by the 
expression of ERs, progesterone receptors (PgRs), and HER2 receptor status into HER2-positive, 
ER-positive/HER2-negative and triple negative clinical subtypes (10). About 75% of breast 
cancers express ER alpha, a hormone regulator transcription factor (11). Estrogen 
receptor-positive breast cancers respond well to therapy targeting ER signaling either through 
competitive binding of ER antagonists, such as tamoxifen, or by blocking the production of 
estrogen by AIs (12). 
According to the National Comprehensive Cancer Network guidelines (Version 1, 2020), 
sequential hormonal therapy (alone or in combination) is the standard of care in the metastatic 
breast cancer setting for ER-positive and HER2-negative participants without rapidly progressing 
visceral or symptomatic metastases. Common classes of drugs used after progression of hormonal 
treatment for this purpose include SERMs (eg, tamoxifen), AIs (eg, letrozole, anastrozole, or 
exemestane), and SERDs (fulvestrant). Because few men have been historically included in breast 
cancer clinical trials, recommendations regarding management of breast cancer in men are 
generally extrapolated from findings in clinical trials focusing on breast cancer in women.  
Unfortunately, not all participants respond to first line hormonal therapy, instead presenting 
primary or de novo resistance. Moreover, some participants who initially respond subsequently 
present breast cancer progression (acquired resistance). Resistance to endocrine therapies is 
frequent but relapsed tumors remain dependent on ER, which is highlighted by patient responses 
to second- and third-line endocrine therapies after failure of an earlier line of hormonal therapy. 
Estrogen receptor alpha signaling reactivation can occur due to changes in ligand sensitivity and 
specificity or by new mutations of estrogen receptor 1 gene (ESR1) (13). Estrogen receptor 1 gene 
mutation was recently evaluated in clinical studies with a high prevalence (25% to 40%) reported 
in relapse participants after AI therapy and limited benefit with current monotherapy (14). The 
continued dependence of breast cancer tumors on ERs provides a strong rationale to continue 
targeting ERs in both first line and relapsed/advanced settings. 
Selective ER degraders are competitive ER antagonists that also induce conformational changes 
that degrade ERs via a ubiquitin-proteasome system (15). This unique dual-function of SERDs 
may enable them to block ER signaling in cellular settings where other endocrine agents, such as 
tamoxifen or AIs, have failed. The clinical effect of fulvestrant as a treatment for recurrent 
endocrine-resistant disease supports this matter. Although fulvestrant has served as an important 
proof of concept for the SERD approach, this therapy is limited by its poor pharmaceutical 
properties which require IM administration and limit the applied dose, exposure, and receptor 
engagement (16, 17). The fulvestrant 500 mg regimen (500 mg on Days 1, 15, 29; monthly 
thereafter) exhibited improvement in PFS and overall survival (OS) over the initially marketed 
250 mg dose (18). However, the fulvestrant 500 mg dose does not fully saturate ER binding in 
participants, as the inhibition of 18FES-PET scan uptake was incomplete in 38% (6/16) of 
participants. This lack of receptor occupancy was associated with lack of clinical benefit (17, 19).  
These data demonstrate that SERDs have the potential to provide effective and well-tolerated 
therapy for postmenopausal women with advanced breast cancer and highlight the need for the 
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development of new SERD compounds with optimized characteristics: improved route of 
administration (PO versus IM), bioavailability, and long-term maintenance of ER receptor 
blockade combined with a strong antitumor activity. It would also be important to further 
understand the potential benefit and safety of SERDs in men with breast cancer, in alignment with 
the Food and Drug Administration draft guidance “Male Breast Cancer: Developing Drugs for 
Treatment”, which recommends the inclusion of both men and women in breast cancer clinical 
trials. 
2.3 
BENEFIT/RISK ASSESSMENT  
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of amcenestrant may be found in the Investigator’s Brochure (IB). Information on the 
selected control (endocrine therapy of choice of the physician) should be found in the approved 
package label. 
2.3.1 Benefits  
2.3.1.1 Amcenestrant  
Amcenestrant has been administered to humans since November 2017, in the FIH TED14856 
study. Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria in 16 participants; the best overall responses (BOR) have been partial 
response (PR) in 1 participant treated at 150 mg, stable disease (SD) in 8 participants, and PD in 
7 participants. Long-term SD (24 weeks or more) was seen in 7 participants so far. Clinical 
benefit (PR + SD ≥24 weeks) was therefore observed in 8 participants (29 May 2019). 
2.3.1.2 Fulvestrant  
Fulvestrant monotherapy is indicated for the treatment of ER-positive, locally advanced or 
metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy 
or with disease relapse or progression on or after antiestrogen therapy. 
Fulvestrant is also indicated in combination with palbociclib for treatment of hormone 
receptor-positive, HER2-negative, locally advanced or metastatic breast cancer in women who 
have received prior endocrine therapy. 
A Phase 3 randomized double-blind study comparing fulvestrant plus palbociclib with fulvestrant 
plus placebo was performed on 521 women with metastatic breast cancer, regardless of their 
menopausal status, whose disease progressed after prior endocrine therapy (2). Efficacy results for 
fulvestrant plus palbociclib and fulvestrant plus placebo included median PFS (9.5 and 
4.6 months, respectively), objective response (19.0% and 8.6%, respectively), and clinical benefit 
(66.6% and 39.7%, respectively). The results from this study give some information on the 
expected PFS with fulvestrant single treatment in a population who relapsed to 1 or more prior 
hormonal-content therapy. 
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2.3.1.3 Aromatase inhibitors  
2.3.1.3.1 Anastrozole  
In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of 
greater than 80%.  
Anastrozole was studied in 2 controlled studies (20) in postmenopausal women with advanced 
breast cancer with PD following tamoxifen therapy for either advanced or early breast cancer. A 
total of 764 patients were randomized to receive either anastrozole or megestrol acetate. In both 
studies, efficacy results (TTP, objective response rate [ORR]), prolonged SD, rate of progression, 
and OS were similar between treatments. 
2.3.1.3.2 Letrozole  
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the aromatase 
CYP, resulting in a reduction of estrogen biosynthesis in all tissues where present. In 
postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed 
plasma concentration of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline in all 
patients treated. With doses of 0.5 mg and higher, many values of estrone and estrone sulfate were 
below the limit of detection in the assays, indicating that higher estrogen suppression is achieved 
with these doses. 
Two letrozole doses (0.5 mg and 2.5 mg) were compared with megestrol acetate and with 
aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer 
previously treated with anti-estrogens (21, 22). Letrozole showed comparable efficacy compared 
with megestrol, with the 2.5 mg dose showing higher objective tumor response and time to 
treatment failure. Compared with aminoglutethimide, letrozole showed better TTP, time to 
treatment failure, and OS. 
2.3.1.3.3 Exemestane  
In postmenopausal women, exemestane significantly lowered serum estrogen concentrations 
starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10 to 25 mg. In 
postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body 
aromatization was reduced by 98%. 
In a randomized controlled clinical study, exemestane at the daily dose of 25 mg has demonstrated 
statistically significant prolongation of survival, TTP, and time to treatment failure as compared to 
a standard hormonal treatment with megestrol acetate in postmenopausal patients with advanced 
breast cancer that had progressed following, or during, treatment with tamoxifen either as 
adjuvant therapy or as first line treatment for advanced disease. 
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2.3.1.4 Selective estrogen receptor modulators  
2.3.1.4.1 Tamoxifen  
In breast cancer patients, at the tumor level, tamoxifen acts primarily as an anti-estrogen, 
preventing estrogen binding to the ER. Tamoxifen leads to reductions in levels of blood total 
cholesterol and low-density lipoproteins in postmenopausal women of the order of 10% to 20%. 
Tamoxifen does not adversely affect bone mineral density. 
2.3.2 Potential and identified risks  
2.3.2.1 amcenestrant  
Based on the nonclinical data available for amcenestrant and the safety profile observed in 
compounds of the same class approved and in development, the following are potential side 
effects and risks anticipated in humans: 
• 
Gastrointestinal toxicities, including anorexia, nausea, vomiting, diarrhea (and possibly 
dehydration and electrolyte imbalance in severe cases), and upper and/or lower abdominal 
pain. 
• 
Changes in liver function, including elevated liver enzymes and bilirubin. 
• 
Hematological toxicities potentially presenting with laboratory abnormalities (leukopenia, 
neutropenia, thrombocytopenia, anemia), infections, and neutropenic fever. 
• 
Effects in the female reproductive system (ovary, uterus, cervix, vagina, mammary glands). 
• 
Risk of male infertility. 
• 
Risk of photosensitivity. 
• 
Risk of severe rash. 
• 
Theoretical risk of osteoporosis, due to the mechanism of action of SAR439849, in case of 
long-term exposure. 
• 
Risk of drug-drug interaction: in vitro, amcenestrant is mainly metabolized by uridine 
5'-diphospho-glucuronosyltransferase (UGT) 1A1 and UGT1A4, and to a lesser extent by 
CYP enzymes (<20%) CYP2C8 and/or CYP3A. Therefore, drugs that are potential 
inhibitors of UGTs (ie, atazanavir and probenecid) should not be administered with 
amcenestrant, as well as drugs that are strong inducers of CYP3A, since they may also 
induce UGTs. In vitro studies results showed that amcenestrant has the potential to induce 
CYP3A4, and to a lesser extent CYP2B6, CYP2Cs, and UGTs. In vivo study result 
showed that amcenestrant is a moderate inducer of CYP3A. 
Preliminary safety results in humans from the FIH TED14856 study are as follows: as of 
29 May 2019, 16 participants have been treated in the dose escalation part at doses from 20 to 
600 mg (Part A) of TED14856 study, and 48 participants have been treated in the dose expansion 
part at the recommended dose of 400 mg (Part B). The safety was assessed in 16 participants in 
the dose escalation part of study. No dose-limiting toxicities were observed during Cycle 1 at any 
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tested dose levels. All of them presented with at least 1 treatment-emergent AE (TEAE), 
regardless of relationship. The most frequently reported TEAEs by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term (PT) were hot flush, diarrhea, constipation, and 
nausea in 6 participants, each (37.5%), decreased appetite in 5 participants (31.3%), asthenia and 
fatigue 4 participants, each (25.0%), hyperesthesia, night sweat, and arthralgia in 3 participants, 
each (18.8%). Updated safety information from July 2019 shows the following results regarding 
liver function tests (LFTs). Two of 16 participants from Part A of the TED14856 study developed 
treatment-emergent LFT abnormalities Grade ≥3. One participant (treated with amcenestrant 
200 mg) developed Grade 3 aspartate aminotransferase (AST) and alkaline phosphatase increase 
with Grade 1 alanine aminotransferase (ALT) increase and normal total bilirubin. Another 
participant (treated with amcenestrant 600 mg) developed Grade 4 AST and total bilirubin 
increase with Grade 3 ALT and alkaline phosphatase increase. Both participants had liver 
metastasis and Grade 1 AST increase at baseline. These LFT abnormalities were observed 
concomitantly with disease progression in the liver. 
Please see the last updated version of the IB for details. 
Details on dose selection are described in Section 4.3. 
2.3.2.2 Fulvestrant  
Risks associated with fulvestrant include bleeding, increased exposure in patients with hepatic 
impairment, injection site reactions, embryo-fetal toxicity, and falsely elevated estradiol levels 
due to fulvestrant interfering with estradiol measurement by immunoassay. 
The most common adverse reactions occurring in ≥10% of patients treated with fulvestrant 
monotherapy include: hypersensitivity reactions, hot flushes, nausea, elevated hepatic enzymes 
(ALT, AST, and alkaline phosphatase), rash, joint and musculoskeletal pain, asthenia, and 
injection site reactions. 
Refer to current local label for further reference safety information. 
2.3.2.3 Aromatase inhibitors  
2.3.2.3.1 Anastrozole  
Risks associated with anastrozole include reduction in bone mineral density, ischemic 
cardiovascular events, increase serum cholesterol, increased exposure in patients with hepatic 
impairment, and hypersensitivity reactions. Anastrozole is contraindicated in patients with 
hypersensitivity to the drug or any excipients (eg, lactose). 
The most common adverse reactions occurring in ≥10% of patients treated with anastrozole 
monotherapy include: vasodilation (hot flushes), asthenia, pain, arthritis, arthralgia, pharyngitis, 
depression, hypertension, nausea, rash, osteoporosis, back pain, fracture, headache, and accidental 
injury (23). 
Refer to current local label for further reference safety information. 
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2.3.2.3.2 Letrozole  
Risks associated with letrozole include reduction in bone mineral density, hypercholesterolemia, 
fatigue, dizziness, increased exposure (two-fold) in patients with cirrhosis and severe liver 
impairment. 
The most common adverse reaction occurring in ≥10% of patients treated with letrozole 
monotherapy (first line treatment in advance breast cancer) include: bone pain, hot flushes, 
dyspnea, back pain, nausea, arthralgia, cough, constipation, and pain in limb. 
The most common adverse reaction occurring in ≥10% of patients treated with letrozole 
monotherapy (second line treatment in advance breast cancer) include: musculoskeletal reaction 
(including musculoskeletal pain, skeletal pain, back pain, leg pain), and nausea.  
Refer to current local label for further reference safety information. 
2.3.2.3.3 Exemestane  
Risks associated with exemestane include reduction in bone mineral density. Exemestane is 
contraindicated in patients with hypersensitivity to the drug or any of excipients (glucose).  
The most common adverse reaction occurring in ≥10% of patients treated with exemestane 
monotherapy (advanced breast cancer) include: fatigue, nausea, hot flushes, pain, depression, 
insomnia, anxiety, and dyspnea.  
Refer to current local label for further reference safety information. 
2.3.2.4 Selective estrogen receptor modulators  
2.3.2.4.1 Tamoxifen  
Risks with tamoxifen include: increased incidence of endometrial changes (including hyperplasia, 
polyps, cancer, and uterine sarcoma), and venous thromboembolism. Tamoxifen is 
contraindicated in patients with galactose intolerance. 
The most common adverse reactions occurring in ≥10% of patients treated with tamoxifen 
monotherapy include: fluid retention, hot flushes, nausea, skin rash, vaginal bleeding, vaginal 
discharge, and fatigue.  
Note: The ATAC trial reports that the most common adverse reactions occurring in ≥10% of 
patients treated with tamoxifen monotherapy include: hot flushes, asthenia, pain, arthralgia, 
pharyngitis, rash, depression, hypertension, nausea, lymphoedema, arthralgia, back pain, 
accidental injury, and urinary tract infection (23). 
Refer to current local label for further reference safety information. 
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2.3.3 Conclusion  
Based on amcenestrant experience and the observed safety profile in the ongoing TED14856 
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 
ACT16105 study.  
Moreover, the clinical benefit is expected to be relevant in patients, as preclinical findings and 
clinical PDy 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 a single 
endocrine therapy of the choice of the physician. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To determine whether amcenestrant 400 mg per os 
improves progression-free survival (PFS) when compared 
with an endocrine monotherapy of the choice of the 
physician, in participants with metastatic or locally 
advanced breast cancer.  
Progression-free survival is defined as the time interval from the 
date of randomization to the date of first documented tumor 
progression as per Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) assessed by independent central review 
(ICR) or death (due to any cause), whichever comes first. 
Secondary 
To compare the overall survival in the 2 treatment arms.  
Overall survival is defined as the time interval from the date of 
randomization to the date of documented death (due to any 
cause). 
To assess the objective response rate in the 2 treatment 
arms.  
Objective response rate is defined as the proportion of 
participants who have a confirmed complete response (CR) or 
partial response (PR), as best overall response (BOR) derived 
from overall response determined by ICR as per RECIST 1.1, 
from the date of randomization to the date of end of treatment.  
To evaluate the disease control rate in the 2 treatment 
arms.  
Disease control rate is defined as the proportion of participants 
who have a confirmed CR, PR, stable disease (SD), or Non-CR/ 
Non-PD as BOR determined by ICR as per RECIST 1.1 from the 
date of randomization to the date of end of treatment.  
To evaluate the clinical benefit rate in the 2 treatment 
arms.  
Clinical benefit rate is defined as the proportion of participants 
who have a confirmed CR, PR, SD, or Non-CR/ Non-PD for at 
least 24 weeks determined by ICR as per RECIST 1.1, from the 
date of randomization to the date of end of treatment.  
To evaluate the duration of response in the 2 treatment 
arms.  
Duration of response is defined as the time from 
first documented evidence of CR or PR until progressive disease 
(PD) as determined by ICR as per RECIST 1.1 or death from 
any cause, whichever occurs first.  
To evaluate the PFS according to the estrogen receptor 1 
gene (ESR1) mutation status in the 2 treatment arms.  
Progression-free survival as per ESR1 status determined at 
Cycle 1 Day 1.   
To evaluate the pharmacokinetics of amcenestrant as 
single agent. 
Amcenestrant plasma concentrations during the treatment 
period.  
To evaluate health-related quality of life in the 2 treatment 
arms.  
Disease-specific and generic health-related quality of life, 
disease and treatment-related symptoms, health state utility, and 
health status will be evaluated using the European Organisation 
for Research and Treatment of Cancer (EORTC) core quality of 
life questionnaire (QLQ-C30), the EORTC QLQ breast cancer 
specific module (BR23) and the EuroQoL questionnaire with 
5◦dimensions and 5 levels per dimension (EQ-5D-5L), from 
Cycle 1 Day 1 until 90 days after last dose of the study 
treatment.  
To evaluate the overall safety profile in the 2 treatment 
arms.  
Adverse events/serious adverse events and laboratory 
abnormalities.  
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Objectives 
Endpoints 
Tertiary/exploratory 
To evaluate in participants the gene mutation profile of the 
tumor over time (baseline and end of treatment) by 
cell-free deoxyribonucleic acid (cfDNA) analysis, and ESR1 
mutation analysis (pre- and on-treatment) by cfDNA. 
The gene mutation profile of the tumor over time (Cycle 1 Day 1 
[pre-treatment] and end of treatment) by cfDNA analysis, and 
ESR1 mutation analysis by cfDNA analysis pre-treatment and at 
Cycle 3 Day 1. 
To evaluate in participants tumor biomarkers over time 
such as estrogen receptor (ER), Ki67, Bcl-2, and 
progesterone receptor (PgR) protein, and ribonucleic acid 
(RNA) gene expression profiles (for participants with tumor 
sites accessible for biopsy who accept biopsies at study 
entry and on treatment). 
Tumor ER, Ki67, Bcl-2, and PgR protein, and RNA gene 
expression profiles in optional paired biopsies at Cycle 1 Day 1 
(pre-treatment) and at Cycle 3, Day 1 (allowed up to Day 15; or 
within 14 days after first radiological tumor assessment after 
baseline). 
To explore pharmacokinetic/pharmacodynamics 
relationship of amcenestrant. 
Pharmacokinetic exposure and response, or safety endpoints 
during the treatment period. 
To evaluate the time to first use of chemotherapy after 
disease progression in the 2 treatment arms. 
Time to first use of chemotherapy after disease progression is 
defined as the time from randomization to start of the first use of 
chemotherapy after disease progression. 
For China, please see Section 10.8 for details. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy, safety, PK, PDy, and patient reported outcomes (PRO) assessments selected 
for this study are considered well established and relevant in an oncology Phase 2 study setting.  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is an international, prospective, open-label, Phase 2 randomized study comparing the 
efficacy and safety of amcenestrant versus a single endocrine therapy of the choice of the 
physician in men, postmenopausal women or premenopausal women on a gonadotropin-releasing 
hormone (GnRH) analog with ER-positive and HER2-negative advanced and/or metastatic breast 
cancer. 
Participants will be randomly assigned (1:1) to either amcenestrant 400 mg QD PO, or a control 
arm (potential control treatment of the choice of the physician depending on each participant’s 
medical condition and in accordance with the approved label). 
The control arm may include 1 of the following treatments to be selected before randomization 
and used as monotherapy: 
• 
Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at 
Day 1 of each treatment 28-day cycle thereafter 
• 
Aromatase inhibitors (PO, QD): 
- 
Anastrozole 1 mg to be taken approximately at the same time every day, regardless of 
food status 
- 
Letrozole 2.5 mg to be taken approximately at the same time every day, regardless of 
food status 
- 
Exemestane 25 mg to be taken approximately at the same time every day after a meal. 
• 
Selective ER modulator (PO, QD or two times a day): 
- 
Tamoxifen 20 mg/day to be taken approximately at the same time every day, 
regardless of food status. 
The population will be stratified according to the presence of visceral metastasis (defined by at 
least 1 liver or lung metastasis) (Yes or No), prior treatment with CDK4/6 inhibitors (Yes or No), 
and Eastern Cooperative Oncology Group (ECOG) status (0 or 1). 
Study duration for an individual participant will include:  
• 
A period to assess eligibility (screening period) of up to 4 weeks (28 days) before 
randomization 
• 
A treatment period of 28 days of study treatment per cycle, and  
• 
An end of treatment (EOT) visit at least 30 days (or until the participant receives another 
anticancer therapy, whichever is earlier) following the last administration of the 
investigational medicinal product (IMP). 
Study treatment may continue until precluded by unacceptable toxicity, disease progression, upon 
participant’s request to stop treatment, or Investigator decision, whichever occurs first. 
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Participants will continue treatment after the last cut-off date (COD). Participants who discontinue 
the study treatment without documented PD will be followed every 8 weeks until PD is 
documented or primary analysis COD, whichever occurs first. 
For the global study, estimated COD for final PFS will be approximately 18 months after first 
randomized participant. No PK sample will be taken after Cycle 6 or COD for final PFS, 
whichever comes first. After the COD for final PFS analysis, no more efficacy assessment will be 
performed except collection of survival status. For all participants alive at the COD for final PFS 
analysis, the first follow-up visit will be conducted at the site and subsequent telephone follow-up 
assessments will be conducted every 2 months to record survival data and further therapies, which 
will be collected until COD for OS analysis, or participant death, or upon participant’s request, 
whichever occurs first. 
If a participant treated continues to benefit from the treatment after the COD for OS analysis, the 
participant may continue until treatment is precluded by toxicity, progression, upon participant’s 
request to stop treatment, or Investigator decision. For cycles completed after the COD for final 
PFS analysis for the main cohort, only all ongoing serious AEs (SAEs) (related or not), all related 
nonserious AEs ongoing at the COD, and all new serious or related AEs occurring post-COD and 
associated concomitant medication, as well as IMP administrations and reason for EOT will 
continue to be collected. 
For the China extension, assuming that the first Chinese participant is planned to be enrolled 
11 months after the first randomized participant of the global part and a 17-month enrollment 
period for the Chinese participants, the estimated China COD will be approximately 5 months 
after last Chinese participant enrolled.  
Study design specific to the China extension is described in Section 10.8. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
There is currently an unmet need in participants with advanced/metastatic breast cancer who have 
failed previous lines of hormonal therapies/chemotherapy. Fulvestrant is an approved SERD for 
participants who fail prior endocrine therapy, but despite demonstrated efficacy, this therapy is 
limited by its poor pharmaceutical properties which require IM administration and limit the 
applied dose, exposure, and receptor engagement (16, 17). Aromatase inhibitors and tamoxifen 
are alternative options that may benefit patients after relapse to prior hormonal therapies. 
Progression-free survival was found to be from 3 to 5 months in this population (2, 3, 4, 5, 6, 7). 
The objective of this study is to compare the efficacy, safety, and PDy of amcenestrant with a 
single agent endocrine therapy in participants with advanced/metastatic breast cancer.  
4.3 
JUSTIFICATION FOR DOSE  
The amcenestrant 400 mg dose was selected based on the preliminary safety, PK, and PDy data 
obtained from the TED14856 Phase 1 study with advanced breast cancer participants (detailed 
below).  
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Pharmacodynamics was assessed using 18FES-PET scans; all the participants had 1 examination at 
baseline and a second one between 11 and 15 days after the first administration of amcenestrant, 
close to the time of PK trough prior to the next dose. Preliminary results show high levels of 
inhibition of the signal from the 150 mg dose level: 100% inhibition at this dose level and more 
than 87% in all participants treated at further dose levels. 18fluoroestradiol-PET has been validated 
as an accurate method for localizing ER-expressing tumors (24, 25) and as a predictive assay for 
breast cancer endocrine therapy (24, 26, 27). The 18FES-PET scan results indicated an inhibition 
of ER binding from 88% to 100% in participants treated with amcenestrant 400 mg QD. 
Pharmacokinetic data of amcenestrant in humans was obtained after a single oral dose in healthy 
postmenopausal women (TDU16074 study) and after single and multiple QD doses in patients 
(TED14856 study). Amcenestrant was generally well absorbed but showed a high within and 
total-participant variability of exposure parameters. Amcenestrant is characterized by a large 
apparent volume of distribution (105 to 158 L) in both healthy and patient populations and a low 
apparent systemic clearance (from 9.8 L/h to 13.4 L/h after single or multiple dose). 
Pharmacokinetic profiles generally showed a biphasic elimination with a mean apparent terminal 
half-life estimated around 24 hours across doses after single dose administration. After multiple 
QD dosing in patients, a moderate accumulation was observed up to 200 mg while no 
accumulation was observed at 400 and 600 mg, suggesting possible non-linearity of amcenestrant 
PK with time. Exposure maximum concentration (Cmax) and area under the curve (AUC) 
increased with dose and did not deviate significantly from dose proportionality after single dose, 
or after multiple doses between 20 and 600 mg. When given with a moderate fat breakfast in pilot 
food effect studies, amcenestrant exposure increased by 27% at 200 and 300 mg in healthy 
participants and by 45% between 200 and 600 mg in patients. Amcenestrant was recommended to 
be given regardless of food status in subsequent clinical studies. Please refer to the IB for more 
information on amcenestrant PK. 
A strong PK/PDy relationship was established between plasma concentrations of amcenestrant, 
measured just before 18FES administration and concomitant inhibition of 18FES-PET signal. 
18FES-PET inhibition >87% was generally observed when plasma concentrations were above 
100 ng/mL. This threshold is considered to allow amcenestrant occupancy of ER.  
Estrogen receptor 1 gene mutations were assessed prior to treatment, with data available on 
16 participants from Part A. In the cell-free deoxyribonucleic acid (cfDNA), 11 of 16 participants 
had detectable ESR1 mutations, and the proportion of the cfDNA that showed an ESR1 mutation 
varied widely between participants (0.1% to 47%). To date, there is no obvious correlation 
between presence of an ESR1 mutation and PK characteristics or 18FES-PET occupancy.  
Based on the aforementioned, PK, PDy, and safety data described in Section 2.3.2, the 
recommended amcenestrant dose was fixed at 400 mg QD. 
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit/last contact of the last participant in the 
study or the last scheduled procedure shown in the SoA (Section 1.3) for the last participant in the 
study globally. 
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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, at the time of signing the informed 
consent or country’s legal age of majority if the legal age is more than 18 years. 
Type of participant and disease characteristics 
I 02. Participants with histological or cytological proven diagnosis of adenocarcinoma of the 
breast.  
I 03. Participants with evidence of either locally advanced not amenable to radiation therapy or 
surgery in a curative intent, and/or metastatic disease. 
I 04. Documentation of ER-positive (≥1% positive stained cells) based on most recent tumor 
cell staining by immunohistochemistry (IHC) assay consistent with local standards. 
- 
Note that if the primary tumor is ER-positive and any further metastatic lesion is 
ER-negative, the participant cannot be selected for inclusion. 
I 05. Documentation of HER2 non over-expressing based on most recent tumor sample by IHC 
(0, 1+), or in situ hybridization-negative based on single-probe average HER2 copy 
number <6.0 signals/cell or dual-probe HER2/centromeric probe for chromosome 17 
(CEP17) ratio <2 with an average HER2 copy number <6.0 signals/cell as per American 
Society of Clinical Oncology guidelines (28). 
- 
Note that if the primary tumor is HER2-negative and any further metastatic lesion is 
HER2-positive, the participant cannot be selected for inclusion. 
I 06. I 06 deleted in amended protocol 03.  
I 07. Prior chemotherapy (including antibody-drug conjugates) or targeted therapy is allowed: 
participants must have received no more than 1 prior chemotherapeutic or 1 targeted 
therapy regimen for advanced/metastatic disease. 
For participants for whom CDK4/6 inhibitors are available (ie, approved in their region 
and can be reimbursed), prior treatment with a CDK4/6 inhibitor in combination with 
fulvestrant or an AI is mandatory. 
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Note: The number of participants naïve to CDK4/6 inhibitors should not be higher than 
20% of the overall sample size. 
I 08. Participants must have received at least 6 months of a continuous prior endocrine therapy 
for advanced breast cancer and have progressed while on endocrine therapy (in single 
agent or in combination). The number of prior hormonal lines will be limited to 2.  
Participants with a relapse while on adjuvant endocrine therapy but after the first 2 years, 
or with a relapse within 12 months of completing adjuvant endocrine therapy are also 
eligible.  
Weight 
Not applicable. 
Sex 
I 09. Male or Female 
A) Postmenopausal women, as defined by one of the following: 
• 
Women ≥60 years of age. 
• 
Women <60 years of age:  
- 
With spontaneous cessation of menses >12 months prior to randomization in the 
absence of chemotherapy, tamoxifen, and toremifene. 
- 
Or with cessation of menses of duration ≤12 months or secondary to hysterectomy 
AND have follicle-stimulating hormone (FSH) level in the postmenopausal range 
according to institutional standards (or >34.4 IU/L if institutional range is not 
available) prior to randomization. 
- 
Or who have received hormonal replacement therapy but have discontinued this 
treatment AND have FSH level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L if institutional range is not available) prior to randomization. 
- 
Or with status post bilateral surgical oophorectomy. 
- 
Or postbilateral ovarian ablation through pelvic radiotherapy. 
B) Pre/perimenopausal women, ie, not meeting the criteria for being postmenopausal.  
C) Male participants. 
Note: Male with no prior bilateral orchiectomy and pre/perimenopausal women should be on a 
GnRH agonist for at least 4 weeks prior to randomization (to be continued during study 
treatment).  
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Informed Consent 
I 10. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
Criteria added in amended protocol 02 
I 11. Participants must be considered clinically eligible by the Investigator to receive single 
agent endocrine therapy. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group performance status ≥2 (Section 10.10 [Appendix 10]). 
E 02. Significant concomitant illness, including psychiatric condition that, in the opinion of the 
Investigator or Sponsor, would adversely affect the participant’s participation in the study. 
E 03. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of 
oral IMP. Participants unable to swallow normally and to take capsules. Predictable poor 
compliance to oral treatment. 
E 04. Participants 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 the study procedures (ie, unwillingness and inability to comply with 
scheduled visits, drug administration plan, laboratory tests, other study procedures, and 
study restrictions). 
E 05. Major surgery within 4 weeks prior to randomization. 
E 06. Participant with any other cancer. Adequately treated basal cell or squamous cell skin 
cancer or in situ cervical cancer or any other cancer from which the participant has been 
disease free for >3 years are allowed. 
E 07. Any medical conditions that are contraindicated to endocrine treatment of physician’s 
choice (refer to approved label for details). 
E 08. Participants with abnormal coagulation profiles or any history of coagulopathy within the 
6 months prior to the first dose of IMP, including history of deep vein thrombosis or 
pulmonary embolism. However, participants with the following conditions will be allowed 
to participate:  
- 
Participants with adequately treated catheter-related venous thrombosis that occurred 
more than 1 month prior to the first dose of IMP.  
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- 
Participants being treated with an anticoagulant (eg, warfarin or heparin) for a 
thrombotic event that occurred more than 6 months before enrollment, or for an 
otherwise stable and allowed medical condition (eg, well-controlled atrial fibrillation), 
provided that 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. 
Exclusion criteria related to the disease 
E 09. Participants with a life expectancy <3 months. 
E 10. E 10 deleted in amended protocol 02. 
E 11. Participants with known brain metastases that are untreated, symptomatic or require 
therapy to control symptoms. Participants with brain metastases are eligible if they: 
- 
Have completed treatment (whole brain radiotherapy, radiosurgery, or combination) at 
least 4 weeks prior to start of study treatment, and 
- 
Have recovered from the effects of this treatment, and 
- 
Are neurologically stable. 
Any corticosteroid use for brain metastases must have been discontinued without the 
subsequent appearance of symptoms for ≥2 weeks prior to first IMP. 
E 12. No improvement of any prior treatment-related adverse reaction to < Grade 2, except for 
alopecia according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 (Section 10.3 [Appendix 3]). 
Prior/concomitant therapy 
E 13. Prior treatment with mammalian target of rapamycin inhibitors or any other SERD 
compound, except fulvestrant if stopped for at least 3 months before randomization. 
E 14. Treatment with drugs that have the potential to inhibit UGT, including, but not limited, to 
atazanavir and probenecid, for less than 2 weeks before randomization or 5 elimination 
half-lives whichever is longer. 
E 15. Treatment with strong CYP3A inducers within 2 weeks before randomization or 
5 elimination half-lives whichever is longer (Section 10.11 [Appendix 11]). 
E 16. Ongoing treatment with drugs that are sensitive substrate of OATP1B1/B3 (asunaprevir, 
atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, 
pravastatin, repaglinide, rosuvastatin, and simvastatin acid). 
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 
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Prior/concurrent clinical study experience 
E 17. Treatment with anticancer agents (including investigational drugs) less than 3 weeks 
before randomization. 
Diagnostic assessments 
E 18. Inadequate hematological function including neutrophils <1.5 × 109/L; platelet 
count <100 × 109/L. 
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 renal function with serum creatinine ≥1.5 × ULN or between 1.0 and 
1.5 × ULN with glomerular filtration rate <60 mL/min/1.73 m2 as estimated using the 
abbreviated Modification of Diet in Renal Disease formula (Section 10.13 [Appendix 13]). 
E 21. Liver function:  
- 
Aspartate aminotransferase >3 × ULN, or ALT >3 × ULN.  
- 
Total bilirubin >1.5 × ULN. 
- 
Note: In the presence of hepatic metastases, AST and ALT <5 × ULN are acceptable. 
Other exclusions 
E 22. Participants accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 23. Participants dependent on the Sponsor or Investigator (in conjunction with Section 1.61 of 
the International Council for Harmonisation-Good Clinical Practice Ordinance E6).  
E 24. Employees of the clinical study site or other individuals directly involved in the conduct of 
the study, or immediate family members of such individuals.  
E 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. 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Activity (Sun protection)  
Preclinical toxicity studies using amcenestrant indicate a potential risk for phototoxicity; in 
addition, 1 participant from Part 1 of the TED14856 study experienced Grade 1 sunburn while 
exposed to the sun without protection, an event considered related to amcenestrant (described in 
the IB). For this reason, participants should avoid direct exposure to natural or artificial sunlight 
during study treatment and for at least 5 days after last IMP dose. It is recommended to advise to 
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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  
Due to anti-estrogenic properties of amcenestrant, fulvestrant, and aromatase inhibitors being 
potent estrogen lowering agents, there exists potential risk of 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. Investigators will monitor Bone Mineral 
Density if clinically indicated, taking into account full medical history of patients, all confounding 
factors, previous anti-cancer treatments and considering the anti-estrogenic properties of the study 
drugs. 
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 publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 
Participants who do not meet the criteria for participation in this study may be retested during the 
screening period (≤28 days) and included, providing they meet at that time all inclusion and 
exclusion criteria. These participants are not considered screen failures. 
Participants who do not meet the criteria for participation during the screening period will be 
labeled screen failures and may be rescreened once. A different participant identification will be 
issued, while the other identification for this participant should be recorded as screen failure. 
There is no requirement for a waiting period between a screen failure date and the rescreening 
date. Participants that are rescreened must sign a new consent form and all screening procedures 
must be repeated.  
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION 
During a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, if the site is unable to adequately follow protocol 
mandated procedures, contingency measures proposed in Section 10.16 (Appendix 16) should be 
considered. 
 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
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 site to the participant via a 
Sponsor-approved courier company where allowed by local regulations and approved by the 
participant (Section 10.16 [Appendix 16]). 
Table 2 - Overview of study interventions administered  
Study 
intervention 
name 
amcenestrant 
Fulvestrant 
(Faslodex®) 
Aromatase inhibitors 
Tamoxifen 
Dosage 
formulation 
Capsules for oral use 
Concentrate for 
solution for 
intramuscularly 
injection  
In accordance with the approved 
label 
In accordance 
with the approved 
label 
Unit dose 
strength(s) 
100 mg capsule 
250-mg (5 mL) solution 
for injections  
 
Anastrozole 
Letrozole 
Exemestane  
In accordance with the approved 
label 
In accordance 
with the approved 
label  
Route of 
administration 
Per os 
Intramuscular 
Per os 
Per os 
Dosing 
instructions 
4 capsules once a day 
given in the morning 
with or without food, at 
approximately the 
same time every day 
(±3 hours)a 
Two 250-mg (5 mL) 
injections for 
intramuscular use in 
Cycle 1 Day 1, Cycle 1 
Day 15, and Day 1 of 
each 28-day cycle 
thereaftera 
Anastrozole 1 mg and letrozole 
2.5 mg: Once daily, approximately 
at the same time every day, 
regardless of food statusa  
Exemestane 25 mg: once daily, 
approximately at the same time 
every day after a meala 
20 mg once daily 
or 10 mg twice a 
day, 
approximately at 
the same time 
every day, 
regardless of 
food statusa 
Packaging and 
labeling 
Study intervention will 
be provided in blisters 
containing capsules. 
Each blister will be 
labeled as required per 
country requirement 
In accordance with the 
approved label 
In accordance with the approved 
label 
In accordance 
with the approved 
label 
Manufacturer 
Sanofi-Aventis R&D 
AstraZeneca 
Not determinedb 
Not determinedb 
a In study visit days, participants should only be dosed after the predosing pharmacokinetic sampling collection. 
b Brand and generic products can be used, according to country availability. 
Aromatase inhibitors approved for breast cancer treatment include letrozole, anastrozole, and exemestane. 
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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 General rules  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study 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. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual and/or monitoring plan.  
Partially-used and used IMP 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 IMP 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. 
Any quality issue noticed with the receipt or use of amcenestrant (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). 
A potential defect in the quality of amcenestrant or any comparator supplied globally 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 
amcenestrant and eliminate potential hazards. When control treatments are recalled, the 
dispensing pharmacist or the site are responsible for notifying the participant, according to local 
regulation. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.2.2 Storage conditions  
Investigators or other authorized persons (eg, pharmacists) will be responsible for storing 
amcenestrant and control treatments in a secure and safe location with restricted access, in 
accordance with local regulations, labeling specifications, policies, and procedures. 
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6.2.2.1 Amcenestrant  
Control of amcenestrant storage conditions, especially temperature (eg, refrigerated storage), and 
information on in-use stability and instructions for handling this IMP should be managed in 
accordance with the rules provided by the Sponsor. 
Amcenestrant is to be stored at +2°C to +8°C (36°F to 46°F) and protected from light. All 
capsules must be kept in their box until use.  
6.2.2.2 Control products  
Please refer to package insert for storage conditions. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an Interactive 
Response Technology (IRT). The IRT generates the participant randomization list and allocates 
the intervention number and the corresponding intervention kits to the participants according to it. 
Before the study is initiated, the telephone number and call-in directions for the Interactive Voice 
Response System and/or the log in information and directions for the Interactive Web Response 
System will be provided to each site. The IRT centralized randomization system will be used to 
prevent the Investigators from knowing in advance the treatment assignment. 
Investigational medicinal product will be dispensed at the study visits summarized in the Schedule 
of Activities (SoA). Participants will be randomized within 3 days prior to first IMP dosing 
(Cycle 1 Day 1). 
Returned study intervention should not be re-dispensed to the participants. 
Participants cannot be randomized more than once.  
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an IRT system. The site will contact the IRT prior to the start of study intervention 
administration for each participant. The site will record the intervention assignment on the 
applicable case report form, if required. Potential bias will be reduced by the following steps:  
• 
Central randomization 
• 
Randomization will be stratified according to the presence of visceral metastasis (defined 
by at least 1 liver or lung metastasis) (Yes or No), prior treatment with CDK4/6 inhibitors 
(Yes or No), and ECOG status (0 or 1) (Note: The number of participants naïve to 
CDK4/6 inhibitors should not be higher than 20% of the overall sample size) 
• 
Assessment of tumor response by independent central review (ICR) blinded to study 
treatment arms. 
During the trial, IMP administration will be open-label, and no attempts will be made to blind 
administration. Blinding rules for the Sponsor study team will be detailed in a separate document. 
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6.4 
STUDY INTERVENTION COMPLIANCE  
A patient diary will be provided to participants receiving oral therapy (amcenestrant or controls 
given PO) at every visit during treatment.  
The person responsible for drug dispensing is required to maintain adequate records of the study 
treatment. These records (eg, product accountability and inventory forms at site level) include the 
date the study treatment is received from the Sponsor, dispensed to the participant and destroyed 
or returned to the Sponsor. The packaging batch number on the pack must be recorded on the drug 
accountability form. 
Compliance to amcenestrant/controls given PO intake will be assessed using the patient diary. On 
Day 1, while the participant is in the clinic, the study staff will demonstrate to the participant how 
to record information in the patient diary. Participants will note every day the hours of 
amcenestrant/controls given PO intake and food conditions. If vomiting occurred after the intake 
of capsules/tablets, they need to report it in the same diary. In case of an early vomiting event, the 
administered dose of amcenestrant/controls given PO should not be repeated, and the participant 
should be instructed not to make it up the next day and resume the treatment the next day as 
prescribed. This information should be recorded in the diary. The diary will then be completed by 
the participant each day for each dose and will be returned to the study personnel at the end of 
each cycle. Participants who inadvertently take 1 extra dose during a day must be instructed to 
skip the next day’s dose. Also refer to Section 8.4 for further details. 
Participants will be requested to return all unused amcenestrant/controls given PO to the study site 
at the end of the treatment period for each cycle for a full compliance assessment. Clinic staff will 
record the study medication dosing information including the actual clock time of each dose based 
on information from the patient diary.  
Administration of fulvestrant will be supervised at the study site by the Investigator or 
Subinvestigator. 
In case of oral dosing omission or IM injection delay greater than 2 weeks, the participant will be 
withdrawn from the study treatment, unless a clear benefit is identified and after discussion with 
the Medical Monitor (Section 6.6). 
6.5 
CONCOMITANT THERAPY  
All treatments being taken by the participant from the date of the consent form to the first study 
treatment administration, at any time during the treatment period and up to 30 days after the 
last dose are regarded as prior and concomitant treatments respectively, and will be reported on 
the appropriate screen of the electronic case report form (eCRF).  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
GnRH analogs, and/or herbal supplements) 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. 
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Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the Investigator and Sponsor, the 
medication will not interfere with the study.  
Bisphosphonates and receptor activator of nuclear factor-kappa Β ligand inhibitors are allowed. 
Special caution should be taken regarding the following therapies: 
• 
No additional investigational or commercial anticancer agents such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy 
other than amcenestrant or the selected control will be permitted during the active 
treatment phase. In general, any drugs containing “for the treatment of breast cancer” on 
the product label are not permitted on study. 
• 
Palliative radiotherapy may be given for control of pain for palliative intents. The Sponsor 
team should be notified to obtain agreement prior to treatment if palliative radiotherapy is 
being considered, and prior to resuming therapy on the study. The irradiated area should 
be as small as possible and should never involve more than 20% of the bone marrow in 
any given 3-week period. In all such cases, the possibility of tumor progression should be 
ruled out by physical and radiological assessments of the tumor. If the only evaluable 
lesions are to be irradiated, the participant will stop the study treatment. The irradiated 
area cannot be used as a parameter for response assessment.  
• 
Drugs which are sensitive substrates of CYP3A, CYP2B6, CYP2Cs, and/or UGT should 
be closely monitored (see list Section 10.12 [Appendix 12]) since there may be loss of 
efficacy of these drugs by concomitant use of amcenestrant due to a potential induction 
effect of amcenestrant. 
The following therapies/medications are prohibited throughout the active treatment phase for the 
amcenestrant treatment arm: 
• 
Drugs that are strong inducers of CYP3A, since they may decrease amcenestrant exposure 
(see full list in Section 10.11 [Appendix 11]).  
• 
Herbal medications and food supplements including St John’s Wort and genistein during 
treatment period, since they could 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.  
• 
Drugs that have UGT inhibition potential and are contraindicated with UGT substrates, 
including, but not limited to, atazanavir and probenecid, since amcenestrant is substrate of 
UGT1A1 and UGT1A4. 
Regarding the control arm, please refer to the approved label of the selected control for 
contraindications and precautions regarding concomitant medications.  
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Prophylactic vaccination is recommended for influenza A and B virus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2; ie COVID-19), Pneumococci, and Haemophilus 
influenza. 
6.5.1 Rescue medicine  
Not applicable. 
6.6 
DOSE MODIFICATION  
Dose adjustment (omission, reduction) is permitted for oral drug IMP only. The fulvestrant dose 
cannot be adjusted; its dosing can only be delayed or interrupted. 
If a dose of PO-given IMP is vomited or omitted, the participant should not take the dose later or 
2 doses at the next planned dose, and this information has to be recorded in the patient diary.  
Oral IMP dose omission is allowed in case of severe toxicity and the reason should be 
documented in the eCRF. Doses omitted for toxicity are not to be replaced within the same cycle. 
Conditions for dose modifications are aligned in Table 3. Please refer to the selected control label 
information on additional specific contraindications and events requiring use precaution. 
In case of oral dosing omission or IM injection delay greater than 2 weeks, the participant will be 
withdrawn from the study treatment, unless a clear benefit is identified and after discussion with 
the Medical Monitor.  
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Table 3 - Recommended dose modification and management of amcenestrant related toxicities  
NCI-CTCAE grade 
Dose modifications 
Amcenestrant-related toxicities other than increase of ALT 
Grade 1 or 2 
No dose adjustment required 
Grade 3 (if persisting despite optimal 
medical treatment) 
Omit amcenestrant until symptoms resolve to Grade ≤1 and administer amcenestrant 
at the same dose.  
In case of recurrence of the same Grade 3 event, and after symptoms resolve to 
Grade ≤1, a dose reduction to 200 mg QD can be considered, but no further 
re-escalation is allowed. 
In case of a second recurrence, if already reduced at first event recurrence, 
amcenestrant will be definitely stopped. 
Grade 4 (if persisting despite optimal 
medical treatment) 
Omit amcenestrant until symptoms resolve to Grade ≤1. After that, reintroduction of 
amcenestrant at the same dose or at reduced dose (200 mg QD) can be considered if 
the participant is clinically benefiting and with the agreement of the Medical Monitor.  
After dose reduction, no further re-escalation is allowed.  
In case of recurrence of the same event at Grade ≥3, and after symptoms resolve to 
Grade ≤1, the dose should be reduced to 200 mg QD (if not previously implemented) 
or permanent discontinuation of the drug could be considered. 
Isolated 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 amcenestrant 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 amcenestrant 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 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; QD = once daily. 
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). 
 
6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
As per discretion of the Investigator. 
In case a new anticancer therapy is administered during the follow-up stage of the study, before 
recovery or consolidation of any related AEs or SAEs, or before documented disease progression 
at the time of study treatment discontinuation, the start date, end date, and the name of further 
therapy until first chemotherapy will be collected in the eCRF. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1.8). 
Pregnancy will lead to permanent treatment discontinuation in all cases. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
Participants may withdraw from study treatment if they decide to do so, at any time and 
irrespective of the reason, or this may be done at the discretion of the Investigator. All efforts 
should be made to document the reason(s) for discontinuation and this should be documented in 
the eCRF. 
Treatment with the study treatment should be discontinued in any of the following cases: 
• 
At the participant’s request, at any time and irrespective of the reason (consent’s 
withdrawal), or at the request of their legally authorized representative. “Legally 
authorized representative” is considered to be an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant to the 
participant’s participation in the procedure(s) involved in the research. Withdrawal of 
consent for treatment should be distinguished from withdrawal of consent for follow-up 
visits and from withdrawal of consent for nonparticipant contact follow-up, eg, medical 
records check. 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 should be explicitly asked about the contribution of possible 
AEs to their decision to withdraw consent, and any AE information elicited should be 
documented. The participant should preferably withdraw consent in writing and, if the 
participant or the participant’s representative refuses or is physically unavailable, the site 
should document any case of withdrawal of consent. 
• 
If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s wellbeing, such as: 
- 
Disease progression 
- 
Unacceptable AE 
- 
Poor compliance to the study protocol 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment. 
• 
Participant is lost to follow-up (Section 7.3). 
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Handling of participants after permanent 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 permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the EOT visit. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed.  
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. 
• 
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. 
• 
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. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
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 explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
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 nonparticipant 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 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.  
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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. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
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. The ICF can be signed more than 28 days prior 
to randomization. Screening time indicates in which time frame examinations used to 
support eligibility have to be done prior to randomization. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples (refer to the study manual for details). 
• 
Assessments should be performed when possible prior to administration of study treatment 
unless otherwise indicated in the SoA (Section 1.3). Every effort should be made to keep 
the SoA on time for each participant. All visits should be performed on the day specified, 
unless otherwise noted.  
• 
Additional safety tests (eg, electrocardiogram [ECG]) can be performed whenever 
clinically indicated.  
Randomization: to take place once the consented participant has completed all the 
necessary screening procedures and is deemed eligible for study entry by the Investigator 
or designee. All eligible participants must be randomized using IRT. Every effort should 
be made to start treatment within 3 working days of randomization. 
• 
Before Cycle 1, evaluations such as body weight, signs and symptoms, physical 
examination, ECG, hematology, coagulation tests, blood chemistry, and urinalysis should 
be repeated within 2 or 3 days before Cycle 1 Day 1 if abnormal or performed more than 
7 days before Cycle 1 Day 1. Pregnancy test will be repeated (by dipstick) at Cycle 1 
Day 1 for premenopausal patients if screening test >7 days before Cycle 1 Day 1. 
• 
During treatment, additional hematology, coagulation, blood chemistry, and urinalysis 
assessments can be performed when clinically indicated. 
• 
Cycle 1 Day 1 refers to the day the participant receives the initial dose of study treatment 
which will be a single administration of amcenestrant, or control selected by the physician.  
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• 
Cycle 1 Day 15 corresponds for participants randomized in the control arm and treated by 
fulvestrant to the second fulvestrant injection. 
• 
A cycle duration is 28 days. Day 1 of Cycle 1 refers to the day the participant receives the 
first study treatment administration. Day 1 of each subsequent cycle corresponds to the 
visit performed on Day 29 ±2 days of previous cycle.  
8.1 
EFFICACY ASSESSMENTS   
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 Criteria for response (antitumor activity)  
The primary and secondary efficacy endpoints will be assessed by the RECIST 1.1 
(Section 10.14 [Appendix 14]) criteria. Tumor assessments will be reviewed centrally by ICR. 
Copies of all imaging sets will be systematically collected for the purpose of ICR (refer to 
imaging charter and manual). 
Tumor assessment will be performed at fixed intervals as described in SoA, and the assessment 
window is not impacted by dose delay or dose omission. 
Chest, abdomen, and pelvis computed tomography (CT) or magnetic resonance imaging (MRI) 
scans and any other examinations as clinically indicated will be performed to assess disease status 
within the screening period and before first study treatment as baseline. Positron emission 
tomography-CT is not authorized. Afterwards, chest, abdomen, and pelvis CT or MRI scans 
(whichever used at baseline) will be performed every 8 weeks or when clinically indicated during 
treatment, whenever disease progression is suspected (eg, symptomatic deterioration), and at the 
end of study treatment (in accordance with RECIST 1.1 for solid tumors). Considering the 
8 weeks period between 2 tumor assessments, the confirmation of PR or CR is not necessary 
4 weeks apart. 
Tumor assessment should not be repeated at EOT if performed at the immediate previous cycle.  
Participants who discontinue the study treatment without documented PD will be followed every 
8 weeks (projected from last tumor assessment) until PD is documented or COD for final PFS, 
whichever occurs first.  
The same evaluation method should be used for all evaluations in the same participant.  
8.1.2 Bone scans  
Bone scans will be performed in line with the SoA (Section 1.3). In the applicable cycles, bone 
scans and tumor assessments (Section 8.1.1) should be performed during the same period. 
If at baseline, lesions are detected in the bone scan but not in the CT/MRI (RECIST 1.1) scan, 
further bone scans should be conducted every 8 weeks ±7 days after randomization until disease 
progression documented or COD for final PFS, whichever occurs first. If the lesions seen in the 
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bone scan are no longer visible, these assessments should be conducted every 16 weeks ±7 days 
after randomization until disease progression documented or COD for final PFS, whichever 
occurs first. 
If bone lesions are detected in the bone scan and in CT/MRI (RECIST 1.1) scan at baseline, 
further bone scans will be conducted every 16 weeks ±7 days after randomization until disease 
progression documented or COD for final PFS, whichever occurs first. 
If at screening, lesions are not detected in the bone scan nor in the CT/MRI (RECIST 1.1) scan, 
further bone scans are not required unless clinically indicated. 
Bone scans will be assessed centrally by ICR. 
8.1.3 Patient reported outcomes  
Patient reported outcomes will be assessed in this study in line with the SoA (Section 1.3). While 
on treatment, PROs are to be administered prior to treatment and prior to discussion of 
participant’s health status. 
The European Organisation for Research and Treatment of Cancer (EORTC) core quality of life 
questionnaire (QLQ-C30) is a cancer specific instrument that contains 30 items and provides a 
multidimensional assessment of health-related quality of life (HRQL) (29, 30, 31). The validity 
and reliability of the QLQ-C30 has been established in various types of cancers (32). This 
instrument provides a comprehensive assessment of the principal HRQL dimensions identified as 
relevant by cancer patients (physical functioning, emotional functioning, cognitive functioning, 
role functioning, social functioning, global HRQL, impact of symptoms, and impact of toxicities). 
The QLQ-C30 is one of the standard instruments used in oncology for the evaluation of new 
cancer therapies.  
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom 
scales (fatigue, nausea and vomiting, and pain), a Global Health Status (GHS)/quality of life scale, 
and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). All of the scales and single-item measures range in score from 0 to 100. A higher 
score for a functional scale/GHS represents a higher/healthier level of functioning/HRQL, where a 
higher score for symptoms/items represents a higher level of symptomatology/problems. 
The recall period for this instrument is 1 week. 
The EORTC QLQ breast cancer specific module (QLQ-BR23) is a disease-specific HRQL 
measure that is used in conjunction with the QLQ-C30. The QLQ-BR23 assesses the impact 
breast cancer and the side effects of treatment in breast cancer patients.  
The QLQ-BR23 contains 23 items: 8 assessing functioning which includes body image (4 items), 
sexual functioning (2 items), sexual enjoyment (1 item), and future perspective (1 item), and 
15 items assessing symptoms of disease or treatment including arm symptoms (3 items), breast 
symptoms (4 items), systemic therapy side effects (7 items), and upset by hair loss (1 item).  
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The QLQ-C30 and QLQ-BR23 are reliable and valid measures of HRQL in cancer patients. The 
2 measures together (53 items) take approximately 9 minutes to complete. The instruments have 
been translated, validated, and used in many countries. 
The EuroQoL questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L) is a 
standardized measure of health status that provides a simple, generic measure of health utility, and 
consists of 2 sections: descriptive and visual analogue scale (VAS). The descriptive section 
consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The VAS records the participant’s self-rated 
health on a 20 cm vertical VAS with endpoints labeled ‘the best health you can imagine’ and ‘the 
worst health you can imagine’. This information can be used as a quantitative measure of health 
as judged by the individual participants.  
The instrument is designed for self-completion by the participants. Response options are 
measured with a 5-point Likert scale with higher scores indicating better HRQL. 
For EQ-5D-5L, VAS will be described as given by the participant and health utility index will be 
calculated according to EuroQoL-specific country algorithms/crosswalk developed by B. van 
Hout (33). In case a specific country algorithm is missing, the value sets based on the United 
Kingdom population will be used to generate health utility scores. 
It is important that the PROs are completed by each study participant, after study participant has 
signed the informed consent and prior to any treatment- or study-related activities, including 
administration of drug, laboratory work, radiological assessments, discussion with the participant 
regarding their treatment or health status, and similar activities. This ensures the objectivity of the 
data.  
Site staff must not complete the PRO data on behalf of participant.  
Detailed site training on PROs will be provided at the Investigator meeting and in separate PRO 
training materials. 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than adverse events which are presented in 
Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• 
A physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height (at screening only) and 
weight will also be measured and recorded. 
• 
Performance status as measured by the ECOG. 
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• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• 
Any new finding or worsening of previous finding during treatment period should be 
reported as a new AE.  
8.2.2 Vital signs  
• 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed by a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• 
Blood pressure, respiratory rate, and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (eg, television, 
cell phones).  
8.2.3 Electrocardiograms  
• 
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.  
• 
Electrocardiograms will be done in accordance with the SoA (Section 1.3), and can be 
repeated as clinically indicated. 
8.2.4 Clinical safety laboratory tests  
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. The laboratory 
reports must be filed with the source documents.  
• 
Liver function tests Grade ≥3 during participation in the study or within 30 days after the 
last dose of study intervention should be repeated until the values return to normal or 
baseline. If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified 
if not related to underlying disease. If related to IMP refer to dose modification Table 3 
(Section 6.6). 
• 
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.  
• 
Any laboratory abnormalities are to be recorded as AEs only if they are serious or impact 
study treatment (ie, lead to dose omission, reduction, delay, or discontinuation).  
8.2.5 Suicidal risk monitoring  
Not applicable. 
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8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
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 or female partner of a male participant 
entered in the clinical study 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.  
• 
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.  
- 
Injectable administration: at least twice the dose during the planned intervals. 
- Of note, asymptomatic overdose has to be reported as a standard AE. 
• 
Increase in 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 
isolated increase of ALT (Table 3, Section 6.6). 
- 
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), total bilirubin (fractionated 
if >2 x ULN direct), GGT, and INR (if total bilirubin >2.5 ULN).  
- 
An ultrasound, or other imaging, 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. 
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to exclude hepato-biliary disorders (eg, hepatotropic virus infections, autoimmune or 
alcoholic hepatitis, Non-Alcoholic Steatohepatitis, etc) or drug induced liver injury.  
- 
Further hepatic virology will be undertaken as per the site’s local guidelines for the 
treatment of cancer patients, taking into account the local and national 
recommendations. 
• 
Photosensitivity 
- 
If photosensitivity 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 6.6 Dose modification). 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. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events 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 IMP (see Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (regardless of seriousness or relationship with IMP) will be collected from the signing of 
the ICF until 30 days after the last dose of the IMP (Section 1.3). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee within 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 information on AEs or SAEs 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. 
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). 
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8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading 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 prespecified study end-date, all SAEs, and 
nonserious AESIs (as defined in Section 8.3), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• 
Prompt notification by the Investigator to the Sponsor of an 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 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• 
The Investigator is obligated to assess the relationship between study intervention (IMP) 
and each occurrence of AE/SAE (Section 10.3). 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. 
• 
Serious adverse events that are considered expected will be specified in the reference 
safety information of the IB or approved label for the control arm. 
• 
An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
other specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB 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 or female partners of male participants 
will be collected after the start of study intervention and until 30 days after the last dose. 
• 
Participants are not expected to be in this situation, assuming that all participants are 
postmenopausal per definition, or receiving long-term GnRH therapy. Non-hormonal 
methods of contraception should be employed during the study in premenopausal 
participants and in male participants without prior orchiectomy on a GnRH analog as per 
label (please see Section 10.4 [Appendix 4] for details).  
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If a pregnancy is reported in female participants or female partners of male participants, the 
Investigator should inform the Sponsor within 24 hours of learning of the pregnancy and should 
follow the procedures outlined in Appendix 4 (Section 10.4). 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
• 
In the event of pregnancy, study treatment should be discontinued.  
• 
Follow-up of pregnancy is mandatory until outcome has been determined. 
8.3.6 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP supplied centrally by Clinical Supplies (amcenestrant and control arm 
treatments in the United States and Poland) must be reported as soon as possible by the 
Investigator to the monitoring team responsible for completing a product complaint form, within 
required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until the 
IMP can no longer be detected systemically (at least 7 days for amcenestrant and 5 times 
the half-life time of the control treatment for the selected control IMP). 
3. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
amcenestrant if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
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8.5 
PHARMACOKINETICS  
• 
Pharmacokinetic sampling is planned only in participants randomized in amcenestrant 
treatment arm. 
• 
Blood samples of approximately 1 mL will be collected for measurement of plasma 
concentrations of amcenestrant as specified in the SoA (Section 1.3) using a validated 
liquid chromatography-mass spectrometry/mass spectrometry assay with a limit 
quantification of 5 ng/mL (method reference DOH1434). Instructions for the collection 
and handling of biological samples will be provided by the Sponsor and detailed in the 
laboratory manual. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• 
Timing of blood sampling for PK assessments will be detailed in the laboratory manual. 
• 
It is of utmost importance to collect all blood samples at the specified time windows and 
according to the specifications (refer to the laboratory manual). 
• 
Samples missed or lost for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. Actual dates and times of previous drug 
administration and food status should also be precisely recorded. 
• 
For the comfort of the participants, some PK samplings may be deleted during the course 
of the study if they are no longer deemed necessary by the Sponsor. 
• 
Pharmacokinetic samplings will be stopped at the end of Cycle 6 or at the COD for final 
PFS, depending which one comes first. 
• 
A population PK analysis will be performed and reported in a standalone report. 
• 
Pharmacokinetic sample handling procedures will be described in the laboratory manual.  
8.6 
PHARMACODYNAMICS  
For additional parameters, please see Section 8.7 and Section 8.8. 
8.6.1 Tumor biopsy to assess estrogen receptor degradation (optional procedures)  
Participants with an accessible tumor who consented to the optional paired biopsy will be asked to 
contribute the most recent archived biopsied tumor (within past 3 months prior to initiation of 
study treatment) or preferably a fresh tumor biopsy that can be collected between the time of ICF 
signature and Cycle 1 Day 1 prior to treatment. After baseline, these participants will be asked to 
provide a biopsy of either a primary or secondary tumor site. This on-treatment biopsy should take 
place at approximately Cycle 3 Day 1 (allowed up to Cycle 3 Day 15 or within 14 days after first 
radiological tumor assessment visit after baseline) and should be taken from the same site as the 
previous biopsy, when feasible (not applicable for archive samples). Tumor biopsy should be 
performed only after radiological assessment has taken place.  
The collected tissue should be fixed and preserved. Approximately 9 formalin fixed paraffin 
embedded (FFPE) slides (5-μm each for IHC analysis) and 3 FFPE slides (10-μm each for 
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ribonucleic acid [RNA] analysis, if possible), or the biopsy tissue block (preferred option) will be 
collected from each biopsy.  
Special procedures for biopsy, tissue fixation, handling, storage and shipment will be described in 
a separate laboratory manual which will be available at the investigational site. 
The presence of ER will be determined by central IHC and the ER score prior to the start of IMP 
treatment and on treatment will be compared to assess ER degradation. Protein expression levels 
of cancer-related proteins, such as Ki67, Bcl-2, and PgR, will also be evaluated by IHC. In 
addition, RNA extracted from the tumor may be used for sequencing and/or other analyses (see 
Section 8.7.3). These data will provide information on the activity of the IMP in the tumor. 
8.6.2 Estradiol  
Estradiol is the natural ligand to ER and amcenestrant antagonizes the binding of estradiol to ER. 
Serum samples will be collected to explore the possible influence of circulating levels of estradiol 
on amcenestrant efficacy. Circulating estradiol will be measured before and after treatment in 
accordance with the SoA (Section 1.3). 
Special procedures for collection, handling, storage and shipment of samples will be described in 
a separate laboratory manual which will be available at the investigational site. 
8.7 
GENETICS  
See Section 10.5 (Appendix 5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the laboratory 
manual.  
8.7.1 Estrogen receptor 1 gene mutation status in cell-free DNA  
Estrogen receptor 1 mutations have emerged as a resistance mechanism to endocrine therapies. 
While rarely present in tumors prior to endocrine therapy, a significant proportion of ER-positive 
breast cancer tumors will acquire ESR1 mutations, the gene encoding ER, after 
prolonged/repeated treatment with endocrine therapies (in particular AIs). The presence of an 
ESR1 mutation is linked to a poor prognosis in these participants. 
Estrogen receptor 1 activating mutations render the ERs no longer dependent on estradiol for 
activity, thereby making the tumor less sensitive to certain endocrine therapies. 
Samples to potentially assess 12 mutations of the ESR1 gene, including hotspot mutations 
described in the ligand domain, will be obtained from all participants at baseline (predose Cycle 1 
Day 1) and at Cycle 3 Day 1, and cfDNA may be extracted from the plasma in order to assess the 
effects of the IMP on the tumor. 
Special procedures for collection, handling, storage and shipment will be described in a separate 
laboratory manual which will be available at the investigational site. 
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8.7.2 Mutation profiling in cell-free DNA  
Cancer gene mutations present in the tumor at baseline might influence the response to the IMP. It 
is also possible that mutations arising during the IMP treatment might constitute the root cause of 
the escape mechanism to the IMP treatment. To evaluate potential intrinsic and emerging 
resistance mutations, plasma will be collected at baseline and at the EOT visit, and cfDNA will be 
extracted.  
In addition, saliva will be collected at baseline to extract DNA which will be used as a normal 
reference tissue for the mutation analysis. The mutation status of cancer-related genes will be 
determined by sequencing, and these data will be used to explore the potential link between 
specific mutations and intrinsic or acquired resistance to the IMP treatment.  
Special procedures for collection, handling, storage and shipment will be described in a separate 
laboratory manual which will be available at the investigational site.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.16 (Appendix 10.16). 
8.7.3 RNA transcriptome analysis  
Transcriptome studies of the optional tumor biopsy may be conducted using microarray, 
sequencing, and/or alternative similar techniques, which facilitates the simultaneous measurement 
of the relative abundances and sequences of thousands of RNAs, resulting in a transcriptome 
profile for each biopsy sample. This will enable the evaluation of changes in transcriptome 
profiles that may correlate with biological response relating to breast cancer or the action of the 
IMP. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
The optional tumor biopsy taken for the assessments referred in Section 8.6.1 can be used for 
these analyses. 
8.7.4 Drug metabolizing enzymes and transporters DNA sample  
In accordance with the SoA (Section 1.3), a blood sample will be collected to investigate allelic 
variants of drug metabolizing enzymes (eg, variants of UGT1A1 and UGT1A4), drug transporters 
and/or other absorption, distribution, metabolism, and excretion-related genes as potential 
intrinsic factors associated with PK or PD variability of amcenestrant. This sample will be used 
for this specific analysis and not for other future research. 
8.8 
BIOMARKERS  
Please see Section 8.6 and Section 8.7 for further details on the collection of samples for 
biomarker research. 
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Samples may be stored for a maximum of 15 years, if future use of samples is consented to, or 
according to local regulations, following the last participant last visit at a facility selected by the 
Sponsor to enable further analysis of biomarker responses to the IMP. 
8.8.1 Future use of samples  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For participants who have consented to it, the samples that are unused or left over 
after testing may be used for other research purposes (including genetic analysis that may provide 
information on the likelihood of developing cancer and related diseases) related to oncology than 
those defined in the present protocol. 
These other research analyses will help to understand either the disease or IMP response, or to 
develop and/or validate a bioassay method, or to identify new drug targets or biomarkers. These 
samples will remain labeled with the same identifiers used during the study. They will be 
transferred to a sanofi site (or a subcontractor site) which can be located outside of the country 
where the study is conducted. The Sponsor has included safeguards for protecting participant 
confidentiality and personal data. 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
This study is designed to test: 
• 
The null hypothesis that the survival distribution functions (SDF) for the PFS of the 
amcenestrant arm is lower than or equal to the SDF of the control arm. 
- 
H0: SDF (amcenestrant) ≤ SDF (Control) 
versus  
• 
The alternative hypothesis that the SDF for the PFS of the amcenestrant arm is superior to 
the SDF of the control arm. 
- 
H1: SDF (amcenestrant) > SDF (Control) 
Similar statistical hypotheses will be tested for the key secondary hypothesis for OS. 
9.2 
SAMPLE SIZE DETERMINATION   
The sample size for the global part of this study is determined based on following assumptions: 
the median PFS for the control arm is assumed to be 4.5 months (2, 3, 4, 5, 6, 7) and an 
improvement of 53% to a median PFS of 6.9 months (corresponding to a HR = 0.65) would be 
considered clinically meaningful.  
A total of 201 ICR-assessed PFS events in the 2 treatment arms for the global part of the study to 
have will provide approximately 86% power to detect an increase in PFS, assuming a true HR of 
0.65 (representing a 53% increase in median PFS from 4.5 to 6.9 months under exponential 
model), tested at a one-sided significance level of alpha = 0.025. 
For the global part of the study, assuming a uniform accrual rate of 23.5 participants per month 
accomplished over a period of about 12 months, an annual dropout rate of 10% and a COD for 
final PFS is approximately 18 months after first participant randomized, a total sample size of 
approximately 282 participants (randomized in a 1:1 ratio) is required. The sample size 
calculation considers 1 futility interim analysis at 50% of the planned number of events. 
Sample size calculation was performed using East 6.5. 
Power calculations for overall survival 
Comparison between treatment arms on the OS will be performed only if the primary analysis of 
the PFS is statistically significant. Therefore, a maximum of 2 analyses are planned for OS. The 
interim analysis of OS is planned at the time of PFS analysis, ie, approximately 18 months from 
the start of study randomization. The final OS analysis is planned to be performed at 
approximately 196 death events (approximately 70% OS data maturity, ie, when approximately 
70% of randomized participants have died).  
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Marginal power calculations for OS with 196 events is provided in Table 4 under several 
hypothetical alternative assumptions. 
Table 4 - Marginal power for overall survival  
OS Hazard Ratio 
Marginal power for OSa 
0.60 
0.95 
0.65 
0.85 
0.70 
0.70 
0.75 
0.52 
0.80 
0.35 
a Marginal power conditional to statistically significance of PFS.  
Note: number have been rounded. Calculations were made using East 6.5 software. 
OS = overall survival; PFS = progression-free survival. 
Assuming the median OS for the control arm is 28 months and an improvement of 33% to a 
median OS of 37 months (corresponding to HR = 0.75) in the amcenestrant arm, the COD for OS 
is approximately 64 months after the first randomized participant (ie, 46 months after PFS 
analysis) assuming a 5% dropout rate.  
Chinese population 
Sample size determination for the Chinese population is described in Section 10.8. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Enrolled  
All participants who sign the ICF. 
Intent-to-treat (ITT) 
All participants from the enrolled population and for whom there is a confirmation of 
successful allocation of a randomization number by IRT. Participants will be 
analyzed according to the treatment arm assigned at randomization. 
Safety 
All participants randomly assigned to study intervention and who took at least 
1 dose of study intervention. Participants will be analyzed according to the 
treatment arm they actually received. 
Pharmacokinetic-evaluable 
All participants from the safety population who receive at least 1 dose of 
amcenestrant and with at least 1 evaluable plasma concentration post-treatment.  
ICF = informed consent form; IRT = Interactive Response Technology; ITT = intention to treat. 
Note: For the Chinese populations on the extension part, refer to Section 10.8. 
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9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.16 (Appendix 10.16). 
Planned date for analysis cut-off for the global part: 
Estimated COD for the final PFS analysis will be approximately 18 months after first randomized 
participant. The COD for final analysis of OS will be approximately 64 months after the first 
randomized participant. 
For the estimated COD for China extension participants please refer to Appendix 8 (Section 10.8). 
Actual COD for final PFS analysis will be the date when approximately 201 PFS events assessed 
by ICR have been observed or when all participants from the global cohort have been followed-up 
for at least 10 months (or discontinued treatment), whichever is earlier. 
Actual COD for final OS analysis will be the date when approximately 196 death events have 
been observed (approximately 70% of the participants have died).  
9.4.1 Efficacy analyses  
All efficacy analyses for the global part will be performed on the intent-to-treat (ITT) population 
unless stated otherwise. All primary and secondary efficacy endpoints based on radiological 
assessments of tumor burden (ie, PFS, BOR, ORR, disease control rate [DCR], clinical benefit 
rate [CBR], and duration of response [DOR]) will be derived using the ICR tumor assessment. 
Analysis based on local radiologist’s/Investigator’s assessment will be considered as supportive 
analyses. 
A summary of efficacy analyses is provided in Table 6. 
Table 6 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
PFS 
 
Stratified logrank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for probabilities of being event free at different time points. 
Key secondary 
OS 
  
 
Stratified logrank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for probabilities of being event free at different time points. 
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Secondary 
ORR, DCR, CBR 
 
No statistical testing will be performed. 
Descriptive statistics by treatment arm and Clopper-Pearson method for CI calculation. 
DOR 
Kaplan-Meier method for probabilities of being event free at different time points. 
PFS by ESR1 mutation 
status 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for probabilities of being event free at different time points. 
Exploratory 
Will be described in the SAP finalized before database lock. 
CBR = clinical benefit rate; CI = confidence interval; DCR = disease control rate; DOR = duration of response; ESR1 = estrogen receptor 1 gene; 
HR = hazard ratio; OS = overall survival; ORR = objective response rate; PFS = progression-free survival; SAP = statistical analysis plan. 
9.4.1.1 Analysis of primary efficacy endpoint  
Progression-free survival is defined as the time from the date of randomization to the date of the 
first documentation of objective PD according to RECIST 1.1 definitions or death due to any 
cause in the absence of documented PD, whichever occurs first. Primary efficacy analysis will 
consist of PFS comparison between the amcenestrant arm and the control arm through a logrank 
test procedure stratified by the stratification factors as entered in the IRT (Section 6.3). A 
one-sided Type I error rate of 2.5% will be used for statistical testing. 
The primary analysis of PFS will be based on the following censoring rules: 
• 
If progression and death are not observed before the COD for final PFS, PFS will be 
censored at the date of the last valid disease assessment with no evidence of a disease 
progression prior to the initiation of a further anticancer therapy (if any). 
• 
A participant without an event (death or disease progression) and without any valid 
postbaseline disease assessments will be censored at the day of randomization (Day 1). 
• 
A participant with an event documented after two or more non-evaluable tumor 
assessments will be censored at the date of the last evaluable tumor assessment 
documenting no progression prior to the initiation of a further anticancer therapy. 
The HR estimates and corresponding 95% two-sided CIs will be provided using the Cox 
proportional hazard model stratified by the same stratification factors as those used for the logrank 
test described above. Progression-free survival for the 2 treatment arms will be summarized using 
Kaplan-Meier methods and displayed graphically. The median event time and associated 95% CI 
will be provided, along with probabilities of being progression-free at different time points. 
Sensitivity analyses (eg, different censoring rules and PFS assessed by the Investigator) and 
subgroup analyses of PFS will be performed as specified in the SAP finalized before database 
lock. 
9.4.1.2 Analysis of secondary efficacy endpoints  
Analysis of response-based endpoints (ie, ORR, DCR, CBR, and DOR) will be performed for the 
global part primarily on the ITT population and supported by the analyses based on the ITT 
population with measurable disease at study entry. Except for OS, secondary endpoints will be 
analyzed at the time of the PFS analysis only. Of note, the BOR for each participant will also be 
summarized by treatment arm. 
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Key secondary endpoint: 
Overall survival 
Overall survival is defined as the time from date of randomization to date of documented death 
due to any cause. In the absence of observation of death, survival time will be censored to the last 
date the participant is known to be alive. In case of statistically significant PFS, OS comparison 
between the amcenestrant arm and the control arm will be performed through a logrank test 
procedure stratified by the stratification factors as entered in the IRT (Section 6.3). Otherwise, 
descriptive statistics of OS will be provided at the time of final PFS analysis. 
The HR estimates and corresponding 95% two-sided CI will be provided using the Cox 
proportional hazard model stratified by the same stratification factors as those used for the PFS 
analysis described above. Overall survival for the 2 treatment arms will be summarized using 
Kaplan-Meier methods and displayed graphically. The median event time and associated 95% CI 
will be provided.  
The 1-year survival probability and its 95% CI will be estimated using the Kaplan-Meier method 
and a log-log approach based on a normal approximation following the Greenwood’s formula. 
Similar approaches will be used for 2-year and 3-year survival probabilities, if appropriate. 
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 OS 
will be performed only if the primary analysis of the PFS is statistically significant.  
Other secondary endpoints: 
Objective response rate 
The ORR on each randomized treatment arm will be estimated by dividing the number of 
participants with objective response (confirmed CR or PR as BOR, according to RECIST 1.1) by 
the number of participants from the analysis population of the respective treatment arm. In 
addition, 95% two-sided CIs will be computed using the Clopper-Pearson method. 
Disease control rate  
The DCR on each randomized treatment arm will be estimated by dividing the number of 
participants with disease control (confirmed CR or PR, SD, or Non-CR/Non-PD as BOR, 
according to RECIST 1.1) by the number of participants from the analysis population of the 
respective treatment arm. In addition, 95% two-sided CIs will be computed using the 
Clopper-Pearson method. 
Clinical benefit rate 
The CBR on each randomized treatment arm will be estimated by dividing the number of 
participants with clinical benefit (confirmed CR or PR as BOR, SD or Non-CR/Non-PD lasting at 
least 24 weeks, according to RECIST 1.1) by the number of participants from the analysis 
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population of the respective treatment arm. In addition, 95% two-sided CIs will be computed 
using the Clopper-Pearson method. 
Duration of response  
The DOR will only be summarized on the subgroup of participants who have achieved objective 
response in the respective analysis population. For participants with ongoing response at the time 
of the analysis, DOR will be censored at the date of the last valid disease assessment not showing 
disease progression performed before the initiation of a new anticancer treatment (if any). 
Duration of response for the 2 treatment arms will be summarized using Kaplan-Meier methods 
and displayed graphically, if appropriate. The median event time and associated 95% CI will be 
provided.  
Progression-free survival according to ESR1 mutation status at baseline 
Progression-free survival according to ESR1 mutation status at baseline will be assessed 
following the procedures in Section 9.4.1.1, with the exception that no statistical test will be 
made. 
9.4.2 Safety analyses  
All safety analyses for the global part will be performed on the safety population. A summary of 
safety analyses is provided in Table 7. 
Table 7 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
No primary endpoint is defined for safety analyses. 
Secondary 
AEs/SAEs and laboratory abnormalities 
 
Descriptive statistics 
Exploratory 
Will be described in the SAP finalized before database lock 
AE = adverse event; SAE = serious adverse event; SAP = statistical analysis plan. 
9.4.2.1 Analyses of adverse events  
The observation period will be divided into 3 segments:  
• 
The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP.  
• 
The on-treatment period is defined as the time from the first dose of IMP up to 30 days 
after the last dose of IMP.  
• 
The post-treatment period is defined as the time starting 31 days after the last dose of IMP 
to study closure.  
Pre-treatment AEs are defined as any AE occurring during the pre-treatment period. 
Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator’s 
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opinion), or become serious during the on-treatment period. Post-treatment AEs are defined as 
AEs that are reported during the post-treatment period. The primary focus of AE reporting will be 
on TEAEs. Pre-treatment and post-treatment AEs will be described separately. 
Treatment-emergent AEs will be coded according to MedDRA. Adverse events will be graded 
according to the NCI-CTCAE v5.0. The grade will be taken into account in the summary. For 
participants with multiple occurrences of the same PT, the maximum grade will be used. 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• 
Treatment-emergent AEs 
• 
Grade ≥3 TEAEs 
• 
Grade 5 TEAEs (any TEAE with a fatal outcome during the on-treatment period) 
• 
Serious TEAEs 
• 
Treatment-emergent AEs leading to definitive treatment discontinuation 
• 
Treatment-related TEAEs 
• 
Treatment-related TEAEs Grade ≥3 
• 
Serious treatment-related TEAEs. 
• 
AESIs 
Number and percentage of participants experiencing TEAEs by primary system organ class and 
PT will be summarized by NCI-CTCAE v5.0 grade (all grades and Grade ≥3) for the safety 
population. Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to 
definitive discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal 
outcome, AESIs, and AEs/SAEs occurring during the post-treatment period. 
9.4.2.2 Analyses of clinical laboratory evaluations  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the on-treatment period will be provided for the 
safety population. 
When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
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9.4.3 Other analyses  
9.4.3.1 Analyses of patient reported outcome endpoints  
Patient reported outcomes endpoints for each of the 3 selected PRO/HRQL and health utility 
instruments (EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L) will be analyzed in participants 
from the safety population who have completed the baseline and at least 1 postbaseline 
assessment. 
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). Reasons for non-completion will be summarized 
on the safety population. For the QLQ-C30 (15 total scales), QLQ-BR23 (8 scales), and 
EQ-5D-5L (health index and VAS) instruments, descriptive statistics on the absolute value and 
changes from baseline will be done for each treatment arm at each time point, at EOT and 60 to 
90 days after the last study administration (follow-up). Between treatment comparisons of the 
change from baseline for each cycle to EOT and to follow-up will be provided for the QLQ-C30 
(15 total scales), QLQ-BR23 (8 scales), and EQ-5D-5L (health index and VAS). 
A more detailed SAP for the 3 PROs will be detailed in the study SAP finalized before database 
lock.  
9.4.3.2 Analyses of other endpoints  
Further therapy, PK, PDy, and biomarker exploratory analyses will be described in the SAP 
finalized before database lock. A population PK analysis will be planned and reported separately 
from the global clinical study report. In case a PK/PDy analysis is planned, a dedicated SAP will 
be prepared. 
9.5 
INTERIM ANALYSES   
9.5.1 Interim analysis for progression-free survival  
An interim analysis on PFS is planned for futility at 50% of the planned total number of PFS 
events (ie, approximately 101 PFS events). Without possible claim for overwhelming evidence of 
efficacy, no Type I error rate adjustment will be performed. The stopping boundary for futility is 
based on the observed HR based on Cox proportional hazard model, ie, an HR>1.1  
A summary of the PFS analyses is provided in Table 8. 
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Table 8 - Progression-free survival analyses  
Analysis 
Months 
after FPI 
(approx. 
under PFS 
HR=0.65) 
Planned 
accrual  
Number of 
events 
(under PFS 
HR=0.65) 
Informatio
n fraction 
Cumulativ
e Power 
(under PFS 
HR=0.65) 
Futility 
boundary 
Efficacy 
boundary 
PFS IA 
(futility only) 
10 
239 
101 
50% 
 
HR > 1.1 
NA 
PFS Final 
analysis 
18 
282 
201 
100% 
86% 
p >0.025 
(HRa >0.758) 
p ≤0.025 
(HRa 
≤0.758) 
a HR is provided only for information purposes. The interim and final decisions will be based on p-values. 
Note: numbers have been rounded. Calculations were made using East 6.5 software. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; PFS = progression-free survival.  
The SAP will describe the planned interim analyses in greater detail. 
9.5.2 Interim analysis for overall survival  
Comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of 2 analyses are planned for OS: at the time of the 
primary analysis of PFS and at the final OS analysis. 
A gamma error spending function (γ = -8) will be used, along with the hierarchical testing strategy 
to strongly control the family-wise error rate (FWER; overall Type I error rate). This guarantees 
the protection of the 2.5% FWER across hypotheses associated with PFS and OS and the repeated 
testing of the OS hypotheses at interim and the final analysis (34). If the value of the test statistic 
exceeds the efficacy boundary (z ≤-3.716, p ≤0.0001), superiority of OS will be claimed but 
survival data will continue to be collected until the end of study when approximately 196 death 
events have been observed. 
A summary of the OS analyses is provided in Table 9. 
Table 9 - Overall survival analyses  
Analysis 
Months 
after FPI 
(approx.) 
Planned 
accrual  
Number 
of deaths 
(approx.) 
Information 
fraction 
Cumulative 
Powera 
(under 
HR=0.75) 
Futility 
boundary 
Efficacy 
boundary 
OS IA (at 
PFS final 
analysis) 
18 
282 
63 
32% 
0.5% 
NA 
p ≤0.0001 
(HRb ≤0.392) 
 
Final analysis  
64 
282 
196 
100% 
52% 
p >0.0249 
(HRb >0.756) 
p ≤0.0249 
(HRb ≤0.756) 
a Marginal power conditional to statistically significance of PFS.  
b HR is provided only for information purposes. The interim and final decisions will be based on p-values. 
Note: number have been rounded. Calculations were made using East 6.5 software. Assume a 5% dropout rate at 64 months after first 
participant randomized. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; OS = overall survival.  
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Selected independent statisticians/programmers will perform the interim analysis; individual 
participant identification will not be released to anyone who is involved in the conduct of the 
study. 
9.5.3 Data Monitoring Committee  
This study will use an independent Data Monitoring Committee (DMC). Details on DMC 
structure and role are presented in Section 10.1.4. 
The first DMC meeting will be set up to review early safety results (eg, after approximately 
25 participants have completed at least 2 cycles in the amcenestrant arm, or after 6 months after 
first participant randomized), and then periodically. Ad hoc DMC meetings may also be held if a 
significant safety issue or an issue deemed important for discussion arises on this or other 
amcenestrant studies. After each meeting, the DMC will make recommendations to the Sponsor’s 
representatives regarding the continued safety of treating ongoing and future study participants, as 
well as the course of action regarding the conduct of the study. 
The DMC will also oversee the interim analyses on PFS detailed in Section 9.5.1.  
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
- 
Applicable laws and regulations. 
• 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require national Health Authority and IRB/IEC 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of serious adverse events (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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
10.1.2 Informed consent process  
• 
The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his/her legally authorized representative and answer 
all questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and 
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Data Protection requirements including those of the Global Data Protection Regulation 
(GDPR) and of the French law, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. Participant agreement will be required to allow any remaining specimens to be 
used for exploratory research. Participants who decline to participate in this optional research will 
not provide this separate signature. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.16 (Appendix 16). 
10.1.3 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
several regulatory agencies (eg, on African American population for the Food and Drug 
Administration or on Japanese population for the Pharmaceuticals and Medical Devices Agency 
in Japan).  
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant.  
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• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.4 Committees structure  
Data Monitoring Committee 
This study will use an independent Data Monitoring Committee (DMC). The DMC membership 
and governance are outlined in a separate charter. The DMC will be in charge of reviewing the 
safety data and the progress of the study (including overseeing interim analyses) and advising the 
Sponsor on potential modifications or communications that may be necessary to ensure the 
participant safety or protect the scientific integrity of the study. The Sponsor will make the final 
decision(s) regarding study participants according to the charter. The DMC will make a 
recommendation as to whether or not the study should continue based on ongoing reviews of 
safety data. 
Independent Central Review 
An independent central review will be assigned to centrally perform tumor assessments within the 
scope of the primary and secondary efficacy endpoints. A third-party entity will provide this 
service.  
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on 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 clinical trial register (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 internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
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10.1.6 Data quality assurance  
• 
All participant data relating to the study will be recorded on electronic case report form 
(eCRF) unless transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. The 
planned frequency and nature of data monitoring during the study will be tailored to the 
specific data priorities and risks identified. 
• 
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 designee is responsible for the data management of this study including 
quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF 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.  
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the end of the clinical study 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.  
10.1.7 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 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. 
• 
Definition of what constitutes source data can be found in the Monitoring plan. 
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10.1.8 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
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 recruitment of participants by the Investigator 
• 
Discontinuation of further study intervention development 
• 
Information on the product leads to doubt as to the benefit/risk ratio 
10.1.9 Publication policy  
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• 
The tests detailed in Table 10 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 10 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistrya,b  
Blood urea nitrogen 
or urea  
Potassium 
Aspartate 
aminotransferase 
(AST)/ Serum 
glutamic-oxaloacetic 
transaminase (SGOT) 
Total and conjugated 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
aminotransferase 
 (ALT)/ Serum 
glutamic-pyruvic 
transaminase (SGPT) 
Chloride 
 
Magnesium 
Calcium 
Alkaline phosphatase 
Serum albumin 
 
Phosphate 
 
GFR 
Glucose 
Lactate 
dehydrogenase 
 
Gamma-glutamyl 
transferase  
Coagulationc 
Prothrombin time 
International normalized ratio (INR) 
 
 
 
Routine urinalysisd 
• 
pH, glucose, protein, blood, ketones, and leukocytes by dipstick 
• 
Microscopic examination (if blood or protein is abnormal), if clinically indicated. 
 
 
Other testse 
• 
Follicle-stimulating hormone and estradiol (as needed in women <60 years of age and 
premenopausal women on a gonadotropin-releasing hormone analog).  
• 
Pregnancy tests (serum and then urine) for WOCBP. 
The results of each test must be entered into the electronic case report form. 
a Hematology to be performed at screening, repeated within 2 or 3 days before randomization, in case of abnormal evaluations on 
parameters such as body weight, signs and symptoms, physical examination, electrocardiogram, hematology, coagulation tests, blood 
chemistry, and urinalysis, and repeated at Cycle 1 Day 1 if screening test >7 days of Day 1 Cycle 1, then performed on Day 1 of every 
subsequent cycle, at the end of treatment visit, and as clinically indicated. In the event of Grade 3 or 4 neutropenia, absolute neutrophil 
count (ANC) is assessed every 2 to 3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L (test to be done 
prior to study treatment administration). Hematological abnormalities will be recorded as adverse events only if they are serious or lead to 
study treatment modification or discontinuation. 
b Clinical chemistry analyses will be performed in accordance with Section 1.3 and when clinically relevant. In case of Grade 3 or higher 
liver function abnormal tests, additional tests will be done every 2 to 3 days until recovery to normal or baseline value. Blood biochemistry 
to be performed at screening and repeated within 1 day prior to Cycle 1 Day 1 if screening test >7 days of Day 1 Cycle 1. Biochemistry 
will be performed prior to study treatment administration on Day 1 for subsequent cycles. 
c Coagulation tests can be performed after Cycle 1 Day 1, if clinically indicated. 
d Urinalysis will be performed in accordance with Section 1.3 and when clinically relevant. Participants with 3+ or greater urine protein 
dipstick reading should undergo further assessment with a 24-hour urine collection for determination of proteinuria. 
e For patients receiving Fulvestrant as IMP, Estradiol will not be needed after screening test. Pregnancy test to be performed at screening, 
repeated (by dipstick) at Cycle 1 Day 1 if screening test >7 days prior to Cycle 1 Day 1. 
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF ADVERSE EVENT (AE) 
Adverse event definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• 
Vital signs and electrocardiogram (ECG) are to be recorded as AEs only if they are 
symptomatic and/or requiring corrective treatment and/or leading to treatment 
discontinuation and/or modification of dosing and/or fulfilling a seriousness criterion.  
• 
Clinically significant laboratory abnormalities are to be recorded as AEs only if they are 
serious or impact study treatment (ie, lead to dose omission, reduction, delay, or 
discontinuation). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
Events NOT meeting the AE definition 
• 
Any 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. 
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DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be a serious AE (SAE) even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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DEFINITION OF UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (eg, Investigator's Brochure for an unapproved investigational medicinal product). 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
Adverse event 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 electronic case 
report form (eCRF). 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it using National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI-CTCAE] v5.0.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50  
Assessment of causality 
• 
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
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• 
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 the Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
Serious AE reporting to Sponsor via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to Sponsor will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
• 
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 monitoring team by fax or email. 
• 
Contacts for SAE reporting can be found in the reference manual. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Male participants 
Not applicable for men with prior bilateral orchiectomy. 
• 
Male participants with heterosexual partners of reproductive potential are eligible to 
participate if they agree to use the following during the protocol-defined timeline: 
- 
Refrain from donating sperm 
and 
- 
Agree to be on a gonadotropin-releasing hormone analog for at least 4 weeks (to be 
continued during study treatment) as per label and use a male condom during 
intercourse during study treatment until 1 week after stopping the study treatment or 
after the time indicated by the GnRH analog label (eg 12 weeks after last injection of 
Goserelin) whichever is the longest, 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. 
• 
Men with a pregnant or breast-feeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
• 
Male participants should consider sperm preservation prior to beginning therapy with 
study IMPs because exposure to amcenestrant has the potential risk of testicular injury 
with partial or permanent infertility. Because exposure to amcenestrant, has the potential 
risk of testicular injury with partial or permanent infertility. 
Woman of childbearing potential (WOCBP) 
Not applicable for postmenopausal women. 
Non-hormonal methods of contraception should be employed during the study in premenopausal 
women on a gonadotropin-releasing hormone analog as per label. These include: intrauterine 
device, bilateral tubal occlusion, vasectomy partner, sexual abstinence. 
The duration of the contraception will be determined from drug-labels, taking into account that 
the duration selected will be the one of the GnRH analog or the IMP, whichever is longer.  
• 
For participants with amcenestrant: 7 days 
• 
For participants with tamoxifen: 9 months 
• 
For participants with fulvestrant: 2 years 
• 
Duration varies among aromatase-inhibitors (eg, letrozole: 3 weeks, exemestane: 4 weeks)  
• 
Duration varies among GnRH analogs (eg, goserelin: 12 weeks) 
 
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COLLECTION OF PREGNANCY INFORMATION:  
Female participants who become pregnant  
• 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date but may 
last up to one year. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
• 
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any poststudy 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 the investigational medicinal product. 
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 up to one year. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.  
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10.5 
APPENDIX 5: GENETICS  
Use/Analysis of deoxyribonucleic acid (DNA)/ ribonucleic acid (RNA) 
• 
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 Institutional Review 
Boards/Independent Ethics Committees allow, a blood and a saliva sample will be 
collected for DNA analysis from consenting participants. In addition, plasma will be 
collected to isolate cell-free DNA (cfDNA) that will be used to assess for tumor mutations, 
including estrogen receptor 1 gene. The saliva sample will be used as a reference 
comparison for the tumor mutation analysis. 
• 
DNA samples will be used for research related to the IMPs or breast cancer and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to IMPs and breast cancer. Genetic research may consist of the analysis of 1 or more 
candidate genes, or the analysis of genetic markers throughout the genome, or analysis of 
the entire genome (as appropriate) and may include sequencing. 
• 
RNA may be isolated from the optional tumor biopsy in order to assess effects of IMP on 
the tumor. Analyses may include microarray, sequencing, and/or alternative similar 
techniques, resulting in a transcriptome profile. The analyses may include RNA of selected 
genes or all of the genome.  
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to amcenestrant or interventions of this class to understand breast 
cancer or related conditions. 
• 
The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• 
The Sponsor will store the DNA/RNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained for up to 5 years, or 15 years if future use of samples is 
consented to, or other period as per local requirements, following the last participant last 
visit. 
10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING   
Not applicable. 
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10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
CHINA EXTENSION STUDY 
1 
INTRODUCTION 
The decision for China to participate in the global study was taken later than for other countries, 
and consequently enrollment of the first Chinese participant may be 11 months after the 
first participant is randomized in the global study. The aims of the China extension study include 
an evaluation of the efficacy, safety, and pharmacokinetics (PK) of amcenestrant in Chinese 
participants. Enrollment of participants in China will continue as an extension study after 
enrollment into the global study is completed, until the required number of Chinese participants 
has been achieved.  
2 
STUDY DESIGN 
The design of the China extension study is the same as that of the global study (Figure 1).  
At the time of Amended Clinical Protocol 02 submission, there was no experience of amcenestrant 
in Chinese patients. However, based on available data, no ethnic difference in amcenestrant safety 
profile is expected between Chinese and non-Chinese patients. For the ACT16105 study, a safety 
observation period will be set for Chinese participants to secure safety. A safety run in step will 
consist in the sequential treatment of 6 participants with amcenestrant (ie, approximately 
12 randomized participants). None of the first 3 participants of amcenestrant arm will be treated 
for first dose on the same day. The safety review will occur when 6 Chinese participants have 
been exposed to amcenestrant and completed a minimum of 1 cycle duration (approximately 
4 weeks) of treatment. If 0 to 1 out of 6 evaluated participants had a treatment related adverse 
event of special interest (AESI) or treatment related AE leading to the treatment discontinuation, 
enrollment will continue in China. If at least 2 out of 6 evaluated amcenestrant treated participants 
have a treatment related AESI, or a treatment related AE leading to treatment discontinuation, 
enrollment will be on hold in China and further safety and PK assessment will be performed. 
3 
OBJECTIVES 
Overall, the main objectives and endpoints of the China extension are the same as those for the 
global study. A secondary objective has been added, to evaluate the full PK profile of 
amcenestrant in 12 Chinese participants in the amcenestrant treatment arm in the extension study. 
Chinese participants in the amcenestrant treatment arm in the global study and all other 
participants in the amcenestrant treatment arm in the extension study will have samples taken for 
sparse PK analysis, consistent with sampling in the global study. 
Table 11 - China extension additional objectives and endpoints  
Objectives 
Endpoints 
Secondary 
To evaluate the pharmacokinetics (PK) of amcenestrant as 
single agent. 
amcenestrant plasma concentrations during the treatment 
period. amcenestrant PK parameters will be evaluated in 
12 participants from the amcenestrant treatment arm 
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4 
STUDY POPULATION 
Participants will be selected based on the study inclusion and exclusion criteria as defined 
in Section 5 of the global study protocol and will have agreed to participate in this extension 
study. A dedicated cohort of up to approximately 90 participants will be included. 
Note: In this extension cohort, previous treatment with a CDK 4/6 inhibitor will not be 
mandatory, and there will be no limitation to the number of participants naïve to CDK4/6 
inhibitors. 
4.1.1 Additional inclusion criteria 
Not applicable. 
4.1.2 Addition exclusion criteria 
Not applicable. 
5 
STUDY INTERVENTION ADMINISTERED 
The study treatment to be administered is the same as that used in the global study and is 
administered in the same way. However, for those participants who will take part in the full PK 
profile assessment, amcenestrant administration at Cycle 1 Day 1 will be done after an overnight 
fast of at least 10 hours. A meal will be authorized from 2 hours after drug administration. 
Then, from Day 2 onwards, the drug will be administered with or without food, as described for 
the global study. From Day 2, the fasting condition (without food) is when no meal is taken within 
2 hours of amcenestrant administration and the fed condition (with food) is when a meal is taken 
within 2 hours of amcenestrant administration. 
Full PK sampling will be collected in accordance with Table 12. 
6 
STUDY PROCEDURES 
Participants enrolled in the extension study will have the main safety and efficacy assessments 
scheduled for the global part (see Section 1.3 of the global study protocol). Specific PK and 
pharmacodynamic evaluations will be performed. Biopsy samples and blood samples will be 
taken in accordance with local regulations for all participants from China (global and extension 
part). 
Pharmacokinetic evaluation  
In the extension study, 12 participants in the amcenestrant arm will have blood samples taken for 
PK analysis according to the following PK flowchart (full PK sampling; Table 12). When 
sampling is difficult for patients, full PK sampling could only be limited to Cycle 1 Day 1/2 and 
Cycle 2 Day 1 samples, other planned samples may be omitted based on investigator decision. For 
the remaining participants of the extension cohort, a sparse sampling approach for PK will be 
taken as presented in the Schedule of Activities (Section 1.3) of the global study protocol. 
Pharmacokinetic procedures (handling procedure and bioanalytical method) will be as described 
for the global study (Section 8.5 of the global study protocol). 
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Table 12 - Pharmacokinetic flowchart for full pharmacokinetic sampling  
Cycle 
Cycle 1 
Day within cycle 
Day 1/2 
Day 15 
Relative nominal 
time 
0h 
0.5h 
1h 
2h 
3h 
4h 
6h 
8h 
10h 
24h 
0h 
Time window 
[-24h, 0h] 
±5m 
±10m 
±15m 
±15m 
±30m 
±30m 
±30m 
±1h 
±1h 
[-1h, 0h] 
Indicative clock time 
8:00 AM 
8:30 
AM 
9:00 AM 
10:00 AM 
11:00 AM 
12:00 
noon 
2:00 PM 
4:00 PM 
6:00 PM 
8:00 AM 
8:00 AM 
Amcenestrant administrationb 
Once daily 
X 
  
  
  
  
  
  
  
  
X 
X 
Amcenestrant pharmacokinetics 
Plasma 
P00a 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P09a 
P10a 
 
 
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Cycle 
 
Cycle 1 
Cycle 2 
Day within cycle Day 22/23 
Day 1 
Relative 
nominal time 
0h 
0.5h 
1h 
2h 
3h 
4h 
6h 
8h 
10h 
24h 
0h 
 
Time window 
[-1h, 0h] 
±5m 
±10m 
±15m 
±15m 
±30m 
±30m 
±30m 
±1h 
±1h 
[-1h, 0h] 
Indicative clock 
time 
8:00 AM 
8:30 
AM 
9:00 
AM 
10:00 
AM 
11:00 
AM 
12:00 
noon 
2:00 
PM 
4:00 
PM 
6:00 
PM 
 
8:00 AM 
8:00 AM 
 
Amcenestrant administrationb 
Once 
X 
  
  
  
  
  
  
  
  
 
X 
Amcenestrant pharmacokinetics 
Plasma 
P11a 
P12 
P13 
P14 
P15 
P16 
P17 
P18 
P19 
P20a 
P21a 
a Sample collected just before amcenestrant administration. 
b Capsules should be taken approximately at the same time every day. 
After Cycle 2, pharmacokinetic sample collection is as described in the study Schedule of Activities (see Section 1.3). 
 
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All blood samples for PK analysis must be collected at the specified times and according to the 
specifications. Samples missed or lost, for any reason should be recorded. Actual times of blood 
collection should be recorded in the electronic case report form. The days of sampling and times 
of drug administration should also be precisely recorded for the day of PK. The total blood 
volumes to be collected from each participant for PK analysis is outlined in Table 13. 
Table 13 - Blood sample volume collected per participant during extension part  
 
 
Volume (mL)/ 
sample 
Number of 
samples 
Volume (mL)/ 
participants 
PK amcenestrant 
Full sampling 
1 mL 
25 
25 mL 
 
Sparse sampling 
1 mL 
10 
10 mL 
PK = pharmacokinetics. 
Pharmacokinetic parameters 
Pharmacokinetic analyses will be carried out by the Pharmacokinetics, Dynamics and Metabolism 
department at Sanofi. Pharmacokinetic parameters will be determined by non-compartmental 
analysis using PKDMS (running Phoenix® software). The parameters will include, but may not 
be limited to, the following (Table 14): 
Table 14 - List of pharmacokinetic parameters and definitions  
Parameters 
Drug 
Matrix 
Definition/calculation 
tlag 
amcenestrant 
Plasma 
Lag time, interval between administration time and the sampling time 
preceding the first concentration above the lower limit of quantification 
tmax 
amcenestrant 
Plasma 
First time to reach Cmax 
Cmax 
amcenestrant 
Plasma 
Maximum concentration observed 
AUC0-24 
amcenestrant 
Plasma 
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (24 hours) 
Ctrough 
amcenestrant 
Plasma 
Plasma concentration observed just before treatment administration during 
repeated dosing 
CLss/F 
amcenestrant 
Plasma 
Apparent total body clearance after repeated extra-vascular (EV) doses of a 
drug at steady state from the matrix (plasma) calculated using the following 
equation: 
 
 
Pharmacodynamic evaluation 
For participants enrolled in China, samples for estrogen receptor 1 gene (ESR1) analysis of 
cell-free deoxyribonucleic acid (cfDNA) will be collected at Cycle 1 Day 1 (predose). The other 
samples for ESR1 analysis of cfDNA will not be collected and exploratory pharmacodynamic 
endpoints will not be assessed in this extension study. 
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Note: These specificities apply also for participants from China enrolled in the global part of the 
study. 
7 
STATISTICAL ANALYSIS 
7.1 
SAMPLE SIZE DETERMINATION  
Chinese participants from the global study and from the China extension part will be pooled for 
the purpose of the analysis of the Chinese population data.  
Assuming the hazard ratio (HR) of progression-free survival (PFS) in the amcenestrant arm 
relative to the control arm is 0.65, a total of 65 PFS events in the Chinese population would 
provide an 80% probability of observing a HR inferior to 0.80 in the Chinese population, given 
that the primary analysis of PFS is statistically significant in the global study. 
Approximately 90 Chinese participants would need to be enrolled to reach 65 PFS events. 
Assuming the first Chinese participant enrolls 11 months after the first randomized participant of 
the global study and Chinese participants have a 17-month enrollment period, the cut-off date 
(COD) for PFS analysis is estimated to occur 5 months after the last Chinese participant is 
enrolled.  
The COD of the Chinese cohort is independent of the COD of the global study. The actual COD 
of the Chinese cohort will be the date with approximately 65 PFS events in Chinese population. 
7.2 
POPULATION FOR ANALYSES 
For purposes of analysis, the following populations are defined (Table 15): 
Table 15 - Populations for analyses  
Population 
Description 
Chinese ITT 
All Chinese participants from the global part of the study and from the China 
extension part who have given their informed consent and for whom there is 
confirmation of successful allocation of a randomization number by the IRT. All 
analyses using this population will be based on the treatment assigned at 
randomization. 
Chinese Safety 
All Chinese ITT participants who took at least 1 dose of study intervention. 
Participants will be analyzed according to the treatment arm they actually received. 
ITT = intent-to-treat; IRT = Interactive Response Technology. 
7.3 
STATISTICAL ANALYSIS 
Definition of the primary endpoint and secondary endpoints and the related analysis methods will 
be as described for the global study. Further details may be specified in a separate document. 
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For the 12 participants of the Chinese cohort with full PK sampling: 
• 
Individual plasma concentrations and PK parameters of amcenestrant will be tabulated 
with standard descriptive statistics. Individual and mean profiles will be presented 
graphically. 
• 
Accumulation ratio (Day 22/Day 1) for Cmax and area under the plasma concentration 
curve within 0 to 24 hours (AUC0-24h) will be estimated with 90% confidence intervals 
using a linear fixed effects model on log transformed parameters. Individual listing will be 
provided. 
• 
Within-participant and total standard deviations for log (Cmax) and log (AUC0-24) will be 
estimated. 
The decision to continue or not with the recruitment of Chinese patients will be based on the 
results of the statistical analyses performed in the global population. 
8 
SAFETY REPORTING 
Adverse events and serious adverse events will be captured and reported in accordance with the 
global study (see Section 8.3). 
9 
ADMINISTRATION 
9.1 
INFORMED CONSENT 
An informed consent (ICF) shall be obtained from participants who voluntarily agree to 
participate in the extension study. Participants who agree to have samples taken for the full PK 
profile assessment will sign a separate section in the informed consent for this aspect of the study. 
The informed consent form reflecting this study and the full PK profile sampling will be 
submitted for review and approval to the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) charged with this responsibility. 
9.2 
CONFIDENTIALITY 
Data collection and handling by the Sponsor for this study will be in accordance with that 
described in the global study protocol (see Section 10.1 [Appendix 1]), and every effort will be 
made to protect participant confidentiality. In case the results are published, they will be done so 
anonymously. 
9.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
This study, the ICFs for this study, and any advertisement for participant recruitment will be 
submitted for review and approval to the IRB/IEC charged with this responsibility. 
9.4 
RECORDS RETENTION 
Investigators must retain records pertaining to this extension as described in the global study 
protocol (see Section 10.1 [Appendix 1]). 
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10.9 
APPENDIX 9: ABBREVIATIONS  
 
18FES: 
18fluoroestradiol 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AI: 
aromatase inhibitor 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
AUC0-24h: 
area under the plasma concentration curve within 0 to 24 hours 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
cfDNA: 
cell-free deoxyribonucleic acid 
CFR: 
Code of Federal Regulations 
CI: 
confidence interval 
COD: 
cut-off date 
CR: 
complete response 
CT: 
computed tomography 
Ctrough: 
plasma concentration observed before treatment administration 
CYP: 
cytochrome P450 
DCR: 
disease control rate 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EORTC: 
European Organisation for Research 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 1 gene 
FIH: 
first in human 
FSH: 
follicle-stimulating hormone 
FWER: 
family-wise error rate 
GCP: 
Good Clinical Practice 
GHS: 
Global Health Status 
GnRH: 
gonadotropin-releasing hormone 
HER2: 
human epidermal growth factor receptor 2 
HR: 
hazard ratio 
HRQL: 
health-related quality of life 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
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ICR: 
independent central review 
IEC: 
Independent Ethics Committee 
IHC: 
immunohistochemistry 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
LFT: 
liver function test 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR: 
objective response rate 
OS: 
overall survival 
PD: 
progressive disease 
PDy: 
pharmacodynamic(s) 
PET: 
positron emission tomography 
PFS: 
progression-free survival 
P-gp: 
P-glycoprotein 
PgR: 
progesterone receptor 
PK: 
pharmacokinetic(s) 
PO: 
per os 
PR: 
partial response 
PRO: 
patient reported outcome 
PT: 
preferred term 
QD: 
once daily 
QLQ-BR23: 
EORTC QLQ breast cancer specific module 
QLQ-C30: 
EORTC core quality of life questionnaire 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
stable disease 
SDF: 
survival distribution functions 
SERD: 
selective estrogen receptor degrader 
SERM: 
selective estrogen receptor modulator 
SoA: 
Schedule of Activities 
SUSARs: 
Suspected unexpected serious advarse reactions 
TEAE: 
treatment-emergent adverse event 
TTP: 
time to progression 
UGT: 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN: 
upper limit of normal 
VAS: 
visual analogue scale 
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10.10 APPENDIX 10: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS  
Table 16 - Eastern Cooperative Oncology Group performance status scale  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. (35) 
10.11 APPENDIX 11: LIST OF STRONG CYP3A4 INDUCERS  
Concomitant administration of medications that are strong CYP3A inducers are not permitted 
throughout the active treatment phase. 
The following table was extracted in October 2020 from the Drug- Drug Interaction Database 
from the University of Washington (www.druginteractioninfo.org). 
STRONG CYP3A INDUCERS 
Inducers 
Therapeutic 
Class 
Victim (oral unless 
otherwise specified) Max AUCR 
Precipitant dose (oral) 
Strong Inducers (AUCR ≤ 0.2 or CL Ratio ≥ 5) 
Rifampin 
Antibiotics 
Budesoinide 
0.003 
600 mg QD (7 days) 
Mitotane 
Other Antineoplastics Midazolam 
0.06 
Maximum of 3.5g TID (chronic 
therapy) 
Avasimibe 
Other Antilipemics 
Midazolam 
0.07 
750 mg/day (7 days) 
Rifapentine 
Antibiotics 
Midazolam 
0.07 
20 mg/kg QD (14days) 
Apalutamide 
Antiandrogens 
Midazolam 
0.08 
240 mg QD (29 days) 
Ivosidenib 
Cancer Treatments 
Midazolam 
0.10 (PBPK) 
1200 mg QD (19 days; PBPK 
modeling) 
Phenytoin 
Anticonvulsants 
Nisoldipine 
0.11 
200-450 mg/day (chronic treatment) 
Carbamazepine 
Anticonvulsants 
Quetiapine 
0.13 
200 mg TID (26 days) 
Enzalutamide 
Antiandrogens 
Midazolam 
0.14 
160 mg QD (85±3 days) 
St John’s Wort 
extract 
Herbal Medicines 
Midazolam 
0.20 
300 mg TID (14 days) 
Lumacaftor 
Cystic Fibrosis 
Treatments 
Ivacaftor 
0.20 
Not provided 
Phenobarbital 
Anticonvulsants 
Verapamil 
0.23 
100 mg QD (21 days) 
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10.12 APPENDIX 12: LIST OF CYP SENSITIVE SUBSTRATES  
In vivo, amcenestrant is a weak to moderate CYP3A inducer, and in vitro a potential inducer of 
CYP2B6 and CYP2Cs family.  Therefore, study participants receiving amcenestrant and treated or 
intended to be treated with the following drugs presented as CYP sensitive substrates should be 
carefully monitored since it may result in loss of efficacy of these agents. 
The tables for CYP sensitive substrates were extracted in October 2020 from the Drug- Drug 
Interaction Database from the University of Washington (www.druginteractioninfo.org). Some 
known substrates of the enzymes may not be listed because they do not have changes in exposure 
reaching sufficient level or may not have DDI studies with AUC/CL changes available. 
In vivo CYP3A Sensitive Substrate 
Drug (oral) 
Therapeutic Class 
alfentanil 
Opioids 
alisporivir 
Antivirals 
almorexant 
Hypnotics - Sedatives 
alpha-dihydroergocryptine 
Dopaminergic Agonists 
aplaviroc 
CCR5 Receptor Antagonists  
aprepitant 
Neurokinin-1 Receptor Antagonists 
asunaprevir 
Antivirals 
atazanavir 
Protease Inhibitors 
atorvastatin 
HMG CoA Reductase Inhibitors (Statins) 
avanafil 
Erectile Dysfunction Treatments 
blonanserin 
Antipsychotics  
brecanavir 
Protease Inhibitors 
brotizolam 
Benzodiazepines 
budesonide 
Corticosteroids 
buspirone 
Anxiolytics  
capravirine 
Antivirals 
casopitant 
Neurokinin-1 Receptor Antagonists 
conivaptan 
Vasopressin Antagonists 
danoprevir 
Antivirals 
darifenacin 
Muscarinic Antagonists 
darunavir 
Protease Inhibitors  
dronedarone 
 Antiarrhythmics 
ebastine 
 H1 Receptor Antagonists 
eletriptan 
Triptans  
eliglustat (in subjects CYP2D6 PMs) 
Glucosylceramide Synthase Inhibitors 
elvitegravir 
HIV-Integrase Strand Transfer Inhibitors 
eplerenone 
Diuretics 
everolimus 
Immunosuppressants  
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Drug (oral) 
Therapeutic Class 
felodipine 
Calcium Channel Blockers  
indinavir 
Protease Inhibitors 
isavuconazole 
Antifungals 
itacitinib 
Kinase Inhibitors 
ivabradine 
Cardiovascular Drugs 
ivacaftor 
Miscellaneous Agents 
levomethadyl (LAAM) 
Drug Addiction Treatments 
lomitapide 
Other Antilipemics 
lopinavir 
Protease Inhibitors 
lovastatin 
HMG CoA Reductase Inhibitors (Statins) 
lumefantrine 
Antimalarials  
lurasidone  
Antipsychotics  
maraviroc 
CCR5 Receptor Antagonists 
midazolam 
Benzodiazepines 
morphothiadin 
Antivirals 
naloxegol 
Gastrointestinal Agents 
nisoldipine 
Calcium Channel Blockers  
paritaprevir 
Antivirals 
perospirone 
Antipsychotics  
quetiapine 
Antipsychotics  
saquinavir 
Protease Inhibitors 
sildenafil 
Erectile Dysfunction Treatments 
simeprevir 
Protease Inhibitors 
simvastatin 
HMG CoA Reductase Inhibitors (Statins) 
sirolimus 
Immunosuppressants  
tacrolimus 
Immunosuppressants 
terfenadine 
H1 Receptor Antagonists  
ticagrelor  
Anticoagulants and Antiplatelets 
tilidine 
Treatments of Pain and Inflammation 
tipranavir 
Protease Inhibitors  
tolvaptan 
Vasopressin Antagonists 
triazolam 
Benzodiazepines  
ubrogepant 
Migraine Treatments 
ulipristal 
Hormones 
vardenafil 
Erectile Dysfunction Treatments 
vicriviroc 
CCR5 Receptor Antagonists 
vilaprisan 
Progesterone Receptor Modulator 
voclosporin 
Immunosuppressants 
NOTES: The present list includes CYP3A substrates with AUC Ratio of at least 5 when coadministrated with strong CYP3 inhibitor 
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In vivo CYP2B6 Sensitive substrate 
Substrate (oral) 
Therapeutic Class 
bupropion 
Anticoagulants and Antiplatelets 
efavirenz  
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 
NOTE: There are no CYP2B6 substrates with AUC Ratio of at least 5, or decrease in oral CL of 80% or more. However, bupropion and 
efavirenz are considered the most sensitive substrates studied. 
 
 
In vivo CYP2C8 Sensitive substrate 
Substrate (oral) 
Therapeutic Class 
daprodustat 
Other 
dasabuvir 
Antivirals 
repaglinide 
Meglitinides 
NOTE: The present list includes CYP2C8 substrates with AUC Ratios ≥5 or CL Ratios ≤0.20. 
In vivo CYP2C9 Sensitive substrate 
Substrate (oral) 
Therapeutic Class 
tolbutamide 
Sulfonylureas 
(S)-warfarin  
Anticoagulants and Antiplatelets 
benzbromarone 
Anticoagulants and Antiplatelets 
celecoxib 
NSAIDS 
ibuprofen 
NSAIDS 
glimepiride 
Sulfonylureas 
glipizide 
Sulfonylureas 
lornoxicam 
NSAIDS 
meloxicam 
NSAIDS 
piroxicam 
NSAIDS 
NOTE: The present list includes CYP2C9 substrates with AUCR ≥ 5 or CL Ratio ≤ 0.20 
In vivo CYP2C9 Sensitive substrate 
Substrate (oral) 
Therapeutic Class 
lansoprazole (dexlansoprazol) 
Proton Pump Inhibitors 
(S)-mephenytoin 
Anticonvulsants 
omeprazole 
Proton Pump Inhibitors 
tilidine 
Treatments of Pain and Inflammation 
(R)-(-)-hexobarbital 
Hypnotics - Sedatives 
(R)-mephobarbital 
Anticonvulsants 
clobazam (parent drug) 
Benzodiazepines 
diazepam 
Benzodiazepines  
gliclazide 
Sulfonylureas 
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Substrate (oral) 
Therapeutic Class 
pantoprazole 
Proton Pump Inhibitors 
proguanil (prodrug) 
Antimalarials 
rabeprazole 
Proton Pump Inhibitors 
NOTE: The present list includes CYP2C19 substrates with an AUCR ≥5, or CL ratio ≤0.20. 
10.13 APPENDIX 13: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA  
GFR (mL/min/1.73 m2) = 175 × (Scr) − 1.154 × (Age) − 0.203 × (0.742 if female) × (1.212 if 
African American) (conventional units) 
 
GFR = glomerular filtration rate; Scr = serum creatinine. 
Source: https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-
rate-calculators/mdrd-adults-conventional-units 
10.14 APPENDIX 14: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1)  
Details provided in bibliographic reference (36). 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable as 
follows: 
Measurable 
• 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:  
- 
Ten millimeters by computed tomography (CT) scan (CT scan slice thickness no 
greater than 5 mm).  
- 
Ten-millimeter caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
- 
Twenty millimeters by chest X-ray. 
• 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed (see Special Issue 15 [36]). See also notes 
below on “Baseline documentation of target and nontarget lesions” for information on 
lymph node measurement. 
Non-measurable 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with 10 to <15 mm short axis) as well as truly nonmeasurable lesions. Lesions 
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considered truly nonmeasurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical examination that 
is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or magnetic 
resonance imaging (MRI) can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. 
• 
Blastic bone lesions are nonmeasurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts.  
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
Methods of measurement 
• 
Measurement of lesions:  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
• 
Method of assessment:  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
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evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical examination. Clinical 
lesions: Clinical lesions will only be considered measurable when they are superficial and 
10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
• 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
• 
Computed tomography, MRI: CT is the best currently available and reproducible method 
to measure lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. Magnetic resonance imaging is 
also acceptable in certain situations (eg, for body scans). 
• 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. 
• 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
• 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
participant to be considered in CR. Specific guidelines for both cancer antigen 125 response 
(in recurrent ovarian cancer) and prostate-specific antigen response (in recurrent prostate 
cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 
developed cancer antigen 125 progression criteria which are to be integrated with 
objective tumor assessment for use in first line trials in ovarian cancer. 
• 
Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (eg, residual lesions in tumor 
types such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (eg, with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease (SD) in order to 
differentiate between response (or SD) and progressive disease. 
Tumor response evaluation 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only participants 
with measurable disease at baseline should be included in protocols where objective tumor 
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response is the primary endpoint. Measurable disease is defined by the presence of at least 
1 measurable lesion. In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether participants having non measurable disease 
only are also eligible. 
Response criteria 
Table 17 - Response criteria, evaluation of target lesions  
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 
Table 18 - Response criteria, evaluation of nontarget lesions  
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph 
nodes must be nonpathological in size (<10 mm short axis). 
Incomplete Response/Stable 
Disease (SD):  
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression (see comments below)a of existing nontarget lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
a Although a clear progression of “nontarget” lesions only is exceptional, in such circumstances, the opinion of the treating physician should 
prevail and the progression status should be confirmed later on by the review panel (or study chair). 
Evaluation of best overall response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 19 
provides a summary of the overall response status calculation at each time point for participants 
who have measurable disease at baseline. If participants have non-measurable (therefore 
non-target) disease only, Table 20 is to be used. 
Table 19 - A summary of overall response status  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
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Target lesions 
Non-target lesions 
New lesions 
Overall response 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
Table 20 - A summary of overall response status for non-measurable disease  
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; SD = stable disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials, so to assign this category when no lesions can be measured is not advised. 
Table 21 - Evaluation of best overall response  
Overall response 
Overall response 
BEST overall response 
First time point 
Subsequent time point 
 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the participant had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease 
The best overall response is determined once all the data for the participant is known. 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline (defined as 42 days). If the minimum time is not met when SD is otherwise the best 
time point response, the participant’s best response depends on the subsequent assessments. For 
eg, a participant who has SD at first assessment, PD at second and does not meet minimum 
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duration for SD, will have a best response of PD. The same participant lost to follow-up after the 
first SD assessment would be considered inevaluable. Complete or partial responses may be 
claimed only if the criteria for each are met at a subsequent time point as specified in the protocol 
(generally 4 weeks later). In this circumstance, the best overall response can be interpreted as in 
Table 21.  
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.15.1 
Amended protocol 01: 08 August 2019  
This amended protocol (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. 
Overall Rationale for the Amendment 
The objective of this amendment is to clarify and improve the feasibility of study procedures, as 
well as to clarify inclusion/exclusion criteria. An extension to the study in China has been added 
to enable the enrollment of sufficient Chinese participants to support analysis of the data for 
participants in China alone. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.2 Schema 
The text in Figure 1 was updated: 
“OS [overall survival] follow-up  
Every 3 2 months until 18 months after PFS 
[progression-free survival] cut-off date.” 
To correct error in the text. 
1.3 Schedule of 
activities 
The tumor assessment schedule has been updated: 
c “If no radiological PD [progressive disease] at EOT 
last tumor assessment during the treatment 
period, disease assessment will continue to be 
performed every 8 weeks ±7 days (projected from 
last tumor assessment) up to PD” 
To clarify the tumor assessment 
schedule. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
The bone scan schedule has been updated: 
a “If at screening, lesions are detected in the bone scan 
but not in the CT/MRI [computed 
tomography/magnetic resonance imaging] (RECIST 
[Response Evaluation Criteria in Solid Tumors] 1.1) 
scan, further bone scans should be conducted every 
8 weeks ±7 days. If the lesions seen in the bone scan 
are no longer visible, these assessments can be 
conducted every 16 weeks ±7 days. 
If lesions are detected in the bone scan and CT/MRI 
(RECIST 1.1) scan, further bone scan assessments 
will be conducted every 16 weeks ±7 days.” 
To clarify the bone scan schedule. 
 
amcenestrant pharmacokinetic assessment schedule has 
been updated:  
“Cycles 2 to 6 3, 4, and 6:  
On the day of tumor assessment: 1 sample Day 1: 
predose.” 
To accommodate the pharmacokinetic 
assessments with participant visits to the 
site. 
 
Tumor specimen/biopsy schedule updated: 
“To be done Cycle 3 Day 1 (allowed up to Cycle 3 
Day 15 or within 14 days after first radiological tumor 
assessment after baseline).” 
To clarify tumor specimen/biopsy 
schedule on Cycle 3. 
 
Clarified that estrogen receptor 1 gene (ESR1) analysis 
of cell-free deoxyribonucleic acid (cfDNA) will be 
performed on Cycle 1 Day 1 and Cycle 3 Day 1. 
To clarify ESR1 analysis on Cycle 3. 
2 Introduction 
The following indication has been added for letrozole: 
“Neoadjuvant treatment of postmenopausal women with 
hormone receptor-positive, HER2 [human epidermal 
growth factor receptor 2]-negative breast cancer where 
chemotherapy is not suitable and immediate surgery not 
indicated (European Union only).” 
To complete all approved indications for 
letrozole. 
2.1 Study rationale 
Cut-off date for the presentation of TED14856 results 
updated from 22 October 2018 to 29 May 2019. 
To align with the updated Investigator’s 
Brochure. 
 
Details on study TED14856 updated: 
Number of participants in Part B updated from 4 to 48 
Part C started in January 2019, with 6 participants 
recruited so far. 
To align with the updated Investigator’s 
Brochure. 
2.2 Background 
Breast cancer statistics updated: 
“In the United States, in 2015, it was estimated that 
231 840 2019, a total of 268 600 new cases of invasive 
breast cancer as well as 60 290 62 930 additional cases 
of in situ breast cancer would be reported are estimated. 
From 2006 to 2015, invasive female breast cancer 
incidence rates increased slightly, by 0.4% per year. 
Approximately 40 290 41 760 women were are expected 
to die from breast cancer in the same year 2019.” 
To provide updated statistics. 
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Brief Rationale 
2.3.1.1 amcenestrant 
amcenestrant benefit information updated:  
Number of participants with stable disease updated from 
7 to 8 
Number of participants with long-term stable disease 
updated from 3 to 7 
Clinical benefit observed in 8 participants so far. 
To align with the updated Investigator’s 
Brochure. 
2.3.2.1 amcenestrant 
amcenestrant safety information updated: 
Updated treatment-emergent adverse event results from 
TED14856 study Part A included 
Remaining information removed and referred to the 
Investigator’s Brochure. 
To align with the updated Investigator’s 
Brochure. 
3 Objectives and 
endpoints 
The following exploratory endpoint has been updated: 
“The gene mutation profile of the tumor over time 
(Cycle 1 Day 1 [pre-treatment] and end of treatment) by 
cfDNA analysis, and ESR1 mutation analysis by cfDNA 
analysis pre-treatment and within 14 days after first 
radiological tumor assessment after baseline at Cycle 3 
Day 1.” 
To align with the updated schedule for 
ESR1 analysis. 
 
The following exploratory endpoint has been updated: 
“Tumor ER [estrogen receptor], Ki67, Bcl-2, and PgR 
[progesterone receptor] protein, and RNA [ribonucleic 
acid] gene expression profiles in paired biopsies at 
Cycle 1 Day 1 (pre-treatment) and at Cycle 3, Day 1 
(allowed up to Day 15; or within 14 days after first 
radiological tumor assessment after baseline).” 
To align with the updated tumor 
specimen/biopsy schedule. 
4.3 Justification for 
dose 
Updated pharmacokinetic information related to 
amcenestrant obtained from healthy volunteers and 
patients has been included. 
To align with the updated Investigator’s 
Brochure. 
5.1 Inclusion criteria 
In I 01, it was added that participants should be of the 
country’s legal age of majority if the legal age is 
>18 years. 
To comply with applicable local 
requirements. 
 
In I 07, the following text was removed: 
 “Participants who received both prior chemotherapy and 
targeted therapy are not allowed.” 
To allow patients receiving 
chemotherapy and targeted therapy 
concomitantly. 
 
In I 07, the following text was added: 
 “For countries where CDK4/6 inhibitors are available 
(ie, approved and can be reimbursed), prior treatment 
with a CDK4/6 inhibitor in combination with fulvestrant or 
an AI [aromatase inhibitor] is mandatory.” 
For clarity and in response to request 
from French Health Authority. 
 
In I 08, the following text was updated: 
“Participants must have progressed after at least 
6 months of a continuous prior endocrine therapy for 
advanced breast cancer (single agent or in combination, 
the number of hormonal lines is not limited will be 
limited to 2), or have progressed within 12 months of 
completion of adjuvant endocrine therapy.” 
Number of prior endocrine therapies 
limited updated in line with the National 
Comprehensive Cancer Network 
guidelines (Version 2, 2019), which 
recommends treating metastatic breast 
cancer with no more than 3 lines of 
hormonal therapy before switching to 
chemotherapy. 
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5.2 Exclusion criteria 
A new exclusion criterion (related to medical conditions) 
has been included: 
“E 08. 
Participants with abnormal coagulation profiles 
or any history of coagulopathy within the 6 months prior 
to the first dose of IMP [investigational medicinal product], 
including history of deep vein thrombosis or pulmonary 
embolism. However, participants with the following 
conditions will be allowed to participate:  
Participants with adequately treated catheter-related 
venous thrombosis that occurred more than 1 month prior 
to the first dose of IMP.  
Participants being treated with an anticoagulant 
(eg, warfarin or heparin) for a thrombotic event that 
occurred more than 6 months before enrollment, or for an 
otherwise stable and allowed medical condition 
(eg, well-controlled atrial fibrillation), provided that 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.” 
To exclude participants with high 
thromboembolic risk, in accordance with 
potential thromboembolic risks 
associated with the IMPs. 
 
In E 13, the following text was updated: 
“Prior treatment with mammalian target of rapamycin 
inhibitors or any other SERD [selective estrogen 
receptor degrader] compound, except fulvestrant if 
stopped for at least 3 months before randomization.” 
To align with current literature, which 
shows poor efficacy of SERD therapies 
in patients who received prior therapy 
with mammalian target of rapamycin 
inhibitors. 
5.3 Lifestyle 
considerations 
It was clarified that direct exposure to natural or artificial 
sunlight should be avoided for at least 30 days after last 
IMP dose. 
For clarity. 
 
The following text was added: 
“… in addition, 1 participant from Part 1 of the TED14856 
study experienced Grade 1 sunburn while exposed to the 
sun without protection, an event considered related to 
amcenestrant…” 
To align with the updated Investigator’s 
Brochure. 
5.4 Screen failures 
The text was updated as follows: 
“Participants who do not meet the criteria for participation 
in this study may be retested during the screening period 
(≤28 days) and included, providing they meet at that time 
all inclusion and exclusion criteria. These participants 
are not considered screen failures.” 
To clarify screen failure criteria. 
6.1 Study 
intervention(s) 
administered 
The following text was added: 
“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 
site to the participant via a Sponsor-approved courier 
company where allowed by local regulations and 
approved by the participant.” 
To clarify dispensing and shipping 
procedures for the IMP in case of Direct 
to Patient shipment of IMPs. 
6.2.1 General rules 
Potential defects in the quality of amcenestrant or any 
comparator supplied globally may be subject to initiation 
of a recall procedure by the Sponsor, as opposed to only 
amcenestrant, as previously stated. 
To clarify recall procedures. 
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The Investigator must not supply any IMP to a third party 
nor dispose of IMP in any manner, as opposed to only 
amcenestrant, as previously stated. 
To clarify procedures for IMP supply and 
disposal. 
6.5 Concomitant 
therapy 
The following sentence has been added: 
“Special caution should be taken with regards to protein 
pump inhibitors (ie, omeprazole): when prescribed 
concomitantly, amcenestrant should preferably be taken 
with food.” 
The absorption of amcenestrant may be 
decreased if the participant is treated 
with protein pump inhibitors. Taking 
amcenestrant with food in this case could 
help normalizing the absorption. 
6.6 Dose modification 
In Table 3, dose modifications and management of 
amcenestrant toxicities were updated to describe the 
management of Grade 3 and 4 adverse events 
separately. 
To clarify dose modifications and 
management of amcenestrant toxicities. 
8.1.2 Bone scans 
If at screening, lesions are not detected in the bone scan 
nor in the CT/MRI (RECIST 1.1) scan, further bone scans 
are not required unless clinically indicated. 
To clarify bone scan procedures when no 
lesions are detected at screening. 
8.3 Adverse events 
and serious adverse 
events 
The following text has been added as an adverse event 
of special interest (AESI):  
“Increase of ALT [alanine transaminase] Grade ≥3. In this 
case, this test will be repeated.” 
Increase of liver enzymes has been 
reported in a recent preclinical toxicity 
study and found in the participants who 
received amcenestrant in clinical trials. 
The Sponsor committed to closely 
monitor participants with an increase of 
liver enzymes. 
8.3.1 Time period and 
frequency for 
collecting AE and 
SAE information 
Text updated as follows: 
“All AEs [adverse events] and SAEs [serious AEs] 
(regardless of seriousness or relationship with IMP) 
will be collected from the signing of the ICF [informed 
consent form] until the last follow-up visit at the time 
points specified in the SoA 30 days after the last dose 
of the IMP (Section 1.3).” 
To clarify AE collection procedures. 
8.3.4 Regulatory 
reporting 
requirements for 
SAEs 
A statement was added clarifying that the Investigator is 
obligated to assess the relationship between the IMP and 
occurrence of AEs and SAEs. 
For clarity. 
8.3.7 Guidelines for 
reporting product 
complaints 
Text updated as follows:  
“Any defect in the IMP supplied centrally by Clinical 
Supplies (amcenestrant and control arm treatments 
in the United States and Poland) must be reported as 
soon as possible by the Investigator to the monitoring 
team that will complete responsible for completing a 
product complaint form, for amcenestrant within required 
timelines.” 
To clarify the applicable IMP supplying 
procedures. 
8.8 Biomarkers 
Samples collected for biomarker analyses and their 
derivatives will be stored from a period of up to 5 years 
after last participant last visit, instead of after completion 
of the final study report. Likewise, samples for future use 
will be stored for 15 years after last participant last visit, 
instead of after completion of the final study report. 
Text updated to comply with the Sponsor 
standard procedures. 
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8.8.1 Future use of 
samples 
Text updated as follows:  
“For participants who have consented to it, the samples 
that are unused or left over after testing may be used for 
other research purposes (excluding including genetic 
analysis providing that may provide information on the 
likelihood of developing cancer and related diseases) 
related to oncology than those defined in the present 
protocol.” 
For clarity. 
9.1 Statistical 
hypotheses 
Null hypothesis updated: survival distribution functions 
(SDF) for the PFS of the amcenestrant arm is lower than 
or equal to the SDF of the control arm. 
Alternative hypothesis updated: SDF for the PFS of the 
amcenestrant arm is superior to the SDF of the control 
arm. 
To clarify the statistical hypotheses 
9.4.1.1 Analysis of 
primary efficacy 
endpoint 
Text updated as follows: 
“If progression and death are not observed before the 
PFS analysis COD [cut-off date], PFS will be censored at 
the date of the last valid disease assessment with no 
evidence of a disease progression or the PFS analysis 
COD, whichever occurs first” 
To clarify the PFS censoring procedures. 
9.4.1.2 Analysis of 
secondary efficacy 
endpoints 
Text updated as follows: 
“For participants with ongoing response at the time of the 
analysis, DOR [duration of response] will be censored at 
the date of the last valid disease assessment not showing 
disease progression performed before the initiation of a 
new anticancer treatment (if any). or the analysis COD, 
whichever occurs first.” 
To clarify the DOR censoring 
procedures. 
10.1.2 Informed 
consent process 
Text updated as follows: 
“A separate signature will be required to document a 
participant's agreement Participant agreement will be 
required to allow any remaining specimens to be used 
for exploratory research.” 
To clarify consenting procedures. 
Appendix 2 
Gamma-glutamyltransferase added as part of the 
laboratory assessments. 
Added to help determine if abnormal liver 
function tests are associated with liver 
metastases. 
 
The following procedures were clarified for hematology 
analyses: 
To be repeated after screening within 2 or 3 days before 
randomization, in case of abnormal evaluations on 
parameters such as body weight, signs and symptoms, 
physical examination, electrocardiogram, hematology, 
coagulation tests, blood chemistry, and urinalysis. 
To be repeated at Cycle 1 Day 1 if screening test >7 days 
of Day 1 Cycle 1. 
To clarify hematology analysis prior to 
Cycle 1 Day 1. 
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Appendix 3 
A definition for unexpected adverse drug reaction has 
been included “An adverse reaction, the nature or 
severity of which is not consistent with the applicable 
product information (eg, Investigator's Brochure for an 
unapproved investigational medicinal product).” 
For clarity. 
Appendix 5 
Samples collected for genetic analyses and their 
derivatives will be stored from a period of up to 5 years 
after last participant last visit, instead of after completion 
of the final study report. Likewise, samples for future use 
will be stored for 15 years after last participant last visit, 
instead of after completion of the final study report. 
Text updated to comply with the Sponsor 
standard procedures. 
Appendix 8 
Inclusion of a China extension study. 
Added to enable a separate analysis of 
efficacy, safety, and pharmacokinetic 
data for participants in China. 
Appendix 14 
A table with overall response status for nonmeasurable 
disease was added. 
To clarify response status attribution for 
nonmeasurable disease. 
 
The following text has been updated: 
“When SD [stable disease] is believed to be best 
response, it must also meet the protocol specified 
minimum time from baseline (defined as 42 days).” 
To clarify the minimum time from 
baseline needed to be met when SD is 
determined as the best response. 
10.15.2 
Amended protocol 02: 13 February 2020  
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment 
The objective of this amendment is to update the protocol on the following topics: 
• 
Study population and inclusion/exclusion criteria: 
- 
Allow the inclusion of male participants in the study. 
- 
Clarify that single-agent endocrine therapy must be considered appropriate for the 
participant. 
- 
Clarify that participants with bone-only metastases are allowed in the study.  
• 
Inclusion of a formal interim analysis for futility with oversight from the Data Monitoring 
Committee. 
• 
Limit the number of participants naïve to CDK4/6 inhibitors to a maximum of 20% of the 
overall sample size.  
• 
Include overall survival as the key secondary endpoint. 
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Minor formatting and editorial updates. 
For clarity and accuracy. 
Title page 
Protocol title updated as follows: 
“An open label randomized Phase 2 trial of amcenestrant, 
versus endocrine monotherapy as per physician’s choice in 
premenopausal and postmenopausal patients with estrogen 
receptor-positive, HER2-negative locally advanced or 
metastatic breast cancer with prior exposure to hormonal 
therapies” 
Short title updated as follows: 
“Phase 2 study of amcenestrant versus physician’s choice in 
premenopausal and postmenopausal patients with locally 
advanced or metastatic ER-positive breast cancer.” 
The protocol title has been updated in 
alignment with the inclusion of male 
participants in this study. 
 
The NCT number has been included: NCT04059484. 
The NCT number is now available. 
Synopsis 
The text below has been updated as follows: 
“The treatment of non-visceral metastatic/advanced breast 
cancer without visceral crisis is based on hormonal 
therapies given as monotherapy (tamoxifen, aromatase 
inhibitors [AI], fulvestrant) and in combination with targeted 
agents such as everolimus + exemestane and AI or 
fulvestrant + CDK4/6 inhibitors.” 
Updated for clarity. 
 
The synopsis text has been updated to keep consistency with 
the changes in the remaining sections. 
Updated for consistency with the 
remaining sections of the protocol.  
1.2 Schema 
The text below from Figure 1 has been updated as follows: 
“OS [overall survival] follow-up  
Every 2 months until 18 months after PFS [progression-free 
survival] cut-off date.” 
Updated for clarity and to simplify the 
schema. 
1.3 Schedule of 
Activities 
A screening assessment for follicle-stimulating hormone and 
estradiol assessment for premenopausal women has been 
added. 
This assessment has been added to 
confirm that premenopausal women 
treated with gonadotropin-releasing 
hormone have the same 
follicle-stimulating and estradiol levels 
as postmenopausal women.  
 
New assessments have been added to the Schedule of 
Activities: 
• 
Estradiol. 
• 
Genetic sampling for drug metabolizing enzymes 
and transporters (amcenestrant treatment arm 
only). 
 
 
Estradiol assessments will be 
performed to explore the possible 
influence of circulating levels of 
estradiol on the efficacy of 
amcenestrant. 
Drug metabolism enzyme genotyping 
has been included to assess the 
possibility of drug metabolism 
enzyme variants (eg, uridine 5' 
diphospho-glucuronosyltransferase 
[UGT] 1A1 and UGT1A4) as potential 
intrinsic factors associated with 
pharmacokinetic/dynamic variability of 
amcenestrant. 
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2 Introduction 
The following text has been removed: 
“amcenestrant showed superior and broader ER [estrogen 
receptor] degrading activity compared to all known SERD 
[selective estrogen receptor degrader] competitors.” 
Sentence removed to keep 
consistency with the amcenestrant 
Investigator’s Brochure and 
bibliographic references.  
2.2 Background 
The following text has been updated: 
” In the United States, in 2019, a total of 268 600 new cases 
of invasive breast cancer as well as 62 930 additional cases 
of in situ breast cancer are estimated. From 2006 to 2015, 
invasive female breast cancer incidence rates increased 
slightly, by 0.4% per year. Approximately 41 760 women are 
expected to die from breast cancer in 2019. In men, breast 
cancer is relatively uncommon, with 2670 new cases of 
invasive breast and 500 deaths estimated in the United 
States, in 2019 (10). 
[…] 
According to the National Comprehensive Cancer Network 
guidelines (Version 2, 2018 Version 1, 2020), sequential 
hormonal therapy (alone or in combination) is the standard of 
care in the metastatic breast cancer setting for ER positive 
and HER2 negative participants without rapidly progressing 
visceral or symptomatic metastases. Common classes of 
drugs used after progression of hormonal treatment for this 
purpose include SERMs [selective estrogen receptor 
modulator] (eg, tamoxifen), AIs (eg, letrozole, anastrozole, or 
exemestane), and SERDs (fulvestrant). Because few men 
have been historically included in breast cancer clinical 
trials, recommendations regarding management of 
breast cancer in men are generally extrapolated from 
findings in clinical trials focusing on breast cancer in 
women. 
[…] 
These data demonstrate that SERDs have the potential to 
provide effective and well-tolerated therapy for 
postmenopausal women with advanced breast cancer and 
highlight the need for the development of new SERD 
compounds with optimized characteristics: improved route of 
administration (PO [per os] versus IM [intramuscular]), 
bioavailability, and long-term maintenance of ER receptor 
blockade combined with a strong antitumor activity. It would 
also be important to further understand the potential 
benefit and safety of SERDs in men with breast cancer, in 
alignment with the Food and Drug Administration draft 
guidance “Male Breast Cancer: Developing Drugs for 
Treatment”, which recommends the inclusion of both 
men and women in breast cancer clinical trials.” 
To provide some background 
information on male breast cancer 
and a rationale for the inclusion of 
men in this study. 
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2.3.1.1 amcenestrant 
The text below has been updated as follows: 
“amcenestrant has been administered to humans since 
November 2017, in the FIH [first in human] TED14856 study. 
Efficacy was assessed using the Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 criteria in 
14 16 participants (2 participants at 600 mg have not yet 
reached Cycle 2); the best overall responses (BOR) have 
been partial response (PR) in 1 participant treated at 150 mg, 
stable disease (SD) in 8 participants, and PD in 
6 7 participants. Long-term SD (24 weeks or more) was seen 
in 7 participants so far. Clinical benefit (PR + SD ≥24 weeks) 
was therefore observed in 8 participants (29 May 2019).” 
Updated in alignment with the current 
version of the Investigator’s Brochure. 
2.3.2.1 amcenestrant 
The following text was included regarding potential 
amcenestrant risks anticipated in humans: 
“Based on the nonclinical data available for amcenestrant 
and the safety profile observed in compounds of the same 
class approved and in development, the following are 
potential side effects and risks anticipated in humans: 
• 
Gastrointestinal toxicities, including anorexia, 
nausea, vomiting, diarrhea (and possibly 
dehydration and electrolyte imbalance in severe 
cases), and upper and/or lower abdominal pain. 
• 
Changes in liver function, including elevated liver 
enzymes and bilirubin. 
• 
Hematological toxicities potentially presenting with 
laboratory abnormalities (leukopenia, neutropenia, 
thrombocytopenia, anemia), infections, and 
neutropenic fever. 
• 
Effects in the female reproductive system (ovary, 
uterus, cervix, vagina, mammary glands). 
• 
Risk of photosensitivity. 
• 
Theoretical risk of osteoporosis, due to the 
mechanism of action of SAR439849, in case of 
long-term exposure. 
• 
Risk of drug drug interaction: in vitro, amcenestrant 
is mainly metabolized by uridine 5' 
diphospho-glucuronosyltransferase (UGT) 1A1 and 
UGT1A4, and to a lesser extent by CYP 
[cytochrome P450] enzymes (<20%) CYP2C8 
and/or CYP3A. Therefore, drugs that are potential 
inhibitors of UGTs (ie, atazanavir and probenecid) 
should not be administered with amcenestrant, as 
well as drugs that are strong or moderate inducers 
of CYP3A and CYP2C8 
• 
, since they may also induce UGTs. In vitro studies 
results showed that amcenestrant has the potential 
to induce CYP3A4, and to a lesser extent CYP2B6, 
CYP2Cs, and UGTs.” 
In consequence, the following text has been removed: 
“No potential and identified risks have yet been reported for 
amcenestrant.” 
Updated to include the most up to 
date information on potential 
amcenestrant risks anticipated in 
humans. 
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The text below has been updated as follows: 
“Preliminary safety results in humans from the FIH 
TED14856 study are as follows: As as of 29 May 2019, 
16 participants have been treated in the dose escalation part 
at doses from 20 to 600 mg (Part A) of TED14856 study, 
and 48 participants have been treated in the dose expansion 
part at the recommended dose of 400 mg (Part B). The 
safety was assessed in 16 participants in the dose escalation 
part of study. No dose limiting toxicities were observed during 
Cycle 1 at any tested dose levels. All of them presented with 
at least 1 treatment emergent AE (TEAE). In Part A of the 
ongoing TED14856 study, as of 29 May 2019, all 16 
participants (100.0%) experienced at least 1 TEAE, 
regardless of relationship.” 
Updated to clarify the dose levels 
used in the TED14856 study. 
 
The following text was included regarding amcenestrant 
updated liver toxicity tests in humans: 
“Updated safety information from July 2019 shows the 
following results regarding liver function tests (LFTs). Two of 
16 participants from Part A of the TED14856 study developed 
treatment-emergent LFT abnormalities Grade ≥3. One 
participant (treated with amcenestrant 200 mg) developed 
Grade 3 aspartate aminotransferase (AST) and alkaline 
phosphatase increase with Grade 1 alanine aminotransferase 
(ALT) increase and normal total bilirubin. Another participant 
(treated with amcenestrant 600 mg) developed Grade 4 AST 
and total bilirubin increase with Grade 3 ALT and alkaline 
phosphatase increase. Both participants had liver metastasis 
and Grade 1 AST increase at baseline. These LFT 
abnormalities were observed concomitantly with disease 
progression in the liver.” 
Section updated to include up to date 
information related with liver safety.  
3 Objectives and 
endpoints 
Overall survival has been relocated as the first secondary 
objective. 
Overall survival has been considered 
the key secondary endpoint, in 
response to the Food and Drug 
Administration recommendations. 
 
The objective response rate (ORR) endpoint has been 
updated as follows: 
“Objective response rate is defined as the proportion of 
participants who have a confirmed complete response (CR) 
or partial response (PR), as best overall response derived 
from overall response determined by ICR [independent 
central review] as per RECIST 1.1, from the date of 
randomization to the date of end of treatment.” 
Updated for accuracy, as the best 
overall response will be derived from 
overall response determined by ICR 
4.1 Overall design 
The text below has been updated as follows: 
“This is an international, prospective, open-label, Phase 2 
randomized study comparing the efficacy and safety of 
amcenestrant versus a single endocrine therapy of the choice 
of the physician in men, postmenopausal women or 
premenopausal women on a gonadotropin-releasing hormone 
(GnRH) analog with ER positive and HER2 negative 
advanced and/or metastatic breast cancer.” 
To clarify that men will be included in 
this study 
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Brief Rationale 
 
The text below has been updated as follows: 
• 
“Selective ER modulator (PO, QD [once daily] or 
two times a day): 
- 
Tamoxifen 20 mg/day to be taken 
approximately at the same time every day, 
regardless of food status.” 
To align with the possible dosing 
regimens for tamoxifen, as per label. 
 
The text below was updated as follows: 
“For the global study, estimated COD [cut-off date] for final 
PFS will be approximately 17 18 months after first 
randomized participant in for the PFS analysis. No PK 
[pharmacokinetic] sample will be taken after Cycle 6 or PFS 
COD for final PFS, whichever comes first. After the COD for 
final PFS analysis, no more efficacy assessment will be 
performed except collection of survival status. For all 
participants alive at the COD for final PFS analysis, the first 
follow-up visit will be conducted at the site and subsequent 
telephone follow-up assessments will be conducted every 
2 months to record survival data and further therapies, which 
will be collected until COD for OS analysis, or participant 
death, or upon participant’s request, whichever occurs first. 
If a participant treated continues to benefit from the treatment 
after the last COD for OS analysis, the participant may 
continue until treatment is precluded by toxicity, progression, 
upon participant’s request to stop treatment, or Investigator 
decision. For cycles completed after the last COD for OS 
analysis, all ongoing SAEs [serious AEs] (related or not), all 
related nonserious AEs ongoing at the COD, and all new 
related AEs (serious or not) occurring post COD and 
associated concomitant medication, as well as IMP 
[investigational medicinal product] administrations and reason 
for EOT [end of treatment] will continue to be collected.” 
The COD projections have been 
updated following the newly added 
futility interim analysis for PFS and 
the inclusion of OS as the key 
secondary endpoint. 
The COD definitions have also been 
updated for clarity. 
 
The text below has been updated as follows: 
“For the China extension, assuming that the first Chinese 
participant is planned to be enrolled 11 months after the first 
randomized participant of the global part and a 9.5 17-month 
enrollment period for the Chinese participants, the estimated 
China COD will be approximately 5 months after last Chinese 
participant enrolled, ie, approximately 9 18 months after the 
PFS analysis of the global study.” 
Recruitment period for the Chinese 
population has been extended after 
the sample size has been revised for 
this population. 
After consultation with the Chinese 
Center for Drug Evaluation, as no 
prior Asian population exposure data 
were provided, the sample size of the 
Chinese extension should not be 
lower than 20% of the sample size of 
the global study and the Chinese 
extension should be powered to 
observe a hazard ratio (HR) lower 
than 0.8. To meet with these 
requirements, the number of 
participants in the China extension 
study has been increased from 42 to 
90. 
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5.1 Inclusion criteria 
In I 07, the following statement has been added: 
“Note: The number of participants naïve to CDK4/6 inhibitors 
should not be higher than 20% of the overall sample size.” 
The proportion of participants naïve to 
CDK4/6 inhibitors has been restricted 
to ensure that the study conclusions 
based on the intent-to-treat 
population can be extrapolated for the 
population previously treated with 
CDK4/6 inhibitors. 
 
In I 08, the following text has been updated: 
“Participants must have progressed after at least 6 months of 
a continuous prior endocrine therapy for advanced breast 
cancer (single agent or in combination, the number of 
hormonal lines will be limited to 2), or have progressed within 
12 months of completion of adjuvant endocrine therapy 
relapsed while on adjuvant endocrine therapy but after 
the first 2 years, or have relapsed within 12 months of 
completing adjuvant endocrine therapy.” 
The definition of secondary endocrine 
resistance has been updated to align 
with the 3rd European School of 
Oncology- European Society for 
Medical Oncology International 
Consensus Guidelines for Advanced 
Breast Cancer. 
 
In I 09, the following text has been updated: 
“Male or Female.” 
Male participants have been 
considered eligible for participation in 
this study, in alignment with the Food 
and Drug Administration draft 
guidance “Male Breast Cancer: 
Developing Drugs for Treatment”, 
which recommends the inclusion of 
both men and women in breast 
cancer clinical trials. 
 
In I 09, the following text has been added: 
“Sexually active males should be on a GnRH analog for at 
least 4 weeks (to be continued during study treatment).” 
Because male participants have been 
considered eligible for this study, 
contraceptive guidance for male 
participants was included. 
 
The following inclusion criterion (I 11) was added: 
“Participants must be considered clinically eligible by the 
Investigator to receive single agent endocrine therapy.” 
Included to confirm that participants 
must be deemed appropriate to 
receive treatment with single 
endocrine agent. 
5.2 Exclusion criteria 
E 10 has been removed, and the text updated as follows: 
“Participants with bone-only metastasis (bone-only 
metastasis was defined as bone metastasis without evidence 
of involvement of any other organ) E 10 deleted in 
amended protocol 02.” 
Participants with bone-only 
metastasis will be allowed in this 
study. 
 
In E 14, the following text has been updated: 
“Treatment with atazanavir, lopinavir (antiviral agents), 
ketoconazole (antifungal), and quercetin (antioxidant) drugs 
that have the potential to inhibit UGT, including, but not 
limited, to atazanavir and probenecid, for less than 
2 weeks before randomization or 5 elimination half-lives 
whichever is longer.” 
Exclusion criteria clarified to include 
all potential UGT inhibitors. 
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In E 15, the following text has been updated: 
“Treatment with strong or moderate CYP3A and CYP2C8 
inducers within 2 weeks before randomization or 5 elimination 
half-lives, whichever is longer (Section 10.11 [Appendix 11]).” 
Concomitant administration of 
moderate CYP2C8 inducers will not 
be permitted in participants receiving 
amcenestrant, since they may 
decrease amcenestrant exposure. 
6.1 Study 
intervention(s) 
administered 
The following text has been updated in Table 2, in the 
amcenestrant dosing instructions section: 
“4 capsules once a day given in the morning with or without 
food, at approximately the same time every day 
(±3 hours).” 
To include a time window for 
amcenestrant dosing. 
 
The following text has been updated in Table 2, in the 
tamoxifen dosing instructions section: 
“20 mg once daily or 10 mg twice a day, approximately at 
the same time every day, regardless of food status.” 
To align with the possible dosing 
regimens for tamoxifen, as per label. 
 
The following text has been updated in the Table 2 footnotes: 
“a 
In study visit days, participants should only be 
dosed after the scheduled study assessments (Section 1.3) 
are performed predosing pharmacokinetic sampling 
collection.” 
Updated to clarify dosing procedures. 
6.3 Measures to 
minimize bias: 
randomization and 
blinding 
The following text has been updated: 
“Randomization will be stratified according to the presence of 
visceral metastasis (defined by at least 1 liver or lung 
metastasis) (Yes or No), prior treatment with CDK4/6 
inhibitors (Yes or No), and ECOG [Eastern Cooperative 
Oncology Group] status (0 or 1) (Note: The number of 
participants naïve to CDK4/6 inhibitors should not be 
higher than 20% of the overall sample size).” 
 The proportion of participants naïve 
to CDK4/6 inhibitors was restricted to 
ensure that the study conclusions 
based on the intent-to-treat 
population can be extrapolated for the 
population previously treated with 
CDK4/6 inhibitors. 
6.4 Study 
intervention 
compliance 
The following text has been updated: 
“In case of oral dosing omission or IM injection delay greater 
than 2 weeks, the participant will be withdrawn from the study 
treatment, unless a clear benefit is identified and after 
discussion with the Medical Monitor (Section 6.6).” 
To allow participants that are 
benefiting from the medication to 
continue treatment after a delay 
longer than 2 weeks. 
6.5 Concomitant 
therapy 
The following text has been added: 
“Bisphosphonates and receptor activator of nuclear factor 
kappa Β ligand inhibitors are allowed.” 
Updated for clarity and in agreement 
with the inclusion of participants with 
bone-only metastasis.  
 
The text in this section has been reorganized as follows, for 
clarity:  
“Special caution should be taken regarding the following 
therapies: 
• 
No additional investigational or commercial 
anticancer agents such as chemotherapy, 
immunotherapy, targeted therapy, biological 
response modifiers, or endocrine therapy other than 
amcenestrant or the selected control will be 
permitted during the active treatment phase. In 
general, any drugs containing “for the treatment of 
Concomitant administration of strong 
and moderate CYP3A4 inducers and 
moderate CYP2C8 inducers will not 
be permitted in participants receiving 
amcenestrant, since they may 
decrease amcenestrant exposure. 
 As amcenestrant is a substrate of 
UGT1A1 and UGT1A4, UGT 
inhibitors may increase amcenestrant 
exposure. 
The remaining medications were 
included in the previous version of the 
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breast cancer” on the product label are not 
permitted on study. 
• 
Palliative radiotherapy may be given for control of 
pain for palliative intents. The Sponsor team should 
be notified to obtain agreement prior to treatment if 
palliative radiotherapy is being considered, and 
prior to resuming therapy on the study. The 
irradiated area should be as small as possible and 
should never involve more than 20% of the bone 
marrow in any given 3-week period. In all such 
cases, the possibility of tumor progression should 
be ruled out by physical and radiological 
assessments of the tumor. If the only evaluable 
lesions are to be irradiated, the participant will stop 
the study treatment. The irradiated area cannot be 
used as a parameter for response assessment.  
• 
Among herbal medications and food products, it is 
recommended to avoid consumption of St John’s 
Wort and genistein during treatment period since 
they could decrease amcenestrant exposure. 
• 
The following therapies since they may increase 
amcenestrant exposure by more than 2-fold and 
are prohibited in this study: 
- 
antiviral agents: atazanavir, lopinavir;  
- 
antifungal: ketoconazole;  
- 
antioxidant: quercetin. 
• 
Strong and moderate CYP3A4 inducers (see full list 
in Section 10.11 [Appendix 11]) since they may 
decrease amcenestrant exposure and are 
prohibited in this study. 
• 
Drugs which are mainly metabolized by sensitive 
substrates of CYP3A, CYP2B6, CYP2Cs, and/or 
UGT should be closely monitored (see list 
Section 10.12 [Appendix 12]) since the there may 
be loss of efficacy of these drugs may be 
decreased by concomitant use of amcenestrant due 
to a potential induction effect of amcenestrant. 
• 
Drugs that are substrate of P-gp [P-glycoprotein] 
should be avoided (dabigatran, digoxin, 
fexofenadine) since amcenestrant may increase 
their absorption. 
• 
Special caution should be taken with regards to the 
proton pump inhibitors (ie, omeprazole): when 
prescribed concomitantly, amcenestrant should 
preferably be taken with food. 
The following therapies/medications are prohibited 
throughout the active treatment phase for the 
amcenestrant treatment arm: 
• 
Drugs that are strong and moderate inducers of 
CYP3A and CYP2C8, since they may decrease 
protocol, but were reworded to clarify 
which medications were not allowed 
in participants receiving 
amcenestrant. 
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amcenestrant exposure (see full list in Section 
10.11 [Appendix 11]).  
• 
Herbal medications and food supplements 
including St John’s Wort and genistein during 
treatment period, since they could decrease 
amcenestrant exposure. 
• 
Drugs that are sensitive substrates of P-gp 
including dabigatran, digoxin, and 
fexofenadine, since amcenestrant is a potential 
inhibitor of P-gp and may increase their 
absorption.  
• 
Drugs that have UGT inhibition potential and 
are contraindicated with UGT substrates, 
including, but not limited to, atazanavir and 
probenecid, since amcenestrant is substrate of 
UGT1A1 and UGT1A4.” 
6.6 Dose 
modification 
The following text has been updated: 
“In case of oral dosing omission or IM injection delay greater 
than 2 weeks, the participant will be withdrawn from the study 
treatment, unless a clear benefit is identified and after 
discussion with the Medical Monitor.” 
To allow participants that are 
benefiting from the medication to 
continue treatment after a delay 
longer than 2 weeks. 
8.1.1 Criteria for 
response (antitumor 
activity) 
The text below has been updated as follows: 
 “Participants who discontinue the study treatment without 
documented PD will be followed every 8 weeks (projected 
from last tumor assessment) until PD is documented or 
primary analysis COD for final PFS, whichever occurs first.” 
Updated for clarity. 
8.1.2 Bone scans 
The text below has been updated as follows: 
“If at Cycle 1 Day 1, lesions are detected in the bone scan but 
not in the CT [computed tomography]/MRI [magnetic 
resonance imaging] (RECIST 1.1) scan, further bone scans 
should be conducted every 8 weeks ±7 days until disease 
progression documented or PFS COD for final PFS, 
whichever occurs first. If the lesions seen in the bone scan 
are no longer visible, these assessments can be conducted 
every 16 weeks ±7 days until disease progression 
documented or PFS COD for final PFS, whichever occurs 
first. 
If bone lesions are detected in the bone scan and in CT/MRI 
(RECIST 1.1) scan at Cycle 1 Day 1, further bone scans will 
be conducted every 16 weeks ±7 days until disease 
progression documented or PFS COD for final PFS, 
whichever occurs first.” 
Updated for clarity. 
8.2.2 Vital signs 
The text below has been updated as follows: 
“Oral temperature Temperature, pulse rate, respiratory rate, 
and blood pressure will be assessed.” 
Updated for improved feasibility. 
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8.3 Adverse events 
and serious adverse 
events 
The following text has been updated, regarding adverse 
events of special interest (AESI): 
• 
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 or 
female partner of a male participant entered 
in the clinical study will be qualified as an SAE 
only if it fulfills one of the seriousness criteria 
(see Appendix 3 [Section 10.3]).” 
Updated in alignment with the 
inclusion of men in this study, to 
consider pregnancy events of female 
partners of male participants. 
8.3.5 Pregnancy 
The text below has been updated as follows: 
“Details of all pregnancies in female participants or female 
partners of male participants will be collected after the start 
of study intervention and until 30 days after the last dose.” 
Updated in alignment with the 
inclusion of men in this study, to 
consider pregnancy events of female 
partners of male participants. 
 
The text below has been updated as follows: 
“If a pregnancy is reported in female participants or female 
partners of male participants, 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).” 
Updated in alignment with the 
inclusion of men in this study, to 
consider pregnancy events of female 
partners of male participants. 
8.5 Pharmacokinetics 
The text below has been updated as follows: 
“Pharmacokinetic samplings will be stopped at the end of 
Cycle 6 or at the primary analysis COD for final PFS, 
depending which one comes first.” 
Updated for clarity. 
8.6.2 Estradiol 
A new section has been included for estradiol assessments, 
which have been added in this amendment.  
Estradiol assessments have been 
included to explore the possible 
influence of circulating levels of 
estradiol on the efficacy of 
amcenestrant. 
8.7.4 Drug 
metabolizing 
enzymes and 
transporters DNA 
sample 
A new section has been included for investigation of allelic 
variants of drug metabolizing enzymes and/or drug 
transporters. 
Included to assess the possibility of 
drug metabolism enzyme variants 
(eg, UGT1A1 and UGT1A4) as 
intrinsic factors associated with 
pharmacokinetic/dynamic variability of 
amcenestrant. 
9.1 Statistical 
hypotheses 
Clarified that the statistical hypotheses defined for the primary 
endpoint will also be tested for the OS key secondary 
endpoint. 
To clarify the statistical hypotheses 
for the key secondary endpoint (OS). 
9.2 Sample size 
determination 
The following text has been updated regarding the global 
sample size calculation rationale: 
“The sample size for the global part of this study is 
determined based on following assumptions: the median PFS 
for the control arm is assumed to be 4.5 months (2, 3, 4, 5, 6, 
7) and an improvement of 35 53% to a median PFS of 
6.9 months (corresponding to a HR = 0.65) would be 
considered clinically meaningful.  
The sample size calculation has been 
updated in accordance with the newly 
added futility interim analysis for PFS. 
The improvement in median PFS was 
corrected from 35 to 53%. 
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A total of 195 201 ICR assessed PFS events will be required 
in the 2 treatment arms for the global part of the study to 
have an approximately 85% power to detect an increase in 
PFS, assuming a true HR [hazard ratio] of 0.65 (representing 
a 35 53% increase in median PFS from 4.5 to 6.9 months, 
under exponential model), tested at a one-sided 
significance level of alpha = 0.025. 
For the global part of the study, assuming a uniform accrual 
rate of 23.5 participants per month accomplished over a 
period of about 12 months, a duration of approximately 
17 months from the start of study randomization to final PFS 
analysis, and an annual dropout rate of 10%, a total sample 
size of approximately 282 participants (randomized in a 
1:1 ratio) is required. The sample size calculation 
considers 1 futility interim analysis at 50% of the planned 
number of events. Under this current assumption, the 
COD for final PFS is approximately 18 months after first 
participant randomized.” 
 
The power calculations for OS analysis have been included in 
this section. The following will be applied for this endpoint: 
• 
The interim analysis of OS is planned at the time of 
PFS analysis, ie, approximately 18 months from the 
start of study randomization.  
• 
The final OS analysis is planned to be performed 
when 196 randomized participants have died (ie, at 
approximately 70% OS data maturity). 
• 
The COD for OS is approximately 64 months after 
the first randomized participant. 
The power calculations for OS 
analysis have been added in 
accordance with the inclusion of OS 
analysis as key secondary endpoint. 
9.3 Populations for 
analyses 
In Table 5, the response-evaluable population has been 
removed. 
This population has been removed 
from the study in consistency with the 
other studies from the same program. 
The analyses that were to be 
performed in this population will be 
performed in the intent-to-treat (ITT) 
participants with measurable disease 
at study entry, regardless of 
postbaseline assessment availability. 
This ITT analysis will provide a more 
accurate estimation of the ORR. 
9.4 Statistical 
analyses 
The text below has been updated as follows: 
“Estimated COD for the final PFS analysis will be 
approximately 17 18 months after first randomized 
participant. The COD for final analysis of OS will be 18 
approximately 64 months after the PFS analysis first 
randomized participant.”  
The COD projections have been 
updated following the newly added 
futility interim analysis for PFS and 
the inclusion of OS as the key 
secondary endpoint. 
9.4.1 Efficacy 
analyses 
The analysis methods for OS have been updated to include a 
formal comparison between the 2 treatment arms (stratified 
logrank for statistical testing). 
To clarify the statistical method used 
for the formal comparison between 
the 2 treatment arms on OS. 
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9.4.1.1 Analysis of 
primary efficacy 
endpoint 
The text below has been updated as follows 
“If progression and death are not observed before the PFS 
analysis COD for final PFS, PFS will be censored at the date 
of the last valid disease assessment with no evidence of a 
disease progression.” 
Updated for clarity 
9.4.1.2 Analysis of 
secondary efficacy 
endpoints 
The text below has been updated as follows: 
“Analysis of response-based endpoints (ie, ORR, DCR 
[disease control rate], CBR [clinical benefit rate], and DOR 
[duration of response]) will be performed for the global part 
primarily on the ITT population and supported by the 
analyses based on the response-evaluable ITT population 
with measurable disease at study entry.” 
This population has been removed 
from the study in consistency with the 
other studies from the same program. 
The analyses that were to be 
performed in this population will be 
performed in the ITT participants with 
measurable disease at study entry, 
regardless of postbaseline 
assessment availability. This ITT 
analysis will provide a more accurate 
estimation of the ORR. 
 
Overall survival was relocated as the key secondary objective 
in place of ORR and the analysis methods for OS have been 
updated to include a formal comparison between the 
2 treatment arms. 
Overall survival has been considered 
the key secondary endpoint, in 
response to the Food and Drug 
Administration recommendations. 
9.5 Interim analyses 
An interim analysis for futility has been planned to be carried 
out at 50% of the planned total number of PFS events. An 
interim analysis on OS is also planned at the time of final PFS 
analysis, if PFS is statistically significant. Interim analyses will 
be overseen by the Data Monitoring Committee (DMC). The 
details of these analyses have been included in 2 new 
sections: 
• 
“9.5.1 Interim analysis for progression-free survival” 
• 
“9.5.2 Interim analysis for overall survival” 
To clarify the methodology used for 
the interim analyses. 
9.5.3 Data Monitoring 
Committee 
The following text has been added: 
“The DMC will also oversee the interim analyses detailed in 
Section 9.5.1 and Section 9.5.2.” 
To clarify that the DMC will be 
overseeing the interim analyses 
planned for this study. 
Appendix 1 
In Section 10.1.1, the following text has been updated: 
• 
“Any amendments to the protocol will require 
national Health Authority and Institutional Review 
Board [IRB]/Independent Ethics Committee [IEC] 
approval before implementation of changes made 
to the study design, except for changes necessary 
to eliminate an immediate hazard to study 
participants.” 
Updated after requested by the 
Health Authorities. 
 
In Section 10.1.4, the following text has been updated: 
“The DMC will be in charge of reviewing the safety data and 
the progress of the study (including overseeing interim 
analyses) and the safety data and advising the Sponsor on 
potential modifications or communications that may be 
necessary to ensure the participant safety or protect the 
scientific integrity of the study.” 
To clarify that the DMC will be 
overseeing the interim analyses 
planned for this study. 
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Appendix 3 
In Section 10.3, the following text has been removed from 
“Follow-up of AEs and SAEs”: 
“If a participant dies during participation in the study or during 
a recognized follow-up period, the Investigator will provide 
Sponsor with a copy of any postmortem findings including 
histopathology.” 
The text has been updated to reflect 
the procedures that will be carried out 
for the follow-up of AEs and SAEs. 
Appendix 4 
The following text has been added: 
“Male participants 
• 
Male participants with heterosexual partners of 
reproductive potential are eligible to participate if 
they agree to use the following during the protocol 
defined timeline: 
- 
Refrain from donating sperm 
and 
- 
At least 1 of the following condition applies: 
- 
Are and agree to remain abstinent from penile 
vaginal intercourse on a long-term and 
persistent basis, when this is their preferred 
and usual lifestyle 
or 
- 
Agree to be on a gonadotropin releasing 
hormone analog for at least 4 weeks (to be 
continued during study treatment) as per label  
and use a male condom during intercourse 
during study treatment until 1 week after 
stopping the study treatment 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. 
• 
Men with a pregnant or breast-feeding partner must 
agree to remain abstinent from penile vaginal 
intercourse or use a male condom for the time 
defined in the protocol.” 
Because male participants have been 
considered eligible for this study, 
contraceptive guidance for male 
participants was included. 
 
The following text has been updated: 
“Non hormonal methods of contraception should be employed 
during the study in premenopausal women on a gonadotropin 
releasing hormone analog as per label. These include: 
intrauterine device, bilateral tubal occlusion, vasectomy 
partner, male or female condom with or without 
spermicide, cap, diaphragm, or sponge with spermicide.” 
Updated to clarify allowed 
contraceptive methods for women of 
childbearing potential. 
Appendix 5 
The following text has been updated: 
“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 
To accommodate the new 
assessments on drug metabolizing 
enzymes and transporters added to 
this amendment. 
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molecular subtype of the disease being treated. Therefore, 
where local regulations and Institutional Review 
Boards/Independent Ethics Committees allow, a blood and a 
saliva sample will be collected for DNA analysis from 
consenting participants.” 
Appendix 8 
The following text has been included in Section 2 of this 
Appendix (Study design): 
“At the time of Amended Clinical Protocol 02 submission, 
there was no experience of amcenestrant in Chinese 
patients. However, based on available data, no ethnic 
difference in amcenestrant safety profile is expected between 
Chinese and non-Chinese patients. For the ACT16105 study, 
a safety observation period will be set for Chinese 
participants to secure safety. A safety run in step will consist 
in the sequential treatment of 6 participants with 
amcenestrant (ie, approximately 12 randomized participants). 
None of the first 3 participants of amcenestrant arm will be 
treated for first dose on the same day. The safety review will 
occur when 6 Chinese participants have been exposed to 
amcenestrant and completed a minimum of 1 cycle duration 
(approximately 4 weeks) of treatment. If 0 to 1 out of 6 
evaluated participants had a treatment related adverse event 
of special interest (AESI) or treatment related AE leading to 
the treatment discontinuation, enrollment will continue in 
China. If at least 2 out of 6 evaluated amcenestrant treated 
participants have a treatment related AESI, or a treatment 
related AE leading to treatment discontinuation, enrollment 
will be on hold in China and further safety and 
pharmacokinetic (PK) assessment will be performed.” 
This section has been updated after a 
request has been made by the 
Chinese Center for Drug Evaluation, 
in order to account for a possible 
higher PK variability in this 
population. 
 
In Section 4 of this Appendix (Study population), the text 
below has been updated as follows: 
“A dedicated cohort of up to approximately 42 90 participants 
will be included.” 
After consultation with the Chinese 
Center for Drug Evaluation, as no prior 
Asian population exposure data were 
provided, the sample size of the 
Chinese extension should not be lower 
than 20% of the sample size of the 
global study and the Chinese extension 
should be powered to observe a HR 
lower than 0.8. To meet with these 
requirements, the number of participants 
in the China extension study has been 
increased from 42 to 90. 
 
In Section 6 of this Appendix (Study procedures) the text on 
pharmacodynamic evaluation specific to the China extension 
study has been updated as follows: 
“For patients participants enrolled in China, samples for 
mutation profiling in estrogen receptor 1 gene (ESR1) 
analysis of cell free deoxyribonucleic acid (cfDNA) will be 
collected at baseline, Cycle 3 Day 1, and end of treatment 
visit Cycle 1 Day 1 (predose). Separate The other samples 
for estrogen receptor 1 gene ESR1 analysis of cfDNA will not 
be collected and exploratory pharmacodynamic endpoints 
will not be assessed in this extension study.” 
In the China extension study, the only 
biomarker to be collected from 
participants will be the estrogen 
receptor 1 gene mutation status, for 
evaluation of PFS according to ESR1 
mutation status (secondary objective). 
Biomarkers for exploratory objectives 
will not be collected from these 
participants. 
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In Section 7.1 of this Appendix (Sample size determination) 
the text below has been updated as follows: 
“Assuming the hazard ratio (HR) of progression free survival 
(PFS) in the amcenestrant arm relative to the control arm is 
0.65, a total of 25 65 PFS events in the Chinese population 
would provide an 86 80% probability of observing a HR 
inferior to 1 0.80 in both the Chinese and non-Chinese 
populations, given that the primary analysis of PFS is 
statistically significant in the global study. 
Approximately 42 90 Chinese participants would need to be 
enrolled to reach 25 65 PFS events,. assuming Assuming 
the first Chinese participant enrolls 11 months after the first 
randomized participant of the global study and Chinese 
participants have a 9.5 17-month enrollment period., the 
cut-off date (COD) for PFS analysis is estimated to occur 
5 months after the last Chinese participant is enrolled. 
This number of events would provide a 79% probability 
of observing a HR inferior to 0.80 in Chinese population, 
given that the primary analysis of PFS is statistically 
significant in the global study” 
After consultation with the Chinese 
Center for Drug Evaluation, as no 
prior Asian population exposure data 
were provided, the sample size of the 
Chinese extension should not be 
lower than 20% of the sample size of 
the global study and the Chinese 
extension should be powered to 
observe a HR lower than 0.8. To 
meet with these requirements, the 
number of participants in the China 
extension study has been increased 
from 42 to 90. 
 
In Section 7.3 of this Appendix (Statistical analysis), the 
following text has been added: 
“The decision to continue or not with the recruitment of 
Chinese patients will be based on the results of the statistical 
analyses performed in the global population.” 
To clarify the impact of global 
population interim analysis on the 
China expansion cohort. 
Appendix 11 
Concomitant administration of moderate CYP2C8 inducers 
will not be permitted in this study. For this reason, a list of 
moderate CYP2C8 inducers has been included in this 
Appendix. 
Concomitant administration of 
moderate CYP2C8 inducers will not 
be permitted in participants receiving 
amcenestrant, since they may 
decrease amcenestrant exposure. 
10.15.3 
Amended protocol 03: 30 June 2020  
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment 
The objective of this amendment is to update the protocol on the following topics: 
• 
Study population and inclusion/exclusion criteria: 
- 
Define the paired biopsies planned in the study as optional procedures (I 06), 
- 
Clarification on inclusion criteria regarding sex (I 09).  
• 
Introduction of study name AMEERA 3. 
• 
Contingency measures for a regional or national emergency information have been added 
in Section 5.5 Criteria for temporary delaying, Section 6.1 Study intervention(s) 
administered, Section 9.4 Statistical analysis, and Section 10.1.2 Informed consent process. 
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Minor formatting and editorial updates. 
For clarity and accuracy. 
Title page 
Protocol title updated as follows: 
An open label randomized Phase 2 trial of amcenestrant, 
versus endocrine monotherapy as per physician’s choice in 
patients with estrogen receptor-positive, HER2-negative 
locally advanced or metastatic breast cancer with prior 
exposure to hormonal therapies (AMEERA 3). 
The study name is now available. 
 
Short title updated as follows: 
“Phase 2 study of amcenestrant versus physician’s choice in 
patients with locally advanced or metastatic ER-positive 
breast cancer (AMEERA 3).” 
 
Synopsis 
Protocol title updated as follows: 
An open label randomized Phase 2 trial of amcenestrant, 
versus endocrine monotherapy as per physician’s choice in 
patients with estrogen receptor-positive, HER2-negative 
locally advanced or metastatic breast cancer with prior 
exposure to hormonal therapies (AMEERA 3). 
Short title updated as follows: 
“Phase 2 study of amcenestrant versus physician’s choice in 
patients with locally advanced or metastatic ER-positive 
breast cancer (AMEERA 3).” 
The study name is now available. 
1.3 Schedule of 
Activities 
 
Vitals signs information has been updated: 
For Vitals signs 
a In C1D1, vital signs will also be assessed approximately 
2 hours after dosing. 
Updated to allow some flexibility in the 
assessment of the vital signs following 
the first intake of the IMP. 
Tumor specimen/ biopsy information has been updated: 
For Tumor specimen/ biopsy (optional procedures)  
a   Most recent archived biopsied tumor within past 3 months 
prior to initiation of study treatment, or fresh tumor biopsy 
collected from time of inclusion to C1D1 pre-treatment 
(optional). 
b Cycle 3 Day 1 (allowed up to Cycle 3 Day 15 or within 
14 days after first radiological tumor assessment after 
baseline). Tumor biopsy should be performed only after 
radiological assessment (optional). 
The status of this procedure has been 
updated as “optional”, to limit the 
burden of the participants in the study, 
and to promote their recruitment.  
 
Removed follow-up visit mark “X” for “Follicle-stimulating 
hormone and estradiol (premenopausal women only)”. 
The GnRH agonist treatment for 
pre/perimenopausal participants will 
not be administered during the 
follow-up period: the ovarian function 
suppression will not be monitored 
after the end-of-treatment. 
 
Created a new footnote “a Predose Cycle 1 Day 1” for 
cross-referred to “Estradiol (serum) for Cycle 1, Day 1 Visit”. 
To specify Estradiol sampling at 
predose. 
 
The following text has been updated for footnote for Normal 
tissue reference DNA (Saliva) 
• 
Section 8.7.2 and Section 10.16. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 2.3.2.1 
Amcenestrant 
Added the following text: 
• 
Risk of severe rash. 
 
This potential risk related to 
amcenestrant has been added, as 
2 Japanese participants have 
presented an episode of 
maculopapular rash in the TED15954 
Phase I study. These 2 events 
(Grade 2 and Grade 3) led to study 
drug discontinuation. 
Section 3 Objectives 
and endpoints 
Table 1 Objectives 
and endpoints 
Tertiary/exploratory 
The following tertiary/exploratory objective and endpoint have 
been updated: 
Objective: To evaluate in participants tumor biomarkers over 
time such as estrogen receptor (ER), Ki67, Bcl 2, and 
progesterone receptor (PgR) protein, and ribonucleic acid 
(RNA) gene expression profiles (for participants with tumor 
sites accessible for biopsy who accept biopsies at study entry 
and on treatment). 
Endpoint: Tumor ER, Ki67, Bcl 2, and PgR protein, and RNA 
gene expression profiles in optional paired biopsies at 
Cycle 1 Day 1 (pre-treatment) and at Cycle 3, Day 1 (allowed 
up to Day 15; or within 14 days after first radiological tumor 
assessment after baseline). 
Updated to indicate that the biopsies 
are optional. 
Section 5.1 Inclusion 
criteria 
 
 
 
 
In I 05, the following statement has been updated: 
“Either the primary tumor or any metastatic site must be 
Documentation of HER2 non over-expressing based on 
most recent tumor sample by IHC (0, 1+), or in situ 
hybridization-negative based on single-probe average HER2 
copy number <6.0 signals/cell or dual-probe 
HER2/centromeric probe for chromosome 17 (CEP17) 
ratio <2 with an average HER2 copy number <6.0 signals/cell 
as per American Society of Clinical Oncology guidelines (28). 
Note that if the primary tumor is HER2-negative and any 
further metastatic lesion is HER2-positive, the participant 
cannot be selected for inclusion.” 
To clarify and harmonize the definition 
of HER non over-expressing tumors. 
5.1 Inclusion criteria 
 
 
 
 
In I 06, the following text has been updated: 
“I 06 deleted in amended protocol 03. For participants with 
tumor accessible for paired biopsy at study entry: baseline 
samples, formalin fixed paraffin embedded (FFPE) archived 
biopsy samples (within 3 months prior initiation of study 
treatment) can be used, but preferably fresh biopsies from 
primary tumor or recurrence or metastasis, will be collected. It 
is recommended that the second biopsy is collected at the 
same location as the baseline biopsy, whenever possible.” 
Deleted as the biopsy procedures has 
been categorized as “optional”, to limit 
the burden of the participants in the 
study, and to promote their 
recruitment.  
In I 07, the following text has been updated: 
 “For countries where participants for whom CDK4/6 
inhibitors are available (ie, approved in their region and can 
be reimbursed), prior treatment with a CDK4/6 inhibitor in 
combination with fulvestrant or an AI is mandatory.” 
Approval and reimbursement may 
vary according to participant’s region 
or situation within the same country. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
In I 08, the following text has been updated: 
“Participants must have received progressed after at least 
6 months of a continuous prior endocrine therapy for 
advanced breast cancer and have progressed while on 
endocrine therapy (in single agent or in combination). The 
number of prior hormonal lines will be limited to 2”.  
“Participants with a relapse or have relapsed while on 
adjuvant endocrine therapy but after the first 2 years, or have 
relapsed with a relapse within 12 months of completing 
adjuvant endocrine therapy are also eligible.” 
To align with the definition of 
secondary endocrine resistance as 
defined in the 3rd European School of 
Oncology European Society for 
Medical Oncology International 
Consensus Guidelines for Advanced 
Breast Cancer. 
In I 09, the following text has been updated: 
“Male or Female.” 
“A) Postmenopausal women Female participants must be 
postmenopausal, as defined by one of the following: 
Or participants are premenopausal women on a GnRH analog 
for at least 4 weeks (to be continued during study treatment). 
Sexually active males should be on a GnRH analog for at 
least 4 weeks (to be continued during study treatment). 
B) Pre/perimenopausal women, ie, not meeting the 
criteria for being postmenopausal. 
C) Male participants. 
Note: Male with no prior bilateral orchiectomy and 
pre/perimenopausal women should be on a GnRH 
agonist for at least 4 weeks prior to randomization (to be 
continued during study treatment).” 
The definition of a “sexually active 
male” has been clarified, as required 
by regulatory agency request. 
Section 5.3 Lifestyle 
considerations 
The following text has been updated: 
For this reason, participants should avoid direct exposure to 
natural or artificial sunlight during study treatment and for at 
least 30 5 days after last IMP dose. 
To update the duration of avoiding the 
natural or artificial sunlight exposure 
to 5 days, as it is 5 times the half-life 
of the IMP (24 hours). 
Section 5.5 Criteria 
for temporarily 
delaying 
Added a new section to the protocol and the following text has 
been updated:  
“Section 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 10.16 (Appendix 16) 
should be considered”. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
Section 6.1 Study 
intervention(s) 
administered 
The following text has been updated: 
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 site to the 
participant via a Sponsor-approved courier company where 
allowed by local regulations and approved by the participant 
(Section 10.16 [Appendix 16]).   
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.6.1 Tumor 
biopsy to assess 
estrogen receptor 
degradation 
(optional 
procedures) 
The following text has been updated: 
8.6.1 Tumor biopsy to assess estrogen receptor degradation 
(optional procedures) 
Participants with an accessible tumor who consented to the 
optional paired biopsy will be asked to contribute the most 
recent archived biopsied tumor (within past 3 months prior to 
initiation of study treatment) or preferably a fresh tumor 
biopsy that can be collected between the time of ICF 
signature and Cycle 1 Day 1 prior to treatment. 
To clarify the assessment of the 
estrogen receptor degradation with 
the biopsies, defined as “optional”. 
Section 8.7.2 
Mutation profiling in 
cell-free DNA 
The following text has been added: 
“For a regional or national emergency declared by a 
governmental agency, contingency measures are 
included in Section 10.16 (Appendix 10.16)”. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
Section 8.7.3 RNA 
transcriptome 
analysis 
The following text has been updated: 
Transcriptome studies of the optional tumor biopsy may be 
conducted using microarray, sequencing, and/or alternative 
similar techniques, which facilitates the simultaneous 
measurement of the relative abundances and sequences of 
thousands of RNAs, resulting in a transcriptome profile for 
each biopsy sample. 
The optional tumor biopsy taken for the assessments 
referred in Section 8.6.1 can be used for these analyses. 
To clarify the transcriptome studies of 
the biopsies, defined as “optional”. 
Section 8.8 
Biomarkers 
The following text has been updated: 
Samples may be stored for a maximum of 5 years, or 15 
years, if future use of samples is consented to, or according 
to local regulations, following the last participant last visit at a 
facility selected by the Sponsor to enable further analysis of 
biomarker responses to the IMP. 
To harmonize the wording of the 
samples’ storage with the informed 
consent form. 
Section 9.4 
Statistical analysis 
The following text has been added: 
“For a regional or national emergency declared by a 
governmental agency, contingency measures are 
included in Section 10.16 (Appendix 16)”. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
Section 9.5.3 Data 
Monitoring 
Committee 
The following text has been updated: 
The DMC will also oversee the interim analyses on PFS 
detailed in Section 9.5.1 and Section 9.5.2. 
To clarify the scope of Data 
Monitoring Committee (DMC) 
responsibility - as the interim analyses 
on Overall Survival will happen at the 
time of final Progression Free 
Survival, treatment will be unblinded 
and thus there is no need for DMC at 
that time. 
Section 10.1.2 
Informed consent 
process 
The following text has been added: 
“For a regional or national emergency declared by a 
governmental agency, contingency measures are 
included in Section 10.16 (Appendix 16)”. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
Section 10.5 
Appendix 5: 
Genetics 
The following text has been updated: 
RNA may be isolated from the optional tumor biopsy in order 
to assess effects of IMP on the tumor. Analyses may include 
Updated to indicate that the biopsies 
are optional. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
microarray, sequencing, and/or alternative similar techniques, 
resulting in a transcriptome profile. The analyses may include 
RNA of selected genes or all of the genome. 
Section 10.8 
Appendix 8: 
Country-specific 
requirements  
The following text has been updated: 
4 STUDY POPULATION 
Participants will be selected based on the study inclusion and 
exclusion criteria as defined in Section 5 of the global study 
protocol and will have agreed to participate in this extension 
study. A dedicated cohort of up to approximately 
90 participants will be included. 
Note: In this extension cohort, previous treatment with a 
CDK 4/6 inhibitor will not be mandatory, and there will be 
no limitation to the number of participants naïve to 
CDK4/6 inhibitors. 
To specify that the previous treatment 
with a CDK 4/6 inhibitor and the 
limitation to the number of participants 
naïve to CDK4/6 inhibitors does not 
apply to the participants of the 
extension study. 
Section 10.16 
Appendix 16: 
Contingency 
Measures for a 
regional or national 
emergency that is 
declared by a 
governmental 
agency 
New section 10.16 has been inserted in the protocol and 
added the following text: 
“APPENDIX 16: CONTINGENCY MEASURES FOR A 
REGIONAL OR NATIONAL EMERGENCY THAT IS 
DECLARED BY A GOVERNMENTAL AGENCY 
Continuation of the study in the event of a regional or 
national emergency declared by a governmental agency: 
A regional or national emergency declared by a 
governmental agency (eg, public health emergency, 
natural disaster, pandemic, and terrorist attack) may 
prevent access to the clinical trial site. 
Contingency procedures are suggested for an emergency 
that prevents access to the study site, to ensure the 
safety of the participants, to consider continuity of the 
clinical study conduct, protect trial integrity, and assist in 
maintaining compliance with GCP in Conduct of Clinical 
Trials Guidance. Sponsor agreement MUST be obtained 
prior to the implementation of these procedures for the 
duration of the emergency. 
The decision for each individual participant to remain 
and/or start in the study should be made on a case by 
case basis based on best Investigator medical judgment. 
The clinical judgment of the treating physician should 
guide the management plan of each participant based on 
individual benefit/risk assessment and the evolving 
situation at the site (Section 5.5). However, in case new 
participant eligible for the trial, the PI/site should assess 
the capacity to maintain these patients into the trial 
before any screening procedures will start. If the site 
cannot guarantee an accurate follow-up in the context of 
the trial, alternative treatment outside the clinical trial 
should be proposed. 
When participants are already randomized and/or treated, 
attempts should be made to perform all assessments in 
accordance with the protocol to the extent possible. 
To implement the instructions related 
to a regional or national emergency in 
the protocol. 
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Brief Rationale 
 
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 at every other cycle). The deviations from 
the study protocol (eg, treatment delay, omission, tests 
not performed…) should be documented in the source 
document and collected in the appropriate pages of the 
eCRF. 
Procedures to be considered in the event of a regional or 
national emergency declared by a governmental agency: 
• 
If onsite visits are not possible, remote visits 
(eg, with home nurses, home health vendor, etc) 
may be planned for the collection of possible 
safety and/or efficacy data (eg safety 
assessments, efficacy assessments especially 
the tumor assessment, PRO) 
• 
If onsite visits are not possible visit windows 
may be extended for assessment of safety 
and/or efficacy data that cannot be obtained 
remotely 
• 
Use of local clinic or laboratory locations may 
be allowed 
• 
The Direct-to-Patient (DTP) supply of the IMP 
from the site/sponsor where allowed by local 
regulations and agreed upon by participant. 
(Section 6.1) 
• 
When collection of saliva sample is not feasible, 
the procedure will not be done. In that case, 
extraction of the DNA from the blood sample for 
genotyping and drug metabolizing enzyme and 
transporters may be considered. 
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. (Section 9.4) 
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 10.1.2).” 
 
 
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10.15.4 
Amended protocol 04: 17 December 2020  
This amended protocol 04 (Amendment 04) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The objective of this amendment is to update the protocol on the following topics: 
• 
To update exclusion criteria E15 and E16 with new data available on drug interactions 
(BCRP substrates, CYP3A and CYP2C8 inducers) 
• 
To revise the futility analysis 
• 
To add the risk of male fertility  
• 
To add risk minimization strategies for pregnancy, osteoporosis induced by endocrine 
therapies, hepatic toxicity, and photosensitivity  
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
• 
Minor formatting and editorial updates. 
• 
Changed the name of SAR439859 IMP to 
“Amcenestrant”. 
• 
For clarity and accuracy. 
• 
Availability of amcenestrant 
INN for SAR439859. 
Synopsis (Objective 
and Endpoints); 
Section 3 Objective 
and endpoints 
(Table 1); 9.4.1 
Efficacy analyses 
The definitions of Disease Control Rate (DCR) and Clinical Benefit 
Rate (BCR) have been updated to add the “Non-Complete 
Response/Non-Progressive Disease” in the endpoint’s descriptions. 
 
To take in account the participants with 
only non-measurable disease in the 
definitions of DCR and CBR. 
1.3 Schedule of 
Activities; Section 8 
Study assessments 
and procedures,  
 
A specification has been added to local “Follicle stimulating hormone 
and estradiol” samples: “a. For patients receiving Fulvestrant as 
IMP, the local estradiol sample will not be required”. 
Section updated to take in account that 
Estradiol levels can be high due to 
Fulvestrant intake. 
A pregnancy test has been added for WOCBP in screening, at D1 of 
each cycle and at EOT. 
Pregnancy test added to follow the CTFG 
guidelines “Recommendations related to 
contraception and pregnancy testing in 
clinical trials” Version 1.1, taking in 
account the suspected risk of fetotoxicity 
of amcenestrant. 
1.3 Schedule of 
Activities; 8.1.2 Bone 
scans 
 
The section has been updated as follow: 
a “If at screening, lesions are detected in the bone scan but not in 
the CT/MRI (RECIST 1.1) scan, further bone scans should be 
conducted every 8 weeks ±7 days after randomization. If the 
lesions seen in the bone scan are no longer visible, these 
assessments can should be conducted every 16 weeks ±7 days 
after randomization. 
If lesions are detected in the bone scan and CT/MRI 
(RECIST 1.1) scan, further bone scan assessments will be 
conducted every 16 weeks ±7 days after randomization.” 
To add clarification on bone scans 
schedule. 
2.3.2 Potential and 
identified risks 
For amcenestrant, risk of male infertility has been added. 
Amcenestrant has the potential to impair 
reproductive function and fertility in male 
humans based on clinical findings in dogs, 
attributed to the pharmacology of 
Amcenestrant in the testes.  The 
reference to the label for safety 
information has been omitted in previous 
version for the IMP fulvestrant 
2.3.2 Potential and 
identified risks; 5.2 
Exclusion criteria; 6.5 
Concomitant therapy; 
10.12 List of CYP 
inducers 
Updated data on amcenestrant allows the moderate inducers of 
CYP3A and CYP2C8 to be administered with amcenestrant.  
The Exclusion Criteria E 15. has been updated as follow:  
“Treatment with strong or moderate CYP3A and CYP2C8 inducers 
within 2 weeks before randomization or 5 elimination half-lives 
whichever is longer” 
“Potential and identified risks”, “Concomitant therapy” sections and 
Appendix 11 have also been updated accordingly. 
To update the protocol with available data 
showing that there is a modest decrease 
(30%) of amcenestrant with strong CYP3A 
inducers. 
5.2 Exclusion Criteria; 
6.5 Concomitant 
therapy 
The Exclusion Criteria E 16. has been updated as follow: 
“Ongoing treatment with drugs that are sensitive substrate of P-
glycoprotein (P-gp) (dabigatran, digoxin, fexofenadine), and of 
Breast Cancer Resistance Protein (BCRP) (rosuvastatin, 
sulfasalazine) since amcenestrant is a potential inhibitor of P-gp 
and BCRP”. 
“Concomitant therapy” section has also been updated accordingly. 
Amcenestrant has a potential inhibitory 
effect on BCRP substrates, leading to 
increase their absorption: exclusion 
criteria and concomitant medication 
section has been updated accordingly. 
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Section # and 
Name 
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Brief Rationale 
5.3 Lifestyle 
considerations  
5.3.1 Sun protection section has been updated: 
“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.” 
To ensure that the recommendations 
provided for sun protection are adequate. 
5.3.2 Osteoporosis section has been added: 
“Due to anti-estrogenic properties of amcenestrant, fulvestrant, 
and aromatase inhibitors being potent estrogen lowering 
agents, there exists potential risk of 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.” 
Amcenestrant, fulvestrant and aromatase 
inhibitors have a risk of osteoporosis 
because of their anti-estrogenic 
properties. The implemented changes are 
added as part of risk minimization 
strategy. 
6.5 Concomitant 
therapy  
Following statement has been added: 
Prophylactic vaccination is recommended for influenza A and B 
virus, severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2; ie COVID-19), Pneumococci, and Haemophilus influenza. 
To recommend some prophylactic 
vaccinations for the study participants. 
6.6 Dose modification 
The table 3 “Recommended dose modification and management of 
Amcenestrant related toxicities” has been updated to specify 
guidance on the management of isolated increase in alanine 
transaminase (ALT) Grade 3. 
The dose modification table has been 
updated to provide guidance in case of 
isolated ALT increase. 
Section 8 Adverse 
events and serious 
adverse events 
For AESI ALT increase Grade ≥3: the following text has been added: 
• 
“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 isolated 
increase of ALT (Table 3 Section 6.6). 
• 
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), total bilirubin (fractionated if >2 x ULN 
direct), GGT, and INR (if total bilirubin >2.5 ULN).  
• 
An ultrasound, or other imaging, 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 
The AESI section has been updated to 
provide guidance in case of an ALT 
increase. 
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patients, taking into account the local and national 
recommendations”. 
“Photosensitivity” has been added as an AESI: 
“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 6.6 Dose modification). 
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.” 
Preclinical studies using amcenestrant 
indicate a potential risk for phototoxicity. 
Photosensitivity events has been added 
as an AESI in order to collect relevant 
information. 
8.3.5 Pregnancy; 
Section 10.4 
Contraceptive 
guidance and 
collection of pregnancy 
information 
The contraception guidance has been updated: 
• 
to specify that male participants contraceptive guidance 
does not apply for men with prior bilateral orchiectomy 
• 
to keep consistency in the protocol that all male 
participants without prior bilateral orchiectomy must be on 
a GnRH analog 
• 
to add a recommendation for male participants: “Male 
participants should consider sperm preservation 
prior to beginning therapy with study IMPs because 
exposure to amcenestrant has the potential risk of 
testicular injury with partial or permanent infertility. 
Because exposure to amcenestrant, has the potential 
risk of testicular injury with partial or permanent 
infertility.” 
• 
to update the list of methods of contraception to present 
only “highly-effective” contraceptive measures 
• 
to clarify the duration of the contraception following the 
last IMP intake 
• 
Non-hormonal methods of contraception should be 
employed during the study in premenopausal participants 
and in male participants without prior orchiectomy on a 
GnRH analog as per label (please see Section 10.4 for 
details).  
To clarify and update the section to follow 
the CTFG guidelines “Recommendations 
related to contraception and pregnancy 
testing in clinical trials” Version 1.1, taking 
in account the suspected risk of 
fetotoxicity of IMPs, and the risk of male 
fertility with amcenestrant per request 
from health authorities. 
8.3.6 Disease-related 
events and/or disease-
related outcomes not 
qualifying as AEs or 
SAEs 
This section has been deleted. 
To delete a section which could be 
misunderstood in the AEs/SAEs reporting 
process. 
9.4.3.1 Analyses of 
patient reported 
outcome endpoints 
The following text has been updated: 
“Reasons for non-completion will be summarized on the safety 
population. For the QLQ-C30 (15 total scales), QLQ-BR23 
(8 scales), and EQ-5D-5L (health index and VAS) instruments, 
descriptive statistics on the absolute value and changes from 
baseline will be done for each treatment arm at each time point, at 
EOT and 60 to 90 days after the last study administration 
(follow-up).” 
Clarification on PROs schedule, to take in 
account that EOT visit can be performed 
before 30 days following last IMP (if 
further therapy is started). 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.5.1 Interim analysis 
for progression-free 
survival; 1.1 Synopsis 
The following text has been updated: 
“The stopping boundary for futility is based on the observed HR 
based on Cox proportional hazard model, ie, an HR>1.1. The 
stopping boundary for non-binding futility will be derived based on 
the O’Brien and Fleming β-spending function. If the value of the test-
statistic exceeds the O’Brien and Fleming non-binding futility 
boundary (z >-0.435, p >0.332), the study may be stopped for 
futility.” 
 
The same statement in the section 1.1 Synopsis has also been 
updated accordingly. 
To revise the futility analysis strategy in 
order to recommend stopping the study 
only in case of observed increase risk of 
PFS events in the experimental arm 
compared to the control arm. 
10.1.6 Data quality 
assurance 
The following section has been added:  
“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.”  
To allow remote-monitoring when allowed 
by local regulations, if on-site monitoring is 
not possible 
10.2, Clinical 
Laboratory Test  
Table 10 was updated with the addition of GFR assessment 
To clarify that renal function calculation is 
needed on top of the creatinine level for all 
patients. 
10.4 Contraceptive 
guidance and 
collection of pregnancy 
information 
Pregnancy outcome follow-up duration has been updated to up to 
one year. 
As requirements of Health Authorities vary 
across countries, pregnancy outcome 
follow-up may last up to one year. 
The following text has been added: 
“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 up to one year. 
Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.” 
To mention in the “collection of pregnancy 
information” section the pregnant partners 
of male participants on top of the pregnant 
participants. 
10.13 List of CYP 
sensitive substrates 
List of CYP sensitive substrates has been updated. 
To help investigators to monitor efficacy of 
CYP sensitive substrate drugs, for 
participants receiving amcenestrant. 
10.17 Patient reported 
outcomes 
Added a copy of the following PROs English-language 
questionnaires: EORTC QLQ-C30, EORTC BR-23 (for female and 
male participants) and EQ-5D-5L.   
As required by Health Authority. 
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10.15.5 
Amended protocol 05: 23 September 2021  
Amended protocol 05 (23 September 2021) 
This amended protocol 05 (Amendment 05) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
Overall rationale for the amendment 
The objective of the amendment is to update the protocol with the following key changes: 
• 
To update exclusion criteria and concomitant medication section with results from recent 
in vitro and clinical drug-drug interaction studies. 
• 
To update some safety guidance regarding osteoporosis risk following Belgium Health 
Authority commitment. 
• 
To update in the Chinese extension cohort the procedures required in the full-PK sampling 
population, and to clarify how the cut-off date for PFS analysis is determined. 
Protocol amendment summary of changes table 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 4.1 
Overall design 
For planned cutoff date (previously database lock date) for 
the global study, the following sentence “For cycles 
completed after the COD for OS analysis, all ongoing SAEs 
(related or not), …” has been changed to “For cycles 
completed after the COD for final PFS analysis for the main 
cohort, only all ongoing SAEs (related or not), …” 
To clarify that after COD for final PFS 
analysis, data collected will be limited 
to exposure data, reason of EOT, and 
safety events and its related 
information when adverse event is 
serious or related to IMP. 
1.1 Synopsis and 4.1 
Overall design 
For planned cutoff date (previously database lock date) for 
the Chinese participants, the following sentence has been 
removed “ie, approximately 18 months after the PFS analysis 
of the global study”. 
Both global and China study are 
event-driven, the cut-off dates are 
independent of each other. Therefore, 
removed the dependency on timing of 
global analysis, to bring more clarity. 
5.2 Exclusion criteria 
Exclusion criterion 16 was adjusted to remove sensitive 
substrates of P-gp and BCRP and add sensitive substrates of 
OATP1B1/B3. And a note was added under this exclusion 
criteria to refer to FDA website. 
A recent clinical drug-drug interaction 
study showed that amcenestrant 
given at a higher dose of 400 mg has 
no clinically relevant effect on P-gp 
sensitive substrate (Dabigatran). 
Since inhibitory potential on BCRP is 
lower, no effect is anticipated either. 
In addition, it was identified in vitro 
that amcenestrant is a potential 
inhibitor of OATP1B1/1B3. 
6.5 Concomitant 
therapy 
 
Sensitive substrates of P-gp and BCRP related information 
has been removed; sensitive substrates of OATP1B1/B3 
related information has been added. 
Caution to be taken with the proton pump inhibitors has been 
removed. 
To update recommendation following 
the most recent available data of 
drug-drug interaction studies. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.3.2 Osteoporosis 
The following sentence was added “Investigators will monitor 
Bone Mineral Density if clinically indicated, taking into account 
full medical history of patients, all confounding factors, 
previous anti-cancer treatments and considering the anti-
estrogenic properties of the study drugs.” 
To clarify the responsibilities for the 
monitoring, as a commitment to 
Belgium HA requirement.  
6.6 Dose modification 
In Table 3, “Omit endocrine therapies administration” has 
been updated to “Omit amcenestrant administration” for 
Grade 2 and Grade 3 for isolated increase of ALT part of the 
table. 
To clarify that only amcenestrant is in 
scope of this ‘recommended dose 
modification’ table. 
9.4.2.1 Analyses of 
adverse events 
“AESIs” have been added as a bullet under the “The number 
and percentage of participants who experience any of the 
following will be provided”. 
For clarity and consistency. 
10.8 Country-specific 
requirements (China 
extension study) 
 
In Section 6, under pharmacokinetic evaluation, some 
flexibility has been added to the required samples in the “full-
PK sampling” population in the extension cohort of China: 
samples on top of Cycle 1 Day 1/2 and Cycle 2 Day 1 may be 
omitted based on investigator decision. 
To lighten the required PK samples of 
the “full-PK” population in China, 
when sampling is difficult for patients. 
In the section 6. “Procedures”: 
• 
The following sentence has been modified: “Biopsy 
samples and blood samples will be taken in 
accordance with local regulations for all 
participants from China (global and extension 
part). 
• 
The following sentence has been added: “Note: 
These specificities apply also for participants from 
China enrolled in the global part of the study.” 
To clarify that specificities regarding 
exploratory endpoints in China per 
local regulations apply also for 
participants from China enrolled in the 
global part of the study. 
• 
In the sample size determination section, the 
following sentence has been removed “This number 
of events would provide a 79% probability of 
observing a HR inferior to 0.80 in the Chinese 
population, given that the primary analysis of PFS is 
statistically significant in the global study”. 
• 
The following sentence “It is anticipated to occur 
5 months after the last Chinese participant is 
enrolled” has been changed to “The actual COD of 
the Chinese cohort will be the date with 
approximately 65 PFS events in Chinese 
population”. 
To clarify the sample size 
determination section, and to clarify 
the current definition of the COD rule 
for the Chinese population. 
In the informed consent section, “A separate informed 
consent (ICF) shall be obtained... will sign a separate 
informed consent for this aspect of the study” has been 
changed to “An informed consent (ICF) shall be obtained ... 
will sign a separate section in the informed consent for this 
aspect of the study”. 
To clarify that participants who agree 
to have samples taken for the full PK 
assessments will have to sign a 
separate section of the ICF rather 
than a separate ICF. 
Entire document 
Editorial changes, updates as per latest One Document 
protocol template (OneDocument Version 6.0). 
Correction of typographical errors and 
minor inconsistencies across different 
sections, and clarifications. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
To be aligned with latest One 
Document protocol template. 
 
10.16 APPENDIX 16: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials 
Guidance. Sponsor agreement MUST be obtained prior to the implementation of these procedures 
for the duration of the emergency. 
The decision for each individual participant to remain and/or start in the study should be made on 
a case by case basis based on best Investigator medical judgment. The clinical judgment of the 
treating physician should guide the management plan of each participant based on individual 
benefit/risk assessment and the evolving situation at the site (Section 5.5). However, in case new 
participant eligible for the trial, the PI/site should assess the capacity to maintain these patients 
into the trial before any screening procedures will start. If the site cannot guarantee an accurate 
follow-up in the context of the trial, alternative treatment outside the clinical trial should be 
proposed. 
When participants are already randomized and/or treated, attempts should be made to perform all 
assessments in accordance with the protocol to the extent possible. 
When possible, the focus should be on Investigational Medicinal Product (IMP) administration 
and safety blood collection (eg, biochemistry and hematology). However, all efforts should be 
made to perform the measurements of key parameters for efficacy endpoints (eg, tumor 
assessments at every other cycle). The deviations from the study protocol (eg, treatment delay, 
omission, tests not performed…) should be documented in the source document and collected in 
the appropriate pages of the eCRF. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• 
If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data (eg safety 
assessments, efficacy assessments especially the tumor assessment, PRO). 
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• 
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 site/sponsor where allowed by 
local regulations and agreed upon by participant. (Section 6.1). 
• 
When collection of saliva sample is not feasible, the procedure will not be done. In that 
case, extraction of the DNA from the blood sample for genotyping and drug metabolizing 
enzyme and transporters may be considered. 
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 (Section 9.4). 
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 10.1.2 [Appendix 1]). 
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10.17 APPENDIX 17: PATIENT REPORTED OUTCOMES  
10.17.1 
EORTC QLQ-C30  
 
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10.17.2 
EORTC QLQ-B23  
• For male participants: 
 
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• For female participants: 
 
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10.17.3 
EQ-5D-5L  
 
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11 
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47. 
 
 
 
 
 
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Page 1
STATISTICAL ANALYSIS PLAN 
An open-label randomized Phase 2 trial of amcenestrant (SAR439859), versus 
endocrine monotherapy as per physician’s choice in patients with estrogen 
receptor-positive, HER2-negative locally advanced or metastatic breast cancer 
with prior exposure to hormonal therapies 
SAR439859-ACT16105 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 10-Dec-2021 
Total number of pages: 
83 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
LIST OF FIGURES .......................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 6 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 8 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 8 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Tertiary/exploratory objectives ......................................................................................................... 9 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10 
1.4 
STUDY PLAN ................................................................................................................................. 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 11 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 13 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 15 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 15 
2.1.1 
Demographic and baseline characteristics .................................................................................... 15 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 19 
2.1.3 
Efficacy endpoints .......................................................................................................................... 20 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 20 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 20 
2.1.4 
Safety endpoints ............................................................................................................................ 22 
2.1.4.1 
Adverse events variables ............................................................................................................... 22 
2.1.4.2 
Deaths ............................................................................................................................................ 23 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 23 
2.1.4.4 
Vital signs variables ....................................................................................................................... 24 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 24 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 24 
2.1.6 
Pharmacodynamic, genomics and biomarker endpoints ............................................................... 24 
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2.1.7 
Quality-of-life endpoints ................................................................................................................. 25 
2.1.8 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 27 
2.1.9 
Impact of COVID-19pandemic ....................................................................................................... 27 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 28 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 29 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 29 
2.3.1 
Intent-to-treat population ................................................................................................................ 30 
2.3.2 
Safety population ........................................................................................................................... 30 
2.3.3 
Pharmacokinetic-evaluable population .......................................................................................... 30 
2.4 
STATISTICAL METHODS ............................................................................................................. 30 
2.4.1 
Demographics and baseline characteristics .................................................................................. 30 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 31 
2.4.3 
Prior anticancer therapies .............................................................................................................. 31 
2.4.4 
Extent of investigational medicinal product exposure and compliance ......................................... 31 
2.4.4.1 
Extent of investigational medicinal product exposure .................................................................... 32 
2.4.5 
Analyses of efficacy endpoints ....................................................................................................... 33 
2.4.5.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 34 
2.4.5.2 
Analyses of secondary efficacy endpoints ..................................................................................... 40 
2.4.5.3 
Multiplicity issues ........................................................................................................................... 42 
2.4.6 
Analyses of safety data .................................................................................................................. 42 
2.4.6.1 
Analyses of adverse events ........................................................................................................... 43 
2.4.6.2 
Deaths ............................................................................................................................................ 45 
2.4.6.3 
Analyses of laboratory variables .................................................................................................... 46 
2.4.6.4 
Analyses of vital sign variables ...................................................................................................... 47 
2.4.6.5 
Analyses of electrocardiogram variables ....................................................................................... 47 
2.4.7 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 47 
2.4.7.1 
Analysis of pharmacokinetic variables ........................................................................................... 47 
2.4.7.2 
Analysis of Pharmacodynamics/genomic and biomarkers variables ............................................. 48 
2.4.8 
Analyses of quality of life ............................................................................................................... 49 
2.4.9 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 51 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 52 
2.5.1 
General conventions ...................................................................................................................... 52 
2.5.2 
Data handling conventions for primary efficacy variables.............................................................. 52 
2.5.3 
Data handling conventions for secondary efficacy variables ......................................................... 54 
2.5.4 
Missing data ................................................................................................................................... 54 
2.5.5 
Unscheduled visits ......................................................................................................................... 58 
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2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 58 
2.5.7 
Statistical technical issues ............................................................................................................. 58 
3 
INTERIM ANALYSIS ..................................................................................................................... 59 
3.1.1 
Interim analysis for progression-free survival ................................................................................ 59 
3.1.2 
Interim analysis for overall survival ................................................................................................ 60 
3.1.3 
Data Monitoring Committee ........................................................................................................... 60 
4 
DATABASE LOCK ........................................................................................................................ 61 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 62 
6 
REFERENCES ............................................................................................................................... 63 
7 
LIST OF APPENDICES ................................................................................................................. 65 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ....................... 66 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ......................................................................... 67 
APPENDIX C 
INTERNATIONALLY AGREED SOC ORDER .................................................................... 71 
APPENDIX D 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1) ....................... 72 
APPENDIX E 
DESCRIPTION OF CENSORING AND EVENT RULES FOR PRIMARY AND 
SENSITIVITY ANALYSES OF PFS ............................................................................................... 77 
APPENDIX F 
EORTC QLQ-C30 AND QLQ-BR23 ITEMS, SCALES AND SCORES ............................... 82 
 
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LIST OF TABLES  
Table 1 - Primary objective and endpoint ........................................................................................................ 8 
Table 2 - Secondary objectives and endpoints ............................................................................................... 8 
Table 3 - Tertiary/exploratory objectives and endpoints ................................................................................. 9 
Table 4 - Protocol amendment statistical changes ....................................................................................... 11 
Table 5 - Major changes in statistical analysis plan ...................................................................................... 13 
Table 6 - Cross-tabulation of ICR and investigator assessments of PFS outcome ...................................... 37 
Table 7 - Cross-tabulation of ICR and investigator assessments of documented PD .................................. 38 
Table 8 - Subgroups analyses: covariates investigated ................................................................................ 39 
Table 9 - Analysis visit for PRO analyses ..................................................................................................... 50 
Table 10 - Progression-free survival analyses .............................................................................................. 59 
Table 11 - Overall survival analyses ............................................................................................................. 60 
Table 12 - Response criteria, evaluation of target lesions ............................................................................ 75 
Table 13 - Response criteria, evaluation of nontarget lesions ...................................................................... 75 
Table 14 - A summary of overall response status for measurable disease .................................................. 75 
Table 15 - A summary of overall response status for non-measurable disease ........................................... 76 
Table 16 - A summary of overall response status for non-measurable disease ........................................... 76 
Table 17 - PFS Primary analysis ................................................................................................................... 77 
Table 18 - PFS sensitivity analysis #1 (ignoring further anti-cancer therapy) ............................................... 78 
Table 19 - PFS sensitivity analysis #2 (PFS considering events occurring after two or more non-evaluable 
tumor assessment as event and ignoring further anticancer therapy) .......................................................... 79 
Table 20 - PFS sensitivity analysis #3 (PFS considering events occurring after two or more non-evaluable 
tumor assessment as event and back-dating at the next schedule assessment and ignoring further 
anticancer therapy) ........................................................................................................................................ 80 
Table 21 - PFS supportive #3 analysis for investigator assessment (taking clinical/non-radiological 
progression as event) .................................................................................................................................... 81 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 11 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
AI: 
aromatase inhibitor 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
cfDNA: 
cell-free deoxyribonucleic acid 
CI: 
confidence interval 
COD: 
cut-off date 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DCR: 
disease control rate 
DI: 
dose intensity 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EDR: 
early discrepancy rate 
EORTC: 
European Organisation for Research and Treatment of Cancer 
EOT: 
end of treatment 
EQ-5D-5L: 
EuroQoL questionnaire with 5 dimensions and 5 levels per dimension 
ESR1: 
estrogen receptor 1 gene 
FWER: 
family-wise error rate 
GGT: 
gamma-glutamyltransferase 
GHS/QoL: 
Global Health Status and Quality-of-Life Scale 
HLGT: 
high-level group term 
HLT: 
high-level term 
HR: 
hazard ratio 
HRQL: 
health-related quality of life 
ICF: 
informed consent form 
ICR: 
Independent Comitee Review 
IHC: 
immunohistochemistry  
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
LDR: 
late discrepancy rate 
LLT: 
lower-level term 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NCI: 
National Cancer Institute 
ODR: 
outcome discrepancy rate 
OS: 
overall survival 
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PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PFS: 
progression free survival 
PS: 
performance status 
PT: 
preferred term 
QLQ: 
Quality of Life Questionnaire 
RD: 
relative dose 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
SDF: 
survival distribution function 
SERD: 
selective estrogen receptor down-regulator 
SERM: 
selective estrogen receptor modulator 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
VAS: 
visual analogue scale 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is an international, prospective, open-label, Phase 2 randomized study. Men, postmenopausal 
women and premenopausal women on a gonadotropin-releasing hormone analog with locally 
advanced or metastatic breast cancer will be randomly (1:1) assigned to one of the following 
treatment arms: amcenestrant (SAR439859) or an endocrine monotherapy of the choice of the 
physician. 
The population will be stratified according to the presence of visceral metastasis (defined by at 
least 1 liver or lung metastasis) (Yes or No), prior treatment with CDK4/6 inhibitors (Yes or No), 
and Eastern Cooperative Oncology Group status (0 or 1). 
Overall, 282 participants will be randomly assigned to study intervention with a balanced 
randomization ratio of 141 participants randomized per treatment arm from approximately 
110 sites. The number of participants naïve to CDK4/6 inhibitors should not be higher than 20% 
of the overall sample size. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
Table 1 - Primary objective and endpoint  
Objective 
Endpoint 
Primary 
To determine whether SAR439859 400 mg per os 
improves progression-free survival (PFS) when compared 
with an endocrine monotherapy of the choice of the 
physician, in participants with metastatic or locally 
advanced breast cancer. 
Progression-free survival is defined as the time interval from the 
date of randomization to the date of first documented tumor 
progression as per Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) assessed by independent central review 
(ICR) or death (due to any cause), whichever comes first. 
1.2.2 Secondary objectives  
Table 2 - Secondary objectives and endpoints  
Objectives 
Endpoints 
Secondary 
To compare the overall survival in the 2 treatment arms. 
Overall survival is defined as the time interval from the date of 
randomization to the date of documented death (due to any 
cause). 
To assess the objective response rate in the 2 treatment 
arms. 
Objective response rate is defined as the proportion of 
participants who have a confirmed complete response (CR) or 
partial response (PR), as best overall response (BOR) derived 
from overall response determined by ICR as per RECIST 1.1, 
from the date of randomization to the date of end of treatment.  
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Objectives 
Endpoints 
To evaluate the disease control rate in the 2 treatment 
arms. 
Disease control rate is defined as the proportion of participants 
who have a confirmed CR, PR, stable disease (SD), or Non-CR/ 
Non-PD as BOR determined by ICR as per RECIST 1.1 from the 
date of randomization to the date of end of treatment.  
To evaluate the clinical benefit rate in the 2 treatment 
arms. 
Clinical benefit rate is defined as the proportion of participants 
who have a confirmed CR, PR, SD, or Non-CR/ Non-PD for at 
least 24 weeks determined by ICR as per RECIST 1.1, from the 
date of randomization to the date of end of treatment.  
To evaluate the duration of response in the 2 treatment 
arms. 
Duration of response is defined as the time from 
first documented evidence of CR or PR until progressive disease 
(PD) as determined by ICR as per RECIST 1.1 or death from 
any cause, whichever occurs first. 
To evaluate the PFS according to the estrogen receptor 1 
gene (ESR1) mutation status in the 2 treatment arms. 
Progression-free survival as per ESR1 status determined at 
Cycle 1 Day 1.  
To evaluate the pharmacokinetics of amcenestrant as 
single agent. 
Amcenestrant plasma concentrations during the treatment 
period. 
To evaluate health-related quality of life in the 2 treatment 
arms. 
Disease-specific and generic health-related quality of life, 
disease and treatment-related symptoms, health state utility, and 
health status will be evaluated using the European Organisation 
for Research and Treatment of Cancer (EORTC) core quality of 
life questionnaire (QLQ-C30), the EORTC-QLQ breast cancer 
specific module (BR23) and the EuroQoL questionnaire with 
5◦dimensions and 5 levels per dimension (EQ-5D-5L), from 
Cycle 1 Day 1 until 90 days after last dose of the study 
treatment. 
To evaluate the overall safety profile in the 2 treatment 
arms. 
Adverse events/serious adverse events and laboratory 
abnormalities. 
1.2.3 Tertiary/exploratory objectives  
Table 3 - Tertiary/exploratory objectives and endpoints  
Objectives 
Endpoints 
Tertiary/exploratory 
To evaluate in participants the gene mutation profile of the 
tumor over time (baseline and end of treatment) by cell-free 
deoxyribonucleic acid (cfDNA) analysis, and ESR1 mutation 
analysis (pre- and on-treatment) by cfDNA. 
The gene mutation profile of the tumor over time (Cycle 1 
Day 1 [pre-treatment] and end of treatment) by cfDNA 
analysis, and ESR1 mutation analysis by cfDNA analysis 
pre-treatment and at Cycle 3 Day 1. 
To evaluate in participants tumor biomarkers over time such 
as estrogen receptor (ER), Ki67, Bcl-2, and progesterone 
receptor (PgR) protein, and ribonucleic acid (RNA) gene 
expression profiles (for participants with tumor sites 
accessible for biopsy who accept biopsies at study entry and 
on treatment). 
Tumor ER, Ki67, Bcl-2, and PgR protein, and RNA gene 
expression profiles in optional paired biopsies at Cycle 1 
Day 1 (pre-treatment) and at Cycle 3, Day 1 (allowed up to 
Day 15; or within 14 days after first radiological tumor 
assessment after baseline). 
To explore pharmacokinetic/pharmacodynamics relationship 
of amcenestrant. 
Pharmacokinetic exposure and response, or safety endpoints 
during the treatment period. 
To evaluate the time to first use of chemotherapy after 
disease progression in the 2 treatment arms. 
Time to first use of chemotherapy after disease progression is 
defined as the time from randomization to start of the first use 
of chemotherapy after disease progression. 
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1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size for this study is determined based on following assumptions: the median PFS for 
the control arm is assumed to be 4.5 months (1, 2, 3, 4, 5, 6) and an improvement of 53% to a 
median PFS of 6.9 months (corresponding to a hazard ratio [HR] = 0.65) would be considered 
clinically meaningful.  
A total of 201 ICR-assessed PFS events will be required in the 2 treatment arms for the study to 
have approximately 85% power to detect an increase in PFS, assuming a true HR of 0.65 
(representing a 53% increase in median PFS from 4.5 to 6.9 months), tested at a one-sided 
significance level of alpha = 0.025. 
For the global part of the study, assuming a uniform accrual rate of 23.5 participants per month 
accomplished over a period of about 12 months and an annual dropout rate of 10%, a total sample 
size of approximately 282 participants (randomized in a 1:1 ratio) is required. The sample size 
calculation considers 1 futility interim analysis at 50% of the planned number of events. Under 
this current assumption, the COD for final PFS is approximately 18 months after first participant 
randomized. 
Sample size calculation was performed using East 6.5. 
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1.4 
STUDY PLAN  
Figure 1 - Graphical study design  
 
C = Cycle; D = day; IM = intramuscular; IMP = investigational medicinal product; OS = overall survival; PD = progressive disease; 
PFS = progression-free survival; R = randomization. 
The complete schedule of activities (SoA) is presented in Section 1.3 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The protocol amendment history Table 4 gives the version number, description and rationale of 
major changes to the protocol statistical section. All changes were performed after the first patient 
randomized (12-Nov-2019) and before the planned primary PFS analysis (early 2022). 
Table 4 - Protocol amendment statistical changes  
Amendment # 
Description of Change 
Brief Rationale 
02 
Overall survival has been updated as the key secondary 
objective. The analysis methods for OS have been 
updated to include a formal comparison between the 
2 treatment arms (stratified logrank for statistical testing). 
Overall survival has been considered the 
key secondary endpoint, in response to 
the Food and Drug Administration 
recommendations. 
 
The objective response rate (ORR) is no longer key 
secondary endpoint. Its definition has been updated to 
clarify that BOR will be derived from overall response 
determined by ICR. 
Updated for accuracy, as the best overall 
response will be derived from overall 
response determined by ICR 
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Amendment # 
Description of Change 
Brief Rationale 
02 
The sample size calculation has been updated. The total 
number of required ICR assessed PFS events has been 
updated to 201 from 195. The COD for final PFS has been 
updated to 18 months after first randomized participant. 
 
The power calculations for OS analysis have been 
included. The following will be applied for this endpoint: 
• 
The interim analysis of OS is planned at the time 
of PFS analysis, ie, approximately 18 months 
from the start of study randomization.  
• 
The final OS analysis is planned to be 
performed when 196 randomized participants 
have died (ie, at approximately 70% OS data 
maturity). 
• 
The COD for OS is approximately 64 months 
after the first randomized participant. 
The sample size calculations and COD 
projections have been updated following 
the newly added futility interim analysis 
for PFS and the inclusion of OS as the 
key secondary endpoint. 
 
02 
A new section has been included for estradiol 
assessments, which have been added in this amendment.  
Estradiol assessments have been 
included to explore the possible influence 
of circulating levels of estradiol on the 
efficacy of SAR439859. 
02 
The response-evaluable population has been removed. 
This population has been removed from 
the study in consistency with the other 
studies from the same program. The 
analyses that were to be performed in 
this population will be performed in the 
intent-to-treat (ITT) participants with 
measurable disease at study entry, 
regardless of postbaseline assessment 
availability. This ITT analysis will provide 
a more accurate estimation of the ORR. 
02 
An interim analysis for futility has been planned to be 
carried out at 50% of the planned total number of PFS 
events. An interim analysis on OS is also planned at the 
time of final PFS analysis, if PFS is statistically significant.  
To clarify the methodology used for the 
interim analyses. 
03 
The following text has been added: 
“The DMC will also oversee the interim analyses on PFS 
detailed in Section 9.5.1”. 
To clarify that the DMC will be overseeing 
the PFS interim analyses planned for this 
study. 
04 
The definitions of Disease Control Rate (DCR) and 
Clinical Benefit Rate (BCR) have been updated to add the 
“Non-Complete Response/Non-Progressive Disease” in 
the endpoint’s descriptions. 
To take in account the participants with 
only non-measurable disease in the 
definitions of DCR and CBR. 
04 
The stopping boundary for futility has been updated to: 
based on the observed HR based on Cox proportional 
hazard model, ie, an HR>1.1. 
To revise the futility analysis strategy in 
order to recommend stopping the study 
only in case of observed increase risk of 
PFS events in the experimental arm 
compared to the control arm. 
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Amendment # 
Description of Change 
Brief Rationale 
04 
Photosensitivity has been added as AESI 
Preclinical studies using amcenestrant 
indicate a potential risk for phototoxicity. 
Photosensitivity events has been added 
as an AESI in order to collect relevant 
information. 
06 
The definition of the COD for the final PFS and OS 
analysis has been changed 
To allow more flexibility for the COD 
definition for final PFS and OS analyses. 
06 
The definition of the censoring and event scheme for the 
PFS analysis has been changed. 
To align AMEERA-3 with the general 
FDA recommendation to censor patients 
after initiation of further anti-cancer 
therapy or if the documented progression 
or death occurred after two or more non-
evaluable tumor assessments. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The statistical analysis plan history Table 5 below gives the version number, description and 
rationale for major changes to the statistical analysis features in the statistical analysis plan. 
The initial SAP was approved on 23-Oct-2019. Interim analysis was performed on 24-Mar-2021. 
The primary PFS analysis is planned for early 2022. 
Table 5 - Major changes in statistical analysis plan  
SAP 
Version 
Approval 
Date 
Description of Change 
Brief Rationale 
1.0 
23-Oct-2019 
Not Applicable 
Original version 
2.0 
11-Jan-2021 
Overall survival has been updated as the key secondary 
objective. The analysis methods for OS have been 
updated to include a formal comparison between the 
2 treatment arms (stratified logrank for statistical 
testing). 
Overall survival has been considered 
the key secondary endpoint, in 
response to the Food and Drug 
Administration recommendations. 
 
 
The sample size calculation has been updated. The 
total number of required ICR assessed PFS events has 
been updated to 201 from 195. The COD for final PFS 
has been updated to 18 months after first randomized 
participant. The power calculations for OS analysis have 
been included. 
The sample size calculations and 
COD projections have been updated 
following the newly added futility 
interim analysis for PFS and the 
inclusion of OS as the key secondary 
endpoint. 
 
 
The analysis plan for interim PFS futility and interim OS 
at the time of final PFS analysis (if PFS is statistically 
significant) has been described. 
To clarify the methodology used for 
the interim analyses. 
 
 
Prior anti-cancer therapies endpoints are updated and 
reorganized. 
To better organize the summary of 
prior anti-cancer treatment. 
 
 
Response-evaluable population has been removed from 
the analysis population. 
Change as per protocol amendment 
02. 
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SAP 
Version 
Approval 
Date 
Description of Change 
Brief Rationale 
 
 
RMST in case of non-proportional hazard has been 
added. 
 
To clarify supportive analysis that 
may be performed in case of non-
proportional hazard. 
 
 
Subgroup analyses for OS and sensitivity analyses 
adjusting OS for switch to subsequent anti-cancer 
treatment have been added. 
To clarify subgroup analysis and 
supportive analysis that may be 
performed for OS. 
 
 
The algorithm of PFS censoring under the condition of 
“documented progression (or death) after two or more 
non-evaluable tumor assessment” has been updated to 
“An event occurring at least 18 weeks (excluded) after 
the last evaluable tumor assessment”. 
To cover the 7-day window before 
and after the scheduled tumor 
assessment. 
 
 
Updated censoring rule for the primary PFS analysis, 
sensitivity analysis #1 and sensitivity analysis for 
investigator assessment. 
Updated based on feedback from 
health authorities on AMEERA-5. 
 
 
The wording in 2.5.2 has been modified for Date of 
tumor assessment. 
Rephrased the wording for 
clarification. 
3.0 
10-Dec-2021 
Wording of the censoring rule for the primary PFS and 
OS analyses has been updated. 
To clarify the censoring rule for all 
possible scenarios for the primary 
PFS analyses. 
 
 
The definition of the COD for the final PFS and OS 
analysis has been changed. 
To allow more flexibility for the COD 
definition for final PFS and OS 
analyses. 
. 
 
Baseline definition has been added for biomarker data 
and clinical laboratory/vital sign/ECG data that, 
“baseline is defined as the last sample collection prior to 
the first administration of the IMP.” 
To clarify the baseline definition for 
biomarker and clinical laboratory/vital 
sign/ECG data. 
 
 
Photosensitivity has been added as AESI (after protocol 
amendment 04). 
AESI added following protocol 
amendment 04. 
 
 
Analysis visit for PRO analyses has been added and 
longitudinal repeated measures analysis has been 
clarified. 
To estimate the treatment effect on 
quality of life according to the real 
duration of exposure. 
 
 
Analyses of the time to sustained deterioration for all 
EORTC QLQ-C30 and EORTC QLQ-BR23 scales have 
been added. 
To better characterize the effect of 
SAR439859 on Quality of Life. 
 
 
The definition of “as-treated” has been changed to 
“analyzed according to the randomized arm if the 
participant has received at least one administration of 
the as-randomized intervention”. 
Participants will be classified to the 
randomized arm if receiving at least 
one administration of as-randomized 
intervention. This definition is aligned 
with AMEERA-5 study for project level 
consistency. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last value or measurement taken up to the date of 
randomization. This definition applies for all variables unless otherwise specified.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.6 and 
Section 2.4.5). 
Demographic characteristics 
Demographic variables are age in years (quantitative and qualitative variable : 18 to 64, 65 to 84, 
≥85), gender, race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, Unknown), ethnicity (Hispanic or Latino, not Hispanic or 
Latino, Not reported, Unknown), weight (kg), eastern cooperative oncology group (ECOG) 
performance status (PS) and menopausal status for females (peri/premenopausal, postmenopausal) 
at baseline. 
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor. 
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at diagnosis   
The following disease characteristics at initial diagnosis will be described: 
• Time from initial diagnosis of breast cancer to randomization date (in years) 
• Histology (diagnosis type as collected in eCRF) 
• Disease location and laterality (as collected in eCRF) 
• Histopathology type (undifferentiated, poorly differentiated, moderately differentiated, 
well differentiated and other) 
• Stage of the disease (as collected in eCRF) 
Disease status at study entry 
The following disease characteristics at study entry will be described: 
• Extent of the disease (metastatic, locally advanced, other) 
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• Number of organ(s) involved (as collected in eCRF and per ICR) 
• Type of organ(s) involved (as collected in eCRF and per ICR) 
• Type of disease: Visceral metastases (ie, liver or lung) or not visceral metastases (as 
collected in eCRF and per ICR) 
• HER2 status (as collected in eCRF) 
• ER status (as collected in eCRF) 
• PgR status (as collected in eCRF) 
• Disease status (measurable disease, non-measurable disease), as collected in eCRF and per 
ICR) 
Prior anticancer therapies 
Prior anti-cancer treatments are collected by regimen in the eCRF. The following variables will be 
collected/derived: 
• Intent of prior anti-cancer therapy according to the following categories: neoadjuvant only, 
adjuvant only, advanced only, both neoadjuvant and adjuvant, both neoadjuvant and 
advanced, both adjuvant and advanced, neoadjuvant and adjuvant and advanced. 
• Time from last relapse/progression to randomization date 
• Number of prior lines of treatment in advanced setting descriptive statistics and by class 0, 
1, 2 or ≥3. A line of therapy in the advanced setting consists of a single agent, combination 
or a sequential therapeutic strategy with several drugs, given until a PD is documented. It 
corresponds to a regimen in advanced setting. 
• Intent of the last prior anti-cancer therapy according to the following categories: no prior 
treatment, neoadjuvant or adjuvant, advanced and unknown. 
• Endocrine resistance status according to the following categories: 
- 
Primary resistance, defined as relapse <24 months after the start of adjuvant 
hormonotherapy, for patients without advanced hormonotherapy; progression 
<6 months after the start of the last prior advanced hormonotherapy, for patients with 
advanced hormonotherapy. 
- 
Secondary resistance, defined as relapse >= 24 months after the start and <12 months 
after the end of adjuvant hormonotherapy, for patients without advanced 
hormonotherapy; progression >= 6 months after the start of the last prior advanced 
hormonotherapy, for patients with advanced hormonotherapy.  
- 
Sensitive, defined as relapse >= 12 months after the end of adjuvant hormonotherapy 
and hormonotherapy-naïve in advanced therapy.  
• Type of prior anticancer therapy in neoadjuvant setting (targeted therapy, hormonotherapy, 
chemotherapy, immunotherapy or other as collected in eCRF), 
• Type of prior anticancer therapy in adjuvant setting (targeted therapy, hormonotherapy, 
chemotherapy, immunotherapy or other as collected in eCRF), 
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• Time from start of adjuvant therapy to relapse in adjuvant setting (years), for participants 
who relapsed during adjuvant therapy 
• Time from end of adjuvant therapy to relapse in adjuvant setting (years), for participants 
who relapsed after completion of adjuvant therapy 
• Duration of adjuvant therapy (years) 
• Among patients with prior adjuvant hormonotherapy,  
- 
Number of patients with relapse <24 months after the start of adjuvant 
hormonotherapy 
- 
Number of patients with relapse ≥24 months after the start and <12 months after the 
end of adjuvant hormonotherapy 
- 
Number of patients with relapse ≥12 months after the end of adjuvant 
hormonotherapy  
• Type of prior anticancer therapy in advanced setting (targeted therapy, hormonotherapy, 
chemotherapy, immunotherapy or other as collected in eCRF), 
• Reason for discontinuation of the last prior line in advanced setting, 
• Best response to the last prior line in advanced setting, 
• Time to progression of last prior line in advanced settings (ie, start date of the first drug 
within the last prior line of treatment up to last progression) (months) 
• Duration of last prior line in advanced settings (last line end date - last line start date + 1) 
(months) 
• Among prior hormonotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, advanced only, both 
neoadjuvant and adjuvant, both neoadjuvant and advanced, both adjuvant and 
advanced, neoadjuvant and adjuvant and advanced 
- 
Number of prior hormonotherapy-based lines in advanced setting by category (0, 1, 2 
or ≥3) 
- 
Type of prior hormonotherapy in neoadjuvant or adjuvant settings:  
- 
Aromatase inhibitor (AI) 
- 
SERM (eg, Tamoxifen) 
- 
SERD (eg, Fulvestrant) 
- 
Other 
- 
Type of prior hormonotherapy in advanced setting: 
- 
AI 
- 
SERM (eg Tamoxifen) 
- 
SERD (eg Fulvestrant) 
- 
Other 
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• Among prior chemotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, advanced only, both 
neoadjuvant and adjuvant, both neoadjuvant and advanced, both adjuvant and 
advanced, neoadjuvant and adjuvant and advanced, 
- 
Number of prior chemotherapy lines in advanced setting by category (0, 1, 2 or ≥3) 
- 
Type of prior chemotherapy in neoadjuvant or adjuvant settings and Type of prior 
chemotherapy in advanced settings: 
- 
Anthracycline 
- 
Taxane 
- 
Capecitabine 
- 
Other 
• Among prior targeted therapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, advanced only, both 
neoadjuvant and adjuvant, both neoadjuvant and advanced, both adjuvant and 
advanced, neoadjuvant and adjuvant and advanced, 
- 
Number of prior targeted-based lines in advanced setting by category (0, 1, 2 or ≥3) 
- 
Type of prior targeted therapy in neoadjuvant or adjuvant settings and Type of prior 
targeted therapy in advanced settings: 
- 
Anti-HER2 
- 
CDK4/6 inhibitor 
- 
mTOR inhibitor 
- 
PI3K inhibitor 
- 
PARP inhibitor 
- 
Other 
• Among prior immunotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, advanced only, both 
neoadjuvant and adjuvant, both neoadjuvant and advanced, both adjuvant and 
advanced, neoadjuvant and adjuvant and advanced, 
- 
Number of prior immunotherapy lines in advanced setting by category (0, 1, 2 or ≥3) 
- 
Type of prior immunotherapy in neoadjuvant or adjuvant settings and Type of prior 
targeted therapy in advanced settings: 
- 
Anti PD-1 
- 
Anti PD-L1 
- 
Other 
• Prior anti-cancer therapies in combination with endocrine therapy 
- 
Type of prior endocrine-based combinations in advanced settings: 
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- 
CDK4/6 inhibitor + AI 
- 
CDK4/6 inhibitor + SERD 
- 
AI + SERD 
- 
AI + SERM 
- 
PI3K inhibitor + SERD 
- 
mTOR inhibitor + AI 
- 
mTOR inhibitor + SERD 
- 
Other 
• Prior surgery: number (n, %) of patients with any prior surgery related to breast cancer, 
type of procedure (Preferred Term) and time from the last surgery to the randomization 
date (months). 
• Prior radiotherapy: number (n, %) of patients with any prior external radiotherapy related 
to breast cancer, intent, intent of last prior external radiotherapy, time from the last 
external radiotherapy to the randomization date (months) overall and by intent (curative 
and palliative) and location of prior external radiation therapy by intent. Prior internal 
radiotherapy will be listed. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.4.  
2.1.2 Prior or concomitant medications (other than anticancer therapies)  
All medications taken from the signed informed consent date up to the randomization date and 
until 30 days after the end of treatment are to be reported in the eCRF. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the patient used from the date of informed consent until first 
study treatment administration intake.  Prior medications can be discontinued before 
first administration or can be ongoing during treatment phase.   
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from first study treatment administration to the end of treatment + 30 days.  A given 
medication can be classified both as a prior medication and as a concomitant medication.  
Concomitant medications do not include medications started during the posttreatment 
period (as defined in the observation period in Section 2.1.4). 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.4. 
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2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint(s)  
The primary endpoint is Progression Free Survival (PFS) defined as the time from the date of 
randomization to the first documented date of the first documentation of objective PD according 
to RECIST 1.1 definitions (see Appendix D ) or death due to any cause, whichever comes first.  
The following censoring rules will be used: 
• If documented progression or death are not observed before the analysis cut-off or the date 
of initiation of further anticancer therapy, PFS will be censored at the date of the last 
evaluable tumor assessment not showing documented progression prior to the initiation of 
a further anticancer therapy (if any).  
• A participant without PFS event (death or documented progression) and without any 
evaluable post-baseline tumor assessments will be censored at the day of randomization 
(Day 1).  
• A participant with an event documented after two or more non-evaluable tumor 
assessments will be censored at the date of the last evaluable tumor assessment 
documenting no progression prior to the initiation of a further anticancer therapy. 
Clinical/non-radiological progression (as collected in the eCRF) will not be considered as 
documented progression for primary PFS analysis. 
An independent central review (ICR) blinded to the randomization arm and to the patient 
characteristics will be conducted to evaluate overall response at each tumor assessment and 
determine disease response including progression status per RECIST 1.1 definitions  
(Appendix D). The full details regarding the determination of the progressive disease are provided 
in protocol and the ICR charter. The ICR will stop after the cut-off date (COD) for PFS analysis 
because no more efficacy assessment will be performed except collection of survival status. 
Additional details regarding the definition of PFS and handling of events and censoring are given 
in Section 2.5.2 and Appendix E. 
2.1.3.2 Secondary efficacy endpoint(s)  
Overall Survival 
Overall survival is defined as the time from date of randomization to date of death due to any 
cause. In the absence of observation of death, survival time will be censored to last date the 
participant is known to be alive (last contact date as defined in Section 2.5.3). 
Objective response rate 
The Best Overall Response will be determined by ICR according to RECIST v1.1 (see ICR 
charter for definition). Confirmation of responses (CR or PR) is necessary. As a supportive 
analysis, BOR according to the investigator assessment will also be determined.  
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The ORR on each randomized treatment arm will be estimated by dividing the number of 
participants with objective response (confirmed CR or PR as BOR assessed by ICR, according to 
RECIST 1.1) by the number of participants from the analysis population of the respective 
treatment arm.  
As a supportive analysis, ORR according to the investigator assessment will also be determined. 
In addition, in order to evaluate the tumor shrinkage of the target lesions, best relative change 
from baseline in tumor size will be assessed for each patient with measurable disease.  Additional 
details are given in Section 2.5.3. 
Disease control rate  
The DCR on each randomized treatment arm will be estimated by dividing the number of 
participants with disease control (confirmed CR or PR, or SD or Non-CR/Non-PD as BOR 
assessed by ICR, according to RECIST 1.1) by the number of participants from the analysis 
population of the respective treatment arm. 
As a supportive analysis, DCR according to the investigator assessment will also be determined. 
Clinical benefit rate 
The CBR on each randomized treatment arm will be estimated by dividing the number of 
participants considered as clinical benefit responders based on ICR assessment, by the number of 
participants from the analysis population of the respective treatment arm. For patients with 
measurable disease at baseline, they will be considered as clinical benefit responders if they 
achieve a CR or PR as BOR, or SD with an overall response recorded as SD or better at 
24-1=23 weeks or later from randomization, allowing for the ±7 days visit window for tumor 
assessment. For patients with non-measurable disease at baseline, they will be considered as 
clinical benefit responders if they achieve a CR as BOR or Non-CR/Non-PD with an overall 
response recorded as Non-CR/Non-PD or better at least 23 weeks after randomization. 
As a supportive analysis, CBR according to the investigator assessment will also be determined. 
Duration of response  
The DOR is defined as the time from the date of the first tumor assessment at which the overall 
response was recorded as CR or PR that is subsequently confirmed to the first date of tumor 
assessment at which the overall response was recorded as PD or death, whichever comes first. For 
participants with ongoing response at the time of the analysis, DOR will be censored at the date of 
the last valid disease assessment not showing documented progression performed before the 
initiation of a new anticancer treatment (if any).  
DOR is determined only for patients who have achieved a BOR of PR or better. 
As a supportive analysis, DOR according to the investigator assessment will also be determined. 
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2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, vital signs, weight, electrocardiogram (ECG) and 
Eastern Cooperative Oncology Group (ECOG) performance status (PS). 
Observation period  
The observation period will be divided into 3 epochs: 
• The pretreatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP.  
• The on-treatment period is defined as the time from the first dose of IMP up to 30 days 
after the last dose of IMP.  
• The post-treatment period is defined as the time starting 31 days after the last dose of 
IMP to study closure.  
2.1.4.1 Adverse events variables  
Adverse event observation period  
• Pretreatment AEs are defined as any AE occurring during the pretreatment period. 
• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the 
Investigator’s opinion), or become serious during the on-treatment period.  
• Post-treatment AEs are defined as AEs that are reported during the post-treatment period. 
All adverse events (including serious adverse events and adverse events of special interest) will be 
graded according to National cancer institute common terminology for adverse events (NCI-
CTCAE) v5.0 and coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), 
high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of MedDRA currently in effect at Sanofi at the time of database lock. 
Adverse events of special interest 
Specific analyses will be performed for the following AEs (see Section 2.1.4.1): 
• Pregnancy of female participant entered in a study with IMP, 
• Symptomatic overdose (serious or non-serious) with IMP. 
• Increase in alanine aminotransferase (ALT) ≥ Grade 3. 
• Photosensitivity (when occurred after local approval of protocol amendment 4)  
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2.1.4.2 Deaths  
The deaths will be summarized as follows: 
• Deaths on-study: includes all deaths occurring from the first IMP up to study closure: 
- 
Death on-treatment: includes all deaths occurring from the first IMP up to the end of 
treatment + 30 days, 
- 
Death post-treatment: includes all deaths occurring after the end of treatment + 30 days 
up to study closure. 
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables.  
Blood samples for clinical laboratories will be taken as defined in the SoA (Section 1.3 of the 
protocol) and as clinically indicated. Urinalysis tests on dipstick will be assessed at baseline and at 
End of treatment (EOT) and if clinically relevant. Patients with 3+ or greater urine protein 
dipstick reading should undergo further assessment with a 24-hour urine collection for 
determination of proteinuria.   
The laboratory parameters will be classified as follows:  
• Hematology  
- 
Red blood cells and platelets and coagulation:  hemoglobin, hematocrit, red blood 
cell count, platelet count, prothrombin time and international normalized ratio (INR) 
- 
White blood cells:  white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry  
- 
Metabolism:  glucose, albumin 
- 
Electrolytes:  sodium, potassium, chloride, calcium, phosphate, magnesium  
- 
Renal function: creatinine, eGFR (as collected in the eCRF at baseline), blood urea 
nitrogen, urea  
- 
Liver function:  alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, lactate dehydrogenase, total bilirubin, gamma-
glutamyltransferase (GGT) 
• Urinalysis 
- 
Qualitative urinalysis by dipstick:  proteins, glucose, ketones, leukocytes, 
erythrocytes   
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2.1.4.4 Vital signs variables  
Vital signs include heart rate, systolic and diastolic blood pressure, weight and ECOG PS (0, 1, 2, 
3, 4).   
For a given parameter, a patient will be considered as evaluable if at least one measure of this 
parameter is available during the on-treatment period. 
2.1.4.5 Electrocardiogram variables  
The incidence of patients with at least 1 abnormal ECG at any time during the on-treatment period 
will be summarized irrespective of the baseline level and/or according to the following baseline 
status categories: 
• Normal/missing 
• Abnormal 
2.1.5 Pharmacokinetic variables  
SAR439859 plasma concentrations will be determined at the predefined time point according to 
the SoA presented in Section 1.3 of the protocol. In addition, population PK approaches will be 
used to calculate individual PK estimates. The population PK analysis will be described in a 
separate report. 
PK estimates may also be used to conduct the exploratory exposure-response analyses for safety 
(eg, incidence of AEs) and efficacy (eg, BOR, CBR, DOR). 
2.1.6 Pharmacodynamic, genomics and biomarker endpoints  
Estrogen receptor 1 gene mutation status in circulating free DNA 
The mutation status (wild type, mutant) of twelve specific mutations of the ESR1 gene will be 
determined at baseline and on Cycle 3 Day 1 by multiplex droplet digital PCR (ddPCR), including 
their mutant frequency and concentration. For each ESR1 mutation the type of mutation will be 
also specified (missense, frameshift, inframe, etc). 
Mutational profiling in circulating free DNA  
The mutations of a panel of 77 cancer genes (Roche AVENIO panel) will be determined at 
baseline. The type of mutation (missense, frameshift, inframe, etc), the mutant frequency and the 
mutant concentration will be also specified. In addition, other genomic aberrations such as the 
copy number variants or the fusion genes may be highlighted. 
Estrogen receptor degradation and tumor biopsy biomarkers 
The expression of ER will be determined by immunohistochemistry (IHC) at baseline and on 
treatment at Cycle 3 in tumor biopsy samples in both treatment arms. Change in ER expression 
will be used to assess ER degradation in patients with accessible tumor. 
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In addition, expression levels of biomarkers such as Ki67, Bcl-2, and PgR will also be evaluated 
by IHC. From tumor biopsies, tumor gene expression profiles related to ER degradation (and 
other gene signature and pathways) will be also obtained. These analyses will be performed on 
transcriptome (mRNA). 
Estradiol 
Circulating level of estradiol will be measured at baseline and at Cycle 3 Day 1.  
2.1.7 Quality-of-life endpoints  
Health-related quality of life (HRQL) will be assessed using: 
• The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Cancer specific module with 30 items (EORTC QLQ-C30) (7, 8, 9).  
• The EORTC QLQ-BR23 breast cancer-specific module with 23 items (EORTC QLQ-
BR23) (10). 
• The EuroQol measure with 5-dimensions and 5-levels per dimension EQ-5D-5L (11). 
EORTC QLQ-C30 
The EORTC core quality of life questionnaire (QLQ-C30) is a cancer-specific instrument that 
contains 30 items and provides a multidimensional assessment of HRQL (7, 8, 9) evaluating 
symptoms as well as functioning.  
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
5 functional scales (physical, role, emotional, cognitive, and social functioning), 9 symptom 
scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties), and a Global Health Status/quality of life scale (GHS/QoL). 
The recall period is the past week. All items are scored 1 (“not at all”) to 4 (“very much”) except 
for the items contributing to the global health status (GHS)/quality of life (QoL), which are scored 
1 (“very poor”) to 7 (“excellent”). All scales are transformed from raw scores to linear scales 
ranging from 0 to 100 (see Appendix F). A higher score for functional and GHS/QoL scales 
represents a higher/healthier level of functioning/HRQL; whereas a higher score for symptoms 
scales represents a higher symptom burden. A 10-point change is often used as a conservative 
indicator of clinically meaningful change from baseline (12). 
The following endpoints will be derived: 
• Change from baseline in scores for each scale, calculated at each visit.  
• The time to sustained deterioration for each scale, defined as the first time from first IMP 
date to the time of a worsening from baseline ≥10 in on-treatment (including EOT) post-
baseline scores before cutoff date and start of further anticancer therapy, among patients 
for whom all subsequent scores meet the 10-point or greater post-baseline threshold (ie, an 
increase from baseline for symptom scales, and a decrease from baseline for the functional 
scales/GHS/QoL). In the absence of a sustained worsening from baseline in scales, the 
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time to sustained deterioration will be censored to the date of the last EORTC QLQ-C30 
evaluation before the start of further anticancer therapy, last contact date, lost to follow-up, 
death or withdrawal of consent or the cutoff date, whichever occurs first. In case of 
sustained deterioration after start of further anticancer therapy or cutoff date, the patient 
will be censored using the same rules previously described.  
EORTC QLQ-BR23 
The EORTC QLQ breast cancer specific module (QLQ-BR23) is a disease-specific HRQL 
measure that is used in conjunction with the QLQ-C30. The QLQ-BR23 assesses the impact 
breast cancer and the side effects of treatment in breast cancer patients.  
The QLQ-BR23 contains 23 items. It is composed of both multi-item scales and single-item 
measures. 4 functional scales (body image, sexual functioning, sexual enjoyment, future 
perspective) and 4 scales related to symptoms of disease or treatment (arm symptoms, breast 
symptoms, systemic therapy side effects, and upset by hair loss). The recall period is the past 
week. All items are scored 1 (“not at all”) to 4 (“very much”). All scales are transformed from raw 
scores to linear scales ranging from 0 to 100 (see Appendix F). A higher score for functional 
scales represents a better outcome; whereas a higher score for symptoms scales represents a 
higher symptom burden for symptoms of disease or treatment. Currently, there are no robust 
published estimates for clinically meaningful thresholds of within-patient change in EORTC 
QLQ-BR23 scores. A 10-point change from baseline is commonly applied in this setting (13, 14, 
15). 
Rules of handling with missing items are detailed in Appendix F for the EORTC questionnaires. 
The following endpoints will be derived: 
• Change from baseline in scores for each scale, calculated at each visit.  
• The times to sustained deterioration for each scale, defined as the first time from first IMP 
date to the time of a worsening from baseline ≥10 in on-treatment (including EOT) post-
baseline scores before cutoff date and start of further anticancer therapy, among patients 
for whom all subsequent scores meet the 10-point or greater post-baseline threshold (ie, an 
increase from baseline for symptom scales, and a decrease from baseline for the functional 
scales). In the absence of a sustained worsening from baseline in scales, the time to 
sustained deterioration will be censored to the date of the last EORTC QLQ-BR23 
evaluation before the start of further anticancer therapy, last contact date, lost to follow-up, 
death or withdrawal of consent or the cutoff date, whichever occurs first. In case of 
sustained deterioration after start of further anticancer therapy or cutoff date, the patient 
will be censored using the same rules previously described. 
EQ-5D-5L 
The EuroQoL questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L) is a 
standardized measure of health status, designed for self-completion by the participants, that 
provides a simple, generic measure of health for clinical and economic appraisal, and consists of 
2 sections: descriptive system and visual analogue scale (VAS). The descriptive section consists 
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of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, 
and extreme problems. The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions; this 
results in a 1-digit number expressing the level for that dimension. The digits for 5 dimensions 
can be combined in a 5-digit number describing the respondent’s health state. The VAS records 
the participant’s self-rated health on a 20 cm vertical VAS ranging from “the worst health you can 
imagine (0)” to “the best health state you can imagine (100)”. This information can be used as a 
quantitative measure of health as judged by the individual participants. The recall period is today. 
VAS will be described as given by the participant. The health state will be converted into a single 
utility index value by using the value sets based on UK population and according to the crosswalk 
algorithm developed by B. van Hout (11).  
Change from baseline in VAS and utility index will be calculated at each visit. 
2.1.8 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
Further therapies after discontinuation of IMP include further anti-cancer therapy, surgery and 
radiotherapy.  
Time to first use of chemotherapy after disease progression or treatment discontinuation 
(without disease progression)  
The time to first use of chemotherapy after disease progression or treatment discontinuation 
(without disease progression) is defined as the time from date of randomization to start of the first 
use of chemotherapy after disease progression or treatment discontinuation (without disease 
progression). In the absence of chemotherapy after disease progression or treatment 
discontinuation (without disease progression), time will be censored to last contact date or the 
cutoff date, whichever occurs first. In the unlikely event if a patient starts chemotherapy while on 
study treatment without disease progression, it will be considered as an event. 
2.1.9 Impact of COVID-19pandemic  
The impact of Covid-19 pandemic may be evaluated with below endpoints: 
• Premature EOT due to COVID-19 
• Premature EOS due to COVID-19 
• Critical or major protocol deviations related to COVID-19 
• Adverse events related to COVID-19  
• Sensitivity analysis on primary PFS may be performed, with patients diagnosed with 
COVID-19 censored at the date of diagnosis. 
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2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the informed consent. 
Randomized patients (ie, Intent-to-treat (ITT) population) consist of all patients from the enrolled 
population (ie, with a signed informed consent form) who have been allocated a randomization 
number by the Interactive Response Technology (IRT), regardless of whether the patient was 
treated or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a summary table: 
• Nonrandomized but treated patients 
• Randomized patients 
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who discontinued study treatment with main reason for permanent treatment 
discontinuation 
• Patients still on treatment 
• Status at the cut-off date (Alive/Death) 
Number of screened patients, number of screen failure patients and reasons for screen failure will 
be summarized in a separate table. In addition, number and percentage of screened patients by 
country and sites will be presented. 
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator.   
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. 
Additionally, the following analysis populations will be summarized. 
• Intent-to-treat (ITT) population 
• Safety population 
• Pharmacokinetic-evaluable population 
Definition of study populations are provided in Section 2.3. 
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2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a patient is randomized based on an incorrect stratum or a patient is randomized 
twice 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or a 
nonrandomized patient is treated with IMP reserved for randomized patients. This 
irregularity is applicable only for patients in SAR439859 arm and for patients randomized 
in the control arm for countries dispensed by the IRT.  
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages). Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
Number of patients (%) in the stratification factors from IRT and derived from eCRF data will be 
displayed in the same table and the number of patients (%) with at least one wrong stratum will be 
calculated, by treatment and overall. 
2.3 
ANALYSIS POPULATIONS  
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
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2.3.1 Intent-to-treat population  
All participants from the enrolled population (ie, who sign the 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. 
2.3.2 Safety population  
All participants randomly assigned to study intervention and who took at least 1 dose of study 
intervention. For participants receiving more than one study intervention during the study, they 
will be analyzed according to the randomized arm if the participant has received at least one 
administration of the as-randomized intervention. 
In addition:  
• Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
2.3.3 Pharmacokinetic-evaluable population  
All participants from the safety population who received at least one dose of SAR439859 and 
with at least 1 available plasma concentration post treatment with adequate documentation of date 
and time of dosing and date and time of sampling. 
2.4 
STATISTICAL METHODS  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group. One-sided tests will be used in this study for the primary endpoint (PFS) and key 
secondary endpoint (OS) at the 1-sided alpha of 2.5%. Confidence intervals will be estimated as 
two-sided and will be used for descriptive purposes only. 
2.4.1 Demographics and baseline characteristics  
Parameters will be summarized on the ITT population analyzed in the treatment group to which 
they were randomized.  Analyses for the safety population will be included in the appendices if 
the size of the safety population is different (>10%) from the size of that in the primary analysis 
population for any treatment group. 
Parameters described in Section 2.1.1 may be summarized by treatment group, according to the 
class of treatment (AI, SERM and SERD) for the control arm and overall using descriptive 
statistics, depending on the number of patients by class of treatment (AI, SERM, SERD). 
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The medical and surgical history will be summarized according to the SOC and PT (SOC will be 
sorted according to the internationally agreed order (see Appendix C) and PT by overall 
decreasing frequency). 
2.4.2 Prior or concomitant medications (other than anticancer therapies)  
The prior and concomitant medications will be presented for the ITT population.  
Medications will be summarized by treatment group and according to the class of treatment (AI, 
SERM and SERD) for the control arm according to the WHO-DD dictionary, considering the first 
digit of the anatomic category (ATC) class (anatomic category) and the first 3 digits of the ATC 
class (therapeutic category).  All ATC codes corresponding to a medication will be summarized, 
and patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore, patients may be counted several times for the same medication.  
The table for prior medications will be sorted decreasing frequency of ATC followed by all other 
therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence in the SAR439859 group.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
2.4.3 Prior anticancer therapies  
In addition, the following specific medications will be summarized: 
• A table for prior anti-cancer therapies will be provided using the ATC code (chemical 
class) and the standardized medication name. This table will be sorted by decreasing 
frequency of ATC followed by medication names based on the overall incidence. In case 
of equal frequency regarding ATCs, the alphabetical order will be used. 
• The same table will be provided for prior anti-cancer therapies in advanced setting. 
Summary tables will be displayed by treatment group, according to the class of treatment (AI, 
SERM and SERD) for the control arm and overall using descriptive statistics. 
2.4.4 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure will be assessed and summarized by actual treatment within the 
safety population (Section 2.3.2), by treatment group, by class of treatment (AI, SERM, SERD) 
and according to each drug for the control arm.  
In addition, class of treatment and drug will be summarized in the safety population. A shift table 
of planned drug versus actual taken drug will be provided. 
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2.4.4.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and actual dose 
information, by class of treatment (AI, SERM, SERD) and for each drug for the control arm. 
The extent of exposure will be assessed for each patient as: 
• Number of cycles started, defined by the number of cycles in which at least one dose of 
any study treatments is administered. 
• Duration of exposure (week) is defined as [(Last day of exposure – first day of exposure 
+ 1)/7]. 
• The first date of exposure is defined as the first administration date with non-zero dose 
whichever the IMP (SAR439859, Anastrozole, Letrozole, Exemestane, Tamoxifen or 
Fulvestrant).  
The last date of exposure is defined as: 
- 
The last administration date for SAR439859, Anastrozole, Letrozole, Exemestane or 
Tamoxifen.  
- 
For Fulvestrant, min(last administration date + 14 - 1 days if last cycle is Cycle 1 or 
last administration date + 28 - 1 days if last cycle is Cycle 2 or later ; date of death) 
Total number of cycles started, number of cycles started by patient as a quantitative variable and 
by category (ie, number (%) of patients having started at least 1 cycle, at least 2 cycles, etc), and 
duration of exposure will be summarized by descriptive statistics. 
The following parameters will be calculated for each drug: 
• Cumulative dose (mg): the cumulative dose is defined as the sum of all doses during the 
study treatment exposure. 
• Dose intensity (DI, in mg/day) is defined as  
DI (mg/day) =
Cumulative dose (mg)
Duration of exposure (week)×7 
• Total planned dose (mg):  
- 
For SAR439859, Anastrozole, Letrozole, Exemestane or Tamoxifen: Total Planned 
Dose = Planned dose at Cycle 1 Day 1 × 7 × duration of exposure (week) 
- For Fulvestrant: Total Planned Dose = Planned dose at Cycle 1 Day 1 × Theoretical 
total number of doses during started cycles (2 for Cycle 1 and 1 for Cycle 2 or later)   
• The relative dose (RD, in %) is defined as:  
Relative Dose = Cumulative dose
Total planned Dose ×100 
Note: for SAR439859, Anastrozole, Letrozole, Exemestane or Tamoxifen the RD 
corresponds to a Relative Dose Intensity. 
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Summary statistics will be provided for DI (for SERD, SERM, and by each drug for the control 
arm) and RD. For RD, categorical summaries will also be presented according to the following 
categories: 0-80%, 80-100%, >100%. 
Dose or cycle modifications 
For each drug, the following variables will be calculated: 
• Dose reduction:  a dose is deemed to have been reduced if the dose taken by a patient is 
lower than the dose taken on the previous day or the day before dose(s) omitted. For 
C1D1, a dose is deemed to have been reduced if the dose taken is lower than the planned 
dose.  
• Dose omission (per os treatment only): one omission corresponds to a dose not taken or 
equal to 0 mg/day between two non-zero doses. For SAR439859, Anastrozole, Letrozole, 
Exemestane or Tamoxifen, several consecutive dose omissions will be counted as one 
episode of omission. Dose omission is not applicable for Fulvestrant. 
For Fulvestrant only, the following variable will be calculated: 
• Cycle delays: a cycle is deemed to have been delayed if start date of current cycle – start 
date of previous cycle >30 days (28+2 days). 
Dose modification variables will be summarized descriptively. Analyses will be performed based 
on the number of patients. The number of patients with at least one dose modification with the 
following details will be provided: 
• Number (%) of patients with at least one dose modification (reduction, omission or cycle 
delay)  
• Number (%) of patients with at least one dose reduction 
• Number (%) of patients with at least one dose omission for SAR439859, Anastrozole, 
Letrozole, Exemestane or Tamoxifen 
• Number (%) of dose reductions by patient according to the following categories: 0, 1, >1 
• Number (%) of episodes of dose omissions by patient for SAR439859, Anastrozole, 
Letrozole, Exemestane or Tamoxifen according to the following categories: 0, 1, >1 
• Number (%) of patients with at least 7 consecutive days of dose omission for SAR439859, 
Anastrozole, Letrozole, Exemestane or Tamoxifen 
• Number (%) of patients with at least one cycle delay for fulvestrant 
2.4.5 Analyses of efficacy endpoints  
All efficacy analyses will be performed on the ITT population unless stated otherwise. Analyses 
by class of treatment will be performed according to the planned class of treatment for participants 
randomized to the control arm. All primary and secondary efficacy endpoints based on 
radiological assessments of tumor burden (ie, PFS, BOR, ORR, DCR, CBR, and DOR) will be 
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derived using the ICR tumor assessment. Analysis based on local radiologist’s/Investigator’s 
assessment will also be performed but considered as supportive analyses. 
2.4.5.1 Analysis of primary efficacy endpoint(s)  
Primary efficacy analysis will consist of PFS comparison between the SAR439859 arm and the 
control arm through a logrank test procedure stratified by the stratification factors as entered in the 
IRT (ie, presence of visceral metastasis, prior treatment with CDK4/6 inhibitors and ECOG). A 
one-sided Type I error rate of 2.5% will be used for statistical testing. Following hypotheses will 
be tested: 
• The null hypothesis that the survival distribution functions (SDF) for the PFS of the 
SAR439859 arm is lower than or equal to the SDF of the control arm. 
- 
H0: SDF (SAR439859) ≤ SDF (Control) 
versus 
• The alternative hypothesis that the SDF for the PFS of the SAR439859 arm is superior to 
the SDF of the control arm. 
- 
H1: SDF (SAR439859) > SDF (Control) 
The cut-off date for the analysis of PFS is the actual date when approximately 201 PFS events 
(first occurrence of either documented progression assessed by ICR or death due to any cause) 
have been observed or when all participants from the global cohort have been followed-up for at 
least 10 months (or discontinued treatment), whichever is earlier. It is approximately estimated 
18 months after first randomized participant assuming a 12 months uniform enrollment and a 
median PFS of 4.5 months in the control arm and a hazard ratio of 0.65.  
The actual cut-off date will be prospectively determined based on the timeline prediction to reach 
201 ICR-assessed PFS events or the requirement of minimum of 10-month follow-up since the 
last participant randomized. The actual number of events may be slightly different from 201 at the 
data cut-off date for the primary PFS analysis. 
In addition, the following estimates will be provided: 
• PFS data will be analyzed using the Kaplan-Meier method by treatment group: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
95% confidence interval (CI) will be provided. The 95% CIs will be constructed using 
a log-log transformation of the survival function and the methods of Brookmeyer and 
Crowley. 
- 
Number of patients at risk as well as the probabilities of being event-free at least 2, 4, 
6, 8, 10 and 12 months with 95% CIs will be estimated for each treatment group using 
the Kaplan-Meier method and a log-log approach based on a normal approximation 
following the Greenwood’s formula. Additional timepoints may be considered based 
on the actual data. 
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- 
Kaplan-Meier curves will be plotted. These plots will include the number of patients at 
risk at key time points by treatment group. 
• The hazard ratio (HR) and its 95% CIs will be estimated using the Cox proportional 
hazards model stratified by the same stratification factors as those used for the log-rank 
test described above. Ties will be handled using the exact method. Underlying 
assumptions of the Cox Proportional hazards model will be assessed by graphical methods 
(ie, log-log graphical methods). 
• For patients with events, the type of event (documented progression or death) will be 
summarized by treatment group using counts and percentages.  
• For patients who died without documented progression, the time from the last evaluable 
disease assessment to the death will be summarized by treatment group using descriptive 
statistics. 
• The number (%) of censored patients, the reason and timing of their censoring 
(ie, censored at randomization, censored at the last evaluable tumor assessment before the 
initiation of further anti-cancer therapy, or censored at last evaluable tumor assessment 
before the cut-off date), and the time from the last evaluable disease assessment to the cut-
off date will be summarized by treatment group. For each censoring reason, when 
applicable, distinction will be made between cases where no event was observed and cases 
where an event was observed after the censoring. 
• Follow-up duration (months) will be estimated using the reverse Kaplan-Meier approach, 
where censored data are treated as events and events are treated as censored data. Kaplan-
Meier estimates of the 25th, 50th and 75th percentiles will be provided. 
2.4.5.1.1 Sensitivity analyses  
Different censoring and events rules 
The same statistical methods used in the primary analysis will be applied using different censoring 
and event rules as defined below. 
The sensitivity analyses will include the following censoring rules: 
• Ignoring further anti-cancer therapy. 
• Ignoring further anti-cancer therapy and considering events (documented progression or 
death) occurring after two or more non-evaluable tumor assessment as event. 
• Ignoring further anti-cancer therapy and events (documented progression or death) 
occurring after exactly one or two or more non-evaluable tumor assessment are considered 
as event and back-dated to the next schedule assessment. 
Additional details are provided in Appendix E. 
Sensitivity analysis #1 (Ignoring further anti-cancer therapy) 
PFS will be analyzed based on ICR assessment, ignoring further anti-cancer therapy.  
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Sensitivity analysis #2 (PFS considering events occurring after two or more non-evaluable tumor 
assessment as event and ignoring further anti-cancer therapy) 
PFS will be analyzed based on ICR assessment, including events (documented progression or 
death) occurring after two or more non-evaluable tumor assessment as event. The date of 
progression (or death) will be used for date of outcome. Further anti-cancer therapy will be 
ignored. 
Sensitivity analysis #3 (PFS considering events occurring after two or more non-evaluable tumor 
assessment as event and back-dating at the next schedule assessment and ignoring further anti-
cancer therapy) 
If more than 10% patients have two or more consecutive non-evaluable assessments prior to PFS 
event, PFS will be analyzed based on ICR assessment, including events (documented progression 
or death) occurring after two or more non-evaluable tumor assessment as event. The date of the 
next schedule assessment will be used for date of outcome. Further anti-cancer therapy will be 
ignored. 
Stratification factors 
The same statistical methods used in the primary analysis will be applied using different 
stratification rules as defined below.  
Sensitivity analysis #4 (PFS analysis using stratification factors derived from eCRF data) 
If more than 10% patients have a discordance between the strata as entered in the IRT system and 
as derived from eCRF data, PFS will be analyzed based on ICR assessment stratified by the 
stratification factors as derived from eCRF data. 
Non-proportional hazard 
As mentioned above, underlying assumptions of the Cox Proportional hazards model will be 
evaluated to assess the relevance of estimating the treatment effect from hazard ratio. In case the 
proportional hazards assumption may not be valid, Restricted Mean Survival Time (RMST) 
method (16) may be conducted for PFS with the primary analysis censoring rule. The RMST 
methodology is valid under any distribution of the time to event in the treatment groups and 
provide an estimate of the expected PFS between randomization and a common timepoint denoted 
by τ. The timepoint τ should be limited to the largest event time: 
• 𝜏𝑚𝑎𝑥 = minimum of (largest observed PFS event time for SAR43985 arm, largest observed 
PFS event time for control arm). 
The RMST estimate up to 𝜏𝑚𝑎𝑥 and associated 95% CI for each treatment arm will be provided. 
The treatment effect will be estimated based on the difference between the two treatment arms in 
RMST up to 𝜏𝑚𝑎𝑥. Similar analysis will be performed using clinical meaningful truncation points 
(eg, up to 12 months if possible based on the largest event time within each treatment arm). 
Additionally, the RMST estimate within each arm will be plotted against time τ, with τ varying 
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from 0 to the largest observed PFS event time for the respective arm. Treatment effect based on 
the difference in RMST between the two treatment arms and associated 95% CI will also be 
provided against time τ, varying from 0 to 𝜏𝑚𝑎𝑥. 
Similar analyses may be performed for the comparison of SAR439859 and each class of treatment 
for the control arm. For these analyses, 𝜏𝑚𝑎𝑥 will be recalculated based on the minimum of the 
largest observed PFS event time for SAR43985 arm and largest observed PFS event time for the 
comparator. 
2.4.5.1.2 Supportive analyses  
PFS analysis will be supported by the following analysis based on the investigator/local 
radiologist’s assessment: 
• Supportive analysis #1: Same event/censoring rules as for the PFS primary analysis (see 
Table 17) 
• Supportive analysis #2: Same event/censoring rules as for the sensitivity analysis #2 (see 
Table 19) 
• Supportive analysis #3: Same event/censoring rules as for the supportive analysis #1 but 
considering the clinical/non-radiological progression as event, with the date of 
clinical/non-radiological progression as date of outcome (see Table 21) 
Additional supportive analyses based on the investigator/local radiologist’s assessment could be 
performed using different censoring and event rules or stratification rules as defined in 
Section 2.4.5.1.1, if relevant. 
Concordance of PFS outcome 
A comparison of PFS outcome (ie, "Event", "Censored") between the ICR and the investigator 
assessments will be summarized for each treatment group.  
Table 6 - Cross-tabulation of ICR and investigator assessments of PFS outcome  
Investigator/local 
radiologist 
ICR 
Event 
 
Censored 
Event 
𝑛11  
 
𝑛12  
 
 
 
 
Censored 
𝑛21  
 
𝑛22 
The PFS Outcome Discrepancy Rate (PFS ODR) will be calculated for each treatment arm as 
follow. 
PFS ODR = 
𝑛12 + 𝑛21
𝑛11 + 𝑛12 + 𝑛21 + 𝑛22
 
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Concordance of tumor assessment evaluation 
The differential discordance between the ICR and the investigator assessment of documented 
progression will be assessed using the Pharmaceutical Research and Manufacturers of America 
(PhRMA) method (17). The early discrepancy rate (EDR) and late discrepancy rate (LDR) 
differences between the two treatment arms will be calculated as follows: 
Table 7 - Cross-tabulation of ICR and investigator assessments of documented PD  
Investigator/local radiologist 
ICR 
Documented PD 
No documented PD 
Documented PD 
a = a1 + a2 + a3 
b 
No documented PD 
c 
d 
Only documented PD component of PFS is considered; if death occurs without prior PD, a subject is counted under ‘No documented PD’ 
a1: number of agreements on timing and occurrence of documented PD 
a2: number of times investigator declares documented PD later than ICR 
a3: number of times investigator declares documented PD earlier than ICR 
The timing of investigator/local radiologist and ICR (for participants with agreement on 
documented PD) will be considered to agree if they occur within ±7 days of each other, aligned 
with the protocol-specified window for tumor assessments. 
The EDR is defined as: 
𝐸𝐷𝑅= 𝑏+ 𝑎3
𝑎+ 𝑏 
The EDR quantifies the frequency with which the investigator declares progression early relative 
to ICR as a proportion of the total number of investigator assessed PDs, within each arm. 
The LDR is defined as: 
𝐿𝐷𝑅= 
𝑐+ 𝑎2
𝑏+ 𝑐+ 𝑎2 + 𝑎3
 
The LDR quantifies the frequency with which the investigator declares progression later than ICR 
as a proportion of the total number of discrepancies, within each arm.  
If the distribution of discrepancies is similar between the arms then this suggests the absence of 
evaluation bias favoring a particular arm. 
The EDR and LDR will be calculated for each treatment arm and the differential discordance 
(DD) for each measure will be summarized as the rate on the SAR439859 arm minus the rate on 
the control arm. A negative differential discordance for the EDR and/or positive differential 
discordance for the LDR are suggestive of a bias in the investigator favoring the experimental 
arm. 
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2.4.5.1.3 Subgroups analyses  
Evaluation of consistency 
The consistency of the results from the primary analysis will be evaluated across pre-defined 
subgroups in patients available in the subgroup of consideration. The definition of each subgroup 
is defined in Table 8. Depending upon the study results, additional subgroups may be examined, 
and subgroups with small sample sizes may be pooled to create a larger meaningful subgroup. For 
each subgroup, Kaplan-Meier estimates of the median and its associated 95% CI will be provided 
for each treatment arm along with the HR and its 95% CI estimated using the unstratified Cox 
proportional hazards model. A forest plot summarizing the results for each subgroup will be 
provided. 
Table 8 - Subgroups analyses: covariates investigated  
Subgroup 
Description 
Presence of visceral metastasis as per IRT 
Yes or No 
Prior treatment with CDK4/6 inhibitors as per IRT 
Yes or No 
ECOG as per IRT 
0 or 1 
Age  
<65 years or ≥65 years 
Race 
Asian or White or Other 
Geographical region 
Europe or North America or Asia or Other 
Intent of last anti-cancer therapy 
Neoadjuvant/Adjuvant or Advanced 
Number of prior hormonotherapy lines in advanced setting 
0 or 1 or 2 or ≥3 
Prior chemotherapy 
No prior chemotherapy or early breast cancer only or 
advanced metastatic  
PgR status 
PgR+ or PgR- 
ESR1 mutational status  
Wild type or mutated 
Number of organs involved based on ICR assessment at 
baseline 
<3 or ≥3 
Menopausal status at study entry 
Peri/premenopausal or Postmenopausal 
Bone-only metastases based on ICR assessment at baseline 
Yes or No 
Note: In case of discrepancy between IRT and eCRF stratification factors, subgroup analyses will also be performed according to the 
stratification factors as per eCRF. Some subgroups may be pooled based on the number of patients within each subgroup. 
Evaluation of interactions 
For each pre-defined factor defined in Table 8, PFS will be analyzed using an unstratified Cox 
proportional hazards model with terms for the factor, treatment and their interaction. The 2-sided 
p-value of the test of interaction will be provided for descriptive purposes. 
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Evaluation of confounding 
Since the results from the primary analysis could be impacted by confounding factors, any 
potential issues will be examined and, if confirmed, exploratory analysis of the primary endpoint 
will be done accordingly. A multivariate Cox proportional hazards model will be used to identify 
prognostic factors among the demographic and baseline characteristics factors described in the 
Table 8 using a stepwise selection procedure with a 15% 2-sided significance level for removing 
effects. For significant prognostic factors identified in the multivariate model, the balance 
between treatment groups will be assessed. If major confounding is identified through screening 
for treatment group imbalances in a prognostic factor at baseline, an exploratory analysis of PFS 
will be done after adjusting for the prognostic factors in the multivariate Cox proportional hazards 
model. Differences between the adjusted and unadjusted models will be discussed in the clinical 
study report. 
2.4.5.1.4 Exploratory analysis  
An exploratory analysis on the PFS according to ICR and to investigator/local radiologist’s 
assessment will be performed by the class of treatment (AI, SERM, SERD) of the control group. 
Same statistical method as the primary analysis will be used, except that formal statistical testing 
will not be performed. 
2.4.5.2 Analyses of secondary efficacy endpoints  
Analysis of response-based endpoints (ie, ORR, DCR, CBR, and DOR) will be performed 
primarily on the ITT population and supported by the analyses based on the ITT population with 
measurable disease at study entry (for analysis based on ICR, measurability will be based on ICR 
assessment of lesions; for analysis based on investigator, measurability will be based on 
investigator assessment of lesions). The other secondary analyses will be performed on ITT 
population only.  
The results will be presented by treatment group, and also displayed for the control arm according 
to the class of treatment (AI, SERM and SERD). 
Overall survival (OS) 
Overall survival (OS) will be evaluated as a key secondary efficacy endpoint. A hierarchical 
testing strategy will be used to ensure a strong control of the overall Type I error rate at one-sided 
2.5%. In other words, comparison between arms on the OS will be performed only if the primary 
analysis of the PFS is statistically significant.  
In case of statistically significant PFS, OS will be compared between treatment arms through a 
logrank test procedure stratified by the stratification factors as entered in the IRT. Following 
hypotheses will be tested: 
• The null hypothesis that the survival distribution functions (SDF) for the OS of the 
SAR439859 arm is lower than or equal to the SDF of the control arm. 
- 
H0: SDF (SAR439859) ≤ SDF (Control) 
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versus 
• The alternative hypothesis that the SDF for the OS of the SAR439859 arm is superior to 
the SDF of the control arm. 
- 
H1: SDF (SAR439859) > SDF (Control) 
Otherwise, descriptive statistics of OS will be provided at the time of final PFS analysis. 
The COD for final OS analysis will be the date when approximately 196 death events have been 
observed (approximately 70% of the participants have died).  
The following estimates will be provided for OS: 
• OS data will be analyzed using the Kaplan-Meier method by treatment group in the ITT 
population: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
95% CIs will be provided. The 95% Cis will be constructed using a log-log 
transformation of the survival function and the methods of Brookmeyer and Crowley. 
- 
Number of patients at risk as well as the probabilities of surviving at least 6, 12, 18 and 
24 months with 95% CI will be estimated for each treatment group using the Kaplan-
Meier method and a log-log approach based on a normal approximation following the 
Greenwood’s formula. Additional timepoints may be considered based on the actual 
data. 
- 
Kaplan-Meier curves will be plotted. These plots will include the number of patients at 
risk at key time points by treatment group. 
• The hazard ratio (HR) and its 95% CI will be estimated using the Cox proportional 
hazards model stratified with the stratification factors as entered in the IRT. Ties will be 
handled using the exact method. Underlying assumptions of the Cox proportional hazard 
model will be assessed by graphical methods (ie, log-log graphical methods). 
• The number of censored patients, the reasons for their censoring (ie, alive at the cut-off 
date, alive at the last contact before the cut-off date, and lost to follow-up) and the time 
between the date of last contact and the cut-off date will be summarized by treatment 
group. 
• Follow-up duration (months) will be defined as the time interval from the date of 
randomization to the date of last contact (see Section 2.5.3) with the patient. Patients who 
have died will be censored on their date of death. Kaplan-Meier estimates of the 25th, 50th 
and 75th percentiles will be provided. 
A multivariate Cox proportional hazards model may be used to identify prognostic factors among 
the demographic and baseline characteristics factors described in the Table 8. In addition, 
sensitivity analyses adjusting OS for switch to subsequent anti-cancer treatment could also be 
performed at interim and/or final analyses (eg, using inverse probability of censoring weighting 
(IPCW) method) (18). 
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Response-based endpoints 
ORR, DCR and CBR according to ICR and investigator assessments (supportive analysis) will be 
summarized by treatment arm with descriptive statistics at the time of the primary analysis on PFS 
(based on data collected up to the PFS analysis cut-off date). In addition, 95% two-sided CIs will 
be computed using the Clopper-Pearson method. 
The DOR will only be summarized on the subgroup of participants who have achieved objective 
response (confirmed CR or PR as BOR). Duration of response by treatment arm will be 
summarized according to ICR and investigator assessments (supportive analysis), using Kaplan-
Meier methods and displayed graphically, if appropriate. The median DOR and associated 95% 
CI will be provided for each treatment group based on the Kaplan-Meier method using the log-log 
transformation of the survival function and the methods of Brookmeyer and Crowley. Percentage 
of responders with DOR greater or equal to different timepoints (eg, 2 months, 4 months, 
6 months, etc) and associated 95% CI will also be estimated for each treatment group using the 
Kaplan-Meier method and a log-log approach based on a normal approximation following the 
Greenwood’s formula. 
Of note, the BOR for each participant will also be summarized according to ICR and investigator 
assessments. 
Exploratory analyses of response-based endpoints may be provided according to subgroups of 
interest (Table 8). 
Waterfall plots will be used to display the best relative change from baseline in tumor size 
observed for each patient. It will be sorted by decreasing order of best relative change from 
baseline in patients with measurable disease at study entry. BOR will be displayed. Only patients 
with post-baseline target lesions measurement will be included in the plot. 
Progression-free survival according to ESR1 mutation status at baseline 
Progression-free survival according to ESR1 mutation status at baseline will be assessed with the 
same censoring rules as the primary analysis of PFS, and same statistical methods will be used 
with the exception that no statistical test will be made. Supportive analysis based on the 
investigator assessments will be performed. 
2.4.5.3 Multiplicity issues  
Hypothesis testing of the key secondary efficacy endpoint will be carried out. 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 OS will be performed only if the 
primary analysis of the PFS is statistically significant. 
2.4.6 Analyses of safety data  
The summary of safety results will be presented by treatment group, and also displayed for the 
control arm according to the class of treatment (AI, SERM and SERD). 
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General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.  Relative risks versus control and their 95% confidence intervals may 
be provided, if relevant 
2.4.6.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same adverse event, the maximum (worst) grade by period of observation is 
used. Summaries will be provided for all grades and for grade ≥3 (including Grade 5). Missing 
grades, if any, will be included in the “all grades” category. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified.  Sorting will be based on results 
for the SAR439859 arm.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
- 
Treatment-emergent AEs (TEAE) 
- 
Grade ≥3 TEAEs 
- 
Grade 5 TEAEs (any TEAE with a fatal outcome during the on-treatment period) 
- 
Serious TEAEs 
- 
TEAEs leading to treatment discontinuation 
- 
Treatment-related TEAEs 
- 
AESI 
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• All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least 1 treatment-emergent adverse event sorted by the SOC internationally agreed 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
• All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order and 
by decreasing incidence of PTs within each SOC in the SAR439859 arm.  This sorting 
order will be applied to all other tables, unless otherwise specified. 
• Most frequent (≥5% of patients in any treatment arm, on PT) TEAE by primary SOC and 
PT, sorted by the sorting order defined in the TEAEs summary table. 
• All treatment-related TEAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 treatment-related TEAE, sorted by the sorting order defined in the TEAEs 
summary table. 
Analysis of all treatment emergent serious adverse event(s) 
• All serious TEAEs by primary SOC, HLGT, HLT, and PT, showing the number (%) of 
patients with at least 1 serious TEAEs, sorted by the internationally agreed SOC order.  
The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
• All serious TEAEs by primary SOC and PT, showing the number (%) of patients with at 
least 1 serious TEAE, sorted by the order defined in the TEAEs summary table. 
• All serious treatment-related TEAEs, by primary SOC and PT, showing the number (%) of 
patients with at least 1 serious related TEAE, sorted by the order defined in the TEAEs 
summary table.  
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAE leading to treatment discontinuation by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE leading to treatment discontinuation, sorted 
by the order defined in the TEAEs summary table. 
Analysis of all treatment-emergent adverse event(s) leading to dose modification  
• All TEAEs leading to dose modification by primary SOC and PT, showing the number 
(%) of patients with at least 1 TEAE leading to dose reduction and/or dose delay/drug 
interruption (for Fulvestrant), sorted by the sorting order defined in the TEAEs summary 
table. 
• All TEAEs leading to dose reduction by primary SOC and PT, showing the number (%) of 
patients with at least 1 TEAE leading to dose reduction, sorted by the sorting order defined 
in the TEAEs summary table. 
• A listing of TEAEs leading to dose delay by primary SOC and PT will be provided for 
patients who take Fulvestrant. 
• A listing of TEAEs leading to drug interruption by primary SOC and PT will be provided 
for patients who take Fulvestrant. 
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Analysis of adverse events of special interest (AESI) 
A listing of patients with at least one AESI mentioned in Section 2.1.4.1 will be provided. This 
listing will include the category of AESI, the cycle of occurrence, the seriousness and the 
outcome. 
Analysis of pretreatment and posttreatment adverse events  
• All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
frequency of PT in the SAR439859 arm. 
• All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and 
decreasing frequency of PT in the SAR439859 arm. 
2.4.6.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
• Number (%) of patients who died by study period (on-treatment period and post-treatment) 
and reasons for death (disease progression, AE and other). 
• Listing of deaths in non-randomized patients or randomized but not treated patients (this 
listing will be generated on the screened patients). 
• All TEAEs leading to death (regardless of the date of death/period) by primary SOC and 
PT, sorted by the order defined in the TEAEs summary table. 
• Summary of AEs leading to death including fatal TEAEs (Grade 5 during treatment or any 
grade AE leading to death post-treatment) and Grade 5 post-treatment AEs, presented by 
primary SOC and PT.  These tables will be provided for death occurring: 
- 
in the context of disease progression (death within 30 days from last study treatment 
administration and the cause of death is disease progression), 
- 
in the context other than disease progression (death within 30 days from last study 
treatment administration and for whom cause of death is not disease progression or the 
death occurred more than 30 days from last study treatment administration and the 
cause of death is adverse event). 
• Overview of Grade 5 AEs will be provided with the following categories: 
- 
Grade 5 AE (TEAE and post-treatment). 
- 
TEAE leading to death (regardless date of death/period). 
- 
Grade 5 TEAE with a fatal outcome during the treatment period,  
- 
Any Grade TEAE with a fatal outcome during the post-treatment period.  
- 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period). 
• Listing of deaths 
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2.4.6.3 Analyses of laboratory variables  
For clinical laboratory data, baseline is defined as the last sample collection prior to the first 
administration of the IMP. 
Hematology and biochemistry 
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters defined in Section 2.1.4.3. Each test result will be graded by NCI-CTCAE version 5.0, 
whenever applicable. 
For hematological parameters and for some selected biochemistry parameters, Sanofi sponsor 
generic ranges (LLN, ULN) are defined and will be used for grading. For other biochemistry 
parameters (eg, for hepatic enzymes ALT, AST, Alkaline phosphatase, total bilirubin), grading 
will be derived using local laboratory normal ranges. 
The number of patients with abnormal laboratory tests at baseline will be presented by grade and 
all grades together. The frequency of patients in each grade and all grades of laboratory 
abnormalities during treatment will be summarized. For patients with multiple occurrences of the 
same laboratory variable during the treatment, the maximum grade (worst) per patient will be 
used. The denominator used for percentage calculation is the number of patients with at least 
1 evaluation of the laboratory test during the considered observation period. When appropriate, 
the summary table will present the frequency of patients with any grade of abnormal laboratory 
tests and with Grade 3-4 abnormal laboratory tests. 
In addition, for hematology and biochemistry toxicities, shift tables showing the number of 
patients in each grade at baseline by worst grade during the on-treatment period will be provided.  
Urinalysis 
For dipstick analyses, a frequency table of results for each parameter (leukocytes, erythrocytes, 
proteins, glucose, and ketones) will be provided using the worst value observed on-treatment. 
A summary of baseline results will also be provided for dipstick analyses. 
For laboratory tests for which NCI-CTCAE V5.0 scale is not applicable, potentially clinically 
significant abnormalities (PCSA) values are defined as abnormal values considered medically 
important by the Sponsor according to predefined criteria/thresholds based on literature review. 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment period, 
taking into account all evaluations performed during the on-treatment period, including 
nonscheduled or repeated evaluations. The incidence of PCSA any time during the on-treatment 
period will be summarized by treatment group irrespective of the baseline level. 
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2.4.6.4 Analyses of vital sign variables  
Vital signs parameters are described in Section 2.1.4.4. Baseline is defined as the last sample 
collection prior to the first administration of the IMP. 
A shift table of baseline ECOG PS versus last and worst ECOG PS on treatment will be provided. 
For blood pressure, heart rate and weight parameters, potentially clinically significant abnormality 
(PCSA) values are defined as abnormal values considered medically important by the Sponsor 
according to predefined criteria/thresholds based on literature review (Appendix A). PCSA 
criteria will determine which patients had at least 1 PCSA during the on-treatment period, taking 
into account all evaluations performed during the on-treatment period, including nonscheduled or 
repeated evaluations. The number of all such patients will be the numerator for the on-treatment 
PCSA percentage. The treatment-emergent PCSA denominator by group for a given parameter 
will be based on the number of patients assessed for that given parameter in the treatment-
emergent adverse event period by treatment group on the safety population 
The incidence of PCSAs at any cycle during the on-treatment period will be summarized by 
treatment group irrespective of the baseline and/or according to the following baseline categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
In addition, for blood pressure and heart rate a graph describing mean changes from baseline and 
associated +/- SEM will also be done throughout the on-treatment period. 
2.4.6.5 Analyses of electrocardiogram variables  
For ECG, baseline is defined as the last sample collection prior to the first administration of the 
IMP. The incidence of patients with at least 1 abnormal ECG at any time during the on-treatment 
period will be summarized irrespective of the baseline level and/or according to the following 
baseline status categories:  
• Normal/missing 
• Abnormal  
2.4.7 Analyses of pharmacokinetic and pharmacodynamic variables  
2.4.7.1 Analysis of pharmacokinetic variables  
Plasma concentrations will be summarized for SAR439859 treatment arm by time point using 
descriptive statistics (such as the number of observations, arithmetic and geometric mean, median, 
standard deviation (SD), coefficient of variation (CV)%, minimum, and maximum). 
In addition, steady state Ctrough concentrations, defined as the median Ctrough of individual patient 
across study duration (plasma concentrations of predose samples at Day 15 Cycle 1 and Day 1 
Cycles 2, 3, 4 and 6), will be summarized using standard descriptive statistics. 
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Plasma concentrations will be included in the descriptive statistics if actual sampling occurs in the 
following time windows: within 2 hours before administration for predose samples on Day 15 
Cycle 1 and Day 1 Cycles 2, 3, 4 and 6; [1-2h] and [3-5h] for samples at 1.5 and 4h post dose, 
respectively on Day 1 Cycle 1 and Day 1 Cycle 2; [7-9h] for samples at 8h post dose on Day 1 
Cycle 2.  
In addition, a listing of individual concentration data by cycle and visit day will be provided. 
Concentrations reported as below the limit of quantification (BLQ) will be replaced by 0 for 
descriptive statistics. Geometric mean will not be computed in case at least one concentration is 
below LLOQ. 
Descriptive statistics and graphical presentation of SAR439859 PK parameters of interest may be 
done in regards of safety/efficacy endpoints.  
2.4.7.2 Analysis of Pharmacodynamics/genomic and biomarkers variables  
The main analyses of pharmacodynamics/genomics and biomarker variables are provided in this 
section. Additional exploratory biomarker analyses may be conducted depending on information 
obtained during SAR439859 studies or from the literature. This may be described in a separated 
SAP. 
Baseline for biomarker data is defined as the last sample collection prior to the first administration 
of the IMP. 
Estrogen receptor 1 gene mutation status in circulating free DNA 
Descriptive statistics of the ESR1 mutational status (wild-type or mutated: at least one ESR1 
mutation detected) and each of the twelve mutations will be provided at baseline and over time by 
comparing baseline and Cycle 3 Day 1 for each treatment arm. The evolution of mutant allele 
frequency and concentration will be also described. 
In addition to the association with the PFS (Section 2.4.5), the ESR1 mutational status and/or the 
presence of some specific mutations may be described for other efficacy endpoints in the two 
treatment arms. The ESR1 mutational status may be also described according to prior anti-cancer 
therapies. On-treatment changes in ESR1 mutation may be also associated with efficacy endpoints 
for exploratory purpose. 
Mutational profiling in circulating free DNA  
Descriptive statistics of the genomic aberrations of the 77 genes will be provided at baseline for 
each treatment arm and by prior anti-cancer therapies. The baseline mutant allele frequency and 
concentration for some genes of interest may be also described. 
The relationship between some genes of interest and efficacy endpoints (eg, PFS) may be 
explored in the two treatment arms. 
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Estrogen receptor degradation and tumor biopsy biomarkers 
Descriptive statistics of the baseline and the change over time of tumor biomarkers such as ER 
expression, Ki67, Bcl-2, and PgR will be provided. The relationship between the change of each 
protein expression and efficacy endpoints (eg, PFS) may be explored in the two treatment arms. 
Some tumor gene signatures (such as the ER activation signature and other gene signature of 
interest) may be also derived and described.  
Estradiol 
Descriptive statistics of the circulating level of estradiol will be provided at baseline and over time 
by comparing baseline and Cycle 3 Day 1 for each treatment arm. The relationship between 
baseline circulating levels of estradiol and clinical response may be explored in the two treatment 
arms. On-treatment changes in circulating level of estradiol may be also associated with efficacy 
endpoints for exploratory purpose. 
2.4.8 Analyses of quality of life  
Patient reported outcomes endpoints for each of the 3 selected PRO/HRQL and health utility 
instruments (EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L) will be analyzed in participants 
from the safety population. The baseline value is defined as the last questionnaire assessment 
before or on the first IMP date. 
Compliance rate 
For each questionnaire the compliance profile over time will be summarized based on the cycle 
reported in the eCRF on the safety population (number and percentage of forms received versus 
expected, and number and percentage of forms evaluable versus expected). A questionnaire is 
considered received if at least one item on the form is completed. A questionnaire is expected as 
defined in the SoA (Section 1.3 of the protocol) and based on the number of cycles started by the 
patient. A questionnaire is evaluable if at least one scale is complete according to scale developer 
scoring algorithms (Appendix F).  
Change from baseline analysis 
For the QLQ-C30 (15 total scales), QLQ-BR23 (8 scales), and EQ-5D-5L (health index and visual 
analogue scale) instruments, descriptive statistics on the absolute value and changes from baseline 
will be done for each treatment arm at each analysis visit, at EOT and follow-up based on the 
safety population. Analysis visit will be derived based on the study day of assessment, defined as 
date of assessment – first IMP date + 1.  
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Table 9 - Analysis visit for PRO analyses  
Planned visit 
Planned study day 
Analysis visit study 
day window 
Analysis visit 
C1D1 
1 
Before or on first IMP date 
Baseline 
C2D1 
29 
[2;42] 
C2D1 
C3D1 
57 
[43;70] 
C3D1 
C4D1 
85 
[71;112] 
C4D1 
C6D1 
141 
[113;168] 
C6D1 
C8D1 
197 
[169;224] 
C8D1 
CxD1 
(x-1)*28+1 
[(x-1)*28+1-28; (x-
1)*28+1+27] 
CxD1 
EOT 
IMP date + 30 
[last IMP date+1; min(last 
IMP date+35; start of further 
anticancer therapy)] 
EOT 
FUP 
 IMP date + 90 
[min(last IMP date+35; start 
of further anticancer 
therapy)+1; last IMP 
date+95] 
FUP 
Note: only assessments performed up to and including the last IMP can be mapped into a CxD1 analysis visit.  
In the case of multiple assessments falling in the same analysis visit window, the assessment 
closest to the planned study day will be used. If 2 assessments falling within the same analysis 
visit window are equidistant from the planned study day, then the assessment obtained prior to 
target date will be used. 
For each scale of each instrument, comparison between the two treatment arms will be based on a 
longitudinal repeated measures analysis using a mixed effects model on the change from baseline 
in patients from the safety population who have completed the baseline and at least 1 postbaseline 
on-treatment assessment. Only on-treatment assessments will be included in the model (ie, up to 
but excluding EOT). Fewer analysis visits (eg, visits with at least 10 participants in each arm, 
visits with at least 15 participants in each arm, etc) may be considered in case of model 
convergence issue after unblinding. The variables included in the model will be treatment, time, 
treatment-by-time, with baseline value and stratification factors used as covariates. Time will be 
considered as categorical variable based on the analysis visit defined in Table 9. Parameter 
estimates will be initially based on a restricted maximum likelihood method and an unstructured 
covariance matrix will be used. The structure of the correlation matrix will be investigated and 
simplified using likelihood ratio tests if appropriate. The following covariance structure may be 
investigated: Toeplitz, Autoregressive(1). The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. The least square means (LS means) and associated 
standard error (SE) for each treatment arm and differences in LS means with the corresponding 2-
sided 95% CI and 2-sided p-values will be presented at each analysis visit (for descriptive 
purposes only). A graphical display of the LS means (SE) of the changes from baseline for each 
treatment arm over time will also be provided for each scale of each instrument. Overall LS means 
and associated SE for each treatment arm, overall difference in LS means (95% CI) and associated 
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2-sided p-value (for descriptive purposes only) will be provided along with the 2-sided p-value of 
the interaction term treatment-by-time. 
For each of the EOT and FUP visit, comparison between the two treatment arms will be based on 
a linear model for the change from baseline with treatment, baseline value and stratification 
factors used as covariates. LS means (SE) for each treatment arm and differences in LS means 
(95% CI) will be presented. Two-sided p-values will be presented (for descriptive purposes only). 
As p-values will be presented for descriptive purposes only, no statistical hypotheses will be 
tested and no adjustments for multiple comparisons will be made. 
Time to sustained deterioration in EORTC QLQ-C30 and EORTC QLQ-BR23 scales 
The time to sustained deterioration for each EORTC QLQ-C30 and QLQ-BR23 scale will be 
analyzed using the Kaplan-Meier method by treatment group in patients from the safety 
population who have completed the baseline and at least 1 postbaseline on-treatment assessment, 
and who have baseline scales scores that allow for a 10-point deterioration (ie, no greater than 
90 for symptom scales, and no lower than 10 for the functional scales and GHS/QoL): 
• Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 95% 
CI) will be provided. The 95% CIs will be constructed using a log-log transformation of 
the survival function and the methods of Brookmeyer and Crowley. 
• Number of patients at risk as well as the probabilities of having no deterioration at least 6, 
12, 18 and 24 months with 95% CIs will be estimated for each treatment group using the 
Kaplan-Meier method and a log-log approach based on a normal approximation following 
the Greenwood’s formula. 
The number (%) of censored patients and the reasons for their censoring will be summarized by 
treatment group. 
The Kaplan-Meier curves will be plotted. These plots will include the number of patients at risk at 
key time points by treatment group. 
The hazard ratio (HR) for sustained deterioration and its 95% CIs may be estimated using the Cox 
proportional hazards model stratified by the stratification factors as entered in the IRT. Ties will 
be handled using the exact method.  
2.4.9 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
A summary table will be provided for further therapies based on WHO-DD coding.  Similar 
analysis will be performed for further radiotherapy and further surgery. 
Time to first use of chemotherapy after disease progression or treatment discontinuation 
(without disease progression) 
The following estimates will be provided for the time to first use of chemotherapy after disease 
progression or treatment discontinuation (without disease progression): 
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• Time to first use of chemotherapy after disease progression or treatment discontinuation 
(without disease progression) data will be analyzed using the Kaplan-Meier method by 
treatment group in the ITT population: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
95% CIs will be provided. The 95% CIs will be constructed using a log-log 
transformation of the survival function and the methods of Brookmeyer and Crowley. 
- 
Number of patients at risk as well as the probabilities of being free of use of 
chemotherapy at least 6, 12, 18 and 24 months with 95% CI will be estimated for each 
treatment group using the Kaplan-Meier method. 
• The number of censored patients, the reasons for their censoring (ie, alive without use of 
chemotherapy, death, and lost to follow-up) will be summarized by treatment group. 
• Kaplan-Meier curves will be plotted. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Time unit 
A month length is 30.4375 days (365.25 / 12). If duration is to be reported in months, duration in 
days is divided by 30.4375. If duration is to be reported in years, duration in days will be divided 
by 365.25. 
Duration  
Unless otherwise specified, difference between two dates (Date A ≤ Date B) will be calculated as 
follows: 
Duration (days) = Date B – Date A + 1 
2.5.2 Data handling conventions for primary efficacy variables  
The following formulas will be used for computation of PFS endpoint. 
Date of tumor assessment 
It is acknowledged that an assessment may include several methods of evaluation performed over 
a period of several days within a window of time around an expected assessment date. For each 
tumor assessment, a single date will be derived according to the overall response of that 
assessment.  
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The date of target lesion(s) assessment will be derived based on the date of the last assessment of 
target lesion(s). 
When the overall response is different from PD, the date of tumor assessment is defined as the 
date of the last evaluation included in the series of evaluations performed within that time point 
(ie, target lesion(s), non-target lesions(s) and new lesion(s) assessments). 
When the overall response is PD, the date of tumor assessment is the date when progression was 
first demonstrated according to the target lesion(s), non-target lesion(s) and new lesion(s), as 
specified below: 
• For progression based on new lesion(s) the date of progression is the earliest date a new 
lesion has been detected. 
• For progression based on non-target lesion(s), the date of progression is the earliest date a 
non-target lesion was considered as PD. 
• For progression based on target lesion(s), the date of progression is the date of the last 
assessment of target lesion(s). 
If progression is based on several events within the same tumor assessment (eg, new lesion(s) 
seen along with target lesion(s) progression), the earliest date of progression, according to the 
rules listed above, will be the date of assessment. 
Evaluable tumor assessment 
An evaluable tumor assessment is defined as a tumor assessment with an overall response 
different of non-evaluable (NE).  
Date of documented progression 
The date of documented progression is defined as the first date of tumor assessment at which the 
overall response was recorded as progressive disease. 
Date of death 
The date of death is defined as the date of death recorded in the eCRF. 
Date of next scheduled assessment 
The date of next scheduled assessment is the date of the next scheduled tumor assessment as per 
protocol schedule of assessment. This date may be used if back-dating is considered when the 
event occurred beyond the acceptable time window for the next tumor assessment (eg, 1 or 2 non-
evaluable tumor assessment).  
Date of last evaluable tumor assessment 
The date of the last evaluable tumor assessment is defined as the last date of tumor assessment at 
which the overall response was recorded as CR, PR, SD or Non-CR/Non-PD before a censoring 
reason occurred. 
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2.5.3 Data handling conventions for secondary efficacy variables  
The following formulas will be used for computation of secondary endpoint. 
Best relative change from baseline in tumor size 
Tumor size is defined as the sum of the longest diameters of the target lesions as per RECIST 1.1. 
It can be calculated only for measurable patients.  
Relative change from baseline in tumor size at tumor assessment t will be calculated as follows: 
Relative change (%) from baseline in tumor size (t) = 100*(Tumor Size(t) – Tumor 
Size(baseline))/ Tumor Size(baseline) 
Best relative change from baseline in tumor size will be the smallest relative change from baseline 
in tumor size. 
Date of first documented response 
The date of the first documented response is defined as the date of the first tumor assessment at 
which the overall response was recorded as CR or PR that is subsequently confirmed. 
Date of last contact 
The last contact date is derived for patients not known to have died at the analysis cut-off date 
based on the latest date among the following: 
• Date of visits 
• Assessment dates (eg, laboratory, vital signs, ECOG performance status, ECG, tumor 
assessment, PK assessment, EOT completion etc). 
• Medication and procedures dates including study medication, concomitant medications, 
surgical and medical procedures, further anti-cancer therapies administered after treatment 
discontinuation. 
• Adverse event start and end dates 
• “Date of Last Available Information” collected on the “Subject status” page 
• Study treatment start/end date 
• Randomization date 
The last contact date is defined as the latest date from the above list or the cut-off date, whichever 
comes first. The last contact date could be used for censoring of patients in time to event analysis.  
2.5.4 Missing data  
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with non-
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missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
Handling of disease characteristics missing/partial dates 
• If the day is missing, it will be imputed by 1. 
• If the month is missing, it will be imputed by 1 (only for medical history variables). 
• If the year is missing, no imputation will be performed. 
Incomplete date of cancer diagnosis:  
• If the day of the cancer diagnosis is missing, the date will be imputed to the first day of the 
month. 
• If day and month of the cancer diagnosis are missing, no imputation will be done. 
Handling of medication missing/partial dates  
No imputation of medication (other than anti-cancer therapies) start/end dates or times will be 
performed. If a medication date or time is missing or partially missing and it cannot be determined 
whether it was taken prior or concomitantly, it will be considered a prior, concomitant, and post-
treatment medication. 
For prior anti-cancer therapies, following rules will be applied: 
• Incomplete start date of prior anti-cancer therapy: if the day of the start date of the prior 
regimen is missing, the date will be imputed to the first day of the month; if the month is 
missing, the date will be imputed to the first month of the year. 
• Incomplete end date of prior anti-cancer therapy: if the day of the end date of last prior 
regimen is missing, the date will be imputed to the last day of the month; if the month is 
missing, the date will be imputed to the last month of the year. 
Imputation of incomplete date for post anti-cancer treatment start date  
For post anti-cancer treatments, if the medication start date is missing, it will be imputed as 
follows: 
• If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date + 1. 
• If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 
• If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start date will be set to the treatment end 
date + 1. 
• If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
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• If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
• If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set 
to 01. 
• If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date + 1. 
Handling of other missing dates 
Incomplete date of progression for the last prior regimen:  
• If the day of the progression for the last prior regimen is missing, the date will be imputed 
to the to the earliest of the end day of the month and the randomization date 
• If day and month of the progression for the last prior regimen are missing, no imputation 
will be done. 
Incomplete date of prior surgery:  
• If the day of the prior surgery is missing, the date will be imputed to the earliest of the end 
day of the month and the randomization date. 
• If day and month of the prior surgery are missing, no imputation will be done. 
Incomplete end date of prior radiotherapy: 
• If the day of the end date of the prior radiotherapy is missing, the date will be imputed to 
the earliest of the end day of the month and the randomization date. 
• If the day and month of the end date of the prior radiotherapy are missing, no imputation 
will be done. 
Handling of questionnaires dates 
If the date is incomplete, it will be imputed by: 
• If the day is missing, it will be imputed by the day of the visit date if year and month are 
the same. Otherwise, it will be imputed by 1 if same year but a later month compared to 
the visit date or to the end day of the month if same year but an earlier month. 
• If the day and month are missing, it will be imputed by the day and the month of the visit 
date if years are the same. Otherwise, if the year of visit is later, missing date will be 
imputed by the last day of the year of the questionnaire; if the year of visit is earlier, 
missing date will be imputed by the first day of the year of the questionnaire. 
• In other cases of incomplete date or missing date, it will be imputed by the visit date. 
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Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.   
Missing grade 
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done and missing grades will be summarized in the 
“all grades” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline, he/she will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or > ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Handling of Estradiol data below quantification limit 
For Estradiol data with values below the quantification limit, the data will be imputed to half of 
the quantification limit. 
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2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues  
Not applicable. 
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3 
INTERIM ANALYSIS  
3.1.1 Interim analysis for progression-free survival  
An interim analysis on PFS is planned for futility at 50% of the planned total number of PFS 
events (ie, approximately 101 PFS events). Without possible claim for overwhelming evidence of 
efficacy, no Type I error rate adjustment will be performed. The stopping boundary for futility is 
based on the observed HR based on Cox proportional hazard model, ie, an HR >1.1. If the 
observed HR >1.1, then the study may be stopped for futility.    
A summary of the PFS analyses is provided in Table 10. The observed HR based on Cox 
proportional hazard model stratified by the stratification factors as entered in the IRT system will 
be compared with the futility boundary. As described in Section 2.4.5.1, PFS data will be 
analyzed using the Kaplan-Meier method by treatment group; HR and its 95% CIs will be 
estimated; the type of PFS event will be summarized; for patients who died without documented 
progression, the time from the last evaluable disease assessment to the death will be summarized; 
the number of censored patients, the reason and timing of censoring and the time from the last 
evaluable disease assessment to the cut-off date will be summarized; median follow-up duration 
will be estimated. Supportive PFS analysis according to investigator/local radiologist’s 
assessment, with the same censoring rules as for the PFS primary analysis, will be provided. 
Demographics and baseline characteristics, prior or concomitant medication, extent of IMP 
exposure and compliance, AEs (TEAE, death, SAE, TEAE leading to discontinuation, AESI), and 
laboratory variables (abnormality of hematological and chemistry test) will be analyzed at interim 
analysis.  If needed, more data will be analyzed to inform the futility decision including additional 
efficacy, PK, and biomarker. 
Table 10 - Progression-free survival analyses  
Analysis 
Months 
after FPI 
(approx. 
under 
PFS 
HR=0.65) 
Planned 
accrual  
Number 
of events 
(under 
PFS 
HR=0.65) 
Information 
fraction 
Cumulative 
Power 
(under PFS 
HR=0.65) 
Futility 
boundary 
Efficacy 
boundary 
PFS IA 
(futility only) 
10 
239 
101 
50% 
 
HR>1.1 
NA 
PFS Final 
analysis 
18 
282 
201 
100% 
86% 
p >0.025 
(HRa >0.758) 
p ≤0.025 
(HRa 
≤0.758) 
a HR is provided only for information purposes. The final decisions will be based on p-values. 
Note: numbers have been rounded. Calculations were made using East 6.5 software. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; PFS = progression-free survival.  
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3.1.2 Interim analysis for overall survival  
Comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of 2 analyses are planned for OS: at the time of the 
primary analysis of PFS and at the final OS analysis. 
A gamma error spending function (γ = -8) will be used, along with the hierarchical testing strategy 
to strongly control the family-wise error rate (FWER; overall Type I error rate). If the value of the 
test statistic exceeds the efficacy boundary (z ≤-3.716, p ≤0.0001, assuming 63 OS events are 
observed), superiority of OS will be claimed but survival data will continue to be collected until 
the end of study when approximately 196 death events have been observed. The actual efficacy 
boundary will be adjusted according to the observed number of events at interim analysis. 
A summary of the OS analyses is provided in Table 11. The test statistic obtained from a logrank 
test procedure stratified by the stratification factors as entered in the IRT system will be compared 
with the futility boundary. As described in Section 2.4.5.2, OS data will be analyzed using the 
Kaplan-Meier method by treatment group; HR and its 95% CIs will be estimated; the type of OS 
event will be summarized; the number of censored patients, reasons for censoring (ie, alive at the 
cut-off date, alive at the last contact before the cut-off date, and lost to follow-up) and the time 
between the date of last contact and the cut-off date will be summarized by treatment group. 
Table 11 - Overall survival analyses  
Analysis 
Months 
after FPI 
(approx.) 
Planned 
accrual  
Number 
of deaths 
(approx.) 
Information 
fraction 
Cumulative 
Powera 
(under 
HR=0.75) 
Futility 
boundary 
Efficacy 
boundary 
OS IA (at 
PFS final 
analysis) 
18 
282 
63 
32% 
0.5% 
NA 
p ≤0.0001 
(HRb ≤0.392) 
Final analysis  
64 
282 
196 
100% 
52% 
p >0.0249 
(HRb >0.756) 
p ≤0.0249 
(HRb ≤0.756) 
a Marginal power conditional to statistically significance of PFS.  
b HR is provided only for information purposes. The interim and final decisions will be based on p-values. 
Note: number have been rounded. Calculations were made using East 6.5 software. Assume a 5% dropout rate at 64 months after first 
participant randomized. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; OS = overall survival.  
3.1.3 Data Monitoring Committee  
This study will use an independent DMC. The first DMC meeting will be set up to review early 
safety results (eg, after approximately 25 participants have completed at least 2 cycles in the 
SAR439859 arm, or after 6 months after first participant randomized), and then periodically. Ad 
hoc DMC meetings may also be held if a significant safety issue or an issue deemed important for 
discussion arises on this or other SAR439859 studies. After each meeting, the DMC will make 
recommendations to the Sponsor’s representatives regarding the continued safety of treating 
ongoing and future study participants, as well as the course of action regarding the conduct of the 
study. The DMC will also oversee the interim analyses on PFS detailed in Section 3.1.1. 
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4 
DATABASE LOCK  
Estimated COD will be approximately 18 months after first randomized participant for the PFS 
analysis. No pharmacokinetic sample will be taken after Cycle 6 or PFS COD, whichever comes 
first. After COD for PFS analysis, no more efficacy assessment will be performed except 
collection of survival status. The COD for analysis of OS will be approximately 64 months after 
the first patient randomization.  
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
Biomarkers analyses will be generated using R version 3.3.2. 
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6 
REFERENCES  
1. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus 
palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-
negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-
3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet 
Oncol. 2016;17(4):425-39. 
2. Kornblum N, Zhao F, Manola J, Klein P, Ramaswamy B, Brufsky A, et al. Randomized phase 
II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone 
receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer 
resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556-
63. 
3. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, 
randomized placebo controlled trial of fulvestrant compared with exemestane after prior 
nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-
positive, advanced breast cancer: Results from EFECT. J Clin Oncol. 2008;26(10):1664-70. 
4. Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus 
plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final 
progression-free survival analysis. Adv Ther. 2013;30:870-84. 
5. Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus 
exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-
negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 
2014;25:2357-62. 
6. Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, et al. Fulvestrant plus 
anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase 
inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet 
Oncol. 2013;14:989-98. 
7. Aaronson NK, Ahmedzai S, Bullinger M, Crabeels D, Estape J, Filiberti AN, et al. The 
EORTC core quality of life questionnaire: interim results of an international field study. In: 
OSOBA D, editor. Effect of cancer on quality of life. Vancouver. 1991;185-202. 
8. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-7. 
9. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels: 
EORTC, 2001. 
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10. Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A, Muller M, et al. The 
European Organization for Research and Treatment of Cancer breast cancer-specific quality-
of-life questionnaire module: first results from a three-country field study. J Clin Oncol. 
1996;14(10):2756-68. 
11. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim 
scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 
2012;15:708-15. 
12. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-44. 
13. Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, Andre F, et al. Quality of life with 
palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative 
metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Annals of 
Oncology. 2016;27(6):1047-54. 
14. Kaufman PA, Toi M, Neven P, Sohn J, Grischke EM, Andre V, et al. Health‐related quality 
of life in MONARCH 2: Abemaciclib plus fulvestrant in hormone receptor‐positive, 
HER2‐negative advanced breast cancer after endocrine therapy. The Oncologist. 
2020;25(2):e243. 
15. Verma S, O’Shaughnessy J, Burris HA, Campone M, Alba E, Chandiwana D, et al. Health-
related quality of life of postmenopausal women with hormone receptor-positive, human 
epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib+ 
letrozole: results from MONALEESA-2. Breast cancer research and treatment. 
2018;170(3):535-45. 
16. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for 
the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res 
Methodol. 2013;13(1):152. 
17. Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J, et al. Blinded 
independent central review of progression in cancer clinical trials: results from a metaanalysis. 
Eur J Cancer. 2011;47(12):1772-8.  
18. Watkins C, Huang X, Latimer N, Tang Y, Wright EJ. Adjusting overall survival for treatment 
switches: commonly used methods and practical application. Pharm Stat. 2013;12(6):348-57. 
19. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 2009;45(2):228-
47. 
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7 
LIST OF APPENDICES  
Appendix A 
Potentially clinically significant abnormalities criteria .............................................................. 66 
Appendix B 
Summary of statistical analyses .............................................................................................. 67 
Appendix C 
Internationally agreed SOC order ........................................................................................... 71 
Appendix D 
Response Evaluation Criteria in Solid Tumors (recist 1.1) ..................................................... 72 
Appendix E 
Description of censoring and event rules for primary and sensitivity analyses of PFS .......... 77 
Appendix F 
EORTC QLQ-C30 and QLQ-BR23 items, scales and scores ................................................. 82 
 
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Appendix A Potentially clinically significant abnormalities criteria  
 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
Laboratory 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Basophils 
>0.1 Giga/L 
 
Monocytes 
>0.7 Giga/L 
 
RBC 
≥6 Tera/L 
 
Hematocrit 
≤0.37 v/v (Male); ≤0.32 v/v (Female) 
≥0.55 v/v (Male); ≥0.5 v/v (Female) 
 
pH 
≤4.6 
≥8 
 
 
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Appendix B Summary of statistical analyses  
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Sensitivity analysis 
Supportive analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
PFS according to ICR 
ITT 
Stratified Log-
rank test 
Kaplan-Meier 
Cox proportional 
hazards model 
#1 Ignoring further anti-cancer 
therapy 
#2 PFS considering events 
occurring after two or more non-
evaluable tumor assessment as 
event and ignoring further anti-
cancer therapy 
#3 PFS considering events 
occurring after two or more non-
evaluable tumor assessment as 
event and back-dating at the next 
schedule assessment and 
ignoring further anti-cancer 
therapy 
#4 PFS analysis using stratification 
factors derived from eCRF data 
- PFS according to investigator 
assessment (same censoring 
rules as for the PFS primary 
analysis, sensitivity analysis 
#2, PFS considering the 
clinical/non-radiological 
progression as event, and 
same rules as the sensitivity 
analyses if relevant) 
- Concordance of PFS outcome 
(PFS ODR) 
- Concordance of tumor 
assessment evaluation (EDR 
and LDR) 
- RMST if non-proportional 
hazard assumption is 
suspected 
Yes  
Multivariate Cox 
proportional hazards 
model 
Secondary endpoints 
OS 
ITT 
Stratified Log-
rank test 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
IPCW to account for informative 
censoring due to further anti-
cancer therapy, if relevant  
Yes if relevant 
based on 
subgroups of 
primary endpoint 
Multivariate Cox 
proportional hazards 
model 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Sensitivity analysis 
Supportive analysis 
Subgroup 
analysis 
Other 
analyses 
ORR according to ICR 
ITT 
ITT measurable 
Clopper-Pearson 
95% CI 
No  
 
ORR according to investigator 
Yes if relevant 
based on 
subgroups of 
primary endpoint 
- Best Overall 
Response 
- Best relative change 
from baseline in 
tumor size (waterfall 
plot) 
DCR according to ICR 
ITT 
ITT measurable 
Clopper-Pearson 
95% CI 
 
No 
DCR according to investigator 
Yes if relevant 
based on 
subgroups of 
primary endpoint  
 
CBR according to ICR 
ITT 
ITT measurable 
Clopper-Pearson 
95% CI  
 
No 
CBR according to investigator 
Yes if relevant 
based on 
subgroups of 
primary endpoint  
 
DOR according to ICR 
ITT, for patients 
who have 
achieved 
confirmed CR or 
PR as BOR 
ITT measurable 
Kaplan-Meier 
No 
DOR according to investigator 
Yes if relevant 
based on 
subgroups of 
primary endpoint 
 
PFS according to ESR1 
mutation status at 
baseline based on ICR 
assessment 
ITT 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
PFS according to ESR1 
mutation status at baseline 
based on investigator 
assessment 
No 
 
 
 
 
 
 
 
 
Pharmacokinetics of 
SAR439859 
Pharmacokinetic-
evaluable 
population 
Descriptive 
statistics 
No 
No 
No 
PK parameters 
according to 
safety/efficacy 
endpoints 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Sensitivity analysis 
Supportive analysis 
Subgroup 
analysis 
Other 
analyses 
Tertiary/exploratory endpoints 
ESR1 mutation status 
ITT 
Descriptive 
statistics 
 
 
 
 
Mutation profile 
ITT 
Descriptive 
statistics 
 
 
 
Relationship between 
the mutation status 
and clinical response 
ER degradation and 
tumor biopsy 
biomarkers 
ITT 
Descriptive 
statistics 
 
 
 
Relationship between 
the protein expression 
and clinical response 
Transcriptome profile 
(RNA) 
ITT 
Descriptive 
statistics 
 
 
 
 
Time to first use of 
chemotherapy after 
disease progression or 
treatment 
discontinuation (without 
disease progression) 
ITT 
Kaplan-Meier 
 
 
 
 
BOR: Best overall response, CI: Confidence interval, CR: Complete response, EDR: Early discrepancy rate, ITT: intent-to-treat, LDR: Late discrepancy rate, ODR: Outcome discrepancy rate, ORR: Overall 
response rate, OS: overall survival, PFS: Progression free survival, PR: Partial response 
Stratified analyses are performed with the stratification factors as entered in the IRT ie, presence of visceral metastasis, prior treatment with CDK4/6 inhibitors and ECOG. 
 
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SAFETY ANALYSES 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Adverse events 
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm and according 
to the class of therapy of the control arm  
No 
Deaths 
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm and 
according to the class of therapy of the control arm 
No 
Laboratory  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm and 
according to the class of therapy of the control arm 
No 
Vital signs  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm and 
according to the class of therapy of the control arm 
No 
ECG  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm and 
according to the class of therapy of the control arm 
No 
Health-related quality of life 
(HRQL): EORTC QLQ-
C30, EORTC QLQ-BR23, 
EQ-5D-5L 
Safety  
Descriptive statistics of compliance rate by treatment 
group 
Descriptive statistics by treatment group 
No 
No 
Health-related quality of life 
(HRQL): EORTC QLQ-C30 
and EORTC QLQ-BR23 
scales, EQ-5D-5L index 
score and VAS 
Safety patients who have 
completed the baseline 
and at least 1 post-
baseline assessment 
Mixed model for repeated measures on the change 
from baseline in each scale 
 
No 
No 
Health-related quality of life 
(HRQL): Time to sustained 
deterioration in EORTC 
QLQ-C30 and EORTC 
QLQ-BR23 scales 
Safety patients who have 
completed the baseline 
and at least 1 post-
baseline assessment 
and who have baseline 
scales scores that allow 
for a 10-point 
deterioration 
Kaplan-Meier 
No 
No 
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Appendix C Internationally agreed SOC order  
The internationally agreed order (Guideline on summary of product characteristics, 
December 1999, European commission) for SOC: 
1. Infections and infestations 
2. Neoplasms benign and malignant (including cysts and polyps) 
3. Blood and the lymphatic system disorders 
4. Immune system disorders 
5. Endocrine disorders 
6. Metabolism and nutrition disorders 
7. Psychiatric disorders 
8. Nervous system disorders 
9. Eye disorders 
10. Ear and labyrinth disorders 
11. Cardiac disorders 
12. Vascular disorders 
13. Respiratory, thoracic and mediastinal disorders 
14. Gastrointestinal disorders 
15. Hepato-biliary disorders 
16. Skin and subcutaneous tissue disorders 
17. Musculoskeletal, connective tissue and bone disorders 
18. Renal and urinary disorders 
19. Pregnancy, puerperium and perinatal conditions 
20. Reproductive system and breast disorders 
21. Congenital and familial/genetic disorders 
22. General disorders and administration site conditions 
23. Investigations 
24. Injury and poisoning 
25. Surgical and medical procedures 
26. Social circumstances 
27. Product Issues 
The other terms are sorted by dictionary code order. 
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Appendix D Response Evaluation Criteria in Solid Tumors (recist 1.1)  
Details provided in bibliographic reference (19). 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable as 
follows: 
Measurable 
• Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:  
- 
Ten millimeters by computed tomography (CT) scan (CT scan slice thickness no 
greater than 5 mm).  
- 
Ten-millimeter caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
- 
Twenty millimeters by chest X-ray. 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed (see Special Issue 15 [19]). See also notes 
below on “Baseline documentation of target and nontarget lesions” for information on 
lymph node measurement. 
Non-measurable 
• All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with 10 to <15 mm short axis) as well as truly nonmeasurable lesions. Lesions 
considered truly nonmeasurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical examination that 
is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or magnetic 
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resonance imaging (MRI) can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts.  
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
Methods of measurement 
• Measurement of lesions:  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
• Method of assessment:  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical examination. Clinical 
lesions: Clinical lesions will only be considered measurable when they are superficial and 
10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
• Computed tomography, MRI: CT is the best currently available and reproducible method 
to measure lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size 
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for a measurable lesion should be twice the slice thickness. Magnetic resonance imaging is 
also acceptable in certain situations (eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
participant to be considered in complete response. Specific guidelines for both cancer 
antigen 125 response (in recurrent ovarian cancer) and prostate-specific antigen response 
(in recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer 
Intergroup has developed cancer antigen 125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and complete response (CR) in rare cases if required by protocol 
(eg, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or stable 
disease (SD) in order to differentiate between response (or SD) and progressive disease. 
Tumor response evaluation 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only participants 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint. Measurable disease is defined by the presence of at least 
1 measurable lesion. In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether participants having non measurable disease 
only are also eligible. 
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Response criteria 
Table 12 - Response criteria, evaluation of target lesions  
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) 
must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study 
 
Table 13 - Response criteria, evaluation of nontarget lesions  
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph 
nodes must be nonpathological in size (<10 mm short axis). 
Non-CR/Non-PD:  
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression (see comments below)a of existing nontarget lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
a Although a clear progression of “nontarget” lesions only is exceptional, in such circumstances, the opinion of the treating physician should 
prevail and the progression status should be confirmed later on by the review panel (or study chair). 
Evaluation of best overall response 
It is assumed that at each protocol specified time point, a response assessment occurs. The 
following table (Table 14) provides a summary of the overall response status calculation at each 
time point for participants who have measurable disease at baseline. When patients have non-
measurable (therefore non-target) disease only, Table 15 is to be used. 
Table 14 - A summary of overall response status for measurable disease   
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
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Table 15 - A summary of overall response status for non-measurable disease   
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
Table 16 - A summary of overall response status for non-measurable disease  
Overall response 
Overall response 
BEST overall response 
First time point 
Subsequent time point 
 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the participant had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease 
The best overall response is determined once all the data for the participant is known. 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline (defined as 42 days). If the minimum time is not met when SD is otherwise the best 
time point response, the participant’s best response depends on the subsequent assessments. For 
example, a participant who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD. The same participant lost to follow-up after the 
first SD assessment would be considered inevaluable. Complete or partial responses may be 
claimed only if the criteria for each are met at a subsequent time point as specified in the protocol 
(generally 4 weeks later). In this circumstance, the best overall response can be interpreted as in 
Table 16. 
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Appendix E 
Description of censoring and event rules for primary and sensitivity 
analyses of PFS  
Table 17 - PFS Primary analysis   
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of randomization 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessmentsa 
Date of randomization 
Censored 
No evaluable post-baseline tumor 
assessments 
Alive and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Alive without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after exactly one non-
evaluable tumor assessment  
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmentb 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored  
Event occurred after two or more 
missed tumor assessment 
Clinical/non-radiological progression Ignored 
Ignored 
  
Initiation of further anti-cancer 
therapy 
Date of the last evaluable tumor 
assessment before start date of 
further anti-cancer therapy (if any), 
date of randomization otherwise 
Censored 
 
Initiation of further anti-cancer 
therapy   
a Except if the patient dies within 17 weeks after the date of randomization in which case a death event outcome will be considered for the 
PFS with date of outcome corresponding to the date of death 
b An event occurring at least 18 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 18 weeks corresponds to twice the time between two disease assessments per protocol (every 2*8 weeks), plus the 
7-day window before and after. 
Note: for patients falling in situation with discordant outcomes, the event outcome takes the priority to the censored outcome (eg, death without 
baseline tumor assessment) 
 
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Table 18 - PFS sensitivity analysis #1 (ignoring further anti-cancer therapy)  
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of randomization 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessmentsa 
Date of randomization 
Censored 
No evaluable post-baseline tumor 
assessments 
Alive and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Alive without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after exactly one non-
evaluable tumor assessment  
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmentb 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored  
Event occurred after two or more 
missed tumor assessment 
Clinical/non-radiological progression Ignored 
Ignored 
  
Initiation of further anti-cancer 
therapy 
Ignored 
Ignored 
   
a Except if the patient dies within 17 weeks after the date of randomization in which case a death event outcome will be considered for the 
PFS with date of outcome corresponding to the date of death 
b An event occurring at least 18 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 18 weeks corresponds to twice the time between two disease assessments per protocol (every 2*8 weeks), plus the 
7-day window before and after. 
Note: for patients falling in situation with discordant outcomes, the event outcome takes the priority to the censored outcome (eg, death 
without baseline tumor assessment) 
 
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Table 19 - PFS sensitivity analysis #2 (PFS considering events occurring after two or more non-
evaluable tumor assessment as event and ignoring further anticancer therapy)  
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of randomization 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessmentsa 
Date of randomization 
Censored 
No evaluable post-baseline tumor 
assessments 
Alive and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Alive without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after exactly one non-
evaluable tumor assessment  
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmentb 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Clinical/non-radiological progression Ignored 
Ignored 
  
Initiation of further anti-cancer 
therapy 
Ignored 
Ignored 
  
a Except if the patient dies in which case a death event outcome will be considered for the PFS with date of outcome corresponding to the 
date of death 
b An event occurring at least 18 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 18 weeks corresponds to twice the time between two disease assessments per protocol (every 2*8 weeks), plus the 
7-day window before and after. 
Note: for patients falling in situation with discordant outcomes, the event outcome takes the priority to the censored outcome (eg, death without 
baseline tumor assessment) 
 
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Table 20 - PFS sensitivity analysis #3 (PFS considering events occurring after two or more non-
evaluable tumor assessment as event and back-dating at the next schedule assessment and 
ignoring further anticancer therapy)  
 
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of randomization 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessmentsa 
Date of randomization 
Censored 
No evaluable post-baseline tumor 
assessments 
Alive and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Alive without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after exactly one non-
evaluable tumor assessment 
Date of the next schedule 
assessment 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmentb 
Date of the next schedule 
assessment 
Event 
Documented progression (or Death 
without documented progression) 
Clinical/non-radiological progression Ignored 
Ignored 
 
Initiation of further anti-cancer 
therapy 
Ignored 
Ignored 
 
a Except if the patient diesin which case a death event outcome will be considered for the PFS with date of outcome corresponding to the date 
of death 
b An event occurring at least 18 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 18 weeks corresponds to twice the time between two disease assessments per protocol (every 2*8 weeks), plus the 
7-day window before and after. 
Note: for patients falling in situation with discordant outcomes, the event outcome takes the priority to the censored outcome (eg, death without 
baseline tumor assessment) 
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Table 21 - PFS supportive #3 analysis for investigator assessment (taking clinical/non-radiological 
progression as event) 
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of randomization 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessmentsa 
Date of randomization 
Censored 
No evaluable post-baseline tumor 
assessments 
Alive and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Alive without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after exactly one non-
evaluable tumor assessment 
Date of progression (or Date of 
death) 
Event 
Documented progression (or Death 
without documented progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmentb 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored  
Event occurred after two or more 
missed tumor assessment 
Clinical/non-radiological progression Date of clinical/non-radiological 
progression 
Event 
Non-documented progression 
Initiation of further anti-cancer 
therapy 
Date of the last evaluable tumor 
assessment before start date of 
further anti-cancer therapy (if any), 
date of randomization otherwise 
Censored 
 
 Initiation of further anticancer 
therapy 
a Except if the patient dies within 17 weeks after the date of randomization in which case a death event outcome will be considered for the PFS 
with date of outcome corresponding to the date of death 
b An event occurring at least 18 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 18 weeks corresponds to twice the time between two disease assessments per protocol (every 2*8 weeks), plus the 
7-day window before and after. 
Note: for patients falling in situation with discordant outcomes, the event outcome takes the priority to the censored outcome (eg, death without 
baseline tumor assessment) 
VV-CLIN-0548794 3.0


Statistical Analysis Plan  
10-Dec-2021 
SAR439859-ACT16105 - amcenestrant 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 82 
Appendix F EORTC QLQ-C30 and QLQ-BR23 items, scales and scores  
For QLQ-C30: 
VV-CLIN-0548794 3.0


Statistical Analysis Plan  
10-Dec-2021 
SAR439859-ACT16105 - amcenestrant 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 83 
For QLQ-BR23 
VV-CLIN-0548794 3.0


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