Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1068
Healthy volunteers: no

Brief summary:
Primary Objective:

To determine whether Amcenestrant (SAR439859) in combination with palbociclib improves progression free survival (PFS) when compared with letrozole in combination with palbociclib in participants with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received any prior systemic anticancer therapies for advanced disease.

Secondary Objective:

* To compare the overall survival in both treatment arms.
* To evaluate the objective response rate in both treatment arms.
* To evaluate the duration of response in both treatment arms.
* To evaluate the clinical benefit rate in both treatment arms.
* To evaluate progression-free survival on next line of therapy.
* To evaluate the pharmacokinetics of amcenestrant, and palbociclib.
* To evaluate health-related quality of life in both treatment arms.
* To evaluate the time to first chemotherapy in both treatment arms.
* To evaluate safety in both treatment arms.

Detailed description:
Study duration per participant was approximately 59 months, which includes a 33- month treatment period.

Arms:
arm 1: Participants received letrozole 2.5 milligrams (mg) capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg orally (PO), once daily (QD) from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks). Goserelin once every 4 weeks in pre/peri menopausal women and men. arm 2: Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death, or study cut-off date, whichever comes first (maximum exposure: 109 weeks). Goserelin once every 4 weeks in pre/peri menopausal women and men.

Interventions: intervention 1: Amcenestrant-matching placebo intervention 2: SAR439859 intervention 3: Palbociclib intervention 4: Letrozole intervention 5: Goserelin intervention 6: Letrozole-matching placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Tablets Route of Administration: Oral intervention 2: Pharmaceutical form: Tablets Route of Administration: Oral intervention 3: Pharmaceutical form: Capsules/Tablets Route of Administration: Oral intervention 4: Pharmaceutical form: Capsules Route of Administration: Orally intervention 5: Pharmaceutical form: Depot Injection Route of Administration: Subcutaneous intervention 6: Pharmaceutical form: Capsules Route of Administration: Orally

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: Sanofi OneDocument Version 6.0, dated 25-JUN-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A randomized, multicenter, double-blind Phase 3 study of 
amcenestrant (SAR439859) plus palbociclib versus letrozole 
plus palbociclib for the treatment of patients with ER (+), 
HER2 (-) breast cancer who have not received prior 
systemic anti-cancer treatment for advanced disease  
Protocol number: 
EFC15935 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR439859 
Amcenestrant/Not Applicable 
Brief title: 
Amcenestrant (SAR439859) plus palbociclib as first line 
therapy for patients with ER (+) HER2 (-) advanced breast 
cancer (AMEERA-5) 
Acronym: 
AMEERA-5 
Study phase: 
Phase 3 
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 identifier number(s): 
IND: 
133204 
EudraCT: 
2020-001824-33 
NCT: 
NCT04478266 
WHO: 
U1111-1233-0486 
EUDAMED 
Not applicable 
Other 
Not applicable 
Date: 
02-Sep-2021 
Total number of pages: 171 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document  
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 04 
Amended Clinical Trial Protocol 03 
All 
All 
02 September 2021, version 1 (electronic 5.0) 
13 December 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
30 September 2020, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
27 July 2020, version 1 (electronic 1.0) 
Original Protocol 
All 
02 July 2020, version 1 (electronic 1.0) 
Amended protocol 04 (02 September 2021) 
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 because it either significantly impacts the safety or physical/mental integrity 
of participants or the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The objective of the amendment is to update the protocol with the following key changes: 
• To change the recommendations for amcenestrant 200 mg intake from with or without 
food to now to be taken only with food 
• To remove the restriction to enroll male patients from Japan 
• To add interstitial lung disease as an adverse event of special interest 
• To detail the diagnostic testing in case of suspicion of ILD 
• To update exclusion criteria and concomitant medication section with results from recent 
in vitro and clinical drug-drug interaction studies. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 (Synopsis); 1.3 
(Schedule of Activities -
Study Intervention 
Administration); 2.1 (Study 
rationale); 6.1 (Study 
interventions(s) 
administered); 6.1.1 
((Amcenestrant 
(SAR439859)/Amcenestrant 
(SAR439859)-matching 
placebo); 6.1.2 (Letrozole/ 
letrozole-matching 
placebo); 6.1.3 (Palbociclib) 
Amcenestrant/amcenestrant-matching 
placebo, Letrozole/letrozole-matching 
placebo, and Palbociclib (regardless of 
the administered formulation) should be 
taken with food. 
According to new data from a food effect study, 
when amcenestrant is given with food (high fat 
meal) the exposure to the compound increases. To 
ensure favorable exposure in patients who may 
have lower absorption, it is recommended to take 
amcenestrant/amcenestrant-matching placebo with 
food together with palbociclib, regardless of the 
palbociclib formulation (capsules/tablets). As the 
study intervention is blinded, the recommendation 
on ‘to be taken with food’ applies to 
letrozole/letrozole-matching placebo as well. 
1.1 (Synopsis); 4.1.1 
(Duration of the study 
period) 
Expected duration of treatment for 
participants in control arm was updated. 
Inconsistencies were corrected.  
1.2 (Schema) 
In Figure 1, number of patients in arm A 
and arm B has been updated from 354 
patients to 533 patients. 
For consistency. 
1.3 (Schedule of activities),  
“Hepatitis C antibody or quantitative 
hepatitis C (HCV) ribonucleic acid (RNA)” 
has been changed to “Hepatitis C 
antibody and quantitative hepatitis C 
(HCV) ribonucleic acid (RNA).” 
Correction for clarity.  
1.3 (Schedule of activities), 
8.1 (Efficacy assessments) 
Updated the disease assessment 
requirements in study participants without 
progressive disease per RECIST 1.1 on 
end-of-treatment visit and clarified the 
reference timepoint for disease 
assessment during the follow-up period. 
To bring clarity and to ensure that the disease 
assessment is consistent (every 12 weeks ±7 days 
from randomization) throughout the study period. 
3 (Objective, Endpoints, 
and estimands), 9.2 
(Statistical analyses) 
Primary estimands have been added, 
Table 2 - Summary of primary estimand 
for main endpoints has been added in 
Section 3. 
To define primary estimands for primary and key 
secondary efficacy endpoints. 
5.2 (Exclusion criteria, E 02) 
Modified the exclusion criterion 02: 
Participants with known active hepatitis A 
(positive HA antigen or positive IgM); B 
(either positive HBs antigen or positive 
hepatitis B viral DNA test above the lower 
limit of detection of the assay); C (positive 
hepatitis C antibody result or and 
quantitative hepatitis C (HCV) ribonucleic 
acid (RNA) results greater than the lower 
limits of detection of the assay) infection 
Previously reported incorrect information was 
corrected. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 (Exclusion criteria, E11),  Exclusion criterion 11 was adjusted to 
remove substrates of P-gp and BCRP 
and added substrates of OATP1B1/B3 
substrates. 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. 
6.8 (Concomitant therapy) 
Substrates of P-gp and BCRP related 
information has been removed; 
substrates of OATP1B1/B3 related 
information has been added. 
5.2 (Exclusion criteria, E27), 
Ethics considerations added as part of 
exclusion criteria E27. 
Update as per latest One Document protocol 
template. 
5.5. (Criteria for Temporarily 
Delaying administration of 
study intervention) 
Updated the title of the subsection. 
The following text has been added " that 
results in travel restrictions, confinement, 
or restricted site access" after “During a 
regional or national emergency declared 
by a governmental agency.”. 
To clarify that the temporary delay is related to 
administration of study intervention 
6.2 (Preparation, handling, 
storage, and accountability) 
Term “NIMP” was added to include all 
study treatment sourced centrally.  
For consistency across protocol Section 6.1 and 
6.2. 
6.8 (Concomitant therapy) 
Removed the special caution with 
regards to Proton Pump Inhibitors (PPI) 
(ie, omeprazole) and H2 blockers (ie, 
ranitidine). 
A recent drug-drug interaction study showed that 
acid reducing agent had no clinically relevant effect 
on amcenestrant exposure given with food which is 
now the dosing recommendation in this study for 
both amcenestrant and palbociclib (whatever the 
formulation). 
8.2.6 (Pregnancy testing) 
Pregnancy testing guidance has been 
added into this newly created subsection 
To be aligned with the latest One Document 
protocol template. 
8.3.7 (Adverse events of 
special interest) 
Added ILD/Pneumonitis as an adverse 
event of special interest 
ILD/Pneumonitis is a common (with an incidence of 
1.4% all grades from 3 palbociclib randomized 
trials) adverse drug reaction of palbociclib. Per 
recommendation of Data Monitoring Committee, 
ILD/pneumonitis will be monitored as an AESI, and 
recommendations for diagnostic testing in 
suspicion of ILD/pneumonitis has been detailed.  
8.2.5.1 (Guideline for 
management of specific 
adverse events: Interstitial 
Lung Disease/Pneumonitis) 
Detailed diagnostic testing in case of 
suspicion of ILD/Pneumonitis has been 
added. 
8.4 (Pharmacokinetics) 
Pre-dose and post-dose PK samples 
should be collected even in case of IMP 
dose omission. 
To bring clarity on PK blood sampling  
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Section # and Name 
Description of Change 
Brief Rationale 
8.6 (Pharmacodynamics) in 
previous amended protocol 
03  
Section was removed per latest One 
Document template, considering 
pharmacodynamic assessments will not 
be included in this study.  
To be aligned with latest One Document protocol 
template. 
8.10 (Use of biological 
samples and data for future 
research) 
Samples storage duration after the end of 
the study has been updated to 25 years. 
To be aligned with latest One Document protocol 
template. 
9.1 (Populations for 
analyses) 
In Table 6, descriptions for population 
have been added. 
The following sentence has been 
removed “For any participant randomized 
more than once, only the data associated 
with the first randomization will be used in 
any analysis population.  The safety 
experience associated with any later 
randomization will be reported 
separately.” 
For clarity. 
9.2.1 (General 
considerations) 
New texts have added as per latest One 
Document protocol template. 
For clarity and to be aligned with latest One 
Document protocol template. 
9.2.3 (Secondary 
endpoint(s) analyses 
Previous Efficacy analyses table (Table 
6) has been updated to Efficacy analyses 
for other secondary endpoints (Table 7) 
which includes the secondary endpoints 
only. 
For clarity. 
9.2.5 (Multiplicity 
adjustment) 
A new section of multiplicity adjustment 
has been added. 
To define hypothesis testing of the key secondary 
efficacy endpoint. 
9.2.6.1 (Adverse events) 
The following sentence has been added 
“Similarly, the deaths will be analyzed in 
the pre-treatment, treatment-emergent 
and post-treatment periods.”. 
“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. 
9.2.7.1 (Analyses of patient 
reported outcome 
endpoints) 
The secondary paragraph of statistical 
analysis strategy for the 3 PROs has 
been updated. 
For clarification of analyses that are planned for 
PRO data. 
 
9.3.1 (Interim analyses for 
PFS) 
In Table 9, PFS Final analysis has been 
updated from 49 to 40. 
Typo correction. 
10.2 (Appendix 2: Clinical 
laboratory tests) 
In Table 11, viral serology tests have 
been added for other screening tests and 
pregnancy test has been added. 
For consistency. 
10.6 (Appendix 6: Country-
specific requirements) 
Removed the restriction to enroll male 
patients from Japan 
Based on the feedback received from Japanese 
health authorities  
10.8 (Appendix 8: Protocol 
amendment history) 
Updated by including amendment 
history of amended protocol 03. 
For consistency. 
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Section # and Name 
Description of Change 
Brief Rationale 
Entire document  
Editorial changes, updates as per latest 
One Document protocol template. 
Correction of typographical errors and minor 
inconsistencies across different sections, and 
clarifications.  
To be aligned with latest One Document protocol 
template. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 13 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 25 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 26 
2 
INTRODUCTION............................................................................................................................ 36 
2.1 
STUDY RATIONALE ..................................................................................................................... 36 
2.2 
BACKGROUND ............................................................................................................................. 41 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 42 
2.3.1 
Risk assessment ............................................................................................................................ 43 
2.3.1.1 
Risks in the Context of COVID-19 ................................................................................................. 43 
2.3.2 
Benefit assessment ........................................................................................................................ 44 
2.3.2.1 
Benefits in the context of COVID-19 .............................................................................................. 44 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 44 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 45 
3.1 
APPROPRIATENESS OF MEASUREMENTS  ............................................................................. 47 
4 
STUDY DESIGN ............................................................................................................................ 49 
4.1 
OVERALL DESIGN ........................................................................................................................ 49 
4.1.1 
Duration of the study period ........................................................................................................... 49 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 50 
4.2.1 
Participant input into design ........................................................................................................... 50 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 50 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 51 
5 
STUDY POPULATION .................................................................................................................. 52 
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5.1 
INCLUSION CRITERIA .................................................................................................................. 52 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 53 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 57 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 57 
5.3.2 
Activity (Sun Protection) ................................................................................................................. 57 
5.3.3 
Osteoporosis .................................................................................................................................. 57 
5.4 
SCREEN FAILURES ..................................................................................................................... 57 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION ............................................................................................................................ 58 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 59 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 59 
6.1.1 
Amcenestrant (SAR439859)/Amcenestrant (SAR439859)-matching placebo .............................. 61 
6.1.2 
Letrozole/Letrozole-matching placebo ........................................................................................... 61 
6.1.3 
Palbociclib ...................................................................................................................................... 61 
6.1.4 
Goserelin ........................................................................................................................................ 62 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 62 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 63 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 64 
6.5 
DOSE MODIFICATION .................................................................................................................. 65 
6.5.1 
amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo ............................... 65 
6.5.2 
Palbociclib ...................................................................................................................................... 66 
6.5.3 
Letrozole/Letrozole-matching Placebo .......................................................................................... 66 
6.5.4 
Retreatment criteria ....................................................................................................................... 67 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 67 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 67 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 68 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 71 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 71 
7.1.1 
Permanent discontinuation ............................................................................................................ 71 
7.1.2 
Temporary discontinuation ............................................................................................................. 72 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 72 
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7.3 
LOST TO FOLLOW UP ................................................................................................................. 73 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 74 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 74 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 76 
8.2.1 
Physical examinations ................................................................................................................... 76 
8.2.2 
Vital signs ....................................................................................................................................... 76 
8.2.3 
Electrocardiograms ........................................................................................................................ 76 
8.2.4 
Clinical safety laboratory tests ....................................................................................................... 77 
8.2.5 
Guideline for management of specific adverse events .................................................................. 77 
8.2.5.1 
Interstitial Lung Disease/Pneumonitis ............................................................................................ 77 
8.2.5.2 
Amcenestrant-related Adverse Events .......................................................................................... 78 
8.2.6 
Pregnancy testing .......................................................................................................................... 78 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 79 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 79 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 79 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 79 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 80 
8.3.5 
Pregnancy ...................................................................................................................................... 80 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 81 
8.3.7 
Adverse events of special interest ................................................................................................. 81 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 83 
8.4 
PHARMACOKINETICS .................................................................................................................. 83 
8.5 
GENETICS ..................................................................................................................................... 84 
8.5.1 
cfDNA tumor and germline mutation analysis ................................................................................ 84 
8.5.2 
Drug metabolizing enzymes and related genes DNA samples ..................................................... 84 
8.6 
BIOMARKERS ............................................................................................................................... 85 
8.6.1 
Protein expression ......................................................................................................................... 85 
8.6.2 
Estradiol ......................................................................................................................................... 85 
8.6.3 
RNA transcriptome research .......................................................................................................... 85 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 86 
8.8 
HEALTH ECONOMICS .................................................................................................................. 86 
8.9 
PATIENT REPORTED OUTCOMES ............................................................................................. 86 
8.9.1 
EORTC QLQ-C30 .......................................................................................................................... 86 
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8.9.2 
EORTC QLQ-BR23 ........................................................................................................................ 86 
8.9.3 
EORTC QLQ-BR45 ........................................................................................................................ 87 
8.9.4 
EUROQoL EQ-5D-5L ..................................................................................................................... 87 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 87 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 89 
9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 89 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 89 
9.2.1 
General Considerations ................................................................................................................. 90 
9.2.2 
Primary endpoint(s) analyses ........................................................................................................ 90 
9.2.3 
Secondary endpoint(s) analyses .................................................................................................... 92 
9.2.4 
Tertiary/exploratory endpoint(s) analyses ...................................................................................... 94 
9.2.5 
Multiplicity adjustment .................................................................................................................... 94 
9.2.6 
Safety analyses .............................................................................................................................. 95 
9.2.6.1 
Adverse events .............................................................................................................................. 95 
9.2.6.2 
Laboratory evaluations ................................................................................................................... 96 
9.2.7 
Other analyses ............................................................................................................................... 96 
9.2.7.1 
Analyses of patient reported outcome endpoints ........................................................................... 96 
9.2.7.2 
Analyses of other endpoints ........................................................................................................... 97 
9.3 
INTERIM ANALYSES  ................................................................................................................... 97 
9.3.1 
Interim analyses for PFS ................................................................................................................ 97 
9.3.2 
Interim analyses for OS ................................................................................................................. 98 
9.3.3 
Data Monitoring Committee (DMC) ................................................................................................ 99 
9.4 
SAMPLE SIZE DETERMINATION................................................................................................. 99 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 100 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 100 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 100 
10.1.2 
Financial disclosure ..................................................................................................................... 101 
10.1.3 
Informed consent process ............................................................................................................ 101 
10.1.4 
Data protection ............................................................................................................................. 102 
10.1.5 
Committees structure ................................................................................................................... 104 
10.1.5.1 Steering committee ...................................................................................................................... 104 
10.1.5.2 Independent Data Monitoring Committee .................................................................................... 104 
10.1.5.3 Blinded Independent Review Committee ..................................................................................... 105 
10.1.6 
Dissemination of clinical study data ............................................................................................. 105 
10.1.7 
Data quality assurance ................................................................................................................ 106 
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10.1.8 
Source documents ....................................................................................................................... 106 
10.1.9 
Study and site start and closure ................................................................................................... 107 
10.1.10 Publication policy ......................................................................................................................... 108 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 108 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ....................................................................... 110 
10.3.1 
Definition of AE ............................................................................................................................ 110 
10.3.2 
Definition of SAE .......................................................................................................................... 111 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 112 
10.3.4 
Reporting of SAEs ....................................................................................................................... 114 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 114 
10.4.1 
Definitions .................................................................................................................................... 114 
10.4.2 
Contraception guidance ............................................................................................................... 115 
10.5 
APPENDIX 5: MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION (RECIST 1.1) .............................................................................................................. 117 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 125 
10.7 
APPENDIX 7: RECOMMENDED DOSE MODIFICATION GUIDELINES FOR STUDY 
TREATMENT-RELATED ADVERSE EVENTS ........................................................................... 127 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY ................................................................ 130 
10.9 
APPENDIX 9: LIST OF CYP3A INHIBITORS .............................................................................. 140 
10.10 
APPENDIX 10: LIST OF STRONG CYP3A INDUCERS ............................................................. 142 
10.11 
APPENDIX 11: LIST OF CYP SENSITIVE SUBSTRATES ......................................................... 143 
10.12 
APPENDIX 12: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA .................................................................................................................................... 146 
10.13 
APPENDIX 13: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE .......................................................................................................................... 147 
10.14 
APPENDIX 14: LIST OF DRUGS THAT CAN CAUSE QT PROLONGATION ........................... 148 
10.15 
APPENDIX 15: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 149 
10.16 
APPENDIX 16: DRUGS WITH A NARROW THERAPEUTIC WINDOW METABOLIZED BY 
CYP3A ......................................................................................................................................... 151 
10.17 
APPENDIX 17: PATIENT-REPORTED OUTCOMES ................................................................. 152 
10.17.1 EORTC QLQ-C30 questionnaire ................................................................................................. 152 
10.17.2 EORTC QLQ-BR23 questionnaire (for female participants) ........................................................ 154 
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10.17.3 EORTC QLQ-BR23 questionnaire (for male participants) ........................................................... 156 
10.17.4 EORTC QLQ-BR45 questionnaire (for female participants) ........................................................ 158 
10.17.5 EORTC QLQ-BR45 questionnaire (for male participants) ........................................................... 161 
10.17.6 EQ-5D-5L Health Questionnaire .................................................................................................. 164 
10.18 
ABBREVIATIONS ........................................................................................................................ 166 
11 
REFERENCES............................................................................................................................. 168 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 45 
Table 2 - Summary of primary estimand for main endpoints ........................................................................ 47 
Table 3 - Overview of Study intervention(s) administered ............................................................................ 60 
Table 4 - Dose levels for palbociclib dose reduction ..................................................................................... 66 
Table 5 - PK samples collection for amcenestrant, palbociclib and goserelin .............................................. 83 
Table 6 - Population for Analyses ................................................................................................................. 89 
Table 7 - Efficacy analyses for other secondary endpoints........................................................................... 93 
Table 8 - Safety analyses .............................................................................................................................. 95 
Table 9 - PFS analyses ................................................................................................................................. 97 
Table 10 - OS analyses ................................................................................................................................. 98 
Table 11 - Protocol-required laboratory assessments ................................................................................ 109 
Table 12 - Recommended dose modification or discontinuation ................................................................ 127 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 25 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A randomized, multicenter, double-blind Phase 3 study of amcenestrant (SAR439859) plus 
palbociclib versus letrozole plus palbociclib for the treatment of patients with ER (+), 
HER2 (-) breast cancer who have not received prior systemic anti-cancer treatment for 
advanced disease  
Brief title: 
 
Amcenestrant (SAR439859) plus palbociclib as first line therapy for patients with ER (+) 
HER2 (-) advanced breast cancer (AMEERA-5) 
Rationale: 
The purpose of the proposed study is to demonstrate the superiority of a new oral selective 
estrogen receptor degrader (SERD), amcenestrant, in combination with palbociclib versus 
letrozole in combination with palbociclib in participants with estrogen receptor-positive [ER(+)], 
human epidermal growth factor receptor 2 negative [HER2(-)] advanced or metastatic breast 
cancer who have not received prior systemic anti-cancer treatment for advanced disease. Refer to 
Section 2.1. 
Objectives and endpoints: 
  
Objectives 
Endpoints 
Primary 
 
• 
To determine whether amcenestrant in combination 
with palbociclib improves progression free survival 
(PFS) when compared with letrozole in combination 
with palbociclib in participants with ER+, HER2- 
advanced breast cancer who have not received 
prior systemic anticancer therapies for advanced 
disease 
• 
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 local 
radiologist/investigator or death (due to any cause), 
whichever comes first. 
Secondary 
 
• 
To compare the overall survival (OS) in both 
treatment arms [Key Secondary Objective] 
• 
Overall survival is defined as the time interval from 
the date of randomization to the date of 
documented death (due to any cause). [Key 
Secondary Endpoint] 
• 
To evaluate the objective response rate (ORR) in 
both treatment arms 
• 
ORR is defined as the proportion of participants 
who have a complete response (CR) or partial 
response (PR), as best overall response determined 
as per RECIST 1.1, from the date of randomization 
until disease progression, death, cutoff date, 
initiation of post-treatment anti-cancer therapy, 
whichever occurs first. 
 
 
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• 
To evaluate the duration of response (DOR) in both 
treatment arms 
• 
DOR is defined as the time from first documented 
evidence of CR or PR until progressive disease 
(PD) as determined as per RECIST 1.1 or death 
from any cause, whichever occurs first. 
• 
To evaluate the clinical benefit rate (CBR) in both 
treatment arms 
• 
CBR is defined as the proportion of participants who 
have a confirmed CR, PR, or stable disease (SD) 
for at least 24 weeks determined as per RECIST 
1.1, from the date of randomization until disease 
progression, death, cutoff date, initiation of post 
treatment anti-cancer therapy, whichever occurs 
first. 
• 
To evaluate progression-free survival on next line of 
therapy (PFS2) 
• 
The PFS2 is defined as the time from the date of 
randomization to the date of first documentation of 
PD on the next systemic anti-cancer therapy 
according to investigator or death due to any cause 
in the absence of documented PD on the next 
systemic anti-cancer therapy, whichever occurs 
first. 
• 
To evaluate the pharmacokinetics (PK) of 
amcenestrant, and palbociclib 
• 
Plasma concentrations of amcenestrant, palbociclib 
• 
To evaluate health-related quality of life (HRQL) in 
both treatment arms 
• 
Symptoms and function related to HRQL as 
measured by EORTC QLQ-C30, breast cancer 
specific module (QLQ-BR23/BR45) and EQ-5D-5L  
Disease-specific and generic HRQL, disease and 
treatment-related symptoms, the impact of 
symptoms and treatment, health state utility, and 
health status will be evaluated using the European 
Organization for Research and Treatment of Cancer 
(EORTC) core quality of life questionnaire (QLQ-
C30), the EORTC-QLQ breast cancer specific 
module (QLQ-BR23/BR45) 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 study treatment 
• 
To evaluate the time to first chemotherapy in both 
treatment arms 
• 
Time to chemotherapy is defined as the time 
interval from the date of randomization to the start 
date of the first chemotherapy after study treatment 
discontinuation 
• 
To evaluate safety in both treatment arms 
• 
Treatment emergent adverse events 
(TEAEs)/serious adverse events (SAEs) and 
laboratory abnormalities 
 
 
Exploratory 
 
• 
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). 
• 
Tumor ER, Ki67, Bcl-2, and PgR protein, and RNA 
gene expression profiles in paired biopsies at Cycle 
1 Day 1 (pre-treatment) and optional at end of 
treatment for participants who discontinued 
treatment due to disease progression 
• 
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. 
• 
The gene mutation profile of the tumor by cfDNA 
analysis over time (Cycle 1 Day 1 [pre-treatment], at 
Cycle 4 Day 1 predose (tumor assessment), and 
upon disease progression on treatment or EOT 
whichever comes first) 
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• 
To evaluate exposure/response relationship of 
amcenestrant and palbociclib 
• 
PK of amcenestrant will be correlated with safety 
and/or efficacy 
• 
To evaluate the PK of goserelin 
• 
Plasma concentrations of goserelin 
• 
To evaluate PFS in participants expressing PIK3CA 
and ESR1 mutation in both treatment arms 
• 
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 local 
radiologist/investigator or death (due to any cause), 
whichever comes first. 
 
 
 
 
For China, please see Section 10.6 for details. 
Overall design: 
This is a prospective multicenter, international, randomized, double-blind, double-dummy, 
Phase 3 trial comparing the efficacy and safety of amcenestrant in combination with palbociclib 
versus letrozole in combination with palbociclib in men, pre/peri-menopausal women (with 
goserelin), and postmenopausal women, all with ER(+)/HER2(-) breast cancer who have not 
received prior systemic treatment for advanced disease.  
Eligible participants should have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of either loco-regional recurrent or metastatic disease 
not amenable to radiation therapy or surgery with curative intention, and for whom chemotherapy 
is not indicated. 
Participants who progressed while on or within 12 months from completion of (neo)adjuvant 
endocrine therapy with any of the following agents: aromatase inhibitor (eg, letrozole, 
anastrozole, exemestane); selective estrogen receptor modulator - eg, tamoxifen, toremifene, 
raloxifene; CDK4/6 inhibitors (eg, palbociclib, ribociclib, abemaciclib) will not be eligible. 
Participants should not have received prior systemic anti-cancer therapies for their advanced 
disease. Participants may have measurable disease as per RECIST v.1.1 or non-measurable bone 
only disease with at least one predominant lytic bone lesion or mixed lytic-blastic lesion.  
All eligible participants will be randomly assigned using an Interactive Response Technology 
(IRT) to either amcenestrant plus palbociclib (experimental) arm or letrozole plus palbociclib 
(control) arm in a 1:1 ratio.  
The population will be stratified by: 
• De-novo metastatic disease (Yes or No) 
• Postmenopausal women (Yes or No) 
• Visceral metastasis defined by at least 1 liver, lung, brain metastasis, pleural, or peritoneal 
involvement (Yes or No). 
Participants will continue to receive their assigned treatment until objective disease progression, 
unacceptable toxicity, participant’s request to stop treatment, or investigator’s decision, whichever 
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occurs first. However, participants may continue treatment as assigned at randomization beyond 
the time of RECIST defined disease progression at the discretion of the investigator, if that is 
considered to be in the best interest of the participant and as long as no new anticancer treatment 
is initiated. In these cases, the investigator must discuss the rationale with the sponsor before the 
decision to continue treatment on-study is made. 
Tumor assessments will be performed within 4 weeks (ie, 28 days) prior to randomization, 
followed by every 12 weeks (±7 days) from the date of randomization. Participants with bone 
lesions identified at baseline will also have repeat bone scans performed every 24 weeks (±7 days) 
from the date of randomization for the first 18 months, and then every 12 weeks (±7 days). Each 
assessment will be performed as scheduled regardless of any dosing delay to prevent the 
introduction of bias into the assessment of efficacy.  Tumor assessments will be performed until 
documented PD as per RECIST v.1.1, or final PFS analysis cut-off date (COD), and at EOT (to be 
performed if it falls within the regular disease assessment time window of 12 weeks ±7 days ), 
whichever occurs first. 
Participants discontinuing the active treatment phase will be followed until death or final study 
cut-off date, whichever comes first. Participants who discontinue the study treatment without 
documented PD as per RECIST v.1.1 will be followed every 12 weeks until disease progression.  
In participants with documented disease progression as per RECIST v.1.1, follow-up visits will be 
performed every 24 weeks (±7 days) from the last dose of study intervention for overall survival 
status and collection of data on subsequent anticancer therapies, until death or until the OS cutoff 
date, whichever comes first.  
A blinded Independent Review Committee (BIRC) assessment will be performed retrospectively 
on a sample of participants based on radiographic images and clinical information collected 
on-study. 
An independent data monitoring committee (DMC) will monitor the safety data on a periodic 
basis. The DMC will make recommendations as to whether the trial should continue based on 
ongoing reviews of safety data. The DMC will also evaluate efficacy at the interim analyses and 
make a recommendation regarding study continuation based on observed results of the study. The 
DMC procedures will be detailed in the DMC charter and approved by the DMC members. 
A Study Steering Committee will supervise the progress of the trial and review relevant 
information that may affect the study conduct as well as review DMC recommendations. 
Brief summary:  
This is a parallel, Phase 3, two-arm study for treatment that is blinded for Participant, Investigator, 
and Outcomes Assessor [Study sponsor (except bioanalysts assessing PK samples) and all 
stakeholders (except DMC and independent statistician) involved in study conduct]. 
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Number of participants: 
Approximately 1333 participants will be screened in the study, and 1066 participants will be 
randomly assigned to study intervention with a balanced randomization ratio (533 participants 
randomized per treatment arm). 
Note: Enrolled participants are all participants from screened participants who have been allocated 
to an intervention regardless of whether the intervention was received or not.  
Intervention groups and duration: 
Participants will be randomly assigned (1:1) to either Arm A (experimental) or Arm B (control). 
• Arm A: Amcenestrant (SAR439859) 200 mg + letrozole-matching placebo + palbociclib 
125 mg  
• Arm B: amcenestrant (SAR439859) -matching placebo + letrozole 2.5 mg + palbociclib 
125 mg. 
The treatments in both arms are given orally. During the treatment period, men and 
pre/perimenopausal women will receive goserelin subcutaneously.  
No dose reductions for letrozole and amcenestrant (SAR439859) are permitted but dosing 
omissions are allowed in case of severe toxicity. In the event of significant treatment-related 
toxicity, palbociclib dosing may be omitted or delayed and/or reduced. 
If palbociclib is prematurely permanently discontinued due to treatment-related toxicity, 
participants may continue as per investigator’s discretion on the active treatment phase of the 
study receiving letrozole plus amcenestrant (SAR439859) -matching placebo or amcenestrant 
(SAR439859) plus letrozole-matching placebo.  
Participants discontinuing treatment of either letrozole/letrozole-matching placebo treatment or 
amcenestrant (SAR439859) /amcenestrant (SAR439859) -matching placebo, due to treatment-
related toxicity will be discontinued from the active treatment phase of the study and enter the 
follow-up phase. 
Study intervention(s) 
Investigational medicinal product(s) 
Amcenestrant (SAR439859) and Amcenestrant (SAR439859) -matching placebo 
• Dosage form and strength: 200 mg tablets  
• Route(s) of administration: oral route 
• Dose regimen: the recommended dose is 200 mg once daily, continuously, to be taken 
approximately at the same time each day, with food intake.  
• amcenestrant (SAR439859)-matching placebo will be supplied as tablets identical to 
amcenestrant (SAR439859) 200 mg tablets in appearance. 
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Letrozole and letrozole-matching placebo 
• Dosage form and strength: 2.5 mg tablets over-encapsulated 
• Route(s) of administration: oral route 
• Dose regimen: 1 capsule once daily, continuously, to be taken approximately at the same 
time each day, with food intake. 
• Letrozole-matching placebo will be supplied as capsules identical to letrozole 2.5 mg 
capsules in appearance. 
Palbociclib (Ibrance®)  
• Dosage forms and strengths: 125 mg, 100 mg, 75 mg capsules or tablets. 
• Study to be initiated with the capsules and will be switched to tablets as commercially 
available. 
• Route(s) of administration: oral route 
• Dose regimen: the recommended dose is 125 mg once daily for 21 consecutive days 
followed by 7 days off treatment to comprise a complete cycle of 28 days. To be taken at 
approximately the same time each day. 
• Should be taken with food, regardless of the administered formulation. 
When given the same day, amcenestrant (SAR439859) plus letrozole matching placebo plus 
palbociclib or letrozole plus amcenestrant (SAR439859) matching placebo plus palbociclib will 
be taken at the same time. 
If a dose is vomited or omitted, the participant should not take the dose later or 2 doses at the next 
planned dose. 
Non investigational medicinal product(s) 
Goserelin 
Additional treatment with goserelin is required for men and pre/perimenopausal participants.   
• Dosage form and strength: 3.6 mg injection 
• Route(s) of administration: subcutaneous 
• Dose regimen: administered once every 28 days into the anterior abdominal wall below 
the navel line using an aseptic technique prior to study IMPs. While delay of a few days is 
permissible, every effort should be made to adhere to the 28-day schedule.   
Duration of study intervention 
The expected duration of treatment for participants who benefit from study intervention may vary, 
based on progression date; but median expected duration of study per participant is estimated as 
median 59 months in experimental arm (1 month for screening, 33 months for treatment, and 
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25 months for the EOT and follow-up visits) and 47 months in control arm (1 month for 
screening, 25 months for treatment, and 21 months for the EOT and follow-up visits). 
Statistical considerations: 
Sample size determination 
A total of 516 PFS events assessed by local radiologist/investigator will be needed to reject the 
null hypothesis using a logrank test at the one-sided level of 2.5% and a 90% power under the 
assumption of a HR of 0.75. Assuming proportional hazards under an exponential model and 
based on an anticipated median PFS time of 24.8 months in the letrozole + palbociclib arm, this is 
expected to correspond to a median PFS of 33.1 months in the SAR439859 + palbociclib arm. 
Based on an expected accrual duration of 18 months (15% of total accrual in the first 4.5 months 
and 40% of total accrual in the first 9 months), a PFS analysis cut-off date (COD) 40 months after 
first participant in and an annual dropout rate of 5%, a total of 1066 participants are expected to 
be randomized in a 1:1 ratio into the SAR439859 + palbociclib and letrozole + palbociclib arms. 
The power calculation accounts for two interim analyses at 40% and 70% of the planned number 
of events (as described in the interim analysis part). 
For OS, a total of 632 deaths will be needed to reject the null hypothesis using a logrank test at the 
one-sided level of 2.5% and an 80% power under the assumption of a HR of 0.80. Assuming 
proportional hazards under an exponential model and based on an anticipated median OS of 
46 months in the letrozole + palbociclib arm, this is expected to correspond to a median OS of 
57.5 months in the SAR439859 + palbociclib arm. OS COD is expected 80 months after the first 
participant randomized (assuming an annual dropout rate of 1%). The power calculation accounts 
for two interim analyses at the time of the PFS primary analysis and at 75% of the planned 
number of OS events. 
Analysis populations: 
• Enrolled population: All participants who sign the informed consent form (ICF).  
• 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. 
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• Safety population: All participants randomly assigned to study intervention and who take 
at least 1 dose of study intervention. Participants will be analyzed according to the 
treatment arm they actually received. This population is the primary population for the 
analysis of all safety parameters.  
• Pharmacokinetic-evaluable population: All participants from the safety population who 
receive at least 1 dose of amcenestrant and with at least one evaluable plasma 
concentration post-treatment. 
Primary analysis: 
Primary analysis will consist of PFS according to local radiologist’s/investigator’s assessment 
comparison between amcenestrant + palbociclib arm and letrozole + palbociclib arm through 
a logrank test procedure stratified by the stratification factors as entered in the IRT. An overall 
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 PFS analysis COD, PFS will be 
censored at the date of the last evaluable tumor assessment with no evidence of a disease 
progression before the start of further anti-cancer therapy 
• A participant without an event (death or disease progression) and without any evaluable 
postbaseline tumor assessments will be censored at the day of randomization (Day 1). 
• Documented progression (or death) occurring after two or more non-evaluable tumor 
assessments will be censored at the date of the last evaluable tumor assessment 
documenting no progression.   
Two interim analyses at 40% (206PFS events, non-binding futility only) and 70% (361PFS 
events, efficacy only) of the planned number of events (516PFS events) are planned. The primary 
PFS analysis corresponds either to a positive interim PFS analysis or the final PFS analysis. 
The HR estimates and corresponding 95% two-sided confidence intervals (CI) will be provided 
using the Cox proportional hazard model stratified by the same stratification factors as those used 
for the log rank 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). Subgroup analyses 
of PFS will also be conducted. 
A random sample-audit BIRC approach will be used as an auditing tool to evaluate the 
concordance between local radiologist’s/investigator’s assessment and BIRC on the PFS data. 
Approximately 50% of the randomized participants will be randomly selected and the BIRC will 
assess the tumor progression of these participants based on the review of tumor assessments. 
Participants selected for the sample-audit BIRC will not be known to the investigators. NCI (1) 
and PhRMA (2) methods will be used to provide assurance on the PFS treatment effect based on 
the local radiologist’s/Investigator’s assessment. 
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Analysis of key secondary efficacy endpoint: 
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 at the last date the 
participant is known to be alive or at the OS cut-off date, whichever occurs first. Similar methods 
as for PFS will be used. 
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.  
Analysis of secondary efficacy endpoints: 
Analysis of response-based endpoints (ie, ORR, CBR, and DOR) will be performed primarily on 
the ITT population and supported by the analyses based on the subset of measurable disease 
participants from the ITT population. Analysis of the time to first chemotherapy (TT1C) and 
progression-free survival on the next systemic anti-cancer therapy (PFS2) will be performed on 
the ITT population, using Cox proportional hazard model and Kaplan-Meier method. No formal 
statistical testing will be performed, and only descriptive statistics will be provided. 
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 EORTC QLQ-C30, the breast cancer specific 
module (QLQ-BR23/QLQ-BR45), and the 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 subscales), QLQ-BR23/QLQ-BR45 (13 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 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/QLQ-BR45(13 subscales), 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.  
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• 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 (MedDRA) primary system organ class (SOC) 
and preferred term (PT) will be summarized by National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v5.0 grade (all grades and Grade ≥3) for the safety 
population. Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to 
definitive discontinuation, and premature discontinuation of palbociclib, 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: 
Two interim analyses are planned based on the primary PFS endpoint at 40% (non-binding futility 
only) and 70% (efficacy only) of the planned total number of events expected. 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 efficacy will be derived based on the O’Brien and Fleming 
α- spending functions and depend on the actual number of PFS events observed at the time of the 
interim analysis.  
In case of positive results at interim analysis, disease assessments data will be collected according 
to the protocol until the final analysis cut-off date (defined as the date when 516 PFS events 
assessed by radiologist/Investigator are observed) and PFS results will be updated (non-inferential 
analysis only). 
Comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of three analyses are planned for OS, at the time of 
the primary analysis of PFS, at the 75% of the planned number of OS events and at the final OS 
analysis. 
A gamma error spending function (γ = -10) independent from the O’Brien and Fleming 
α-spending function for PFS will be used, along with the hierarchical testing strategy in order 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 (3).  
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Planned database lock date: 
Estimated COD will be approximately 19.5, 28, and 40 months after first randomized participant 
respectively for the first interim, second interim, and final PFS analysis. After final COD for PFS 
analysis, no more efficacy assessment will be performed except collection of survival status.  
The final OS analysis COD will be the last COD, and it will fall approximately 80 months after 
the first patient randomized. If a participant treated continues to benefit from the treatment after 
the last COD, 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, all ongoing SAEs (related or not), all related non-serious AEs ongoing at the COD, 
and all new related AEs (serious or not) occurring post-COD will be followed until resolution or 
stabilization; as well as IMP administrations, and related concomitant medication, and reason for 
EOT will continue to be collected. 
Data Monitoring/Other committee: Yes 
 
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
D1
R
D-28
D1 (±3)
Dx
D29 (±3)
SAR439859 200 mg (D1 -D28)
Letroz ole-matching placebo (D1 -D28)
Palbociclib 125 mg (D1 -D21)
± goserelin (D1) m en / pre/perim enopausal wom en
ARM  A
533 patients
Follow-up visit
every 12 weeks 
(±7 days) until PD, 
every 24 weeks 
(±7 days) thereafter
Screening
….
….
D21
C2
C1
C3
End of 
Treatment
ARM  B
533 patients
SAR439859-matching placebo (D1 -D28)
Letroz ole 2.5 mg (D1 -D28)
Palbociclib 125 mg (D1 -D21)
± goserelin (D1) m en / pre/perim enopaus al wom en
Death or 
cut-off
Follow-up 
period
Cn
30 days (±5)
after last IM P
C = Cy c le; D = day; IMP = investigational m edic inal produc t; PD = progres sive dis ease; R = randomization.
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
IRT contact 
X 
X 
 
X 
X 
 
 
 
Inclusion/exclusion 
criteria and Informed 
consent  
X 
 
 
 
 
 
 
Informed consent (including genetic sampling) 
may be signed prior to D-28. Recheck clinical 
status before randomization and/or 1st dose of 
study medication. 
Demography, 
medical/surgical and 
disease history, prior 
cancer therapies 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Vital signs, physical 
examination/signs and 
symptoms  
X 
X 
 
X 
X 
 
 
 
ECOG performance 
status, body weight 
X 
X 
 
X 
X 
 
 
 
Follicle-stimulating 
hormone  
 X 
X  
 
X  
X  
 
 
At screening for eligibility in all female study 
participants - local labs.  
On C1D1, then every 4th cycle during study 
treatment and EOT - only in 
pre/perimenopausal women - local labs  
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Estradiol 
Xa 
Xb 
 
Xc 
 
 
 
a. At screening for eligibility in female study 
participants - local labs  
b. Estradiol sampling at predose C1D1 - 
central labs (all participants) 
c. Estradiol sampling at predose C3D1 - 
central labs (all participants) 
Pregnancy test 
(WOCBP only) - Local 
labs 
Xa 
(Xb)  
  
 Xb 
Xb 
Xc 
  
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, at EOT,  
c Urine pregnancy test (dipstick) to be done 
every month, up to 12 weeks after last dose of 
any study intervention. 
Urine pregnancy test must have a sensitivity 
of at least 25 mIU/mL. 
Triplicate 12-lead ECG 
X 
 
 
 
 X 
 
 
Screening, EOT and as clinically indicated - 
To be assessed locally. Triplicate ECGs are 
collected within about a five-minute window at 
a nominal time-point. 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Laboratory 
assessments - Local 
labs 
X 
(X) 
X 
X 
X 
 
  
Hematology/biochemistry panels and 
coagulation to be performed at screening 
within 7 days of C1D1. 
-Complete blood counts and biochemistry: at 
the beginning of each cycle, as well as on 
D15 of the first 2 cycles, and as clinically 
indicated. 
Lipids assessments (total cholesterol, LDL-
cholesterol, HDL-cholesterol): on D1 of each 
cycle until Cycle 6. 
Urine dipstick testing 
(Local labs) 
X 
(X) 
 
X 
X 
 
 
Urinalysis to be performed at screening within 
7 days of C1D1. 
Viral serology tests 
X 
 
Hepatitis A antigen or IgM hepatitis A 
antibody; HBs antigen or hepatitis B viral 
DNA; Hepatitis C antibody and quantitative 
hepatitis C (HCV) ribonucleic acid (RNA). 
Randomization 
X 
 
 
 
 
 
 
Every effort should be made to start treatment 
within 3 working days of randomization. 
Study Intervention Administration: 
Amcenestrant 
(SAR439859) or 
Amcenestrant 
(SAR439859)-
matching placebo  
 
Once daily 
→ 
 
 
 
To be taken with food. 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Palbociclib  
 
D1 to D21 (once daily)  
followed by 7 days off  
→ 
 
 
 
To be taken with food, regardless of the 
administered formulation 
Letrozole or 
letrozole-matching 
placebo  
 
Once daily  
→ 
 
 
 
To be taken with food 
Goserelin 
 
X  
 
X  
 
 
 
In pre/perimenopausal women and men 
AE/SAE review 
=============================→ 
X 
(ongoing related AEs, ongoing 
SAEs at EOT and new related 
AE/SAEs) 
 
Concomitant 
medication review 
X 
=============================→ 
 X 
(related to AE/SAEs listed above) 
From the date of informed consent form up to 
30 days after the last dose of study treatment 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Tumor assessments: 
CT/MRI Scans with 
contrast agent of 
Chest, Abdomen, 
Pelvis, any clinically 
indicated sites of 
disease, and of bone 
lesions; Clinical 
evaluation of 
superficial disease 
Xa 
Xb 
Xc 
Xd 
 
a. Screening:  within 4 weeks (ie, 28 days) 
prior to randomization unless otherwise 
specified. 
b. Post baseline: every 12 weeks (±7 days) 
from randomization (until documented 
progressive disease as per RECIST v.1.1 or 
final PFS analysis cut-off date). 
c. EOT: to be performed if it falls within the 
regular disease assessment time window of 
12 weeks ±7 days (only in participants without 
PD as per RECIST 1.1). 
d. If no PD as per RECIST 1.1 at EOT, 
disease assessment will continue to be 
performed every 12 weeks ±7 days from 
randomization up to documented PD as per 
RECIST v.1.1, or final PFS COD, whichever 
occurs first. 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Radionuclide Bone 
Scan, Whole Body 
Xa 
Xb 
Xc 
Xd 
 
a. Screening: within 12 weeks prior to 
randomization  
b. Post baseline: 
• If bone lesions identified at baseline: to be 
repeated every 24 weeks (±7 days) from 
randomization for the first 18 months, and 
then every 12 weeks (±7 days). 
•  If no bone lesions identified at baseline: to be 
repeated only if clinically indicated. 
c. EOT: to be performed if it falls within the 
regular disease assessment time window of 
12 weeks ±7 days (only in participants without 
PD as per RECIST 1.1 and no bone lesions 
identified at baseline). 
d. If no PD as per RECIST 1.1 at EOT, 
disease assessment will continue to be 
performed from randomization date as 
reference in participants with bone lesions 
identified at baseline, up to documented PD 
as per RECIST v.1.1, or final PFS COD, 
whichever occurs first. During follow-up 
period, bone scan should be performed at the 
same frequency as described in note b.  
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Dual-energy x-ray 
absorptiometry 
(DXA) scan of 
anteroposterior 
spine and total hip 
Xa 
Xb (every 2 years from randomization 
or more frequently if clinically indicated) 
 
 
 
a. Screening: Only in study participants who 
are not on bone-targeted agents (eg, 
bisphosphonates, denosumab) prior to 
initiation of study IMPs (if not done during the 
previous 6 months prior to randomization) 
b. Post baseline: Only in study participants 
who had DXA scan at baseline, or if clinically 
indicated 
Survival Follow-up 
 
 
 
 
 
X 
After discontinuation of study treatment, post-
study survival status (including post-study 
anti-cancer therapies (start/stop date, date of 
PD), and their responses will be collected 
during on-site visits or by contacting the 
patient or family by telephone until death or 
OS cut-off date, whichever comes first. 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Pharmacokinetics 
sampling - central labs 
 
Xa 
Xb 
Xc 
 
 
 
Amcenestrant and palbociclib: 
a. C1D1: Post dose T3h ±1h 
C2D1: Predose, Post dose T3h ±1h  
b. C1D15 and C2D15: Predose 
c. C3D1: Predose 
 
Cycles 4, 7, and 10: Predose at D1 
 
No PK samples will be taken after Cycle 10 or 
PFS cut-off date, whichever comes first 
Goserelin (only in pre/perimenopausal women 
and men): 
a. C1D1 and C2D1 predose 
c. C3D1 predose 
Electronic HRQL: 
QLQ-C30, QLQ-
BR23/QLQ-BR45,  
EQ-5D-5L 
 
Xa 
 
Xa 
Xa 
Xb 
a. Every cycle from Cycle 1 to Cycle 4, then 
every 3 cycles from Cycle 6 and at EOT 
b. First follow-up visit only 
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Procedure 
Screening  
 
up to 28 days 
before 
randomization 
Treatment Period 
EOT 
Post Treatment  
Follow-up period 
 
Cycles  
1 & 2 
Subsequent 
Cycles 
30 Days 
(±5 Days)  
after last study 
treatment 
administration 
Every  
12 weeks 
(±7D) 
until disease 
progression 
Every  
24 weeks 
(±7D) 
after disease 
progression 
Notes 
 
D1 (±3) D15 (±1)  
D1 (±3) 
 
Tumor 
specimen/Biopsy 
Xa 
 
 
 
Xb 
 
 
a. Most recent archived FFPE biopsied tumor 
tissue samples of metastatic/recurrent lesion. 
If archived tumor tissue is not available, then 
fresh tumor biopsy of metastatic/recurrent 
lesion should be collected from time of 
screening to Cycle 1 D1 pre-treatment. 
Original diagnostic tumor tissue sample will 
be used in absence of metastatic/recurrent 
tissue sample and whenever a fresh biopsy of 
the metastatic/recurrent lesion is not feasible. 
b. Fresh tumor biopsy (optional) collected at 
EOT, for study participants who discontinue 
treatment due to disease progression, if 
feasible. It is recommended that the second 
biopsy (optional) is collected at the same 
location as the baseline biopsy, whenever 
possible unless new lesion is identified. 
Molecular profiling in 
cfDNA (plasma) - 
central labs  
 
X 
 
X (Cycle 4) 
X 
 
 
cfDNA sample should be collected at pre-
treatment (Cycle 1 D1), at Cycle 4 Day 1 
predose (at tumor assessment), and upon 
disease progression on treatment or EOT 
whichever comes first. 
DMET genotyping and 
normal tissue reference 
DNA (whole blood) - 
central labs 
 
X 
 
 
 
 
 
To be collected pre-treatment Cycle 1 D1 
All study visits performed during treatment period and follow-up period (in participants without progressive disease per RECIST 1.1 at EOT) are conducted on-site until disease progression. 
On-site visits could be substituted by remote visits in specific circumstances (see Section 10.15).  
Screening: Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening defined timeframe. Informed consent should be signed 
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before any study specific procedures. It can be signed more than 28 days prior to randomization. Screening time indicates in which timeframe exams used to support eligibility have to be done 
prior to randomization.  
In addition to lipid assessments, investigator should monitor bone mineral density using dual-energy x-ray absorptiometry (DXA) scan of anteroposterior spine and total hip in study participants 
who are not on bone-targeted agents (eg, bisphosphonates, denosumab) prior to initiation of study IMPs (if not done during the past 6 months) and then repeated every 2 years during the 
treatment (or more frequently, if clinically indicated). 
Randomization: To take place once the consented patient has completed all the necessary screening procedures and is deemed eligible for study entry by the Investigator or designee. All 
eligible participants must be randomized using Interactive Response Technology (IRT). Every effort should be made to start treatment within 3 working days of randomization.  
Cycle 1 D1 refers to the day the patient receives the initial dose of IMP. (X): Optional assessments: Repeated evaluation of pregnancy test, urine dipstick testing (ie, urinalysis), body weight, 
signs and symptoms, physical examination, hematology and blood chemistry labs is not necessary if performed within 7 days prior to1st IMP administration. If evaluation performed during 
screening was abnormal, repeated evaluation is recommended within 2 days prior to 1st IMP administration. Urine pregnancy test must have a sensitivity of at least 25 mIU/mL. 
Treatment period: All the tests or procedures on D1 should be done prior to IMP administration unless otherwise stated. Men and pre/perimenopausal women will receive goserelin (NIMP) on D1 
of each cycle.  
End of treatment (EOT): should be performed within 30 days (±5 days) after the last IMP and prior to the initiation of any new anti-cancer therapy, whichever comes first. 
Follow-up period:  
-Participants with documented progressive disease (PD) at time of treatment discontinuation: follow-up visit will be done every 24 weeks ±7 days from the date of last study treatment 
administration until death or final OS analysis cut-off date, whichever comes first.  
-Participants without documented PD at time of treatment discontinuation will be followed every 12 weeks ±7 days from randomization until documented progression. After PD participants will be 
followed every 24 weeks ±7 days as described above until death or final OS analysis cut-off date. 
Tumor assessment: The schedule of assessments should be fixed according to the calendar, regardless of treatment delays/omissions. Imaging assessments are to be scheduled using the 
randomization date as the reference date for all time-points and are NOT to be scheduled based on the date of the previous imaging time-point. Imaging assessment delay to conform to 
treatment delay is not permitted. The same tumor assessment technique MUST be used throughout the study for a given lesion/patient.  
Bone scans: Any suspicious abnormalities (ie, hotspots) identified on bone scans at baseline and on subsequent bone scans MUST be confirmed by X-ray, CT scan with bone windows or MRI. 
Baseline brain scans (CT, MRI) only required within 6 weeks before randomization if signs and symptoms suggest presence of metastatic brain disease.  Post-baseline repeat brain scans will 
only be required only if metastases are present at baseline.  
Baseline scans performed before the signing of informed consent as routine procedures (but within the protocol defined timeframe) do not need to be repeated and may be used as baseline 
assessments provided tests were performed using the method requirements outlined in RECIST v.1.1.  
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include color photographs including a metric ruler of all superficial metastatic lesions. 
HRQL assessments: Study participants will complete electronic questionnaires prior to any study or medical procedures or discussion of their health status on D1 of Cycles 1, 2, 3, and 4 and then every 3 cycles 
starting from Cycle 6 D1 (ie, Cycle 6, 9, 12, etc), at end of treatment and at 1st follow-up visit. The time estimated to complete the EORTC QLQ-C30 and EORTC QLQ BR23/BR45 is approximately 15 to 20 minutes, 
and the time estimated to complete the EQ-5D-5L is approximately 5 to 10 minutes (for a total of 20 to 30 minutes to complete all three assessments). In countries where the translated and validated EORTC QLQ-
BR45 questionnaire is not available, study participants can use EORTC QLQ-BR23 questionnaire until the availability of translated and validated EORTC QLQ-BR45 questionnaire. Paper format will be used in case of 
extreme circumstances eg, technical issue making the electronic format temporarily unusable. 
AE = adverse event; C = cycle; cfDNA = cell free deoxyribonucleic acid; COD = cut-off date; 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; FFPE = formalin fixed paraffin embedded;  FSH = follicle-stimulating hormone; HRQL = health-related quality of life; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; PD = 
progressive disease; PFS = progression free survival; PK = pharmacokinetics; QLQ BR23 = EORTC QLQ breast cancer specific module-23 items; QLQ BR45 = EORTC QLQ breast cancer specific module-45 items; 
QLQ C30 = EORTC core quality of life questionnaire. RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event. 
 
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2 
INTRODUCTION  
Invasive breast cancer affects 1 in 8 women in the United States (12.4%) during their lifetime. In 
the United States, in 2020, an estimated 279,100 new cases of invasive breast cancer are expected 
to be diagnosed in United States (4). Breast cancer incidence in Europe in 2018 was estimated to 
be 522513 cases (5).  Male breast cancer is uncommon, comprising <1% of all cases of breast 
cancers, but its treatment is based on the guidelines for female breast cancer. The incidence rate of 
breast cancer increases with age, from 1.5 cases per 100 000 in women 20 to 24 years of age to 
a peak of 421.3 cases per 100 000 in women 75 to 79 years of age; 95% of new cases occur in 
women aged 40 years or older. The median age of women at the time of breast cancer diagnosis is 
61 years (6).  
With early detection and significant advances in treatment, death rates from breast cancer have 
been decreasing over the past 25 years in North America and other parts of the World. However, 
breast cancer remains a serious condition since even an early detection leading to an immediate 
surgery followed by adjuvant therapy does not systematically prevent a potential recurrence of the 
disease, even many years after the diagnosis. Moreover, for patients presenting with advanced 
stages (stage II or III) in the early breast cancer setting, for those with immediate metastatic breast 
cancer and for those who become resistant after one or several lines of anticancer therapy, the 
probability of survival is limited and the medical need for more active agents in this clinical 
setting remains very high. 
2.1 
STUDY RATIONALE  
Study rationale and purpose  
The purpose of the proposed study is to demonstrate the superiority of a new oral SERD, 
amcenestrant, in combination with palbociclib versus letrozole in combination with palbociclib in 
patients with ER(+), HER2(-)advanced or metastatic breast cancer who have not received prior 
systemic anti-cancer treatment for advanced disease. 
The standard of care for decades in first-line was endocrine therapy (ET) with a median PFS 
varying from 6 to 17 months (7, 8, 9, 10, 11, 12) with single hormonal agents such as tamoxifen 
and AIs.  
Recently, targeted therapy such as CDK4/6 inhibitor was combined with ET in the first- and 
second-line of metastatic breast cancer. Multiple trials have evaluated these combinations, either 
with an AI or fulvestrant. Three first-line trials have studied an AI as an endocrine backbone in 
combination with a CDK4/6 inhibitor in postmenopausal women with HR-positive 
HER2-negative advanced or metastatic breast cancer: PALOMA-2, MONALEESA-2 and 
MONARCH 3 (mPFS: 24.8-28.2 months; HR: 0.54-0.58). These studies demonstrated almost 
a doubling of PFS when the CDK4/6 inhibitor was added to ET, with remarkably similar HR 
across trials. However, the initial first-line trials looking at CDK4/6 inhibitors excluded women 
who were premenopausal and taking chemical ovarian suppression agents (13, 14, 15). The 
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American Society of Clinical Oncology (ASCO) guidelines note that patients who are 
premenopausal and able to use ovarian suppression should receive the same treatment as 
postmenopausal women (16). MONALEESA-7 study focused on premenopausal women, 
showing almost similar PFS benefit and HR compared with the ones observed in postmenopausal 
mBC trials. An overall survival benefit from combination endocrine treatment with ribociclib 
demonstrated in MONALEESA-7 has provided an insightful rationale for the treatment of patients 
with premenopausal hormone receptor-positive, HER2-negative metastatic breast cancers (17, 18). 
More recently, data from a Phase 2 trial (YoungPEARL) comparing exemestane plus palbociclib 
with ovarian function suppression vs chemotherapy showed clinical benefit in terms of improved 
progression-free survival (20.1 months, HR 0.65) in premenopausal patients with hormone 
receptor-positive, HER2-negative mBC. This study provides further data to support the use of ET 
with palbociclib and ovarian suppression as first-line treatment for metastatic HR-positive breast 
cancer in premenopausal women (19). 
Endocrine therapy is the backbone of any treatment in the ER+, HER2- advanced or metastatic 
breast cancer regardless of the line of therapy. Unfortunately, these treatments administered alone 
or in combination with targeted therapies, even if they in general significantly improve survival 
without progression, are unable to identify which patients can benefit from one treatment or the 
other, single agent or combination of therapies. 
Fulvestrant, the only approved treatment in SERD class, has demonstrated a significant PFS 
improvement versus anastrozole in the first line setting (20) and in combination with ribociclib 
versus fulvestrant (21, 22).  
SERDs are competitive ER antagonists that also induce conformational ER changes that lead to 
the degradation of ER via an ubiquitin proteasome system. The unique dual-function of SERDs 
(ER antagonism and depletion) may enable them to block ER signaling in cellular settings where 
other endocrine agents, such as tamoxifen or AIs have failed. Although fulvestrant has served as 
an important proof of concept for the SERD approach, this therapy is limited by its poor 
pharmaceutical properties which necessitate intramuscular administration and limits the applied 
dose, exposure and receptor engagement. The fulvestrant 500 mg regimen (500 mg on Days 1, 14, 
and 28; monthly thereafter) does not fully saturate ER binding in some patients as inhibition of 
18Fluoroestradiol Positron-emission tomography (FES-PET) scan uptake was incomplete in 38% 
(6/16) of patients (23). This incomplete receptor occupancy was associated with lack of clinical 
benefit.  
Rationale for dose and regimen selection 
The Phase 1/2 first-in-human (FIH) study with amcenestrant single agent, TED14856, started in 
November 2017 and designed in several parts, includes ER+, HER2-, postmenopausal women 
presenting with measurable advanced/metastatic breast cancer who progressed after several 
therapies. 
Part A was a dose escalation Phase (3 + 3 design) evaluating amcenestrant single agent from 
20 mg to 600 mg in a QD regimen, with the aim of assessing safety (including dose-limiting 
toxicities), pharmacokinetics, and pharmacodynamics and defining the recommended dose as 
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single agent. A total of 16 post-menopausal patients presenting with advanced/metastatic breast 
cancer were treated.  
At the time of the analysis of the data to determine the recommended dose: 
Safety was assessed in 16 patients, all of them presented with at least one treatment-emergent AE 
(TEAE). No DLT was observed during Cycle 1 at any tested dose levels. MTD was not reached. 
Most frequent TEAEs related to treatment were hot flushes (31.3%), diarrhea, nausea (both 25%), 
decreased appetite, constipation, night sweats, asthenia (all 18.8%), arthralgia and fatigue (both 
12.5%); no event was Grade ≥3. Serious adverse events (SAEs) considered to be not associated 
with amcenestrant have been reported in 2 patients (24, 25).  
Pharmacodynamics was assessed using 18FES PET scans performed at baseline and between 
11 and 15 days after the first administration of amcenestrant and close to the time of PK trough, 
prior to the next dose. High levels of inhibition of the signal were observed from the 150 mg dose 
level: 100% inhibition at this dose level, and more than 87% in all patients treated at further dose 
levels when Ctrough was above 100 ng/mL. 
Pharmacokinetic (PK) analysis obtained from a total of 16 patients shows that amcenestrant was 
generally well absorbed but showed a high within and total-subject variability of exposure. After 
multiple QD dosing in patients, a moderate accumulation is 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 (Cmax and AUC0-24h) 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 evaluation, amcenestrant 
exposure increased by 21-77% between 200 and 600 mg in a subset of patients, and up to 71% in 
heathy subjects at 400 mg with a high fat meal. Recommendation is done to give amcenestrant 
with food intake (when given at 200 mg once daily) for all amcenestrant clinical studies, including 
the current study to ensure favorable exposure in patients who may have lower absorption. 
A strong PK/PD 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. 
The best overall responses according to RECIST.1 criterion, were PR in 1 patient treated at 
150 mg QD (6.3%), stable disease (SD) in 8 patients (50.0%), including 7 (43.8%) with long-term 
SD (≥24 weeks) and PD in 7 patients (43.8%).  
Taking into account all these parameters, amcenestrant 400 mg dose level was established as the 
recommended dose for the Part B expansion cohort. 
Part B was the expansion phase of amcenestrant single agent in similar population except 
a limitation to only one prior chemotherapy. A total of 49 heavily pretreated patients received 
amcenestrant 400 mg in this dose expansion. The analyses were conducted in 49 patients of Part B 
in addition to 13 patients of Part A who received amcenestrant 150 mg dose or more.  
Safety was assessed in 62 patients. A total of 38 patients (61.3%) experienced TEAEs that are 
considered to be related to amcenestrant by the Investigator. The most frequently reported related 
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TEAEs by MedDRA PT were hot flushes (16.1%), constipation and arthralgia (9.7%), decrease 
appetite, nausea, diarrhea and vomiting (8.1%). Related TEAEs were Grade 1 and 2 and 
non-serious. None of the 22 SAEs observed in 13 patients (21%) were considered as related to 
amcenestrant. Eighty-two per cent of the events were of Grade ≤3 and were distributed among 
various SOCs.  
Clinical activity was assessed in 59 evaluable patients as well as in a subset of patients naïve from 
targeted therapies and/or fulvestrant.  
The best overall responses based on RECIST1.1 criteria for the 59 patients were: 4 confirmed PRs 
(6.8%), 25 SD (42.4%), and 30 PD (50.8%). More importantly, the CBR (= CR + PR + SD 
≥24 weeks) was of 35.6% in the global population. 
A comparison of the results observed in TED14856 study with those of fulvestrant in the literature 
was undertaken in order to place the results from amcenestrant in the context of historical control. 
A total of 5 comparative studies were selected with fulvestrant given as a single agent, in which 
selection criteria excluded patients with prior targeted therapies (mTOR and CDK 4/6 inhibitors) 
and fulvestrant. The results were consistent between studies with an ORR of 7 to 12% and a CBR 
of 31 to 37%; however, the results observed in the TED14856 were in heavily pre-treated 
population.  
The ORR and CBR in TED14856 study in a similar population, ie, when considering the selected 
subset of 14 patients with neither prior targeted therapies (mTOR or CDK 4/6 inhibitor) nor 
fulvestrant, was of 21.3% and 64.3%, respectively.   
The results of the activity observed with amcenestrant described above in a heavily pretreated 
population indicate a high rate of long stabilization (CBR). In addition, the safety and tolerability 
profiles of amcenestrant QD given as single agent are favorable with TEAEs of low grades. 
Part C was a dose escalation of two dose levels of amcenestrant (200 and 400 mg) in combination 
with a 125 mg fixed dose of palbociclib followed by Part D, an expansion phase with this 
combination at the recommended dose. 
A total of 6 patients were included in the dose escalation part, 3 at each dose level of 
amcenestrant. No DLT was reported. However, a signal of palbociclib exposure decrease was 
observed (compared to literature data), and additional patients were enrolled and treated. 
When compared to amcenestrant monotherapy data after repeated QD dosing, palbociclib 125 mg 
had no effect on the PK of amcenestrant at 200 mg, and had minimal effect (28% decrease of 
amcenestrant exposure) at 400 mg. Conversely, amcenestrant administered QD decreased 
palbociclib exposure, with an increase of the effect when increasing effect from 200 to 400 mg. 
When compared to palbociclib PK historical published data of palbociclib given as single agent 
(or in combination with letrozole) (26, 27), exposure decreased on average by 23% when 
combined with 200 mg amcenestrant QD (N=8) and by 60% with 400 mg amcenestrant QD 
(N=5). 
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Palbociclib clearance is mainly metabolic and showed a 32% decrease of exposure when 
combined with a moderate CYP3A inducer (Modafinil) (28). This extent of decrease was not 
considered as clinically relevant according to palbociclib labelling. 
Considering the facts that more than 90% of target engagement is shown by 18FES-PET inhibition 
from 150 mg and above for amcenestrant, and that a decrease of palbociclib around 23% can be 
considered as not clinically significant, the dose of 200 mg of amcenestrant in combination 
with125 mg of palbociclib was established as the recommended dose. 
The dose expansion part of amcenestrant 200 mg in combination with palbociclib 125 mg is 
ongoing in patients naïve from prior targeted therapies (CDK4/6, PI3K or mTOR inhibitors) who 
progressed during adjuvant therapy or after hormonal therapy for metastatic breast cancer. 
An interim analysis was conducted to assess the safety of the combination in 36 patients treated at 
200 mg (9 from Part C and 27 from Part D) and the activity based on RECIST1.1 criterion in 
19 evaluable patients (6 from Part C who did not receive a prior targeted therapy and 13 from 
Part D). A total of 75% of these patients are still ongoing, 22.2% have 1 cycle or less of treatment 
and 44.4% at least 4 cycles. The median duration of treatment was of 10.4 weeks. The median 
relative dose intensity was about 100% for amcenestrant and 90% for palbociclib in line with 
what was observed in PALOMA-3 study (91.7%). 
Among these 36 patients, 29 patients (80.6%) experienced at least one TEAE (all grades, 
excluding laboratory abnormalities), regardless the relationship to amcenestrant or Palbociclib: 
the most frequently reported TEAEs (>10%) by Medical dictionary for regulatory activities 
(MedDRA) preferred term (PT) were: nausea (22.2%); fatigue (19.4% each); constipation and 
diarrhea (13.9% each), asthenia, cough, dizziness, and dry skin. 
Most of these TEAEs were of Grade 1 and 2. A total of 12/36 (33.3%) patients had at least 
one Grade ≥3 TEAE. Twenty-two patients (61.1%) had TEAEs related to amcenestrant and 
25 patients (69.4%) had TEAE related to palbociclib by the investigator.  
The most frequently reported TEAEs related to amcenestrant by MedDRA PT (≥5%) were mainly 
of Grade 1 with no Grade 3: nausea (16.7%), fatigue (11.1%), asthenia, diarrhea and hot flushes 
(8.3%, each), and dizziness, dry skin, malaise, stomatitis (5.6%, each).  
The most frequently reported TEAEs related to palbociclib by MedDRA PT (≥5%) were the 
following: fatigue (19.4%), nausea and neutropenia (16.7%, each), neutrophil count decreased 
(11.1%), asthenia and dizziness (8.3%, each), diarrhea, dry skin, malaise, stomatitis, and ALT 
increased (5.6%, each). Grade 4 was observed for neutropenia (2.8%) and Grade 3 for neutropenia 
(8.3%), neutrophil count decreased (11.1%) and ALT increased (5.6%). 
A total of 5 patients (13.9%) had at least one SAE. All of them were considered as not related to 
the amcenestrant or Palbociclib intake by the investigator. A total of 3 patients (8.3%) presented 
with SAEs of Grade ≥3: pneumonia and pleurisy in 1 patient, duodenal obstruction in 1 patient, 
gastritis and small intestinal obstruction in 1 patient.  
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The main hematological laboratory abnormality during the TEAE period was neutrophil count 
decrease in 87.9% of the patients; Grade 1, 2, 3 and 4 were observed in 6.1%, 39.4%, 39.4% and 
3.0%, respectively. In a pooled analysis conducted in 1666 patients treated with palbociclib, 
95.2% of patients had neutrophil count decrease; Grade 1, 2, 3 and 4 were observed in 4.4%, 
23.8%, 56.4% and 10.5%, respectively (ref: Investigator’s brochure, Palbociclib. June 2019, 
Table 6.2-13). Liver enzymes increased were very limited with no Grade ≥3 AST increased and 
5.6% of Grade 3 ALT increased.  
The preliminary activity was assessed in 19 evaluable patients naïve from targeted therapies based 
on RECIST1.1 criterion. The best overall responses are:  1 confirmed PR (5.3%), 17 SD (89.5%) 
including two patients who have achieved PR not yet confirmed, and 1 PD (5.3%). The disease 
control rate (CR+PR+SD) is 94.7% and the clinical benefit rate is not mature as most of the 
patients have not reached 24 weeks of treatment yet. Tumor shrinkage was observed in 57.9% 
(11/19) of the patients and tumor size remains stable in 26.3% (5/19) of the patients. 
The preliminary analysis of the combination of amcenestrant with palbociclib indicate a favorable 
safety profile, the related TEAEs to amcenestrant in the combination were similar to the ones 
observed with amcenestrant single agent. The incidence of neutrophil count decreased related to 
palbociclib was in line with palbociclib combined with endocrine therapy literature. The 
preliminary antitumor activity of this combination observed so far in these 19 hormonal resistant 
patients is encouraging with a controlled disease for almost (94.7%) all patients.  
Taken together, these observations suggest that the combination of amcenestrant, a selective ER 
down-regulator, and palbociclib can be an important therapeutic option for patients with ER+ 
metastatic breast cancer. 
2.2 
BACKGROUND  
 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 ER, PR, and HER2 receptor status into HER2-positive, ER-positive/HER2-negative, 
and triple negative clinical subtypes.  About 75% of breast cancers express estrogen ERα which is 
a hormone regulator transcription factor (29).  
There are several classical ET for the treatment of HR+/HER2- advanced breast cancer in 
postmenopausal women: selective ER modulators (SERMs) that act by blocking the ER 
(eg, tamoxifen), nonsteroidal and steroidal AIs which reduce estrogen levels by inhibiting the 
peripheral synthesis of estrogen, and the selective estrogen receptor degrader (SERD) fulvestrant 
(30, 31). 
Amcenestrant is a potent, orally bioavailable, and selective ERα inhibitor that belongs to the 
SERD class of compounds. SERDs have the potential to block endocrine-dependent and 
endocrine-independent ERα signaling by ablation of ERα and have been recognized to offer a 
therapeutic approach to ERα positive breast cancer in both early stage and more advanced 
treatment resistant cases. Amcenestrant antagonizes the binding of estradiol to ER but also 
promotes the transition of ERα to an inactive conformation that leads to up to 98% receptor 
degradation at sub-nanomolar concentrations in cellular assays.  
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These dual properties of amcenestrant translate in a deeper inhibition of ERα pathways and a 
more effective anti-proliferative activity in ERα-dependent breast cancer cell lines driven by 
mutant or wild-type ERα compared to other ERα inhibitors. 
A detailed description of the chemistry, pharmacology, pharmacokinetics, clinical safety, and 
preliminary efficacy of amcenestrant is provided in the Investigator’s Brochure. 
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 versus IM), bioavailability, and long-term maintenance of ER receptor 
blockade combined with a strong antitumor activity. 
2.3 
BENEFIT/RISK ASSESSMENT  
Amcenestrant (a new oral SERD) may represent a new therapeutic option with a better 
benefit/risk ratio than approved endocrine monotherapies, such as AIs, tamoxifen and fulvestrant. 
In the first-line setting, fulvestrant (Faslodex®) single agent, a SERD compound, demonstrated 
a significant superiority versus anastrozole and was recently approved in that indication. 
Combining amcenestrant with palbociclib in animal models led to further growth-inhibitory 
effects compared with monotherapy alone suggesting that the combination of amcenestrant with 
palbociclib could bring more therapeutic benefit to ERα positive breast cancer patients than SERD 
monotherapy. amcenestrant single agent offers a favorable safety profile according to the 
preliminary results obtained in FIH study with limited rate of related Grade 1/2 adverse events. 
With amcenestrant monotherapy, most frequently observed TEAEs regardless of relationship are 
constipation, nausea, vomiting, diarrhea, fatigues, arthralgia, and decreased appetite. With 
amcenestrant in combination with palbociclib. most frequently observed TEAEs regardless 
relationship are neutropenia, nausea, asthenia, diarrhea, cough, and fatigue. The most common 
AEs reported for letrozole monotherapy arm in PALOMA-2 were arthralgia, hot flushes, fatigue, 
headache, and nausea; 5.9% of the patients discontinued for toxicity (13). In addition, in the 
adjuvant setting, angina requiring surgery, new or worsening of angina, myocardial infarction, 
venous thromboembolic events have been reported (Letrozole EU SmPC). Prevention, monitoring 
and management of any cholesterol increase could help decrease risk of cardiac disease. In 
addition, awareness and early recognition of clinical signs of ischemic heart disease (chest pain, 
breathlessness etc) with timely medical assistance help reduce risk of developing life-threatening 
condition. In addition, healthy lifestyle changes can also help reduce the risk.  Tendonitis and 
tendon rapture (rare) may occur. The patients who experienced tendon pain or swelling should be 
closely monitored and appropriate measures (eg, immobilization) must be initiated for the affected 
tendon. 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 
well-being of the participants, the benefit-to-risk assessment is deemed acceptable within the 
context of the planned EFC15935 study. More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events of amcenestrant may be found in the 
Investigator’s Brochure. 
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2.3.1 Risk assessment  
2.3.1.1 Risks in the Context of COVID-19  
The risks in the context of COVID-19 have been evaluated as follows.  
2.3.1.1.1 Risks related to the patient population  
The UK Coronavirus Cancer Monitoring Project (UKCCMP) has shown that the patients with 
breast cancer were at lower risk of contracting or dying from COVID-19, primarily because of 
patients being women rather than inherently lower risk associated with the tumor type (32). A 
cohort study from breast cancer patients from France showed that, breast cancer patients share the 
same risk factors for severe COVID-19 as the general population (33).  
Testing for SARS-CoV-2 infection during the screening phase should be based on investigator 
discretion and should also follow local/international guidelines (eg, asymptomatic but high risk of 
infection patients, patients with symptoms that could be associated with SARS-CoV-2 infection). 
Patients known to have had SARS-CoV-2 infection prior to study entry must be fully clinically 
recovered in order to be eligible for participation in the study. 
During the study, if a study participant is diagnosed with SARS-CoV-2, dose modification of 
study intervention should be based on the recommendations provided in Section 10.7. In addition, 
all investigators are instructed to consult official COVID-19 clinical research guidance from their 
local hospital/institution along with other relevant resources, such as: 
• American society of clinical oncology (ASCO) (34) 
• European Society for Medical Oncology (ESMO) (35). 
2.3.1.1.2 Risks related to study related activity  
It is important to minimize the risk of exposure of patients to COVID-19. In addition to the 
contingency measures described in Section 10.15 following prevention and mitigation plans could 
be implemented at clinical sites. Such plans may include: 
• All participating sites should have implemented measures according to regional/local 
Health Authorities, European medicines agency (EMA), ESMO, ASCO guidelines 
including but not limited to restrictions of access to the hospitals for visitors, physical 
distancing and personal protective equipment (PPE).  
• Study participants should be treated in a dedicated area that is separated from patients with 
COVID-19 infection.  
2.3.1.1.3 Risks related to study treatment  
Amcenestrant is a selective estrogen receptor degrader, and letrozole is a non-steroidal aromatase 
inhibitor. Both amcenestrant and letrozole belong to endocrine therapy, and they do not cause 
myelosuppression unlike other types of anti-cancer treatment (ie, chemotherapy, CDK4/6 
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inhibitor). Thus, the endocrine therapy does not pose additional risk for patients in the context of 
the current COVID-19 pandemic.  
Palbociclib is a CDK4/6 inhibitor, and has myelosuppressive properties (very common - 
leukopenia, and neutropenia). It may predispose patients to infections, while it is unknown if 
palbociclib is known to be associated to viral infections. As described in Section 6.8, in patients 
with treatment-emergent neutropenia or in case of neutropenic complications, G-CSF may be 
given at the discretion of the investigator, if dose modification is not warranted. 
As of 10 September 2020, one patient (67 years, Female, ECOG PS=0 at baseline) who received 
amcenestrant 200 mg QD in combination with palbociclib 100 mg QD in TED14856 study (36) 
experienced Grade 2 serious COVID-19 infection during Cycle 6. The patient was asymptomatic 
with oxygen saturation of 98%, while Chest CT showed subpleural opacities in lower lobes. 
amcenestrant was continued without dose modifications, while palbociclib administration was 
omitted until the recovery of event. Palbociclib was resumed later and currently, the study 
participant is ongoing study treatment with amcenestrant and palbociclib (Cycle 11).  
2.3.2 Benefit assessment  
2.3.2.1 Benefits in the context of COVID-19  
The participants potentially eligible for this trial have locoregional recurrent or metastatic breast 
cancer. Based on the mechanism of action of amcenestrant and clinical data generated as 
monotherapy and in combination with palbociclib, there is the potential for benefit for these 
patients.  
2.3.3 Overall benefit/risk conclusion  
Overall, benefit-risk is deemed acceptable in patients with advanced breast cancer during COVID-
19 pandemic. Sponsor will continue to evaluate benefit-risk during the study period.  
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine whether amcenestrant in combination 
with palbociclib improves progression free survival 
(PFS) when compared with letrozole in combination 
with palbociclib in participants with ER+, HER2- 
advanced breast cancer who have not received 
prior systemic anticancer therapies for advanced 
disease 
• 
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 local 
radiologist/investigator or death (due to any cause), 
whichever comes first. 
Secondary 
 
• 
To compare the overall survival (OS) in both 
treatment arms [Key Secondary Objective] 
• 
Overall survival is defined as the time interval from 
the date of randomization to the date of 
documented death (due to any cause). [Key 
Secondary Endpoint] 
• 
To evaluate the objective response rate (ORR) in 
both treatment arms 
• 
ORR is defined as the proportion of participants 
who have a complete response (CR) or partial 
response (PR), as best overall response determined 
as per RECIST 1.1, from the date of randomization 
until disease progression, death, cutoff date, 
initiation of post-treatment anti-cancer therapy, 
whichever occurs first. 
• 
To evaluate the duration of response (DOR) in both 
treatment arms 
• 
DOR is defined as the time from first documented 
evidence of CR or PR until progressive disease 
(PD) as determined as per RECIST 1.1 or death 
from any cause, whichever occurs first. 
• 
To evaluate the clinical benefit rate (CBR) in both 
treatment arms 
• 
CBR is defined as the proportion of participants who 
have a confirmed CR, PR, or stable disease (SD) 
for at least 24 weeks determined as per RECIST 
1.1, from the date of randomization until disease 
progression, death, cutoff date, initiation of post 
treatment anti-cancer therapy, whichever occurs 
first. 
• 
To evaluate progression-free survival on next line of 
therapy (PFS2) 
• 
The PFS2 is defined as the time from the date of 
randomization to the date of first documentation of 
PD on the next systemic anti-cancer therapy 
according to investigator or death due to any cause 
in the absence of documented PD on the next 
systemic anti-cancer therapy, whichever occurs 
first. 
• 
To evaluate the pharmacokinetics (PK) of 
amcenestrant, and Palbociclib 
 
• 
Plasma concentrations of amcenestrant, palbociclib 
• 
To evaluate health-related quality of life (HRQL) in 
both treatment arms 
• 
Symptoms and function related to HRQL as 
measured by EORTC QLQ-C30, breast cancer 
specific module (QLQ-BR23/BR45) and EQ-5D-5L  
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• 
Disease-specific and generic HRQL, disease and 
treatment-related symptoms, the impact of 
symptoms and treatment, health state utility, and 
health status will be evaluated using the European 
Organization for Research and Treatment of Cancer 
(EORTC) core quality of life questionnaire (QLQ-
C30), the EORTC-QLQ breast cancer specific 
module (QLQ-BR23/BR45) 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 study treatment 
• 
To evaluate the time to first chemotherapy in both 
treatment arms 
• 
Time to chemotherapy is defined as the time 
interval from the date of randomization to the start 
date of the first chemotherapy after study treatment 
discontinuation 
• 
To evaluate safety in both treatment arms 
• 
Treatment emergent adverse events 
(TEAEs)/serious adverse events (SAEs) and 
laboratory abnormalities 
Exploratory 
 
• 
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). 
• 
Tumor ER, Ki67, Bcl-2, and PgR protein, and RNA 
gene expression profiles in paired biopsies at Cycle 
1 Day 1 (pre-treatment) and optional at end of 
treatment for participants who discontinued 
treatment due to disease progression 
• 
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. 
• 
The gene mutation profile of the tumor by cfDNA 
analysis over time (Cycle 1 Day 1 [pre-treatment], at 
Cycle 4 Day 1 predose (tumor assessment), and 
upon disease progression on treatment or EOT 
whichever comes first) 
• 
To evaluate exposure/response relationship of 
amcenestrant and palbociclib 
• 
PK of amcenestrant will be correlated with safety 
and/or efficacy 
• 
To evaluate the PK of goserelin 
• 
Plasma concentrations of goserelin 
• 
To evaluate PFS in participants expressing PIK3CA 
and ESR1 mutation in both treatment arms 
• 
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 local 
radiologist/investigator or death (due to any cause), 
whichever comes first. 
 
 
 
 
 
 
For China, please see Section 10.6 for details. 
Primary estimands defined for primary and key secondary efficacy endpoints are summarized in 
Table 2 below. More details are provided in Section 9.2. 
For both estimands, the comparison of interest will be the comparison of amcenestrant in 
combination with palbociclib versus letrozole in combination with palbociclib. The analysis 
population corresponds to all participants from the intent-to-treat population.     
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  Table 2 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level 
summary 
(Analysis and missing 
data handling) 
Primary objective: to determine whether amcenestrant in combination with palbociclib improves the progression free 
survival (PFS) when compared to letrozole in combination with palbociclib. 
Primary 
endpoint 
(Estimand 1) 
PFS 
ITT 
- Interruption/discontinuation of study 
intervention: PFS will be analyzed based 
on events irrespective of study 
intervention interruption/discontinuation 
(treatment policy strategy). 
- Start of new anti-cancer therapy prior to 
PFS event: PFS will be censored at the 
last evaluable tumor assessment prior to 
a new anti-cancer therapy is initiated 
(hypothetical strategy). 
- PFS event documented after two or 
more non-evaluable tumor assessments: 
PFS will be censored at the last evaluable 
tumor assessment prior to the event 
(hypothetical strategy). 
 
One-sided log-rank test 
stratified by randomization 
stratification factors, as entered 
in the IRT system. 
Hazard ratio (HR) and 
corresponding 95% CI 
estimated using stratified Cox 
proportional hazard model. 
The Kaplan Meier estimate of 
PFS at specified time points, 
PFS quartiles and 
corresponding 95% CI from 
Kaplan Meier method. 
Key secondary objective: to compare overall survival between two treatment arms. 
Key 
secondary 
endpoint 
(Estimand 2) 
OS 
ITT 
- Interruption/discontinuation of study 
intervention: OS will be analyzed based 
on events irrespective of study 
intervention interruption/discontinuation 
(treatment policy strategy). 
- Start of new anti-cancer therapy prior to 
death: OS will be analyzed based on 
events irrespective of start of new anti-
cancer therapy (treatment policy 
strategy). 
 
 
 
One-sided log-rank test 
stratified by randomization 
stratification factors, as entered 
in the IRT system. 
Hazard ratio (HR) and 
corresponding 95% CI 
estimated using stratified Cox 
proportional hazard model. 
The Kaplan Meier estimate of 
OS at specified time points, OS 
quartiles and corresponding 
95% CI from Kaplan Meier 
method. 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS   
Radiographic tumor assessments directly measure components of the disease, and tumor measures 
commonly trigger treatment decisions in clinical practice. Therefore, the tumor measure-based 
endpoint PFS is considered clinically relevant in our study. PALOMA-2 study showed 
a statistically significant PFS benefit in post-menopausal women with on ER+/HER2- breast 
cancer receiving palbociclib and letrozole when compared with letrozole alone. 
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Each of the secondary endpoints (efficacy, safety and QoL assessments) chosen for use in this 
study is considered well established and relevant in a breast cancer study setting. 
In addition, suitable steps have been built into each of these assessments to ensure their reliability 
and accuracy. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a prospective, multicenter, international, randomized, double-blind, double-dummy, 
Phase 3 trial comparing the efficacy and safety of amcenestrant in combination with palbociclib 
versus letrozole in combination with palbociclib in men, pre/peri-menopausal women (with 
goserelin) and postmenopausal women with ER(+)/HER2(-) breast cancer who have not received 
prior systemic treatment for advanced disease.  
Eligible participants should have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of either loco-regional recurrent or metastatic disease 
not amenable to radiation therapy or surgery with curative intention, and for whom chemotherapy 
is not indicated. 
The study will have 3 main periods: screening, active treatment, and follow up. After being 
screened, participants meeting the eligibility criteria will be randomly assigned using an IRT to 
either amcenestrant plus palbociclib (experimental) arm or letrozole plus palbociclib (control) arm 
in a 1:1 ratio.  
• Arm A: Amcenestrant 200 mg + letrozole-matching placebo + palbociclib 125 mg  
• Arm B: Amcenestrant-matching placebo + letrozole 2.5 mg + palbociclib 125 mg 
The study population will be stratified by: 
• De-novo metastatic disease (Yes or No) 
• Postmenopausal women (Yes or No) 
• Visceral metastasis defined by at least 1 liver, lung, brain metastasis, pleural, or peritoneal 
involvement (Yes or No). 
A BIRC assessment will be performed retrospectively on a sample of participants based on 
radiographic images and clinical information collected on-study. 
An independent DMC will monitor the safety data on a periodic basis. The DMC will also 
evaluate efficacy at the interim analyses and make a recommendation regarding study 
continuation based on observed results of the study. 
A Study Steering Committee will supervise the progress of the trial, review relevant information 
that may affect the study conduct as well as review DMC recommendations. 
4.1.1 Duration of the study period  
The duration of the study for each participant will include screening period of up to 28 days and 
active treatment period, for which the duration varies based on the progression date, followed by 
a follow-up period. The cycle duration for both arms is 28 days. 
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Study participants will continue to receive their assigned treatment until objective disease 
progression, unacceptable toxicity, participant’s request to stop treatment, or Investigator’s 
decision, whichever occurs first.  
After study treatment discontinuation, participants will return to the study site approximately 
30 days (+/- 5 days) (for EOT assessments) after the last IMP administration or before the start of 
another anti-cancer therapy, whichever is earlier. 
EOT visit will be followed by FU visits. During the FU visits, the participants will be monitored 
for all ongoing related AEs and all the SAEs (regardless of relationship) until resolution or 
stabilization (ie, an event ongoing without any change for at least 3 months).  
In participants who discontinue the study treatment without documented PD, the FU visits will be 
performed every 12 weeks until disease progression. In participants with documented PD, FU 
visits will be performed every 24 weeks. All study participants will be followed until death or 
final study cut-off date, whichever comes first. For cycles completed after the final analysis for 
PFS cut-off date, all ongoing SAEs (related or not), all related non-serious AEs ongoing at the 
cut-off date, and all new related AEs (serious or not) occurring post cut-off date will be followed 
until resolution or stabilization; as well as IMP administration, related concomitant medication, 
and reason for EOT will continue to be collected. 
The total estimated duration of enrollment will be approximately 18 months. 
The expected duration of treatment for participants who benefit from study intervention may vary, 
based on progression date; but median expected duration of study per participant is estimated as 
median 59 months in experimental arm (1 month for screening, 33 months for treatment, and 
25 months for the EOT and follow-up visits) and 47 months in control arm (1 month for 
screening, 25 months for treatment, and 21 months for the EOT and follow-up visits). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
See Section 2.1 Study Rationale. 
4.2.1 Participant input into design  
Not applicable. 
4.3 
JUSTIFICATION FOR DOSE  
 
A total of 6 patients, enrolled in the Part C of TED14856 study, assessed the dose escalation of 
two dose levels of amcenestrant (200 and 400 mg) in combination with a 125-mg fixed dose of 
palbociclib. 
Pharmacokinetics analysis did not show a major effect of palbociclib 125 mg on amcenestrant 
200 mg or 400 mg exposure after single or repeated administration compared to monotherapy 
exposure. Conversely, amcenestrant administered QD had shown a decrease of palbociclib 
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exposure, with an increase of the effect when increasing amcenestrant dose. When compared to 
PK historical published data of palbociclib given as single agent (or in combination with 
letrozole) (26, 27), exposure decreased on average by 23% when combined with 200 mg 
amcenestrant QD (N=8) and by 60% with 400 mg amcenestrant QD (N=5). Palbociclib clearance 
is mainly metabolic and showed a 32% decrease of exposure when combined with a moderate 
CYP3A inducer (Modafinil) (28). This extent of decrease was not considered as clinically relevant 
according to palbociclib labelling. Considering the facts that more than 90% of target engagement 
is shown by 18FES-PET inhibition from 150 mg and above for amcenestrant, and that a decrease 
of palbociclib around 23% can be considered as not clinically relevant, the dose of 200 mg of 
amcenestrant is proposed to assess the efficacy of the combination of amcenestrant with 125 mg 
of palbociclib. 
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 last scheduled procedure shown in the schedule of activities 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, or country's legal age of majority 
if the legal adult age is >18 years old at the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Participants with histological or cytological proven diagnosis of adenocarcinoma of the 
breast with evidence of either loco-regional recurrent or metastatic disease not amenable to 
radiation therapy or surgery in a curative intent, and for whom chemotherapy is not 
indicated.  
I 03. 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 04. Documentation on the most recently analyzed biopsy (either primary tumor or any 
metastatic site) of HER2 non over-expressing 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 (37). 
- 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 05. Participants previously untreated with any systemic anti-cancer therapy for their 
loco-regional recurrent or metastatic disease. 
I 06. Measurable disease ie, at least one measurable lesion evaluable per RECIST v.1.1, or non-
measurable bone only disease with at least one predominant lytic bone lesion without a 
measurable soft tissue component or mixed lytic-blastic lesion without a measurable soft 
tissue component must be present (criterion modified by amendment 03). 
I 07. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 (criterion 
modified by amendment 02). 
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I 08. Willingness and ability to provide tumor tissues [ie, archived formalin fixed paraffin 
embedded (FFPE) tissues]. If tumor tissue is not available, then a fresh biopsy will be 
required for patient participation.  
Weight (not applicable) 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 09. All   Male, or Female of any menopausal status (pre-, peri- or post-menopausal) are 
eligible. Post-menopausal status is defined in Section 10.4 (Appendix 4). Pre/peri-
menopausal women are those not meeting the criteria for being post-menopausal. 
It is recommended that men with no prior bilateral orchiectomy and pre/perimenopausal 
women are on a GnRH agonist for at least 4 weeks prior to randomization. If participants 
have received an alternative GnRH agonist prior to study entry, they must switch to 
goserelin for the duration of the trial (criterion modified by amendment 03).  
Informed Consent 
I 10. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
Other inclusions 
Not applicable. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participants with known active brain metastases (criterion modified by amendment 02).  
Participants with treated/stable brain metastases are eligible if they: 
- 
Have completed treatment (whole brain radiotherapy, radiosurgery, or combination)/ 
stable brain metastases for at least 4 weeks prior to start of study treatment, and 
- 
Have recovered from the effects of this treatment, and 
- 
Are neurologically stable 
- 
If receiving corticosteroid for central nervous system adverse events, the dose should 
be stable or decreasing over ≥2 weeks prior to first IMP. 
E 02. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of 
amcenestrant (SAR439859) and/or palbociclib. Participants with known active hepatitis A 
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(positive HA antigen or positive IgM); B (either positive HBs antigen or positive 
hepatitis B viral DNA test above the lower limit of detection of the assay); C (positive 
hepatitis C antibody result and quantitative hepatitis C (HCV) ribonucleic acid (RNA) 
results greater than the lower limits of detection of the assay) infection; hepatic cirrhosis. 
Participants unable to swallow normally and to take capsules or tablets. Predictable poor 
compliance to oral treatment. Active inflammatory bowel disease or chronic diarrhea, short 
bowel syndrome, or total gastric resection (criterion modified by amendment 03). 
E 03. Diagnosis of any other malignancy within 3 years prior to randomization. Adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer are allowed. 
E 04. Pregnant or nursing woman, or woman who intends to become pregnant during the study. 
Woman of childbearing potential (WOCBP) unwilling to prevent pregnancy using highly 
effective non-hormonal contraception during treatment, and for at least 12 weeks after 
discontinuation of any study intervention and/or WOCBP unwilling to be tested for 
pregnancy before study treatment, every 28 days during treatment, and for at least 
12 weeks after the last dose of any study intervention. 
 
Note: WOCBP is a woman who is considered fertile following menarche and until 
becoming post-menopausal, unless permanently sterile. 
E 05. Male participants who disagree to practice true abstinence or disagree to use a condom 
during sexual contact with a pregnant woman or a WOCBP while participating in the 
study, and for at least 14 weeks after the last dose of any study intervention. 
 
Note: True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, and 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
E 06. Participants with unrecovered acute toxic effects of prior anti-cancer therapy or surgical 
procedures of NCI CTCAE version 5.0 Grade >1 (except alopecia or other toxicities not 
considered a safety risk for the participant at investigator's discretion, eg, 3-month stable 
Grade 2 peripheral neuropathy), or with Pneumonitis, and Interstitial Lung Disease (ILD). 
E 07. Participants with advanced, symptomatic visceral spread, that are at risk of life-threatening 
complications in the short term (including participants with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis, leptomeningeal carcinomatosis, 
and over 50% liver involvement). 
E 08. 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 09. Participants with abnormal coagulation profiles, or any history of coagulopathy within 
6 months prior to the first dose of IMP, including history of deep vein thrombosis (DVT) 
or pulmonary embolism. However, participants (except pre/perimenopausal women and 
male participants) with adequately treated catheter-related venous thrombosis occurring 
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more than one month prior to the first dose of IMP will be allowed to participate (criterion 
modified by amendment 02). 
E 10. 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. However, participants (except pre/perimenopausal women and 
male participants) being treated with an anticoagulant for a stable and allowed medical 
condition (eg, well controlled atrial fibrillation), provided dose and coagulation parameters 
(as defined by local standard of care) are stable for at least one month prior to the first dose 
of study drug will be allowed to participate 
Prior/concomitant therapy 
E 11. Ongoing treatment with drugs that are sensitive substrates of OATP1B1/B3 (asunaprevir, 
atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, 
pravastatin, repaglinide, rosuvastatin and simvastatin acid) (criterion modified by 
amendment 04).  
NOTE: Refer to FDA website: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table5-1  
E 12. Treatment with strong CYP3A inhibitors and strong CYP3A inducers within 2 weeks 
before first study treatment administration or 5 elimination half-lives whichever is longest 
and cannot be replaced (criterion modified by amendment 03). 
E 13. Criterion removed in amendment 03.  
E 14. Treatment with drugs that have the potential to inhibit UGT (uridine 5'-diphospho-
glucuronosyltransferase), including, but not limited, to atazanavir and probenecid, within 
2 weeks before study treatment administration or 5 elimination half-lives whichever is 
longest and which cannot be replaced. 
E 15. Medical conditions requiring concomitant administration of medications with a narrow 
therapeutic window metabolized by CYP3A (and for which a dose reduction cannot be 
considered. 
E 16. Disease recurrence while on, or within 12 months of completion of (neo)adjuvant 
endocrine therapy with any of the following agents: (criterion modified by amendment 03) 
- 
Aromatase inhibitor - eg, letrozole, anastrozole, exemestane. 
- 
Selective estrogen receptor modulator - eg, tamoxifen, toremifene, raloxifene 
- 
CDK4/6 inhibitors - eg, palbociclib, ribociclib, abemaciclib.  
E 17. Prior (neo)adjuvant treatment with another selective ER down-regulator (SERD). 
E 18. Major surgery or radiotherapy within 4 weeks before randomization.  
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Participants who received prior radiotherapy to ≥25% of bone marrow are not eligible 
independent of when it was received. 
 
E 19. Drugs that are known to prolong the QT interval (premenopausal and male participants 
Prior/concurrent clinical study experience 
E 20. Participation within 4 weeks before randomization in any other clinical study involving an 
investigational study treatment including anti-cancer agents or within 2 weeks before 
randomization for any other type of medical research. 
Diagnostic assessments 
E 21. Inadequate hematological function including: 
- 
Neutrophils <1.5 × 109/L 
- 
Platelet count <100 × 109/L 
E 22. Inadequate renal function estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m² 
as estimated using the abbreviated Modification of Diet in Renal Disease formula 
(see Section 10.12). 
E 23. Inadequate liver function defined as: 
- 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 × ULN 
(>5.0 × ULN if liver metastases present) 
- 
Alkaline phosphatase (ALP) >2.5 × ULN (>5.0 × ULN if bone or liver metastases 
present) 
- 
Total bilirubin >1.5 × ULN (>3.0 × ULN if Gilbert’s disease). 
Other exclusions 
E 24. Known hypersensitivity/contraindicated to goserelin (men and pre/perimenopausal 
participants), palbociclib, letrozole, or any of their excipients, or to any amcenestrant 
(SAR439859) and placebo excipients. 
E 25. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 26. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 27. Any specific situation during study implementation/course that may raise ethics 
considerations, including participants that are dependent on the Sponsor or Investigator (in 
conjunction with Section 1.61 of the ICH-GCP Ordinance E6) (criterion modified by 
amendment 04). 
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E 28. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 29. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 6 (Section 10.6) (country specific requirements). 
 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
Participants are to refrain from consumption of grapefruit, grapefruit hybrids, or products 
containing the juice of each during the study treatment period. 
5.3.2 Activity (Sun Protection)  
Preclinical toxicity studies using amcenestrant indicate a potential risk for phototoxicity; in 
addition, 1 participant from Part A 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 amcenestrant (SAR439859)/amcenestrant 
(SAR439859)-matching placebo dose. It is recommended to advise to wear protective clothing, lip 
balm, and broad-spectrum sunscreen with a high sun protection factor (eg, ≥30) to cover UVA 
and UVB light exposure when outdoors with frequent re-application as necessary. 
5.3.3 Osteoporosis  
Due to anti-estrogenic properties of amcenestrant, and letrozole being a potent estrogen lowering 
agent, 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. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once only. Participants who are rescreened are required to sign a new informed 
consent form, and should be assigned a new study participant number, and all the screening 
procedures should be repeated and entered in the screening visit pages. In case the participant is a 
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temporary screen failure, there is no need to have participant reconsent (ie, new ICF signed) if the 
participant finally participates in the trial. However, if the reason for temporary screen failure is a 
reason that might have altered the initial given agreement of the participant to participate, the 
Investigator should ensure the willingness of the participant to continue or redo some screening 
procedures and his/her participation to the trial. This oral agreement should be documented in the 
participant’s chart. All the tests out of protocol window should be repeated and entered to the 
additional pages.  
5.5 
CRITERIA FOR TEMPORARILY DELAYING 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 10.15 (Appendix 15) 
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), or 
placebo, intended to be administered to a study participant according to the study protocol.  
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
The study interventions (amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching 
placebo, palbociclib, and letrozole/letrozole-matching placebo, goserelin) will be administered as 
a flat-fixed dose, and not by body weight or body surface area. All study IMPs must be taken with 
food, either together or 5 minutes apart, regardless of the order of intake, at approximately the 
same time each day, whenever possible (Table 3). 
Participants will receive study drug diaries for amcenestrant (SAR439859)/amcenestrant 
(SAR439859)-matching placebo, palbociclib, and letrozole/letrozole-matching placebo to 
document study intervention intake, and the completed study drug diaries should be returned to 
the study site at the subsequent study visit.  
Any doses of study intervention that are not taken within 6 hours of the intended time should be 
considered as missed dose. If the participant misses a dose of study intervention, a double dose 
should not be taken the next day to compensate the missed dose. If the participant vomits a dose 
of study intervention, an additional dose should not be taken, and this information has to be 
recorded in the study medication diary. The next prescribed dose should be taken at the usual 
time. 
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Table 3 - Overview of Study intervention(s) administered  
Intervention label 
Amcenestrant (SAR439859) 
Amcenestrant (SAR439859) 
Placebo 
Palbociclib 
Letrozole 
Letrozole Placebo 
Goserelin 
Intervention name 
Amcenestrant 
(SAR439859) 
Amcenestrant 
(SAR439859)-matching 
Placebo 
Palbociclib 
Letrozole 
Letrozole-matching 
Placebo 
Goserelin 
Intervention 
description 
200 mg Tablet PO OD 
Placebo Tablet PO OD 
75 mg, 100 mg, or 125 mg 
Tablet/Capsule PO OD 
2.5 mg Capsule PO OD 
Placebo Capsule PO OD 
3.6 mg subq OD 
Type 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Dose formulation 
Tablets 
Tablets 
Capsules then Tablets 
Capsules 
Capsules 
In accordance with the 
approved label 
Unit dose 
strength(s) 
200 mg 
- 
75 mg, 100 mg, 125 mg 
2.5 mg 
- 
3.6 mg 
Dosage level(s) 
200 mg once daily, 
continuously 
- 
75 mg, 100 mg, 125 mg D1-
D21 every 28 days 
2.5 mg once daily, 
continuously 
- 
3.6 mg once every 28 
days 
Route of 
administration 
Oral 
Oral 
Oral 
Oral 
Oral 
Subcutaneous 
Use 
Amcenestrant (SAR439859) 
active experimental   
Amcenestrant (SAR439859) 
matching placebo 
Palbociclib active 
comparator 
Letrozole active 
comparator  
Letrozole matching 
placebo  
Goserelin active 
comparator  
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
IMP 
NIMP 
Packaging and 
labeling 
Amcenestrant (SAR439859) 
active study intervention will 
be provided in blisters 
containing tablets. Labelling 
will be as required per 
country requirement 
Amcenestrant (SAR439859) 
placebo study intervention 
will be provided in blisters 
containing tablets. Labelling 
will be as required per 
country requirement 
Palbociclib active 
comparator will be provided 
in blisters containing caps 
and then switch during the 
trial to blisters containing 
tablets. Labelling will be as 
required per country 
requirement 
Letrozole active 
comparator will be 
provided in blisters 
containing capsules. 
Labelling will be as 
required per country 
requirement 
Letrozole matching 
placebo will be provided in 
blisters containing 
capsules. Labelling will be 
as required per country 
requirement 
Goserelin active 
intervention for 
subcutaneous 
administration will be 
packaged in accordance 
with the approved label. 
[Current/former 
name(s) or 
alias(es)] 
Amcenestrant (SAR439859) 
Amcenestrant (SAR439859) 
Ibrance 
Letrozole 
Letrozole 
Zoladex 
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Between the protocol-scheduled on-site visits, interim visits may be required for study 
intervention dispensing. As an alternative to these visits, study intervention may be supplied from 
the PI/site to the participant via a Sponsor-approved courier company where allowed by local 
regulations and agreed up on by the participant. 
6.1.1 Amcenestrant (SAR439859)/Amcenestrant (SAR439859)-matching placebo  
Amcenestrant (SAR439859)/Amcenestrant (SAR439859)-matching placebo will be administered 
orally at a dose of 200 mg once daily continuously and at approximately the same time each day 
(±3 hours), together with palbociclib.  
The assigned daily dose is to be taken once in the morning, with food, at approximately the same 
time each day (±3 hours), throughout treatment cycles. The daily dose of amcenestrant 
(SAR439859) tablets is to be swallowed whole with a glass of noncarbonated water and a second 
glass of water is to be used to rinse out the mouth (for a total of approximately 240 mL). Study 
participants should be instructed not to bite or chew on the tablets.  
On days of PK assessment, amcenestrant (SAR439859)/ amcenestrant (SAR439859)-matching 
placebo and palbociclib will be taken together. On other days, they can be taken either together or 
5 minutes apart, regardless of the order of intake.  
6.1.2 Letrozole/Letrozole-matching placebo  
Letrozole/Letrozole-matching placebo will be administered orally at a dose of 2.5 mg once daily 
continuously together with palbociclib.  
Letrozole/Letrozole-matching placebo should be taken with food and should be swallowed whole 
with a glass of water or another liquid.  
Letrozole/letrozole-matching-matching placebo and palbociclib can be taken either together or 
5 minutes apart, regardless of the order of intake.  
Refer to the Letrozole Summary of Product Characteristics for additional administration 
instructions.  
6.1.3 Palbociclib  
Palbociclib will be administered orally at a dose of 125 mg once daily for 21 consecutive days 
followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib (regardless 
of the administered formulation) should be taken with food at approximately the same time each 
day. Only a single strength of palbociclib capsules/tablets will be dispensed to the patient prior to 
each cycle. In case of dose modification, participants should return the previously dispensed 
palbociclib before dispensing new capsules/tablets.  
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Palbociclib capsules/tablets should be swallowed whole (not chewed, crushed or opened prior to 
swallowing). Capsules/tablets should not be ingested if they are broken, cracked, or otherwise not 
intact. The capsules/tablets should be swallowed with a full glass of water (not fruit juices). Refer 
to the Palbociclib Summary of Product Characteristics for additional administration instructions. 
Study will be initiated with palbociclib capsules and will be switched to palbociclib tablets as they 
become commercially available.  
6.1.4 Goserelin  
Goserelin will be administered as an injectable subcutaneous implant on Day 1 of every 28-day 
cycle at a dose of 3.6 mg in pre/peri-menopausal women and men. Refer to the Goserelin 
Summary of Product Characteristics for additional administration instructions. 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).  
Partially used and used study treatments will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
treatment 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/NIMP unless Sanofi provides written 
authorization. Further guidance and information for the final disposition of used and unused study 
medications are provided in the pharmacy manual and/or monitoring plan.  
Any quality issue noticed with the receipt or use of an IMP/NIMP (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 8.3.8). 
A potential defect in the quality of IMP/NIMP may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party, allow the 
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IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner except for DTP shipment, for which a courier company has been 
approved by the Sponsor.  
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
• The randomized intervention kit number list is generated centrally by Sanofi. 
• The IMPs are packaged in accordance with this list. 
• The randomization and IMP allocation are performed centrally by 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. Details of the IRT procedure will be provided in the IRT Site Manual. 
 
WARNING: Randomization will not be possible if study treatment is not available at site. 
Please consider up to 11 days between screening call and arrival of IMP on site. 
• The randomization is stratified by De-novo metastatic disease (Yes or No), 
Postmenopausal women (Yes or No), and Visceral metastasis defined by at least 1 liver, 
lung, brain metastasis, pleural, or peritoneal involvement (Yes or No). 
• A participant cannot be randomized more than once in the study.  
Risk related to blinding 
This is a double-blind, double dummy study. Participants will be randomly assigned in a [1:1] 
ratio to receive study intervention. Study participants, Investigators, Study sponsor (except 
bioanalysts assessing PK samples) and all stakeholders (except DMC and independent statistician) 
involved in study conduct will remain blinded to each participant’s assigned study intervention 
throughout the course of the study.  
Investigator has the sole responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. In case of an AE/SAE, the code can be broken only in exceptional 
circumstances when knowledge of the study IMP is essential for treating the study participant. If 
the Investigator decides that unblinding is warranted, the Investigator should make every effort to 
contact the Sponsor prior to unblinding a participant’s intervention assignment unless this could 
delay emergency treatment of the participant. The IRT will be programmed with blind-breaking 
instructions. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable.  
If the code is broken, the participant must withdraw from IMP administration. 
Methods of blinding 
• Blinding is done using the double-dummy method.  
• IMPs (amcenestrant (SAR439859), Letrozole) and their matching-placebo will be supplied 
in indistinguishable boxes. 
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• During the study, an external independent statistician will perform unblinded safety and 
efficacy analyses for the data review of Data Monitoring Committee (DMC). Access to 
these data and analyses will be restricted to the DMC members. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP/NIMP will be supervised by the Investigator or Sub-investigator.  
The person responsible for drug dispensing is required to maintain adequate records of the 
IMP/NIMPs. These records (eg, drug movement form) include the date the IMP/NIMPs are 
received from the Sponsor, dispensed to the participant and destroyed or returned to the Sponsor. 
The packaging batch number (IP number) and the treatment number on the IMP/NIMP package 
must be recorded on the drug accountability form.   
A record of the number of amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching 
placebo, letrozole/letrozole-matching placebo, palbociclib capsules/tablets, and goserelin 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records.  
On Day 1 of a given cycle, when participants are dispensed with study interventions at the site, 
they will receive study intervention directly from the Investigator or designee, under medical 
supervision. On days when there are no on-site visits, study participants will take the study IMP(s) 
at home. The study staff will demonstrate to the patient how to record information on study 
IMP(s) intake in study medication diary. Study participants will have to complete the study 
medication diary on days when study IMP(s) are omitted and on days prior to PK sampling (time 
of IMP(s) intake, fasting state, vomiting if any), and the completed study medication diary should 
be returned to study site at subsequent site visit. In case of an early vomiting event, the 
administered dose of study IMP(s) should not be repeated. 
When participants take study medication(s) at home, compliance with study intervention will be 
assessed using study medication diaries and study medical record (study source documentation). 
Compliance will also be assessed either by direct questioning, or counting returned 
tablets/capsules, during the site visits and documented in the source documents and clinical 
database.  
Study participants will be requested to return all unused study interventions to the study site at the 
end of the treatment period for each cycle for a full compliance assessment. Site staff will record 
the study intervention dosing information including start and stop dates, including dates for IMP 
omissions and/or dose reductions in the patient chart and then in to the clinical database. 
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6.5 
DOSE MODIFICATION  
Dose modifications are permitted in case of study-treatment related toxicity, and dose could be 
modified based on the following guidelines:  
• Omission of one or more doses until the adequate recovery of toxicity. If a TEAE lead to 
dose omissions, restart of study IMP(s) could occur either within the same cycle or only up 
on the initiation of the subsequent cycle (see Section 10.7, Appendix 7). Doses omitted for 
toxicity should not be replaced.  
• Dose reduction during the current cycle, or during subsequent cycle because of the toxicity 
experienced during previous cycle. This is applicable only to palbociclib, as dose 
adjustment for amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo 
and letrozole/letrozole-matching placebo is managed via dose omission instead of 
continuation at a reduced dose. 
• Delay in the start of subsequent cycle (ie, none of the IMP taken) due to persisting 
toxicities attributed to all IMPs 
Every effort should be made to administer the full planned dose in accordance with treatment 
schedule.  
In case of treatment-related toxicity, dose modifications should be made according to the 
Appendix 7 (Section 10.7). Dose adjustments will be made according to the worst grade of 
adverse event observed within a cycle. If a participant experiences several adverse events and 
there are conflicting recommendations, the most conservative dose adjustment recommended 
should be followed. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation. In case of recurrent adverse events with severity of Grade ≥3, dose 
modification of study IMP(s) is required. Please refer to Appendix 7 (Section 10.7) for details. 
In case of more than 2 weeks without any IMP intake for reasons other than treatment-related 
toxicity, study intervention can be resumed only after discussions with study sponsor. 
6.5.1 amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo  
No dose reduction of amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo 
is permitted, dose adjustment in case of treatment-related toxicity is managed by dose omission of 
amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo.  
In case of hematological toxicities, no dose adjustment of amcenestrant 
(SAR439859)/amcenestrant (SAR439859)-matching placebo is required. Dose modification 
guidelines for amcenestrant (SAR439859)/amcenestrant (SAR439859)-matching placebo in case 
of non-hematological toxicities could be found in Appendix 7 (Section 10.7). 
Participants with definitive discontinuation of amcenestrant (SAR439859)/amcenestrant 
(SAR439859)-matching placebo due to treatment-related toxicity are not allowed to continue with 
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palbociclib alone, will be discontinued from the study treatment and will enter the follow-up 
phase. 
6.5.2 Palbociclib  
Dose modification (omissions/reduction) are allowed for palbociclib in case of treatment-related 
toxicity. In case of dose reduction, palbociclib will be administered as shown in Table 4.  
Table 4 - Dose levels for palbociclib dose reduction  
Starting dose 
125 mg/day 
Dose Level -1  
100 mg/day 
Dose Level -2 
75 mg/daya 
a If further dose reduction below 75 mg/day is required, palbociclib will be permanently discontinued. 
Once palbociclib dose has been reduced, re-escalation back to the previous dose level is not 
allowed. Dose reduction could occur during the current cycle or during the initiation of the next 
cycle. Dose reduction occurring during the current cycle requires that participants should return to 
study site for new supply of palbociclib. 
If palbociclib is definitively discontinued because of treatment-related toxicity, participants may 
continue as per investigator’s discretion on the active treatment phase of the study receiving 
letrozole plus amcenestrant (SAR439859)-matching placebo or amcenestrant (SAR439859) plus 
letrozole-matching placebo.  
Participants should be monitored for any new or worsening of respiratory symptoms and be 
advised to report such symptoms promptly. If participants show any signs or symptoms of 
suspecting interstitial lung disease (ILD)/Pneumonitis (eg, symptoms, such as hypoxia, cough, 
dyspnea), treatment with palbociclib should immediately be omitted, and appropriate diagnosis 
testing should be initiated as well as appropriate treatment if judged necessary by the investigator. 
If participants are diagnosed with ILD/pneumonitis, palbociclib should be permanently 
discontinued (see Section 10.7, Appendix 7). 
6.5.3 Letrozole/Letrozole-matching Placebo  
No dose reduction of letrozole/letrozole-matching placebo is permitted, dose adjustment in case of 
treatment-related toxicity is managed by dose omission of letrozole/letrozole-matching placebo. 
In case of hematological toxicities, no dose adjustment of letrozole/letrozole -matching placebo is 
required. Dose modification guidelines for letrozole/letrozole-matching placebo in case of 
non-hematological toxicities could be found in Appendix 7 (Section 10.7). 
Participants with definitive discontinuation of letrozole/letrozole-matching placebo due to 
treatment-related toxicity are not allowed to continue with palbociclib alone, will be discontinued 
from the study treatment and will enter the follow-up phase. 
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6.5.4 Retreatment criteria  
Retreatment criteria after recovery of the toxicity are described below:  
• Hematological toxicity (applicable only to Palbociclib): National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 Grade ≤2 or to their 
baseline status. 
• Non-hematological toxicity: NCI-CTCAE v5 Grade ≤1 or Grade ≤2 (if not considered 
a safety risk for the patient) or to their baseline status. 
Start of new cycle or restart of study intervention after dose omission occurs only when the above 
criteria are met, and study intervention is administered.  
If these criteria are not met on the scheduled Day 1, the start of the next cycle should be delayed 
until participants recover as defined above. If Day 1 delay is more than 3 days, the reason for 
delay (eg, adverse event) should be documented in eCRF. If retreatment criteria are not met, 
despite 2 weeks of cycle delay, permanent discontinuation of study treatment should be 
considered, unless there is strong evidence of clinical benefit (per investigator’s decision) to 
justify continuation of study intervention. 
If within a cycle, these criteria are not met after dose omission lasting more than 2 consecutive 
weeks, permanent discontinuation of the IMP and/or the study treatment should be considered, 
unless there is strong evidence of clinical benefit (per investigator’s decision) to justify 
continuation of study intervention. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There is no intervention following the end of the study. Additional care provided to participants 
after the completion of the study is based on routine clinical practice. 
6.7 
TREATMENT OF OVERDOSE  
In the event of an overdose, the investigator should: 
1. Contact the Sponsor or Sponsor representative(s)immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor or Sponsor representative(s)based on the clinical evaluation of the 
participant. 
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6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
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 
The Sponsor or Sponsor representative(s)should be contacted if there are any questions regarding 
concomitant or prior therapy. 
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. 
Any medication considered necessary for the patient’s welfare and are unlikely to interfere with 
the IMP may be given at the discretion of the investigator and recorded in the e-CRF. 
Concomitant medication will be recorded in the eCRF from 28 days prior to the first study 
intervention administration, any time during the study treatment period, and for up to 30 days 
after the final dose of study intervention. Once the participant has withdrawn from study 
treatment, concomitant medication should only be recorded if used to treat new or unresolved 
study treatment-related adverse events. 
The following therapies are prohibited throughout the active treatment phase:  
• Concurrent radiotherapy (except palliative radiotherapy) or cancer-related surgery.  
• Palliative radiotherapy in the only evaluable lesions. The irradiated area cannot be used as 
a parameter for response assessment. Participants requiring any of these procedures will be 
discontinued from the active treatment phase and will enter the follow-up phase. 
Participants should have a tumor assessment of the lesion(s) before receiving radiotherapy. 
• Additional investigational or commercial anticancer agents such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy 
other than study medication.  
• Herbal medications and food supplements including St John’s Worth and genistein during 
treatment period since they could decrease amcenestrant (SAR439859) exposure.  
• Drugs that are strong inducers of CYP3A since they may decrease amcenestrant 
(SAR439859) and/or palbociclib exposure. (See Section 10.10 [Appendix 10]) 
• Drugs that have UGT (uridine 5'-diphospho-glucuronosyltransferase) inhibition potential 
and are contra-indicated with UGT substrates, including but not limited to atazanavir and 
probenecid, since amcenestrant (SAR439859) is substrate of UGT1A1 and UGT1A4. 
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• 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. 
• Strong CYP3A inhibitors, since they can increase palbociclib exposure (See Section 10.9 
[Appendix 9]). 
• Medications with narrow therapeutic window metabolized by CYP3A (See Section 10.16 
[Appendix 16]) and for which a dose reduction cannot be considered, since their exposure 
can be increased by palbociclib. 
• In premenopausal women and men, medications that are known to prolong the QT interval 
(see Section 10.14 [Appendix 14]). 
Special caution should be taken with regards to the following therapies: 
• The concomitant use of drugs that are sensitive substrates of CYP3A4, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19 or UGTs since it may result in loss of efficacy of these 
agents. Substitute for these medications or monitor study participants for loss of efficacy if 
use of these medications. (See Section 10.11 [Appendix 11]). 
The following concomitant treatments are permitted during this study: 
• Bisphosphonates and denosumab for the treatment of osteoporosis or management of 
existing bone metastases may be continued for participants who have been receiving them 
at a stable dose for at least 2 weeks prior to randomization. However, the need to initiate 
or increase the dose of these therapies during the study will be considered as indicative of 
disease progression leading to the discontinuation of participant from the active treatment 
phase unless disease progression can be completely ruled out and the exact reason for the 
use of these therapies clearly documented in the participant’s source documentation.  
• At study entry, bone-targeted agents such as bisphosphonates or denosumab is 
recommended in study participants with bone mineral density T score of <-2 or with ≥2 
risk factors for fracture per ESMO clinical practice guidelines on bone health in cancer 
(38). 
• Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic use 
of granulocyte-colony stimulating factors is not permitted but they may be used to treat 
treatment-emergent neutropenia as indicated by the current ASCO guideline. If 
neutropenic complications are observed in a cycle in which primary prophylaxis with 
CSFs was not received, secondary prophylaxis may be given at the discretion of the 
investigator, but only if dose reduction or delay are not considered a reasonable 
alternative.  
• Erythropoietin may be used at the investigator's discretion for the supportive treatment of 
anemia. 
• In case of severe anemia, blood transfusion is permitted as per investigator’s judgment. 
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• Palliative radiotherapy may be given for control of bone pain or for lytic lesions at risk of 
fracture, provided that the lesions were present at study entry. 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. If palliative radiotherapy is initiated after start of study 
treatment, the reason for its use must be clearly documented and disease progression 
should be ruled out. Participants should have a tumor assessment of the lesion(s) before 
receiving radiotherapy. 
• Standard therapies for pre-existing medical conditions, medical complications, and 
palliation. Any medications used for supportive care in routine clinical practice 
(eg, analgesics, antidiarrheals, antiemetics) may also be used at the investigator’s 
discretion. All medications should be recorded. 
• Live vaccines should be avoided. However, given the increased risk of infection with 
palbociclib, routine vaccinations are recommended for the patients and their contacts. 
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. 
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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 10.1.9). 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
Pregnancy of female participant will lead to definitive discontinuation of study intervention in all 
cases. 
7.1.1 Permanent discontinuation  
The study intervention should be continued until the objective progressive disease whenever 
possible. Participants can withdraw their participation at any time during the study. The 
investigator has the right to remove any participant (eg, Poor compliance to the protocol, 
intercurrent illness that prevents further administration of study treatment) from study. Any study 
intervention discontinuation must be fully documented in the e-CRF. 
Study intervention should be discontinued in below circumstances: 
• disease progression,  
• unacceptable adverse event (refer to Section 10.7 [Appendix 7] for some of the adverse 
events leading to definitive/premature discontinuation of study intervention), 
• poor compliance to the study protocol 
• other such as concurrent illness, that prevents further administration of study intervention. 
If participants are clinically stable, and possibly deriving clinical benefit from therapy with 
minimal toxicity, they can continue the study intervention until disease progression, unacceptable 
toxicity, participant’s request to stop treatment, or investigator’s decision. However, participants 
may continue treatment as assigned at randomization beyond the time of RECIST-defined disease 
progression at the discretion of the investigator if that is in the best interest of the participant and 
as long as no new anticancer treatment is initiated. In these cases, the Investigator must discuss 
the rationale with the Sponsor before the decision to continue treatment on-study is made. 
If study intervention is permanently discontinued because of reasons other than documented PD, 
the participant will remain in the study for tumor assessment until documented progressive 
disease or final PFS analysis cut-off date and will be followed for survival status until OS cut-off 
date. In case of documented PD being the reason for definitive treatment discontinuation, 
participants will be followed for survival status until OS cut-off date.  
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
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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. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Not applicable. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
The following describes the criteria for withdrawal of participants from the study: 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an end of treatment visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• The participant who withdraws from the study will be permanently discontinued both from 
the study intervention and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study for 
the follow up visits. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the e-
CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
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In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, 
medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
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, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether 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. 
• 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, imaging) and obtained before signing of the ICF may be utilized for screening 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1 
EFFICACY ASSESSMENTS   
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
Primary criteria 
The primary endpoint is Progression-free survival (PFS) 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 local radiologist/investigator or 
death (due to any cause), whichever comes first. 
Secondary criteria 
The key secondary endpoint is Overall survival (OS), defined as the time interval from the date of 
randomization to the date of documented death (due to any cause). 
The other secondary endpoints related to efficacy are objective response rate (ORR), clinical 
benefit rate (CBR), and the duration of response (DoR). 
Assessments 
Participants may have measurable disease as per RECIST v.1.1, or non-measurable bone only 
disease with at least one predominant lytic bone lesion or mixed lytic-blastic lesion. 
The schedule of tumor assessments should be fixed according to the calendar, regardless of 
treatment delays/interruptions. Imaging assessments are to be scheduled using the randomization 
date as the reference date for all time-points and are NOT to be scheduled based on the date of the 
previous imaging time-point. Imaging assessment delay to conform to treatment delay is not 
permitted. The same tumor assessment technique MUST be used throughout the study for a given 
lesion/patient. 
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Baseline scans performed before the signing of informed consent as routine procedures (but 
within the protocol defined timeframe) do not need to be repeated and may be used as baseline 
assessments as long as tests were performed using the method requirements outlined in 
RECIST v.1.1. 
Tumor assessments using CT/MRI Scans (with contrast agent) of chest, abdomen, pelvis, any 
clinically indicated sites of disease, bone lesions, and clinical evaluation of superficial disease will 
be performed within 4 weeks (ie, 28 days) prior to randomization, followed by every 12 weeks 
(±7 days) from the date of randomization until documented progressive disease or final PFS 
analysis cut-off date, and at EOT (to be done if it falls within the 12 weeks ±7 days time window 
from randomization, and only in participants without PD as per RECIST 1.1). If no PD as per 
RECIST 1.1 at EOT, disease assessment will continue to be performed every 12 weeks ±7 days up 
to documented PD as per RECIST v.1.1, or final PFS COD, whichever occurs first. 
If signs and symptoms suggest presence of metastatic brain disease, brain scans (CT/MRI) are 
required at baseline (within 6 weeks prior to randomization). Post-baseline, brain scans are to be 
repeated only if metastases are present at baseline. 
Whole body radionuclide bone scans should be performed at baseline (within 12 weeks prior to 
randomization). Any suspicious abnormalities (ie, hotspots) identified on bone scans at baseline 
and on subsequent bone scans MUST be confirmed either by X-ray, CT scan with bone windows 
or MRI. If bone lesions are identified at baseline, radionuclide bone scans should be repeated 
every 24 weeks (±7 days) from the date of randomization for the first 18 months, and then every 
12 weeks (±7 days) until documented progressive disease or final PFS analysis cut-off date, and at 
EOT (to be done if it falls within the 12 weeks ±7 days time window from randomization, only in 
participants without documented PD as per RECIST 1.1 and no bone lesions identified at 
baseline). If no PD as per RECIST 1.1 at EOT, disease assessment will continue to be performed 
from randomization date as reference in participants with bone lesions identified at baseline, up to 
documented PD as per RECIST v.1.1, or final PFS COD, whichever occurs first. During follow-
up period, radionuclide whole body bone scan should be performed at the same frequency as done 
during treatment period. 
In addition to the investigators’ tumor assessment, radiographic (and photographical when 
applicable) images and clinical information collected on-study will also be reviewed by a blinded 
independent review committee, in order to verify investigator-reported tumor assessments. For 
this purpose, the tumor assessment images should be transferred to the blinded independent 
review committee for tumor response evaluation. 
Participants who discontinue the study treatment without documented PD will be followed every 
12 weeks (±7 days) from randomization until progressive disease as per RECIST 1.1 or final PFS 
analysis cut-off date (COD), whichever occurs first.  
In participants with documented disease progression, follow-up visits will be performed every 
24 weeks (±7 days) from the last dose of study intervention for survival status and collection of 
data on post-study anti-cancer therapies (start/stop dates, date of PD) and their responses, until 
death or until the OS cutoff date, whichever comes first. 
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8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than adverse events which are presented in  
Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of skin, head & 
neck, eyes, ear, nose, throat, thyroid, breast & regional lymph nodes, and organ systems 
such as cardiovascular, respiratory, gastrointestinal, musculoskeletal and neurological 
systems. Height (only at screening) and weight will also be measured and recorded. 
• Clinical evaluation of superficial disease at the time of tumor assessments which will 
include color photography of all superficial metastatic 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 metric ruler to estimate the size of the lesion is suggested. When 
lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study. All 
lesion measurements must be recorded in the eCRF.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
• Any new finding or worsening of previous finding should be reported as a new adverse 
event 
8.2.2 Vital signs  
• Temperature, pulse rate, and blood pressure will be assessed. Blood pressure and pulse 
measurements will be assessed with a completely automated device, and those 
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (eg, television, cell phones). Manual techniques will be used 
only if an automated device is not available. 
• Vital signs abnormalities are to be recorded as adverse events only if they are symptomatic 
and/or requiring corrective treatment and/or leading to treatment discontinuation and/or 
dose modification and/or fulfilling a seriousness criterion (see Section 10.3 [Appendix 3]). 
8.2.3 Electrocardiograms  
• Triplicate12-lead electrocardiogram (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. Triplicate ECGs are collected within about a 
five-minute window at a nominal time-point. 
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• ECG abnormalities are to be recorded as adverse events only if they are symptomatic 
and/or requiring corrective treatment and/or leading to treatment discontinuation and/or 
dose modification and/or fulfilling a seriousness criterion (see Section 10.3 [Appendix 3]). 
8.2.4 Clinical safety laboratory tests  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (see Section 1.3) for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study. The laboratory reports must be 
filed with the source documents. Clinically significant abnormal laboratory findings are 
those which are not associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. Laboratory 
abnormalities are to be recorded as adverse events only if they lead to treatment 
discontinuation and/or dose modification and/or fulfill a seriousness criterion and/or are 
defined as an AESI (see Section 10.3 [Appendix 3])  
• All laboratory tests with values considered clinically significantly abnormal (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 or are no longer considered 
clinically significant by the Investigator or Sponsor or Sponsor representative(s). 
- 
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. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA  
(Section 1.3).  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the e-CRF.  
8.2.5 Guideline for management of specific adverse events  
8.2.5.1 Interstitial Lung Disease/Pneumonitis  
Study participants should be monitored for any new or worsening of respiratory symptoms and be 
advised to report such symptoms promptly. If participants show any signs or symptoms of 
suspecting interstitial lung disease (ILD)/Pneumonitis (eg, hypoxia, cough, dyspnea), treatment 
with palbociclib should immediately be omitted, and appropriate diagnosis testing should be 
initiated as well as appropriate treatment if judged necessary by the investigator. 
Whenever appropriate, diagnostic testing in study participants with suspected ILD/Pneumonitis 
may include (but not be limited to) the following tests/procedures. 
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• clinical evaluation: assessment of comorbidities, medications, potential exposure to 
occupational and environmental agents, and concurrent adverse events 
• laboratory tests: hematology, biochemistry, and serum markers (such as Kerbs von 
Lungren [KL]-6, Surfactant protein [SP]-A, SP-D, etc.) suggestive of ILD 
• pulmonary function testing: measurement of lung function, resting and exercise pulse 
oximetry 
• imaging: high-resolution computed tomography of the chest 
Bronchoalveolar lavage with sequential lavages should be considered in study participants 
presenting with hemoptysis and radiographic ILD that is acute or rapidly progressive. 
Lung biopsy should be considered in study participants with atypical or progressive signs and 
symptoms, atypical radiographic features, unexplained extrapulmonary manifestations, rapid 
clinical deterioration, or sudden change in radiographic appearance. 
If participants are diagnosed with ILD/Pneumonitis, palbociclib should be discontinued. 
(see Section 10.7 [Appendix 7]).  
For specific AE related to palbociclib intake, refer to the prescribing information or Summary of 
Product Characteristics.  
8.2.5.2 Amcenestrant-related Adverse Events  
Based on preclinical data and clinical data from amcenestrant, it is anticipated that amcenestrant-
related AEs could be managed by standard medical treatment/practice, which will also include but 
not limited to the provision of corrective treatment or medications, supportive care and dose 
omission. Investigators are encouraged to exercise their medical judgment in the management of 
the toxicities.  
Management of the AE related to amcenestrant and palbociclib is also summarized in  
Section 10.7 (Appendix 7). 
8.2.6 Pregnancy testing  
Serum pregnancy test (β-hCG) will be done in WOCBP before starting study intervention.  
Urine pregnancy test (dipstick) will be done on Day 1 of each cycle, at EOT, then monthly until 
12 weeks after last dose of any study intervention, whichever comes last.  
Urine pregnancy test must have a sensitivity of at least 25 mIU/mL. 
 
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8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.7. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study.(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 and SAEs will be collected from the signing of the informed consent form (ICF) at the 
time points specified in the SoA (Section 1.3) and until at least 30 days after administration of the 
last study intervention. After this period, all ongoing related AEs, all ongoing SAEs regardless of 
relationship with study treatment, and all new related AEs (serious or nonserious), are to be 
reported and followed up until resolution or stabilization. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek 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. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AEs of 
special interest (AESI) (as defined in Section 8.3.8), will be followed until resolution, 
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stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Appendix 3  
(Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of 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 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB for amcenestrant, SmPC or package insert for other IMP/NIMPs).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure 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 while participating in the study and, 
female partners of male participants while the male participant is in this study will be 
collected. Pregnancy 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. 
• In order to avoid pregnancy in women of childbearing potential (WOCBP) and female 
partners of male participants, including effects on male fertility and known potential 
genotoxicity with the study IMP, 
- 
WOCBP, should use highly effective non-hormonal methods of contraception (see 
Appendix 4, Section 10.4) during the study, and for at least 12 weeks after last dose of 
any study intervention.  
• Male participants and male partners of female participants must wear a male condom with 
spermicide, in combination with a highly effective method of contraception (see 
Appendix 4, Section 10.4) during the study, and for at least 14 weeks after last dose of any 
study intervention. If a pregnancy is reported in female participants or female partners of 
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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 intervention 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 Adverse events of special interest  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring 
in a female partner of a male participant entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 4 [Section 10.4]). 
- 
In the event of pregnancy in a female participant, study intervention should be 
discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP/non-investigational 
medicinal product (NIMP) 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as at least twice the intended dose within the intended 
therapeutic interval, adjusted according to the tested drug.  
Of note, asymptomatic overdose has to be reported as a standard AE.  
• Increase in alanine transaminase (ALT) ≥ Grade 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 
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baseline grade). Confounding factors such as, liver metastasis, hepato-biliary 
disorders, concomitant medications, etc. should be excluded prior to dose 
modifications. Please refer to the dose modification guidelines for management of 
increase of ALT. (Appendix 7 [Section 10.7]). 
- 
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 of liver, should be considered based on the clinical 
presentation.  
- 
A consultation with a hepatologist should be undertaken if there is,  
- 
Unexplained or persistent Grade ≥3 ALT despite dose omissions.  
- 
ALT >3 ULN and concomitant jaundice (total bilirubin >2.5 ULN), in patients 
with normal ALT and total bilirubin at baseline. 
- 
to exclude hepato-biliary disorders (eg, hepatotropic virus infections, autoimmune 
or alcoholic hepatitis, Non-Alcoholic Steatohepatitis, etc) or drug induced liver 
injury.  
- 
Further hepatic virology will be undertaken as per the site’s local guidelines for the 
treatment of cancer patients, considering the local and national recommendations. 
• Photosensitivity  
- 
If photosensitivity is suspected in study participants, consider dermatologist 
consultation. Confounding factors such as other dermatological disorders, drug 
eruptions resulting from concomitant medication use, etc. should be excluded prior to 
any dose modification (refer to Section 10.7 [Appendix 7] for treatment-related dose 
modification for non-hematological toxicities). In case of study intervention 
discontinuation because of photosensitivity reaction, study participant should be 
followed for possibility of development of other manifestations of photosensitivity 
such as photo-onycholysis, lichenoid reaction or actinic granuloma.  
• Interstitial Lung Disease (ILD)/Pneumonitis, any grade 
- 
Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with 
palbociclib. Study participants should be monitored for pulmonary symptoms 
indicative of ILD/pneumonitis (e.g., hypoxia, cough, dyspnea). Palbociclib should be 
omitted immediately in study participants who have new or worsening respiratory 
symptoms and are suspected to have developed ILD/pneumonitis. Please refer to 
Section 8.2.5.1 for recommendations on diagnostic testing of ILD/pneumonitis. 
Palbociclib should be permanently discontinued if ILD/pneumonitis is diagnosed (refer 
to Section 10.7 [Appendix 7] for dose modification guidelines for management of 
ILD/pneumonitis).  
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8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP or NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS  
 Collection and analysis of pharmacokinetic (PK) samples are described as follows: 
• Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of amcenestrant and palbociclib and approximately 4 mL of whole blood 
for plasma concentration of goserelin, when relevant (see Table 5). Pre-dose and post-dose 
PK samples should be collected even in case of IMP dose omission. Sampling time are 
specified in the SoA (Section 1.3).  
Table 5 - PK samples collection for amcenestrant, palbociclib and goserelin  
Analytes 
Population 
Sample and Visits 
Amcenestrant (SAR439859) 
All participants 
 
Cycle 1: Day 1 post-dose T3h, Day 15 pre-dose 
Cycle 2: Day 1 pre-dose and post-dose T3h; Day 15 pre-dose 
Cycle 3: Day 1 pre-dose 
Cycle 4: Day 1 pre-dose 
Cycle 7: Day 1 pre-dose 
Cycle 10: Day 1 pre-dose 
Palbociclib 
Goserelin 
Men, pre/peri-
menopausal 
women 
Cycle 1: Day 1 pre-dose 
Cycle 2: Day 1 pre-dose 
Cycle 3: Day 1 pre-dose 
 
• The timing of sampling may be altered during the course of the study based on newly 
available data (eg, to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
• Samples will be used to evaluate the PK of amcenestrant, palbociclib, and goserelin. 
Samples collected for analyses of amcenestrant, palbociclib and goserelin concentration 
may also be used to evaluate safety or efficacy aspects related to concerns arising during 
or after the study. 
• A population PK analysis will be performed on amcenestrant and/or palbociclib data and 
reported in a standalone report. 
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Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.  
The bioanalysts responsible for the sample analysis will be unblinded. They will, however, agree 
not to disclose the randomization schedule or the individual unblinded analytical results before the 
official opening of the randomization schedule. 
For China, please see Section 10.6 for details.  
8.5 
GENETICS  
8.5.1 cfDNA tumor and germline mutation analysis  
A 20-mL per time point blood sample for CfDNA isolation will be collected from participants for 
genetic analysis.  
Cancer gene mutations present in the tumor prior to treatment might influence the response to 
amcenestrant. The presence of gene mutations in tumor DNA may be assessed through mutation 
analysis of cfDNA isolated from plasma. 
cfDNA samples will be collected pre-treatment and post treatment. These analyses will focus on 
genes that may increase understanding of disease subtypes, the biology of cancer and related 
conditions, how the body handles amcenestrant, and drug response and toxicity, and possibly to 
identify new drug targets or biomarkers. 
An additional blood sample (6ml) will be used as source of normal reference DNA for 
comparison with the tumor-derived DNA data. Sequencing may be performed on the DNA from 
blood sample. The same blood sample will be used for DMET genotyping (see Section 8.5.2) 
Special procedures for collection, handling, storage, shipment, and destruction of the samples will 
be described in a separate laboratory manual which will be available at the investigational site. 
Samples may be stored for a maximum of 25 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable 
additional analysis of DNA biomarkers to increase understanding of amcenestrant and/or cancer 
or related diseases, and potentially to identify new drug targets or biomarkers. 
Details on processes for collection and shipment of these samples can be found in the laboratory 
manual.  
8.5.2 Drug metabolizing enzymes and related genes DNA samples  
A whole blood sample will be collected pre-dose to obtain deoxyribonucleic acid (DNA) in case 
investigations of allelic variants of UGT were needed to further explore influence on PK, efficacy 
and/or safety profile of amcenestrant.  
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The blood sample, and the DNA that is isolated from it, will remain labelled with the same 
identifiers used during the study (ie, Participant ID). The Sponsor has included safeguards for 
protecting participant confidentiality and personal data. The DNA, and any remaining whole 
blood, will be destroyed after the Drug Metabolism Enzyme and Transporter (DMET) related 
analysis and the main clinical study report have been completed, or as per local regulations. 
Special procedures for storage and shipping of DMET DNA samples will be described in the 
study laboratory manual. 
8.6 
BIOMARKERS  
Special procedures for collection, handling, storage and shipment of samples for biomarker 
analysis will be described in a separate laboratory manual which will be available at the 
investigational site. 
Samples may be stored for a maximum of 25 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarkers related to amcenestrant and/or cancer or related diseases, or to develop 
methods, assays, prognostics and/or companion diagnostics, and potentially to identify new drug 
targets or biomarkers. 
8.6.1 Protein expression  
The expression of several proteins in the tumor will be assessed by IHC of biopsy tissue collected 
pre-treatment (or archival) and at EOT/progression. These proteins will include the ER, the 
progesterone receptor (PgR), B-Cell Lymphoma 2 (BCL2), and potentially other proteins related 
to cancer or the activity of amcenestrant. These studies will be conducted by a central IHC lab. 
These studies will increase the understanding of the activity of amcenestrant and may increase our 
knowledge of cancer or related conditions. 
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). 
8.6.3 RNA transcriptome research  
Genome-wide transcriptome studies of ribonucleic acid (RNA) isolated from tumor biopsies are 
planned in this study by measuring the relative abundances of the RNA transcripts. This will 
enable the evaluation of changes in transcriptome profiles that may increase understanding of the 
pathogenesis of cancer and related conditions, the participant’s response to amcenestrant, and 
disease subtypes, and possibly to identify new drug targets or biomarkers. The samples may be 
analyzed by RNAseq or similar technologies. 
For China, please see Section 10.6 for details. 
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8.7 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity is not evaluated in this study. 
8.8 
HEALTH ECONOMICS  
Not applicable. 
8.9 
PATIENT REPORTED OUTCOMES  
Patient-reported outcomes (PROs) will be measured in both study arms using completion of the 
following questionnaires in electronic format. Paper format will be used in case of extreme 
circumstances eg, technical issue making the electronic format temporarily unusable. Process of 
handling the data captured in paper format will be detailed in the Electronic Clinical Outcome 
Assessment manual. Please refer to Appendix 17 (Section 10.17) for the PROs questionnaires. 
8.9.1 EORTC QLQ-C30  
• Cancer-specific health-related quality of life (HRQL), and disease- and treatment-related 
symptoms and the impact of symptoms will be assessed using the European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) core 
quality of life questionnaire with 30 items (QLQ-C30) (C30). The C30 provides 
a multi-dimensional assessment of HRQL domains identified as relevant by cancer 
patients. The validity and reliability of the EORTC QLQ-C30 has been established in 
various types of cancers. The C30 consists of 2-item scale evaluating global health 
status/quality of life scale (GHS/QoL), 5 functional scales (Physical, Role, Cognitive, 
Emotional, and Social functioning). There are also 3 symptom scales (Fatigue, Pain, and 
Nausea/Vomiting), 5 single symptom items (Dyspnea, Insomnia, Appetite Loss, 
Constipation, Diarrhea), and an item on the perceived financial impact of the disease as 
measured by the Financial Difficulties item. For the GHS/QoL and functional scales, 
a higher score indicates better global health status/better function, while for the symptom 
scales/items and financial difficulties item, lower scores indicate fewer 
symptoms/difficulties. 
8.9.2 EORTC QLQ-BR23  
The EORTC Breast Cancer Module (QLQ-BR23)  
The EORTC QLQ-BR23 (BR23) is meant for use among patients with breast cancer and 
comprised of 23 questions with three symptom subscales (arm/hand, breast, and systemic side 
effects), two functional scales (body image and sexuality), and single items covering sexual 
enjoyment, distress at hair loss, and future perspective). 
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8.9.3 EORTC QLQ-BR45  
The EORTC Breast Cancer Module (QLQ-BR45)  
• The EORTC QLQ-BR45 (BR45) is meant for use among patients with breast cancer and 
comprised of 45 questions to assess body image, future perspective, sexual functioning/ 
enjoyment/symptoms; breast-related symptoms/satisfaction, arm symptoms, hair loss, skin 
mucosis, systemic side effects, endocrine specific symptoms, ie, sexual and any additional 
symptoms). 
• In countries where the translated and validated EORTC QLQ-BR45 questionnaire is not 
available, study participants can use EORTC QLQ-BR23 questionnaire until the 
availability of translated and validated EORTC QLQ-BR45 questionnaire. 
8.9.4 EUROQoL EQ-5D-5L  
The EUROQoL EQ-5D-5L 
• EuroQoL Group measure with 5 dimensions and 5 levels per dimension (EQ-5D-5L) 
addressing mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
• The EQ-5D-5L incorporates the EQ-5D-5L descriptive system to generate a health state 
utility value and the EQ-5D VAS to generate health status (VAS) scores.  
All three questionnaires have been designed for self-completion. Study participants will complete 
the questionnaires prior to any study or medical procedures or discussion of their health status on 
Day 1 of Cycles 1, 2, 3 and 4 and then every 3 cycles starting from Cycle 6 Day 1 (ie, Cycle 6, 9, 
12, etc), at end of treatment and at 1st follow-up visit. 
The time estimated to complete the EORTC QLQ-C30 and EORTC QLQ-BR23/BR45 is 
approximately 15 to 20 minutes, and the time estimated to complete the EQ-5D-5L is 
approximately 5 to 10 minutes (for a total of 20 to 30 minutes to complete all three assessments). 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible toxicity, and can help identify new drug targets or 
biomarkers that predict participant response to treatment. Therefore, data and biological samples 
will be stored and used for future research when consented to by participants (see Section 10.1.3) 
unless prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will 
not be included in the local ICF).  
For participants who consent to the storage and use of their data and remaining (leftover) and/or 
extra (additional) clinical samples, data and samples may be used for future research related either 
to the drug, the mechanism of action, and the disease or its associated conditions. Such research 
may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites.  If future research on genetic material is performed, this will also be limited to the 
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purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
Remaining leftover samples will be used only after the study ends, ie end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. Data and 
samples will be used in alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These coded data 
and samples may be transferred to a Sponsor site (or a subcontractor site), which may be located 
outside of the country where the study is conducted. The Sponsor adopts safeguards for protecting 
participant confidentiality and personal data (see Section 10.1.4). 
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. Any samples remaining at the end of retention period will be destroyed. If a 
participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed and related coded data will be anonymized unless otherwise required by 
applicable laws. 
Participant’s coded datasets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
  
9.1 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 6): 
Table 6 - Population for Analyses  
Population 
Description 
Screened 
All participants who signed the ICF 
 Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by IRT regardless of whether the intervention was received. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the 
treatment arm assigned at randomization. 
Safety 
All randomized participants and who took at least 1 dose of study intervention. 
Participants will be analyzed according to the treatment arm they actually received. 
Pharmacokinetic (amcenestrant) 
 
All participants from the safety population who receive at least 1 dose of 
amcenestrant and with at least 1 evaluable plasma concentration of amcenestrant 
posttreatment. 
Pharmacokinetic (palbociclib) 
All participants from the safety population who receive at least 1 dose of palbociclib 
and with at least 1 evaluable plasma concentration of palbociclib posttreatment.  
Pharmacokinetic (goserelin) 
All participants from the safety population who receive at least 1 dose of goserelin 
and with at least 1 evaluable plasma concentration of goserelin posttreatment. 
Population without trial impact 
(disruption) due to Covid-19 
All randomized participants: 
• 
without any critical or major deviation related to Covid-19  
• 
and who did not permanently discontinue full treatment due to Covid-19  
• 
and who did not permanently discontinue study due to Covid-19. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety 
experience of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
9.2 
STATISTICAL ANALYSES  
The statistical analysis plan will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
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Planned date for analysis cut-off: 
Estimated COD will be approximately 40 months after the first randomized participant for the 
PFS final analysis. The COD for final analysis of OS will be approximately 80 months after the 
first randomized participant.  
9.2.1 General Considerations  
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.  
Unless otherwise specified, analyses will be performed by intervention group (and overall for 
baseline and demographics characteristics). 
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to first IMP administration.  
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days.  
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
9.2.2 Primary endpoint(s) analyses  
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 according to local radiologist’s/investigator’s assessment comparison between the 
amcenestrant + palbociclib arm and the letrozole + palbociclib 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 primary analysis of PFS will be based on the following censoring rules: 
• If progression and death are not observed before the PFS analysis COD, PFS will be 
censored at the date of the last evaluable tumor assessment with no evidence of a disease 
progression before the start of further anti-cancer therapy. 
• A participant without an event (death or disease progression) and without any evaluable 
post-baseline tumor assessments will be censored at the day of randomization (Day 1). 
• Documented progression (or death) occurring after two or more non-evaluable tumor 
assessments will be censored at the date of the last evaluable tumor assessment 
documenting no progression. 
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. The PFS quantiles and probabilities of being progression-free at different 
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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 (eg, different censoring rules and PFS assessed by the BIRC) and subgroup 
analyses of PFS will be performed as specified in the SAP. 
Two interim analyses at 40% (206 PFS events, non-binding futility only) and 70% (361 PFS 
events, efficacy only) of the target number of events (516 PFS events) are planned. The primary 
PFS analysis corresponds either to a positive interim PFS analysis or the final PFS analysis. Detail 
of the interim analyses are provided in Section 9.3.  
A summary of the primary estimand associated with the primary endpoint is provided in Table 2.  
Random sample-audit Blinded Independent Review Committee (BIRC) 
A random sample-audit BIRC approach will be used as an auditing tool to evaluate the 
concordance between local radiologist’s/investigator’s assessment and BIRC on the PFS. 
Approximately 50% of the randomized participants will be randomly selected and the BIRC will 
assess the tumor progression of these participants based on the review of tumor assessments. 
Participants selected for the sample-audit BIRC will not be known to the investigators. The audit 
size calculation approach will be based on the method proposed by Dodd, et al (1). Assuming 
local radiologist’s/investigator’s and BIRC assessments are similar, and the estimated log of 
investigator-based HR is -0.2877 (ie, HR=0.75), the audit size of 50% will ensure that the upper 
bound of a one-sided 95% CI for BIRC-based log-hazard ratio has 83% probability of being 
below 0 (ie, HR <1) if the correlation between local radiologist’s/investigator’s assessment and 
BIRC assessment is 0.65. 
Two methods will be used to summarize the data from the sample-based BIRC assessment of 
PFS.  
• The NCI (National Cancer Institute) method (1), uses an auxiliary variable estimator of the 
log-hazard ratio that combines information from participant level local 
radiologist’s/investigator’s assessment from all participants and the BIRC assessment of 
participants randomly selected for central review. The auxiliary variable estimates and its 
one-sided 95% CI will be provided. 
• The Pharmaceutical Research and Manufacturers of America (PhRMA) method (2) 
estimates the early discrepancy rate (EDR) and late discrepancy rate (LDR) differences 
between the two treatment arms. The EDR and LDR results will also be summarized by 
treatment arm. 
Detail of the two methods will be provided in the SAP. 
Assurance regarding the PFS treatment effect based on local radiologist’s/investigator’s 
assessment will be based on the NCI method. If the upper bound of the one-sided 95% CI of the 
true BIRC log-hazard ratio calculated using the NCI method is below 0, assurance will be 
considered and the full BIRC will not be triggered; otherwise, a full BIRC may be triggered.  
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All efficacy analyses will be performed on the ITT population unless stated otherwise. All 
primary and secondary efficacy endpoints based on radiological assessments of tumor burden 
(ie, PFS, BOR, ORR, CBR, and DOR) will be primarily derived using the local 
radiologist’s/Investigator’s assessment tumor assessment. 
9.2.3 Secondary endpoint(s) analyses  
The secondary endpoints detailed in this section are efficacy secondary endpoints.  
Other secondary endpoints analyses are defined in Section 9.2.6.1 (AE, SAE), Section 9.2.6.2 
(laboratory abnormalities), Section 9.2.7 (PRO, PK, immunogenicity).   
Analysis of response-based endpoints (ie, ORR, CBR, and DOR) will be performed primarily on 
the ITT population and supported by the analyses based on the subset of measurable participant 
from the ITT population. Except for OS, PFS2, and TT1C, secondary endpoints will be analyzed 
at the time of the PFS analyses only. Of note, the BOR for each participant will also be 
summarized by treatment arm. BOR is the best overall response observed from the date of the 
randomization until disease progression, death, cutoff date, initiation of post-treatment anti-cancer 
therapy, whichever occurs first. 
Key secondary endpoint: 
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 at the last date the 
participant is known to be alive or at the OS cut-off date, whichever occurs first.  
Primary efficacy analysis of OS will consist of comparison between the amcenestrant + 
palbociclib arm and the letrozole + palbociclib arm through a logrank test procedure stratified by 
the stratification factors as entered in the IRT. In order to ensure a strong control of the overall 
Type I error rate at a one-sided 2.5%, a hierarchical testing strategy will be used. In other words, 
comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of two analyses are planned for OS 
(see Section 9.3.2). 
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. The OS quantiles and probabilities of being alive 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 OS curves will also be provided. 
Sensitivity analyses (eg, different censoring rules, dealing with informative censoring) and 
subgroup analyses of OS will be performed as specified in the SAP. 
A summary of the estimands associated with the key secondary endpoint is provided in Table 2. 
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Other secondary endpoints: 
A summary of efficacy analyses for other secondary endpoints is provided in Table 7. No 
statistical testing will be performed for other secondary endpoints. 
Table 7 - Efficacy analyses for other secondary endpoints  
Endpoint 
Statistical Analysis Methods 
ORR, CBR 
Descriptive statistics by treatment arm and Clopper-Pearson method for CI calculation. 
DOR, TT1C, PFS2   
Kaplan-Meier method for quantiles and probabilities of being event free at different time points. 
Exploratory 
Will be described in the SAP. 
CBR = clinical benefit rate; CI = confidence interval; DOR = duration of response; HR = hazard ratio; ORR = objective response rate; PFS2: 
progression-free survival on next line of therapy, SAP = statistical analysis plan; TT1C = time to first chemotherapy. 
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. 
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 
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 two treatment arms will be summarized using Kaplan-Meier methods 
and displayed graphically, if appropriate. The DOR quantiles and associated 95% CI will be 
provided.  
Time to first chemotherapy 
The TT1C is defined as the time from the date of randomization to the start date of the first 
chemotherapy after study treatment discontinuation. Study participants alive without further 
treatment with chemotherapy will be censored at the last date the participant is known to be alive 
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or at the cut-off date, whichever occurs first. Participants who died without further treatment with 
chemotherapy will be censored at the date of death or at the cut-off date, whichever occurs first. 
The HR estimates and corresponding 95% two-sided CIs will be provided using the Cox 
proportional hazard model stratified by the stratification factors as entered in the IRT. The TT1C 
quantiles and probabilities of being chemotherapy-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 TT1C curves will also be provided. 
Sensitivity analyses (eg, different censoring rules) and subgroup analyses of TT1C will be 
performed as specified in the SAP. 
Progression-free survival on the next systemic anti-cancer therapy (PFS2) 
The PFS2 is defined as the time from the date of randomization to the date of first documentation 
of PD on the next systemic anti-cancer therapy according to investigator or death due to any cause 
in the absence of documented PD on the next systemic anti-cancer therapy, whichever occurs first. 
Next systemic anti-cancer therapy is defined as the first further anti-cancer therapy initiated after 
discontinuation of study intervention regardless of the discontinuation reason. Study participants 
on their next systemic anti-cancer therapy without PFS2 events will be censored at the last date 
the participant is known to be alive without a first documentation of PD on the next systemic anti-
cancer therapy or at the cut-off date, whichever occurs first. Study participants who discontinued 
their next systemic anti-cancer therapy without PFS2 events will be censored at the end of their 
next systemic anti-cancer therapy or at the cut-off date, whichever occurs first. Detailed 
event/censoring scheme will be provided in the SAP. 
The HR estimates and corresponding 95% two-sided CIs will be provided using the Cox 
proportional hazard model stratified by the stratification factors as entered in the IRT. The PFS2 
quantiles 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 TT1C curves will also be provided. 
Sensitivity analyses (eg, different censoring rules) and subgroup analyses of PFS2 may be 
performed as specified in the SAP. 
9.2.4 Tertiary/exploratory endpoint(s) analyses  
Tertiary/exploratory endpoints analyses will be described in the SAP.  
9.2.5 Multiplicity adjustment  
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. 
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9.2.6 Safety analyses  
All safety analyses will be performed on the Safety Population. A summary of safety analyses is 
provided in Table 8. 
Table 8 - 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 
AE = adverse event; SAE = serious adverse event; SAP = statistical analysis plan.  
9.2.6.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pretreatment AEs are defined as any AE occurring during the pretreatment period.  
• Treatment-emergent AEs (TEAEs) are defined as AEs that develop, worsen (according to 
the Investigator’s opinion), or become serious during the on-treatment period.  
• Post-treatment AEs are defined as AEs that are reported during the post-treatment period.  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary focus of AE reporting will be on TEAEs. Pretreatment 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-emergent AEs leading to premature treatment discontinuation 
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• Treatment-related TEAEs 
• Treatment-related TEAEs Grade ≥3 
• Serious treatment-related TEAEs. 
• AESIs 
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v5.0 grade (all grades and Grade ≥3) for the safety population. 
Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to definitive 
discontinuation, and premature discontinuation of palbociclib, TEAEs leading to dose 
modification, serious TEAEs, TEAEs with fatal outcome, AESIs, and AEs/SAEs occurring during 
the post-treatment period. 
9.2.6.2 Laboratory evaluations  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the on-treatment period will be provided for the 
safety population. 
When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
  
9.2.7 Other analyses  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.15 (Appendix 15: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
9.2.7.1 Analyses of patient reported outcome endpoints  
Analyses of the 3 selected PRO instruments (EORTC C30, QLQ-BR23/BR45, and EQ-5D-5L) 
will be analyzed in participants from the safety population. 
For each questionnaire the compliance profile over time will be summarized on the safety 
population (number and percentage of forms received versus expected). For the C30 (15 total 
scales), QLQ-BR23/BR45 (13 total scales), and EQ-5D-5L (health state utility index and visual 
analogue scale) instruments, descriptive statistics for the absolute value at each time point, for the 
change from baseline for each treatment arm at each time point, until EOT and 90 days after the 
last study administration (follow-up) will be presented on the safety population. Between 
treatment comparisons for the change from baseline over time will be provided for each scale of 
each questionnaire on the safety population who have completed the baseline and at least one 
post-baseline PRO assessment using a MMRM. No formal statistical hypothesis will be tested.  
A more detailed statistical analysis strategy for the 3 PROs will be detailed in the study SAP. 
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9.2.7.2 Analyses of other endpoints  
Pharmacokinetics, genetics, and biomarker exploratory analyses will be described in the SAP. The 
population PK analysis and/or population PK/PD analyses will be presented separately from the 
main clinical study report (CSR).  
9.3 
INTERIM ANALYSES   
9.3.1 Interim analyses for PFS  
Two interim analyses are planned based on the primary PFS endpoint at 40% (non-binding futility 
only) and 70% (efficacy only) of the planned total number of events expected. 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 efficacy will be derived based on the O’Brien and Fleming 
α-spending function and depend on the actual number of PFS events observed at the time of the 
interim analysis.  
A summary of the PFS analyses is provided in Table 9. 
Table 9 - PFS analyses  
Analysis 
Months 
after FPI 
(approx. 
under PFS 
HR=0.75) 
Planned 
accrual 
Number 
of 
events  
Information 
fraction 
Cumulative 
Power 
(under PFS 
HR=0.75) 
Futility 
boundary 
Efficacy 
boundary 
PFS IA 1 
(futility 
only) 
19.5 
1066 
206 
40% 
 
HR >1.1 
NA 
PFS IA 2 
(efficacy) 
28 
1066 
361 
70% 
62% 
NA 
p ≤0.0074 
(HRa 
≤0.7736) 
PFS Final 
analysis 
40 
1066 
516 
100% 
90% 
p >0.0228 
(HRa >0.8386) 
p ≤0.0228 
(HRa 
≤0.8386) 
a 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. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; PFS = progression-free survival 
In case of positive results at interim analysis, disease assessments data will be collected according 
to the protocol until the final PFS analysis cut-off date (defined as the date when 516 PFS events 
assessed by radiologist/investigator are observed) and PFS results will be updated (non-inferential 
analysis only). 
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The Statistical Analysis Plan will describe the planned interim analyses in greater detail. 
9.3.2 Interim analyses for OS  
Comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of three analyses are planned for OS, at the time of 
the primary analysis of PFS, at 75% of the planned number of OS events and at the final OS 
analysis. 
A gamma error spending function (γ=-10) independent from the O’Brien and Fleming α-spending 
function for PFS will be used, along with the hierarchical testing strategy in order 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 (3).  
A summary of the OS analyses is provided in Table 10. 
Table 10 - OS analyses  
Analysis 
Months 
after FPI 
(approx.) 
Planned 
accrual 
Number 
of 
deaths 
(approx.) 
Information 
fraction 
Cumulative 
Powera 
(under 
HR=0.80) 
Futility 
boundary 
Efficacy 
boundary 
Scenario 1: PFS is statistically significant at the PFS IA 2 
OS IA 1 (at 
PFS IA 2) 
28 
1066 
228 
36.1% 
1.2% 
NA 
p ≤4.07×10-5 
(HRb ≤0.5934) 
OS IA 2  
55 
1066 
474 
75% 
32.9% 
NA 
p ≤0.0020 
(HRb ≤0.7680) 
Final 
analysis 
80 
1066 
632 
100% 
80% 
p >0.0248 
(HRb >0.8554) 
p ≤0.0248 
(HRb ≤0.8554) 
Scenario 2: PFS is statistically significant at the PFS final analysis 
OS IA 1 (at 
PFS final 
analysis) 
40 
1066 
348 
55.1% 
8.5% 
NA 
p ≤2.78×10-4 
(HRb ≤0.6408) 
OS IA 2  
55 
1066 
474 
75% 
32.7% 
NA 
p ≤0.0020 
(HRb ≤0.7673) 
Final 
analysis 
80 
1066 
632 
100% 
80% 
p >0.0248 
(HRb >0.8554) 
p ≤0.0248 
(HRb ≤0.8554) 
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 an annual dropout rate of 1%. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; OS = overall survival.  
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9.3.3 Data Monitoring Committee (DMC)  
This study will use an independent DMC. The first DMC meeting will be set up to review early 
safety results (eg, after approximately 50 participants have completed at least 2 cycles, or after 
6 months after first participant randomized), and then periodically. In addition to review of safety 
results, DMC will also evaluate efficacy at the interim analyses and make a recommendation 
regarding study continuation based on observed results of the study. 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. 
9.4 
SAMPLE SIZE DETERMINATION  
For PFS, a total of 516 PFS events assessed by local radiologist/investigator will be needed to 
reject the null hypothesis using a logrank test at the one-sided level of 2.5% and a 90% power 
under the assumption of a HR of 0.75. Assuming proportional hazards under an exponential 
model and based on an anticipated median PFS of 24.8 months in the letrozole + palbociclib arm, 
this is expected to correspond to a median PFS of 33.1 months in the SAR439859 + palbociclib 
arm. Based on an expected accrual duration of 18 months (15% of total accrual in the first 
4.5 months and 40% of total accrual in the first 9 months), a PFS analysis cut-off date (COD) 
40 months after the first participant randomized and an annual dropout rate of 5%, a total of 
1066 participants are expected to be randomized in a 1:1 ratio into the SAR439859 + palbociclib 
and letrozole + palbociclib arms. The power calculation accounts for two interim analyses at 40% 
and 70% of the planned number of events. 
For OS, a total of 632 deaths will be needed to reject the null hypothesis using a logrank test at the 
one-sided level of 2.5% and a 80% power under the assumption of a HR of 0.80. Assuming 
proportional hazards under an exponential model and based on an anticipated median OS of 
46 months in the letrozole + palbociclib arm, this is expected to correspond to a median OS of 
57.5 months in the SAR439859 + palbociclib arm. OS COD is expected 80 months after the first 
participant randomized (assuming an annual dropout rate of 1%). The power calculation accounts 
for two interim analyses at the time of the PFS primary analysis and at 75% of the planned 
number of OS events. 
Calculations were made using East 6.5 software. 
 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC  
- 
Determining whether an incidental finding (as per Sanofi policy) should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the 
finding is returned (an incidental finding is a previously undiagnosed medical 
condition that is discovered unintentionally and is unrelated to the aims of the 
study for which the tests are being performed). The following should be considered 
when determining the return of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant, and answer all questions regarding the study, 
including what happens to the participant when his/her participation ends (post-trial access 
strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Privacy and Data Protection requirements including 
those of the Global Data Protection Regulation (GDPR) and of the French law, 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.  
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• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant.  
Participants who are rescreened are required to sign a new ICF (see Section 5.4). 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.15: Contingency measures for a regional or national emergency that is 
declared by a governmental agency.  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on African American 
population for the FDA or on Japanese population for the Pharmaceuticals and Medical Devices 
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Agency in Japan). They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
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adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
10.1.5.1 Steering committee  
The Steering Committee will include a Chairman, Investigators and Sponsor’s representatives. 
The Steering Committee will be responsible for: 
• Supervising the progress of the trial towards its overall objectives. 
• Reviewing at regular intervals relevant information that may affect the study conduct. 
• Discussing the implementation of the recommendations of the independent DMC. 
10.1.5.2 Independent Data Monitoring Committee  
An independent DMC, consisting of 3 external independent members (2 physicians with breast 
cancer expertise and 1 statistician), not associated with the conduct of the study or other study 
committees will meet regularly to, as specified in the DMC charter: 
• Review the progress of the trial. 
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• Review the safety data. 
• Advise the Sponsor on potential modifications or communications that may be necessary 
to ensure the patient safety or protect the scientific integrity of the trial. The Sponsor will 
make the final decision(s). 
The DMC will also be in charge of evaluating efficacy at the interim analyses and make 
a recommendation regarding study continuation based on observed results of the study. 
10.1.5.3 Blinded Independent Review Committee  
In addition to investigators’ tumor assessments, a Blinded Independent Review Committee 
(BIRC) will assess the radiographic (and photographical when applicable) images and clinical 
information collected on-study per RECIST 1.1 criteria. For this purpose, the tumor assessment 
images should be transferred to the blinded independent review committee for tumor response 
evaluation. No BIRC review will be performed after the final PFS analysis cut-off date. 
10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to peer-
reviewed journals following internal company review for accuracy, fair balance and intellectual 
property. For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
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Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on e-CRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the e-CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the e-CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 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. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations) 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the e-CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
• Every data point recorded in the CRF must have a source document. The 
investigator/delegated site staff will report all the original data in the participant’s medical 
chart or in a study specific source document created by him/her. If such document is used, 
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the template should be reviewed by the CRA. A list of SD and their location will be filed 
in the Investigator Study File. 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the e-CRF or entered in the e-CRF 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. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate therapy and/or follow-up for that participant. 
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10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The laboratory tests detailed in Table 11 will be performed by the local laboratory and the 
results must be entered in the e-CRF.  
• 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  
• Serum pregnancy test (β-hCG) will be done in WOCBP before starting study treatment. 
Urine pregnancy test (dipstick) will be done on Day 1 of each cycle at EOT, then monthly 
until 12 weeks after last dose of any study intervention, whichever comes last. Urine 
pregnancy test must have a sensitivity of at least 25 mIU/mL.  
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Table 11 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
 
Hemoglobin 
Red blood cell 
 
White blood cell (WBC) count with differential: 
 
 
Neutrophils 
 
 
Lymphocytes 
 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
Clinical chemistrya 
Blood urea nitrogen (BUN) or Urea 
 
Creatinine 
Estimated Glomerular Filtration Rate 
 
Glucose (nonfasting) 
 
Potassium 
 
Sodium 
Phosphate 
Lactate dehydrogenase (LDH) 
 
Magnesium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and direct bilirubin, Gamma-glutamyl transferase (GGT) 
 
Albumin 
Coagulation  
INR, Prothrombin time 
Lipid Profile 
Total cholesterol 
LDL-cholesterol 
HDL-cholesterol 
Urinalysis (semi-quantitative test) 
• 
pH, glucose, protein, blood, ketones by dipstick 
Other screening tests 
 
 
 
 
Pregnancy tests 
• 
Follicle-stimulating hormoneb 
• 
Estradiol 
• 
Viral serology tests: Hepatitis A antigen or IgM hepatitis A antibody; HBs antigen 
or hepatitis B viral DNA; Hepatitis C antibody and quantitative hepatitis C (HCV) 
ribonucleic acid (RNA). 
Serum pregnancy test (β-hCG), Urine pregnancy test (dipstick)  
The results of each test must be entered into the e-CRF. 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 1. All events of Grade ≥3 ALT increase should be reported as adverse events of special interest (AESI). 
b During treatment period FSH will be done on C1D1, then every 4th cycle during study treatment and EOT-local labs in pre/perimenopausal 
women only.  
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg,:  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. Laboratory 
abnormalities should be reported as AEs only in case they lead to an action on study 
treatment or if they fulfil the criteria for seriousness or AESI. 
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• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
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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. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for  
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc)  
- 
Development of drug dependency or drug abuse 
- 
Suicide attempt or any event suggestive of suicidality, 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions   
- 
Invasive or malignant cancers. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the e-CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to monitoring team in lieu of completion of the Sanofi/AE/SAE e-CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In such case, care should be taken to ensure that the patient's identity is protected 
and the patient's identifiers in the study are properly mentioned on any copy of a source 
document provided to the Company. For laboratory results, include the laboratory normal 
ranges.  
• 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. 
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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. (39) 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to e-CRF. 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 monitoring team. 
• The Investigator may change his/her opinion of causality in light of the 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 monitoring 
team 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 e-CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
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10.3.4 Reporting of SAEs  
SAE reporting to Sanofi via an electronic data collection tool 
• The primary mechanism for reporting an SAE to Sanofi will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the monitoring team by telephone. 
• Contacts for SAE reporting can be found in Investigator Study File. 
SAE reporting to Sanofi via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the monitoring team 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in Investigator Study File. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
Woman of childbearing potential (WOCBP) 
A woman, who is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. Postmenopausal women as defined by one of the following: 
A) With spontaneous cessation of menses >12 months prior to randomization in the absence 
of physiological or medical cause.  
B) Or with cessation of menses of duration ≤12 months or secondary to hysterectomy AND 
have FSH and estradiol level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L for FSH and <10 pg/mL for estradiol if institutional range is not 
available) prior to randomization, 
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C) Or who have received hormonal replacement therapy but have discontinued this treatment 
AND have FSH and estradiol level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L for FSH and <10 pg/mL for estradiol if institutional range is not 
available) prior to randomization, 
D) Or with status post bilateral surgical oophorectomy, 
E) Or post bilateral ovarian ablation through pelvic radiotherapy.  
NOTE: As per local regulations, to demonstrate postmenopausal status, serial measurements of 
FSH may be required in participants who are not using hormonal contraception or hormonal 
replacement therapy, and in the absence of amenorrhea for at least 12 months. 
10.4.2 Contraception guidance  
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Male Participants: 
- 
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 14 weeks 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.  
Male participants and male partners of female participants must wear a male condom with 
spermicide, in combination with a highly effective method of contraception. 
Male participants should consider sperm preservation prior to beginning therapy with study 
IMPs. Because exposure to SAR439859, has the potential risk of testicular injury with 
partial or permanent infertility. Also, exposure to palbociclib may compromise male 
fertility. 
Women of Childbearing Potential: 
Highly Effective Methodsb That Have Low User Dependency  
Intrauterine device (IUD) 
Bilateral tubal occlusion 
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Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be 
used. Spermatogenesis cycle is approximately 90 days). 
Highly Effective Methodsb That Are User Dependent 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception for this study. Male condom and female condom should not be used 
together (due to risk of failure with friction) 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.  
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date but may last 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.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
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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 for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION (RECIST 1.1)  
 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 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:  
- 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm).  
- 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
- 
20 mm 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). See also notes below 
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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 non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam 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 a particular 
comment: 
Bone lesions: 
• Bone scan, 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 MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) 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 
non-cystic lesions are present in the same patient, 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. 
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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 exam. 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 exam 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.  
• CT, 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. MRI 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 patient to be considered in complete response. Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), 
have been published. In addition, the Gynecologic Cancer Intergroup has developed 
CA125 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 PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
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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 in order to differentiate between 
response (or stable disease) and progressive disease. 
Baseline documentation of “target” and “non-target” lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-
target lesions. Nodes that have a short axis <10 mm are considered non-pathological and should 
not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as “present”, “absent”, or “unequivocal progression”. In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
Special notes on the assessment of target lesions 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: All lesions (nodal and non-nodal) recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
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target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being “too small to measure”. When this 
occurs, it is important that a value be recorded on the CRF. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
When non-nodal lesions “fragment”, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
“coalesced lesion”. 
Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: When 
the participant also has measurable disease; in this setting, to achieve “unequivocal progression” 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. 
When the participant has only non-measurable disease; to achieve “unequivocal progression” on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest “increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in “volume” (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural effusion from 
“trace” to “large”, an increase in lymphangitic disease from localized to widespread, or may be 
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described in protocols as “sufficient to require a change in therapy”. If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The participant’s brain metastases are considered to be constitute PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents new disease. If repeat scans confirm that there is a new 
lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible “new” disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-
PET at follow-up corresponds to a preexisting site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
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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. 
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 “non target” 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 provides a summary of the overall response status calculation at each time point 
for participants who have measurable disease at baseline. 
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 
 
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 
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Overall response 
Overall response 
BEST overall response 
First time point 
Subsequent time point 
 
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 patient 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; PD = progressive disease; PR = partial response; SD = stable disease 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points  
(ie, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient 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 patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: 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 described above. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the patient is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
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on increase in size of the nodes. As noted earlier, this means that patients with CR may not have 
a total sum of “zero” on the CRF. 
In trials where confirmation of response is required, repeated “NE” time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as 
a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
The objective response status of such patients is to be determined by evaluation of target and 
non-target disease. For equivocal findings of progression (eg, very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.  
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).  
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
[Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria 
in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.] 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
CHINA 
CHINA EXTENSION STUDY 
It is planned to enroll approximately 160 Chinese patients in EFC15935, equivalent to 15% of the 
global population. If enrollment of 160 Chinese patients is not achieved at the time of completion 
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of global enrollment (1066 patients), enrollment in China will continue until the target number of 
patients is reached. 
Patients enrolled from sites in China for Global part and extension part shall not fulfill the 
inclusion criterion I 08, as no archived FFPE or fresh tumor sample will not be collected from 
participants enrolled in China. 
For study participants enrolled from clinical sites in China, biological samples related to 
secondary (Pharmacokinetics - except palbociclib and amcenestrant), and exploratory (genetic 
analyses and biomarkers) endpoints will not be collected or analyzed. The impacted biological 
samples are, 
• Collection of blood sample for pharmacokinetics of goserelin in pre/perimenopausal 
women and men on Cycle 1 D1, Cycle 2 D1, and Cycle 3 D1. 
• Collection of archived FFPE or fresh tumor sample during screening, and EOT (optional) 
in all study participants.  
• Collection of plasma sample for Molecular profiling in cfCNA in all study participants on 
Cycle 1 D1, at Cycle 4 Day 1 predose (at tumor assessment), and EOT. 
• Collection of blood sample for DMET genotyping and normal tissue reference DNA in all 
study participants on Cycle 1 D1. 
• Collection of blood sample for estradiol assessment in all study participants on Cycle 1 
D1, and Cycle 3 D1. 
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10.7 
APPENDIX 7: Recommended Dose Modification Guidelines For Study Treatment-Related Adverse Events  
Recommended dose modifications of endocrine therapy (amcenestrant/amcenestrant-matching placebo, Letrozole/Letrozole-matching placebo) 
and Palbociclib are presented in Table 12. 
Table 12 - Recommended dose modification or discontinuation  
NCI CTCAE v5 gradea 
Management of endocrine therapy 
(Amcenestrant/amcenestrant-matching placebo, 
Letrozole/Letrozole-matching (placebo) 
Management of Palbociclib 
Hematological toxicities 
Grade 1 or 2 
No dose adjustment is required. 
Grade 3* 
No dose adjustment is required - continue endocrine therapies without any 
dose omission. 
Day 1 of cycle: Omit palbociclib administration and repeat complete blood 
count monitoring within 1 week. When recovered to Grade ≤2, start palbociclib 
at the same dose within the cycle if recovery occurs before Day 21 of the cycle 
or at Day 1 of the next planned cycle if there is a strong evidence of clinical 
benefit in case of omission >2 weeks. 
Day 15 of first 2 cycles: continue palbociclib at current dose to complete cycle. 
Repeat complete blood count on Day 22.  
Consider palbociclib dose reduction in cases of prolonged (>1 week) recovery 
from Grade 3 neutropenia or recurrent Grade 3 neutropenia in Day 1 of 
subsequent cycles and maintain endocrine therapies at the same dose. 
Grade 3 neutropeniab with 
fever ≥38.5ºC and/or 
infection  
or  
Grade 4* hematological 
toxicity 
No dose adjustment is required - continue endocrine therapy without any 
dose omission 
Omit palbociclib administration, repeat complete blood count monitoring within 
1 week. When recovered to Grade ≤2, administer palbociclib at the next lower 
dose if recovery occurs before Day 21 of the cycle or at Day 1 of the next 
planned cycle if there is a strong evidence of clinical benefit in case of omission 
>2 weeks.  
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NCI CTCAE v5 gradea 
Management of endocrine therapy 
(Amcenestrant/amcenestrant-matching placebo, 
Letrozole/Letrozole-matching (placebo) 
Management of Palbociclib 
Non-hematological toxicities 
Grade 1 or 2 
No dose adjustment is required. 
Grade ≥3 (if persisting 
despite optimal medical 
treatment) 
Day 1 of cycle:  
1. 
Administer cycle as planned if toxicity is not attributed to any of IMPs. 
2. 
If toxicity attributable to both endocrine therapy and palbociclib, delay cycle (ie, delay of all IMPs) until symptoms resolve to Grade ≤1 or Grade ≤2 (if 
not considered a safety risk for the patient). 
When resolved to Grade ≤1 or Grade ≤2 (if not considered a safety risk for the patient), administer  
a. 
endocrine therapy at the same dose  
b. 
and palbociclib at the next lower dose. 
3. 
If toxicity attributable to palbociclib, omit it while continuing the endocrine therapy without changes until symptoms resolve to Grade ≤1 or Grade ≤2 (if 
not considered a safety risk for the patient). Resume the omitted palbociclib at the next lower dose within cycle if recovery occurs before Day 21 of the 
current cycle or at or at Day 1 of the next planned cycle providing omission lasts no more than 2 weeks unless there is a strong evidence of clinical 
benefit. 
In case of first recurrence of the same Grade ≥3 event attributable to palbociclib, a dose reduction of it to next dose level is recommended when 
symptoms resolve to ≤1 or Grade ≤2 (if not considered a safety risk for the patient). If further dose reduction below 75 mg/day is required, palbociclib 
should be permanently discontinued. 
In case of second recurrence of the same Grade ≥3 event, palbociclib should be permanently discontinued. 
4. 
If toxicity attributable to endocrine therapy, omit them while continuing palbociclib without changes until symptoms resolve to Grade ≤1 or Grade ≤2 (if 
not considered a safety risk for the patient). Resume the omitted endocrine therapy at the same dose within cycle or at subsequent cycle providing 
omission lasts no more than 2 weeks unless there is a strong evidence of clinical benefit. 
In case of first recurrence of the same Grade ≥3 event attributable to endocrine therapy, omit them until symptoms resolve to Grade ≤1 or Grade ≤2 
(if not considered a safety risk for the patient), and restart at the same dose. 
In case of second recurrence of the same Grade ≥3 event, all study IMPs should be permanently discontinued 
Within cycle: continue endocrine therapy if toxicity is not attributed to these 
IMPs. If attributable, omit endocrine therapy until symptoms resolve to: 
Grade ≤1 or Grade ≤2 (if not considered a safety risk for the patient). 
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 therapy. 
Within cycle: omit palbociclib until symptoms resolve to: Grade ≤1 or Grade ≤2 
(if not considered a safety risk for the patient) and administer palbociclib at the 
next lower dose within cycle if recovery occurs before Day 21 of the current 
cycle, or at Day 1 of the next planned cycle. 
In case of first recurrence of the same Grade ≥3 event: administer at the next 
lower dose level if restart is possible. If further dose reduction below 75 mg/day 
is required, palbociclib should be permanently discontinued. 
In case of second recurrence of the same Grade ≥3 event: permanently 
discontinue palbociclib. 
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NCI CTCAE v5 gradea 
Management of endocrine therapy 
(Amcenestrant/amcenestrant-matching placebo, 
Letrozole/Letrozole-matching (placebo) 
Management of Palbociclib 
Interstitial Lung Disease/Pneumonitis 
Grade 1 (asymptomatic or 
suspected pneumonitis) or 
Grade 2 (symptomatic new 
or worsening respiratory 
symptoms) 
No dose adjustment is required - continue endocrine therapy without any 
dose omission 
Omit palbociclib, if applicable (ie, within D1 to D21 period of a given cycle); 
evaluate the patient until pneumonitis is diagnosed.  
- If pneumonitis is diagnosed, palbociclib must be permanently discontinued.  
- If pneumonitis is not diagnosed, restart palbociclib at the next lower dose when 
symptoms recover to the baseline level. Restart could be either within current 
cycle if recovery occurs before 21 days (and up to D21 of the cycle) or at the 
next planned cycle Day 1. 
Grade 3 & 4 attributed to 
palbociclib 
No dose adjustment is required - continue endocrine therapy without any 
dose omission 
Permanently discontinue palbociclib 
Increase of ALT 
confounding factors such as, liver metastasis, hepato-biliary disorders, concomitant medications, etc. should be excluded prior to dose modifications 
Grade 0 or 1 
No dose adjustment is required 
Grade 2 
Omit endocrine therapies administration until recovery to Grade ≤1, and 
then restart endocrine therapies at the same dose.  
In case of recurrence of the same Grade 2 event: administer at the same 
dose if restart is possible. 
No dose adjustment is required.  
Grade 3 
Omit endocrine therapies administration. Repeat LFTs within 2-3 days. If 
ALT levels not recovered, monitor LFTs weekly (or more frequently, if 
clinically indicated) until recovery to Grade ≤1 ALT increased (or baseline 
grade). On recovery, restart endocrine therapies at the same dose.  
In case of first recurrence of the same Grade 3 event: administer at the 
same dose if restart is possible. 
In case of second recurrence of the same Grade 3 event: permanently 
discontinue endocrine therapies. 
Omit palbociclib 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) and administer 
palbociclib at the next lower dose within cycle if recovery occurs before Day 21 
of the current cycle, or at Day 1 of the next planned cycle. 
In case of first recurrence of the same Grade ≥3 event: administer at the next 
lower dose level if restart is possible. If further dose reduction below 75 mg/day 
is required, palbociclib should be permanently discontinued. 
In case of second recurrence of the same Grade ≥3 event: permanently 
discontinue palbociclib. 
Grade 4 
Permanently discontinue study treatment 
a Table applies to all hematologic abnormalities except lymphopenia (unless associated with clinical events, eg, opportunistic infections. 
b Absolute neutrophil count (ANC): Grade 1: ANC <LLN -1500/mm3; Grade 2: ANC 1000 -<1500/mm3; Grade 3: ANC 500 -<1000/mm3; Grade 4: ANC 500/mm3 
* Except lymphopenia (unless associated with clinical events, eg, opportunistic infections) 
Liver function tests (LFTs) include AST, ALT, ALP (isoenzymes if Grade >2), total bilirubin (fractionated if >2 x ULN direct), GGT, and INR (if total bilirubin >2.5 ULN).  
Grading according to CTCAE v5.0. 
NCI CTCAE v5 = National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; LLN = lower limit of normal.
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10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY  
Amendment 01 dated 27-Jul-2020 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page (Protocol 
title);  
1.1 (Synopsis); 
2.1 (Study rationale); 
3 (Objectives and 
Endpoints);  
4.1 (Overall Design);  
Updated the protocol title from 
“A randomized, multicenter, double-blind 
Phase 3 study of SAR439859 plus 
palbociclib versus letrozole plus 
palbociclib for the treatment of patients 
with ER (+), HER2 (-) breast cancer who 
have not received any prior systemic anti-
cancer treatment for advanced disease” 
to “A randomized, multicenter, double-
blind Phase 3 study of SAR439859 plus 
palbociclib versus letrozole plus 
palbociclib for the treatment of patients 
with ER (+), HER2 (-) breast cancer who 
have not received prior systemic anti-
cancer treatment for advanced disease”  
“Any” before “prior therapy” is a duplicate. 
Title page 
Removed the field “Study Name” 
Removed as it was not part of the study protocol 
template 
1.1 (Synopsis);. 
1.3 (Schedule of 
Activities); 
3 (objectives and 
Endpoints); 
8.11.2 (EORTC QLQ-
BR23);  
8.11.3 (EORTC QLQ-
BR45); 
8.11.4 (EuroQoL EQ-
5D-5L);  
9.4.3.1 (Analyses of 
patient reported 
outcome endpoints) 
Added the option to use EORTC QLQ-
BR23 questionnaire until the availability 
of translated and validated EORTC QLQ-
BR45 questionnaire. And added the 
description of EORTC QLQ-BR23 
questionnaire in patient reported 
outcomes section. 
EORTC QLQ-BR45 is a relatively new questionnaire, 
and its translation and validation in various languages 
are still ongoing. 
1.3 (Schedule of 
Activities) 
During study treatment period, Follicle-
stimulating hormone will be performed in 
pre/peri-menopausal women every 
4th cylce. Estradiol (local labs) will not be 
performed anymore.  
There exists structural similarity between selective 
estrogen receptor degraders (SERD) and estradiol. 
SERD may interfere with estradiol immunoassays and 
may result in falsely increased levels of estradiol. 
 
Urine pregnancy test to be done at 
12 weeks after last dose of any study 
intervention. 
Correction of inconsistency between schedule of 
activities and main protocol. 
 
Removed the IRT contact on C1D14 and 
C2D14 visits  
No IRT contacts are planned during these visits.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 (Schedule of 
Activities);  
8.5 (Pharmacokinetics) 
Changed the on-site study visit days 
planned Day 14 of Cycles 1 and 2 to 
Day 15 of Cycles 1 and 2. Subsequently 
PK samples will be collected on C1D15 
and C2D15 
To ensure that visits falls on the same day of the weeks. 
 
Pharmacokinetics sampling time were 
updated. 
Changes were made in order to easier interpret the 
data. 
2.1 (Study rationale); 
4.3 (Justification for 
Dose) 
Added the preliminary safety and efficacy 
results from dose escalation and 
expansion cohort of SAR439859 in 
combination with palbociclib from 
TED14856 study.  
Updated the inconsistent numbers in 
provided in “Justification for Dose” 
section. 
Availability of encouraging preliminary safety and 
antitumor activity results of SAR439859 + palbociclib 
combination. 
1.1 (Synopsis);  
Patients who progress while on or within 
12 months from completion of 
(neo)adjuvant therapy with tamoxifen 
could be allowed for enrollment into the 
study. 
Patients progressing while on or within 12 months on 
tamoxifen could still benefit from SAR439859 or 
letrozole in combination with palbociclib. 
5.2 (Exclusion criteria 
“E19”) 
Patients who are involved in any type of 
medical research (except investigational 
study treatment) for at least 2 weeks prior 
to randomization are allowed for 
enrollment into the study. 
Patients who are participating in any medical research 
not related to investigational study treatment 
(eg, molecular research of tumor samples) does not 
need to wait for 4 weeks duration to get enrolled into the 
study.  
5.5 (Criteria for 
temporarily delaying); 
10.15 (Appendix 15: 
Contingency measures 
for a regional or 
national emergency 
that is declared by 
a governmental 
agency) 
New sections were added describing the 
contingency measures for a regional or 
national emergency, that is declared by 
a government agency. 
These measures have been added to help manage the 
study conduct during an emergency (eg, COVID). 
6.4 (study intervention 
compliance) 
Information related to vomiting will not be 
collected in study drug diary 
As vomiting related information are necessary only 
during the days of PK sampling, and the patient is on 
site during PK sampling, there exists no necessity to 
collect this information in the study drug diary. 
8.3.6 (Disease-related 
events and/or disease-
related outcomes not 
qualifying as AEs or 
SAEs) 
The information provided in this section 
has been removed. 
The prior information listed under this section was not 
relevant for oncology studies. 
8.7 (Genetics); 
8.7.1 (cfDNA tumor 
and germline mutation 
analysis);  
8.8.2 (Tumor Protein 
Biomarkers) 
Blood sample volume collected for 
genetic analysis has been updated. 
A new subsection title has been added 
for cfDNA and tumor protein biomarkers. 
Availability of new specifications. 
For clarity purposes, these sections have been added.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.7.2 (Drug 
metabolizing enzymes 
and related genes 
DNA samples) 
The title of the section has been updated 
(word "transporters" has been deleted 
from the section name), and information 
on optional blood sample has been 
removed, as it will be part of mandatory 
study procedures. This section has been 
updated to remove inconsistent text on 
analyses that may be performed with 
DMET genotyping sample.  
Previously reported incorrect information were 
corrected. 
8.8.1 (Estradiol) 
Section Estradiol was moved to 
Biomarkers section and the further 
section numbers were updated. 
This section was initially Incorrectly reported under 
Pharmacodynamics section. 
9.4.3.2 (Analyses of 
other endpoints) 
Pharmacodynamics analyses were 
removed, and genetics analyses were 
added 
Pharmacodynamics analyses are not planned in study, 
and genetic analyses were missing. 
10.2 (Appendix 2: 
Clinical laboratory 
tests) 
FSH (local labs) and Estradiol (local labs) 
levels should be assessed in all study 
participants for eligibility during 
screening. 
Inconsistency in information between schedule of 
activities and appendix 2 has been corrected. 
10.6 (Appendix 6: 
Country-specific 
requirements) 
Information on Chinese extension part 
has been added. 
In order to fulfill the regulatory requirements in China, 
additional number of patients will be enrolled in 
an extension of the Global part of the study. 
 
In participants enrolled from clinical sites 
in China (in both Global part and 
extension part) biological samples related 
to secondary (except PK assessment of 
SAR439859 and palbociclib), exploratory 
(genetic analyses and biomarkers) 
endpoints will neither be collected nor 
analyzed.  
As per HGRAC regulation, sites in China will not 
participate in the several secondary and exploratory 
endpoints assessment. 
10.7 (Appendix 7: 
Recommended Dose 
Modification 
Guidelines for Study 
Treatment-Related 
Adverse Events) 
The dose modification guidelines for 
endocrine therapy (SAR439859/ 
SAR439859-matching placebo, 
Letrozole/Letrozole-matching placebo) 
has been updated. 
As it is a double blind, double dummy study, neither 
patients nor investigators would know, whether the 
patient is receiving SAR439859/ SAR439859-matching 
placebo or Letrozole/Letrozole-matching placebo. 
Therefore, in case of adverse events requiring dose 
modification of the endocrine therapy, both IMPs (Arm 
A: SAR439859 + letrozole-matching placebo; Arm B:  
SAR439859-matching placebo + letrozole) should have 
the same action (dose omission or dose delay).  
Entire document  
Editorial changes 
Correction of typographical errors and minor 
inconsistencies across different sections, and 
clarifications. 
 
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Amendment 02 dated 30-Sep-2020 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 (Synopsis); 
9.4.1.1 (Analysis of primary 
efficacy endpoint) 
 
Updated the censoring rules for PFS analysis 
The censoring rules have been detailed 
based on feedback from regulatory 
authorities. 
9.4.1.1 (Analysis of primary 
efficacy endpoint) 
PFS assessed by the BIRC will be 
considered as supportive analysis of the 
primary PFS analysis even if a full BIRC is 
triggered 
The strategy has been updated based on the 
feedback from regulatory authorities. 
2.3.1 (Benefit and Risks 
assessment in context of 
COVID-19 pandemic); 
2.3.1.1 (Benefits in the 
context of COVID-19); 2.3.1.2 
(Risks in the context of 
COVID-19); 2.3.1.2.1 (Risks 
related to the patient 
population); 2.3.1.2.2 (Risks 
related to study related 
activity); 2.3.1.2.3 (Risks 
related to study treatment); 
Added benefits risks assessment in the 
context of COVID-19 pandemic based on 
feedback from regulatory authorities 
 
5.1 (Inclusion criteria,  
I 09) 
For clarity, the inclusion criterion 09 has been 
reworded.  
 
5.1 (Inclusion criteria,  
I 07) 
Modified the inclusion criterion 07 - 
participants with ECOG performance status 2 
are eligible for enrollment 
The eligibility criterion on performance status 
has been updated for greater generalizability 
of real-life oncology population. 
5.2 (Exclusion criteria, E 01) 
Modified the exclusion criterion 01 to exclude 
participants with active brain metastases. 
Participants with treated/stable brain 
metastases will be eligible 
The eligibility criterion on brain metastases 
has been updated based on 
recommendations from American Society of 
Clinical Oncology (ASCO)-Friends of Cancer 
Research Brain Metastases Working Group 
(40). 
5.2 (Exclusion criteria, E 09, 
E 10) 
Modified the exclusion criterion 09 to exclude 
enrolling pre/perimenopausal women and 
men receiving goserelin, who are fully 
anticoagulated for a past thromboembolic 
event. 
For clarity, the exclusion criterion 09 has 
been split to E 09 and E 10. Consequently, 
the numbering order of exclusion criteria has 
been changed. 
Goserelin is not recommended in patients 
who are fully anticoagulated (INR >2) due to 
the risk of vascular injury and subsequent 
bleeding during administration (Product 
Monograph ZOLADEX; Goserelin. Dec 21, 
2017). 
6.3 (Measures to minimize 
bias: randomization and 
blinding) 
Updated the unblinding rules to allow 
investigators to unblind participant’s 
intervention assignment in case of 
emergency without the requirement for 
consultation with the Sponsor prior to 
unblinding. 
The previous unblinding rules requested 
mandatory consultation with sponsor prior to 
unblinding participant’s intervention 
assignment, which could have delayed the 
unblinding in case of emergency situations. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6 (Dose Modification); 10.7 
(Appendix 7: Recommended 
dose modification guidelines 
for study treatment-related 
adverse events) 
Added the dose modification guidelines for 
recurrent adverse events with a severity of 
Grade ≥3. 
This was previously missing. 
7.1 (Discontinuation of study 
intervention); 8.3.7 (Adverse 
Event of special interest) 
Pregnancy of female participant will lead to 
definitive discontinuation of study intervention 
(IMP and NIMP) 
This was previously missing in the 
discontinuation of study intervention section. 
8.3.5 (Pregnancy); 10.4 
(Appendix 4: Contraceptive 
guidance and collection of 
pregnancy Information)  
Contraception guidelines for male 
participants and male partners of female 
participants were updated. 
Given the contraindication of pregnancy with 
all the study drugs, including effects on male 
fertility and known genotoxicity with the IMP, 
contraception guidelines for men have been 
updated. 
1.3 (Schedule of Activities); 
8.5 (Pharmacokinetics, Table 
4) 
Additional blood samples for PK assessment 
will be collected beyond Cycle 3 
Additional blood samples for PK of 
SAR439859 and palbociclib will be collected 
based on feedback from regulatory 
authorities 
1.3 (Schedule of Activities); 
10.2 (Clinical laboratory tests) 
Pregnancy tests to be performed monthly 
until 12 weeks after the last dose of any study 
intervention 
The monthly pregnancy tests after the last 
dose of any study intervention were missing 
Entire document  
Editorial changes 
Correction of typographical errors and minor 
inconsistencies across different sections, and 
clarifications. 
 
Amendment 03 dated 13-Dec-2020 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 (Synopsis); 9.2 (Sample 
size determination); 
4.1.1 Duration of the Study 
Period; 9.5.1 (Interim 
analyses for PFS) 
Modification of statistical assumptions; 
modification of the study sample size 
from 708 to 1066 patients; addition of 
second interim analysis for OS; and 
change in study duration & estimated cut-
off dates for PFS and OS analyses. 
Revised PFS HR assumption used to power this 
endpoint, revised futility analysis strategy at interim 
analyses and revised dropout assumption due to 
change in PFS censoring scheme. 
Revised OS HR assumption used to power this 
endpoint. 
1.1 (Synopsis); 3 
(objectives and Endpoints, 
other secondary objectives 
and endpoints); 9.4.1 
(Efficacy analyses); 9.4.1.2 
(Analysis of secondary 
efficacy endpoints) 
Addition of PFS2 as secondary endpoint 
and description of how the PFS2 will be 
assessed. 
To assess the PFS after next line of therapy. PFS2 
is a useful endpoint to assess any benefit beyond 
initial disease progression. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 (Synopsis); 3 
(objectives and Endpoints, 
Tertiary/exploratory 
objectives and endpoints) 
Change of PK assessment from 
secondary objective to exploratory 
objective. 
 
The exposure/response relationship of 
palbociclib will be evaluated as 
exploratory objective. 
The potential effect of amcenestrant on goserelin 
Ctrough assessed through PK of goserelin bears 
exploratory nature. Thus, it has been moved to 
exploratory objective. 
As palbociclib will be assessed in both arms with 
possibly different exposure. 
1.1 (Synopsis, Disclosure 
statement);  
Updated the list of stakeholders for whom 
the study is blinded 
To have consistent information between synopsis 
and Section 6.5 (measures to minimize bias: 
randomization and blinding) 
1.1 (Synopsis, Number of 
participants); 
Added the total number of patients that 
will be screened in the current study. 
For clarity purposes. 
1.1 (Synopsis, study 
interventions); 
The dose regimen of Letrozole and 
letrozole-matching placebo was changed 
from “1 tablet once daily” has been 
changed to “1 capsule once daily”. 
Corrected the incorrect description. 
1.1 (Synopsis); 
1.3 (Schedule of Activities); 
3 (objectives and 
Endpoints, 
Tertiary/exploratory 
endpoint); 10.6 (Appendix 
6: Country-specific 
requirements) 
Modified the cfDNA timepoint from “end 
of Cycle 3” to “Cycle 4 Day 1 predose”. 
For clarity purposes. 
1.1 (Synopsis); 
1.3 (Schedule of Activities); 
8.1 (Efficacy Assessments) 
Clarified the disease assessment to be 
performed at EOT visit and during follow-
up period.  
During follow-up period, tumor assessment is 
required only in study participants without 
documented PD as per RECIST 1.1.  
1.3 (Schedule of Activities);  
All study visits conducted during 
treatment period and follow-up period (in 
participants without progressive disease 
per RECIST 1.1 at EOT) are conducted 
on-site until disease progression. On-site 
visits could be substituted by remote 
visits in specific circumstances. 
For clarity purposes. 
1.3 (Schedule of Activities); 
8.2.3 (Electrocardiograms) 
Added the five-minute window at a 
nominal time-point for triplicate ECGs.  
This information was missing. 
1.3 (Schedule of Activities); 
8.5 (Pharmacokinetics) 
Modified the PK sampling time points in 
schedule of activities, and table 4 (PK 
samples collection for amcenestrant, 
palbociclib and goserelin) has been 
updated accordingly. PK sample IDs 
were removed, as they are available in 
laboratory manual; Updated the incorrect 
volume of blood to be collected (from 
2 mL to 4 mL) for goserelin PK 
assessment. 
Optimized the PK sample collection time points in 
such a way that those time points fall on study 
visits when there are additional on-site 
assessments (eg, disease assessments). 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 (Schedule of Activities); 
8.11 (Patient reported 
outcomes)  
PROs (Patient-reported outcomes) will be 
reported in electronic format”. Paper 
format of PROs questionnaires will be 
used in case of extreme circumstances 
eg, technical issue making the electronic 
format temporarily unusable. 
To avoid missing PROs data, which is a secondary 
endpoint of the study. 
1.3 (Schedule of Activities); 
10.2 (Appendix 2: Clinical 
laboratory tests)  
Added the requirement for highly 
sensitive (at least 25mIU/mL) urine 
pregnancy test  
With higher sensitivity, the chances of not 
detecting pregnancies decreases. 
1.3 (Schedule of Activities);  
Goserelin administration on EOT visit has 
been removed 
Administration of goserelin is done every 28 days, 
and its subsequent administration shall not 
necessarily fall at the date of EOT. 
1.3 (Schedule of Activities);  
Dual-energy x-ray absorptiometry (DXA) 
scan of anteroposterior spine and total 
hip will be performed in study participants 
who are not on bone-targeted agents at 
baseline (unless not performed within 6 
months prior and during treatment period 
Endocrine therapies used in EFC15935 study have 
a risk of osteoporosis because of their anti-
estrogenic properties. The implemented changes 
are added as part of risk minimization strategy 
5.1 (INCLUSION CRITERIA 
- I06); 1.1 (Synopsis); 
8.1 (Efficacy assessments) 
Inclusion criterion I06 has been updated 
as: Measurable disease ie, at least one 
measurable lesion evaluable per RECIST 
v.1.1 or non-measurable bone only 
disease with at least one predominant 
lytic bone lesion or mixed lytic-blastic 
lesion without a measurable soft tissue 
component must be present (criterion 
modified by amendment 03).  
Updated the non-measurable disease 
criteria in various sections. 
In addition to measurable disease per RECIST 1.1, 
patients with non-measurable bone-only disease 
are enrolled. In order to avoid confusion on 
interpretation of non-measurable disease and for 
clarity, the inclusion criterion I06 has been 
updated. 
5.1 (INCLUSION CRITERIA 
- I09) 
Modified the inclusion criterion I09 to 
remove the mandatory use of GnRH 
agonist at least 4 weeks prior to 
randomization in men with no prior 
bilateral orchiectomy and 
pre/perimenopausal women. GnRH 
agonist initiation up to 4 weeks before 
starting the study is permitted, but not 
required. 
With the current protocol requirements, 
pre/premenopausal women and men with no prior 
orchiectomy are waiting for the 4-weeks duration 
(under GnRH agonist) to get elapsed prior to 
getting randomized into the study, which is creating 
a delay in the initiation of the study treatment. In 
MONALEESA-7 Phase III study (Lancet Oncol 
2018; 19: 904-15), goserelin was initiated on the 
same day as other study drugs so that patients 
could begin the full treatment regimen without 
delay, and simultaneous initiation did not cause 
any negative effects.  
5.2 (EXCLUSION 
CRITERIA - E02); 
1.3 (Schedule of Activities); 
Updated the exclusion criterion E 02 to 
exclude participants with known active 
hepatitis A/B/C, or hepatic cirrhosis. 
Added the viral serology tests in the 
schedule of activities. 
As the study IMPs have a potential to induce 
hepatic toxicity, the implemented changes are 
added as part of risk minimization strategy. 
5.2 (EXCLUSION 
CRITERIA - E12) 
Updated the exclusion criterion E12 to 
remove treatment with moderate CYP3A 
inducers.  
Availability of new data showing that there is a 
modest decrease (30%) of amcenestrant with 
strong  CYP3A inducers. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 (Exclusion criteria - 
E13); 6.5 (Concomitant 
therapy); 10.10 (Appendix 
10: List of Strong CYP3A 
Inducers); 
Removed exclusion criterion E13 - 
“Treatment with strong or moderate 
CYP2C8 inducers within 2 weeks before 
first study treatment administration or 
5 elimination half-lives whichever is 
longest and cannot be replaced” and 
adapted the list of prohibited concomitant 
therapies with regards to CYP2C8 
inducers.  
Availability of new data showing that there is 
Availability of new data showing that there is a 
modest decrease (30%) of amcenestrant with 
strong CYP3A inducers and considering that there 
is no known strong CYP2C8. 
5.2 (EXCLUSION 
CRITERIA - E16) 
Updated the exclusion criterion E 16 to 
exclude participants with recurrent 
disease, who have primary or secondary 
resistance to prior (neo)adjuvant 
endocrine therapy 
To ensure that the enrolled study population with 
recurrent disease is homogenous with endocrine 
sensitive disease. 
5.3.1 (Sun protection) 
Added recommendations for using broad 
spectrum sunscreens filtering both UVA 
and UVB light exposure 
To ensure that the recommendations provided for 
sun protection are adequate. 
5.3.3 (Osteoporosis) 
A new subsection “Osteoporosis” has 
been added under “Life-style 
considerations”, to reduce the risk of 
osteoporosis 
Endocrine therapies used in EFC15935 study have 
a risk of osteoporosis because of their anti-
estrogenic properties. The implemented changes 
are added as part of risk minimization strategy. 
5.4 (Screen failures) 
Added information on management of 
temporary screen failures 
The signed informed consent form is valid beyond 
28 days. In case of temporary screen failures, 
there is no necessity to have participant 
reconsented with new ICF signed, if participant 
finally participates in the study. The process of 
handling such cases are described. 
6.1 (Study interventions 
administered); 10.15 
(Appendix 15: Contingency 
measures for a regional or 
national emergency that is 
declared by a governmental 
agency) 
Removed sponsor from the list of entities 
for direct to patient IMP dispensation 
service. 
With direct to patient IMP dispensation service, 
IMPs could be supplied only from the PI or study 
site to the study participant. 
6.4 (Study intervention 
compliance) 
Updated the rules for completion of study 
medication diary; updated the term from 
“study drug diary” to “study medication 
diary; 
Patients do not complete the study medication 
diary every day, but only on days when doses are 
omitted and on days prior to PK sampling. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5 (Concomitant therapy)  
Added recommendations for study 
participants with bone mineral density T 
score of < -2 or with ≥2 risk factors for 
fracture per ESMO clinical practice 
guidelines on bone health in cancer. 
 
Provided guidance on the administration 
of vaccines during the study. 
 
Added the description for prohibited 
medications that could prolong QT 
interval in premenopausal women and 
men, as they are contraindicated when 
co-administered with goserelin. 
Endocrine therapies used in EFC15935 study have 
a risk of osteoporosis because of their anti-
estrogenic properties. The implemented changes 
are added as part of risk minimization strategy.  
 
With the increased rate of infections associated 
with palbociclib, and with availability of vaccines to 
SARS-COV-2, this guidance has been added. 
 
To be aligned with exclusion criterion E 19 
6.5 (Concomitant therapy); 
8.2.4 (Clinical safety 
laboratory assessments); 
8.4 (Treatment of 
Overdose) 
Replaced “medical monitor” by “Sponsor 
or Sponsor representative(s)”. 
Change in terminology. 
7.1.1 (Definitive 
discontinuation) 
Provided the reference to adverse events 
leading to definitive/premature 
discontinuation of study intervention. 
For clarity purposes. 
8.2.3 (Vital signs) 
Removed the AE reporting guidance for 
vital signs abnormalities, when they are 
defined as AESI 
Vital signs abnormalities are not AESI per current 
study protocol  
8.3.4 (Regulatory reporting 
requirements for SAEs) 
Updated the suspected unexpected 
serious adverse reactions (SUSARs) 
reporting timelines 
In order to be aligned with the pharmacovigilance 
(PV) guidelines. 
8.3.5 (Pregnancy); 10.4 
(Appendix 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. 
 
8.3.7 (Adverse event of 
special interest) 
Added “Photosensitivity” as a new 
adverse event of special interest (AESI) 
Preclinical studies using SAR439859 indicate a 
potential risk for phototoxicity. Photosensitivity 
events has been added as an AESI in order to 
collect relevant information. 
8.3.7 (Adverse event of 
special interest) 
Added guidance on the management of 
Increase in alanine transaminase (ALT) ≥ 
Grade 3 
As the study IMPs have a potential to induce 
hepatic toxicity, the implemented changes are 
added as part of risk minimization strategy.  
8.7.1 (cfDNA tumor and 
germline mutation analysis) 
Removed the requirement of replacement 
genetic blood sample. 
Considering the exploratory nature of the analyses, 
replacement genetic blood sample will not be 
requested in case of DNA extraction failure. 
8.8 (Biomarkers); 8.8.1 
(Protein expression); 8.8.3 
(RNA transcriptome 
research) 
Rearranged the text related to samples 
storage under the main section 
biomarkers. 
For clarity purposes. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.8.1 (Protein expression) 
A new subsection title has been added 
“Protein expression” 
For clarity purposes. 
8.8.4 (Future use of 
samples); 8.9 (Use of 
biological samples and data 
for future research) 
Section 8.8.4 “Future use of samples” 
has been removed and substituted with a 
new Section 8.9 “Use of biological 
samples and data for future research”. 
The new section provides information on 
streamlined process for accessing clinical 
data/samples for secondary use. 
9.2 (Sample size 
determination); 
10.6 (Appendix 6: Country-
Specific Requirements) 
Removed descriptions for China 
extension study including objective, 
population and sample size 
consideration. 
In Nov 2020, an enrollment plan for China was 
adopted that targeted the completion of enrollment 
at the same time as global population. It is possible 
that an extension study is no longer needed. 
Therefore, relevant descriptions for sub-study are 
removed and flexible statement regarding the 
enrollment plan has been added. Consideration on 
patient number was also removed as all study 
participants from China may be treated within the 
global study. Specific sample size consideration 
will be provided in separate regulatory packages 
submitted to China National Medical Products 
Administration -  
Center for Drug Evaluation (NMPA-CDE). 
10.1.3 (Informed consent 
process) 
Updated the informed consent process 
To provide a clear description on the ICF process, 
especially in case of amendments. 
10.1.4 (Data protection) 
Updated data protection of participants 
and professionals involved in study 
GDPR compliance related to Investigators and 
staff data, as well as service providers, experts, 
Ethics Committee members. 
10.1.5 (Committees 
structure) 
Information about Blinded Independent 
Review Committee (BIRC) has been 
added. 
Information on BIRC was missing within the 
relevant “committees structure” section, where 
description on all study committees are provided. 
10.1.6 (Dissemination of 
clinical study data) 
Added the study disclosure information in 
China and added information on what 
could be publicly disclosed and 
communicated to relevant authorities by 
sponsor. 
GDPR compliance related to Investigators and 
staff data, as well as service providers, experts, 
Ethics Committee members. 
10.3.2 (Definition of SAE) 
Added a list of medically important 
events. 
Guideline for the investigator for SAE reporting. 
10.4 (Appendix 4: 
Contraceptive guidance and 
collection of pregnancy 
Information) 
Added the reason for sperm preservation 
prior to beginning therapy with study 
IMPs. 
Per request from health authorities. 
10.7(Appendix 7: 
Recommended Dose 
Modification Guidelines For 
Study Treatment-Related 
Adverse Events) 
Added dose modification guidelines for 
study IMPs in case of increase in ALT 
levels, and updated the palbociclib dose 
modification guidelines for Grade 3 
hematological toxicity in order to be 
aligned with palbociclib SmPC. 
As the study IMPs have a potential to induce 
hepatic toxicity, the implemented changes are 
added as part of risk minimization strategy.  
10.8 (Appendix 8: Protocol 
amendment history) 
Updated by including amendment history 
of amended protocol 02. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
10.9 (Appendix 9: List of 
CYP3A Inhibitors); 10.10 
(Appendix 10: List of Strong 
CYP3A Inducers); 10.11 
(Appendix 11: List of CYP 
Sensitive Substrates) 
The list of strong CYP3A 
inhibitors/inducers, CYP sensitive 
substrates has been updated. 
With the availability of updated data from October 
2020 extraction - from the DDI database of 
University of Washington. 
10.16 (Appendix 16: Drugs 
with a narrow therapeutic 
window metabolized by 
CYP3A) 
Added the list of drugs with a narrow 
therapeutic window metabolized by 
CYP3A  
For clarity purposes. 
10.17 (Appendix 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); EORTC 
BR-45 (for female and male participants); 
EQ-5D-5L.   
As paper questionnaires are allowed in extreme 
circumstances, these sample questionnaires are 
added for use by study sites. 
Several sections of protocol 
have been impacted 
Changed the name of “SAR439859” IMP 
to “Amcenestrant’ 
Availability of amcenestrant INN for SAR439859 
Entire document 
Editorial changes 
Correction of typographical errors and minor 
inconsistencies across different sections, and 
clarifications. 
 
 
10.9 
APPENDIX 9: LIST OF CYP3A INHIBITORS  
Concomitant administration of medications that are strong CYP3A inhibitors 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 INHIBITORS 
CYP3A inhibitors 
Precipitant Therapeutic 
Class 
Victim (oral, unless otherwise 
specified) 
AUC Ratio 
Potent CYP3A Inhibitors (yielding substrate AUCratio >5) 
Telaprevir 
Antivirals 
midazolam 
13,5 
Indinavir/RIT 
Protease inhibitors 
alfentanil 
36,50 
Tipranavir/RIT 
Protease inhibitors 
midazolam 
26,91 
Ritonavir 
Protease inhibitors 
midazolam 
26,41 
Cobicistat (GS-9350) 
None 
midazolam 
19,03 
Indinavir 
Protease inhibitors 
 midazolam 
9.67 
Ketoconazole 
Antifungals 
midazolam 
17.08 
Troleandomycin 
Antibiotics 
midazolam 
14,80 
Saquinavir/RIT 
Protease inhibitors 
midazolam 
12,48 
Itraconazole 
Antifungals 
midazolam 
10,80 
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STRONG CYP3A INHIBITORS 
CYP3A inhibitors 
Precipitant Therapeutic 
Class 
Victim (oral, unless otherwise 
specified) 
AUC Ratio 
Potent CYP3A Inhibitors (yielding substrate AUCratio >5) 
Voriconazole 
Antifungals 
midazolam 
9,63 
Mibefradil 
Calcium Channel Blockers 
midazolam 
8,86 
Clarithromycin 
Antibiotics 
midazolam 
8,39 
Danoprevir/RIT 
Antivirals 
midazolam 
13,42 
Lopinavir/RIT 
Protease inhibitors 
alfentanil 
11,47 
Elvitegravir/RIT 
Treatments of AIDS 
midazolam 
12,80 
Posaconazole 
Antifungals 
midazolam 
6,23 
Telithromycin 
Antibiotics 
midazolam 
6,2 
Grapefruit Juice DS 
Food Products 
midazolam 
5,95 
Conivaptan 
Diuretics 
midazolam 
5,76 
Nefazodone 
Antidepressants 
midazolam 
5,44 
Nelfinavir 
Protease inhibitors 
midazolam 
5,29 
Saquinavir 
Protease inhibitors 
midazolam 
5,18 
Boceprevir 
Antivirals 
midazolam 
5,05 
Idelalisib 
Kinase inhibitors 
midazolam 
5,15 
LCL161 
Cancer treatments 
midazolam 
8,80 
VIEKIRA PAK 
Antivirals 
tacrolimus 
55,76 
Mifepristone 
Antiprogestins 
simvastatin 
estimated 9.55 
Ceretinib 
Kinase inhibitors 
midazolam 
5.84 (PBPK) 
Ribociclib 
Kinase inhibitors 
midazolam 
5.17 
Tucatinib 
Kinase inhibitors 
midazolam 
5.74 
Josamycin 
Antibiotics 
ivabradine 
7.70 
 
 
 
 
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10.10 APPENDIX 10: LIST OF STRONG CYP3A INDUCERS  
Concomitant administration of medications that are strong CYP3A inducers are not permitted 
throughout the active treatment phase. 
The following tables were 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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10.11 APPENDIX 11: 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 or matching 
placebo 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 
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Drug (oral) 
Therapeutic Class 
eplerenone 
Diuretics 
everolimus 
Immunosuppressants  
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 
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Drug (oral) 
Therapeutic Class 
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 
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 
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In vivo CYP2C9 Sensitive substrate 
Substrate (oral) 
Therapeutic Class 
lansoprazole (dexlansoprazol) 
Proton Pump Inhibitors 
(S)-mephenytoin 
Anticonvulsants 
omeprazole 
Proton Pump Inhibitors 
tilidine 
Treatments of Pain and Inflammation 
(R)-(-)-hexobarbital 
Hypnotics - Sedatives 
(R)-mephobarbital 
Anticonvulsants 
clobazam (parent drug) 
Benzodiazepines 
diazepam 
Benzodiazepines  
gliclazide 
Sulfonylureas 
pantoprazole 
Proton Pump Inhibitors 
proguanil (prodrug) 
Antimalarials 
rabeprazole 
Proton Pump Inhibitors 
NOTE: The present list includes CYP2C19 substrates with an AUCR ≥5, or CL ratio ≤0.20. 
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the 
clinical relevance is unknown. Caution is therefore indicated when giving letrozole/letrozole-
matching placebo concomitantly with medicinal products whose elimination is mainly dependent 
on these isoenzymes and whose therapeutic index is narrow. 
10.12 APPENDIX 12: ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE 
FORMULA  
Glomerular Filtration Rate (GFR) (mL/min/1.73 m2) = 175 × (SCr) -1.154 × (Age)-0.203 × (0.742 if 
Female) × (1.212 if African-American). 
Abbreviation: SCr = Serum creatinine in mg/dL; Age in years 
 
 
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10.13 APPENDIX 13: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE  
Performance Status Description 
0 
Fully active, able to carry on all pre-disease 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 house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 
50% of waking hours. 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair. 
5 
Dead. 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 
 
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10.14 APPENDIX 14: LIST OF DRUGS THAT CAN CAUSE QT PROLONGATION  
Anti-arrhythmic drugs 
• Amiodarone, disopyramide, dronedarone, flecainide, sotalol 
Other cardiac drugs 
• Ranolazine  
Antibiotics 
• macrolides (eg, erythromycin, clarithromycin, azithromycin), quinolones 
(eg, levofloxacin, moxifloxacin) 
Antifungals 
• Fluconazole, ketoconazole 
Antimotility and antiemetic agents 
• Domperidone, granisetron, ondansetron 
Antimalarials 
• Quinine, chloroquine 
Antihistamines 
• Hydroxyzine 
Antipsychotics 
• Chlorpromazine, clozapine droperidol, fluphenazine, haloperidol, olanzapine, pimozide, 
paliperidone, quetiapine, risperidone 
Antidepressants 
• Amitriptyline, citalopram, escitalopram, dosulepin doxepin, fluoxetine, imipramine, 
lofepramine 
Miscellaneous 
• Methadone, antiretrovirals (eg, foscarnet) 
 [Source: BMJ 2016;353:i2732; BMJ 2016;354:i4331] 
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10.15 APPENDIX 15: 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). The deviations from the study protocol (eg, treatment delay, omission, tests not 
performed) should be documented in the source document and collected in the appropriate pages 
of the eCRF. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
mobile applications, etc) may be planned for the collection of possible safety and/or 
efficacy data (eg safety assessments, efficacy assessments especially the tumor 
assessment, PRO). 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed. 
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• The Direct-to-Patient (DTP) supply of the IMP from the PI/site where allowed by local 
regulations and agreed upon by participant. (Section 6.1). 
Contingencies implemented due to emergency will be documented. 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (Section 10.1.2). 
 
 
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10.16 APPENDIX 16: DRUGS WITH A NARROW THERAPEUTIC WINDOW METABOLIZED 
BY CYP3A  
Alfentanil 
Cyclosporine 
Dihydroergotamine 
Ergotamine 
Everolimus 
Fentanyl 
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus 
The list is not exhaustive. 
 
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10.17 APPENDIX 17: PATIENT-REPORTED OUTCOMES  
10.17.1 
EORTC QLQ-C30 questionnaire  
 
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10.17.2 
EORTC QLQ-BR23 questionnaire (for female participants)  
 
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10.17.3 
EORTC QLQ-BR23 questionnaire (for male participants)  
 
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10.17.4 
EORTC QLQ-BR45 questionnaire (for female participants)  
 
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10.17.5 
EORTC QLQ-BR45 questionnaire (for male participants)  
 
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10.17.6 
EQ-5D-5L Health Questionnaire  
 
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10.18 ABBREVIATIONS  
 
AESI: 
adverse event of special interest 
AI: 
aromatase inhibitor 
ALT: 
alanine aminotransferase 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase 
BIRC: 
blinded independent review committee 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CEP17: 
centrometric probe for chromosome 17 
cfDNA: 
cell free deoxyribonucleiic acid 
CI: 
confidence interval 
COD: 
cut-off date 
CT: 
computed tomography 
CYP: 
cytochrome P450 
DMC: 
Data Monitoring Committee 
DMET: 
drug metabolizing enzymes and transporters 
DOR: 
duration of response 
DXA: 
dual-energy x-ray absorbtiometry 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
EDR: 
early discrepancy rate 
EHA: 
European hematology association 
EMA: 
European Medicines Agency 
EOT: 
end of treatment 
EQ-5D-5L: 
EuroQoL questionnaire with 5 dimensions and 5 levels per dimension 
ESMO: 
European society for medical oncology 
ET: 
endocrine therapy 
FES-PET: 
Fluoroestradiol Positron-emission tomography 
FFPE: 
formalin fixed paraffin embedded  
FWER: 
family wise error rate 
GCP: 
good clinical practice 
HR: 
hazard ratio 
HR+: 
hormone receptor positive 
HRQL: 
health-related quality of life 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
LDR: 
late discrepancy rate 
MRI: 
magnetic resonance imaging 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIMP: 
noninvestigational medicinal product 
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OS: 
overall survival 
PPE: 
personal protective equipment 
PRO: 
patient reported outcomes 
PS: 
performance status 
QLQ-BR23: 
EORTC QLQ breast cancer specific module 
QLQ-C30: 
EORTC core quality of life questionnaire 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
SD: 
stable disease 
SERD: 
selective estrogen receptor degrader, selective estrogen receptor degrader 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
UGT: 
uridine 5'-diphospho-glucuronosyltransferase 
 
 
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11 
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ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-16. 
19. Park YH, Kim TY, Kim GM, Jung KH, Kang SY, Park IH, et al. Palbociclib plus exemestane 
with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women 
with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a 
multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20:1750-9. 
20. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, et al. Combination 
anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435-44. 
21. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III 
Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human 
Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J 
Clin Oncol. 2018;36(24):2465-72. 
22. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Overall survival 
with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382:514-24. 
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23. Van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M, Kema 
IP, et al. Measuring residual receptor estrogen receptor availability during fulvestrant therapy 
in patients with metastatic breast cancer. Cancer Discov. 2015;5:72-81. 
24. Bardia A, Linden HM, Ulaner GA, Chandarlapaty S, Gosselin A, Doroumian S, et al. Poster: 
Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader 
(SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Journal 
of Clinical Oncology. 2019;37(15_suppl):1054. 
25. Campone M, Bardia A, Ulaner GA, Chandarlapaty S, Gosselin A, Doroumian S, et al. P5-11-
02: Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in 
postmenopausal women with estrogen receptor-positive and human epidermal growth factor 
receptor 2-negative metastatic breast cancer. SABCS 2019. 
26. Flaherty KT, LoRusso PM, DeMichele A, Abramson VG, Courtney R, Randolph SS, et al. 
Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD0332991, 
administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 
2012;18(2):568-76. 
27. NCT00721409. Clinical Trials.gov 
28. Hoffman JT, Loi CM, Plotka A, O’Gorman M, Shi H, Mori A, et al. A phase I open-label 
fixed-sequence two-period crossover study of the effect of multiple doses of modafinil on 
palbociclib (PD-0332991) pharmacokinetics in healthy volunteers. [abstract]. In: Proceedings 
of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-
20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl): Abstract 
LB-198. 
29. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and 
prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):R6. 
30. Rugo HS, MD Current developments in the management of breast cancer. Clinical Advances 
in Hematology & Oncology Volume 17, Issue 10 October 2019. 
31. Ciruelos E, Pascual T, Arroyo Vozmediano ML, Blanco M, Manso L, Parrilla L, et al. The 
therapeutic role of fulvestrant in the management of patients with hormone receptor positive 
breast cancer. Breast. 2014;23(3):201-8. 
32. Lee LYW, Cazier J-B, Angelis V, Arnold R, Bisht V, Campton NA, et al. COVID-19 
mortality in patients with cancer on chemotherapy or other anticancer treatments: a 
prospective cohort study. Lancet. 2020;395(10241):1919-26. 
33. Vuagnat P, Frelaut M, Ramtohul T, Basse C, Diakite S, Noret A, et al. COVID-19 in breast 
cancer patients: a cohort at the Institut Curie hospitals in the Paris area. Breast Cancer Res. 
2020;22(1):55. 
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34. ASCO. COVID-19 Patient Care Information. [Online]. [cited 2020 Sep 30]. Available from: 
URL:https://www.asco.org/asco-coronavirus-information/care-individuals-cancer-during-
covid-19/ 
35. ESMO. COVID-19 AND CANCER. [Online]. [cited 2020 Sep 30]. Available from: 
URL:https://www.esmo.org/covid-19-and-cancer/ 
36. Identifier: NCT03284957; EudraCT Number: 2017-000690-36. Clinicaltrials.gov. 
37. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: 
American Society of Clinical Oncology/College of American Pathologists clinical practice 
guideline update. J Clin Oncol. 2013;31(31):3997-4013. 
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Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol. 
2017;35(33):3760-73. 
 
 
 
 
 
 
 
 
 
 
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According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A randomized, multicenter, double-blind Phase 3 
study of amcenestrant (SAR439859) plus palbociclib 
versus letrozole plus palbociclib for the treatment of 
patients with ER (+), HER2 (-) breast cancer who 
have not received prior systemic anti-cancer 
treatment for advanced disease 
Protocol number: 
EFC15935  
Compound number 
(INN/Trademark): 
SAR439859 
(Amcenestrant/not applicable) 
Study phase: 
Phase 3  
Short title: 
Amcenestrant (SAR439859) plus palbociclib as first 
line therapy for patients with ER (+) HER2 (-) 
advanced breast cancer 
(AMEERA-5) 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
11-May-2021
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
133204 
2020-001824-33 
NCT04478266 
U1111-1233-0486 
Total number of pages: 74 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
VERSION HISTORY ....................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 9 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 12 
3 
ANALYSIS POPULATIONS .......................................................................................................... 13 
4 
STATISTICAL ANALYSES ........................................................................................................... 14 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 14 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 14 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 15 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 15 
4.3.2 
Main analytical approach ............................................................................................................... 15 
4.3.3 
Sensitivity analysis ......................................................................................................................... 17 
4.3.4 
Supplementary analyses ................................................................................................................ 19 
4.3.5 
Evaluation of BIRC data ................................................................................................................. 19 
4.3.6 
Subgroup analyses ........................................................................................................................ 22 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 23 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 23 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 23 
4.4.1.2 
Main analytical approach ............................................................................................................... 24 
4.4.1.3 
Sensitivity analysis ......................................................................................................................... 24 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 24 
4.4.2.1 
Definition of endpoint(s) ................................................................................................................. 24 
4.4.2.2 
Main analytical approach ............................................................................................................... 26 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 27 
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4.6 
MULTIPLICITY ISSUES ................................................................................................................ 27 
4.7 
SAFETY ANALYSES ..................................................................................................................... 27 
4.7.1 
Extent of exposure ......................................................................................................................... 27 
4.7.1.1 
Overall exposure ............................................................................................................................ 28 
4.7.1.2 
Amcenestrant/Letrozole exposure ................................................................................................. 29 
4.7.1.3 
Palbociclib exposure ...................................................................................................................... 30 
4.7.2 
Adverse events .............................................................................................................................. 31 
4.7.3 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 35 
4.8 
OTHER ANALYSES....................................................................................................................... 36 
4.8.1 
PK analyses ................................................................................................................................... 36 
4.8.2 
Quality of life analyses ................................................................................................................... 37 
4.8.3 
Biomarker analyses........................................................................................................................ 40 
4.8.3.1 
Tumor biopsy biomarkers .............................................................................................................. 40 
4.8.3.2 
cfDNA tumor and germline mutation analysis ................................................................................ 40 
4.8.3.3 
Estradiol ......................................................................................................................................... 40 
4.8.3.4 
Genotyping analysis ....................................................................................................................... 41 
4.8.4 
Exposure response analysis .......................................................................................................... 41 
4.8.5 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 41 
4.9 
INTERIM ANALYSES .................................................................................................................... 41 
4.9.1 
Interim analyses for PFS ................................................................................................................ 41 
4.9.2 
Interim analyses for OS ................................................................................................................. 42 
4.9.3 
Data Monitoring Committee (DMC) ................................................................................................ 43 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 44 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 44 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 45 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 46 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 49 
5.4.1 
General conventions ...................................................................................................................... 49 
5.4.2 
Data handling conventions for primary efficacy variables.............................................................. 50 
5.4.3 
Data handling conventions for secondary efficacy variables ......................................................... 51 
5.4.4 
Missing data ................................................................................................................................... 52 
5.4.5 
Unscheduled visits ......................................................................................................................... 55 
5.4.6 
Pooling of centers for statistical analyses ...................................................................................... 55 
5.4.7 
Statistical technical issues ............................................................................................................. 55 
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5.5 
APPENDIX 5 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......... 55 
5.6 
APPENDIX 6 SUMMARY OF STATISTICAL ANALYSES ............................................................ 56 
5.7 
APPENDIX 7 INTERNATIONALLY AGREED SOC ORDER ........................................................ 59 
5.8 
APPENDIX 8 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1) ........... 60 
5.9 
APPENDIX 9 DESCRIPTION OF CENSORING AND EVENT RULES FOR PRIMARY AND 
SENSITIVITY ANALYSES OF PFS ............................................................................................... 65 
5.10 
APPENDIX 10 EORTC QLQ-C30, QLQ-BR23, AND QLQ-BR45 ITEMS, SCALES AND 
SCORES ........................................................................................................................................ 69 
6 
REFERENCES ............................................................................................................................... 73 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 6 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints ........................................................................ 10 
Table 4 - Populations for analyses ................................................................................................................ 13 
Table 5 - Cross-tabulation of ICR and investigator assessments of documented PD .................................. 21 
Table 6 - Cross-tabulation of ICR and investigator assessments of PFS outcome ...................................... 22 
Table 7 - Subgroups analyses: covariates investigated ................................................................................ 22 
Table 8 - Sorting of AE tables ....................................................................................................................... 32 
Table 9 - Analyses of adverse events ........................................................................................................... 33 
Table 10 - Selections for AESIs .................................................................................................................... 34 
Table 11 - PFS analyses ............................................................................................................................... 42 
Table 12 - OS analyses ................................................................................................................................. 43 
Table 13 - Major statistical changes in protocol amendment(s) .................................................................... 45 
Table 14 - Response criteria, evaluation of target lesions ............................................................................ 63 
Table 15 - Response criteria, evaluation of nontarget lesions ...................................................................... 63 
Table 16 - A summary of overall response status for measurable disease .................................................. 63 
Table 17 - A summary of overall response status for non-measurable disease ........................................... 64 
Table 18 - Evaluation of best overall response ............................................................................................. 64 
Table 19 - PFS Primary analysis ................................................................................................................... 65 
Table 20 - PFS sensitivity analysis #1 (PFS considering events occurring after two or more non-evaluable 
tumor assessment as event and ignoring further anticancer therapy) .......................................................... 66 
Table 21 - PFS sensitivity analysis #2 (PFS considering events occurring after two or more non-evaluable 
tumor assessment as event and back-dating at the next scheduled assessment) ....................................... 67 
Table 22 - PFS supplementary analysis for investigator assessment (taking clinical/non-radiological 
progression as event) .................................................................................................................................... 68 
 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study EFC15935 is based on the protocol amendment 03 
dated 13-Dec-2020. The first participant was randomized on 19-Nov-2020. This SAP is approved 
before the first interim analysis is conducted.  
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1 
11-May-2021 
Not Applicable 
Original version 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a prospective multicenter, international, randomized, double-blind, double-dummy, 
Phase 3 trial comparing the efficacy and safety of amcenestrant in combination with palbociclib 
versus letrozole in combination with palbociclib in men, pre/peri-menopausal women (with 
goserelin), and postmenopausal women, all with ER(+)/HER2(-) breast cancer who have not 
received prior systemic treatment for advanced disease.  
All eligible participants will be randomly assigned using an Interactive Response Technology 
(IRT) to either amcenestrant plus palbociclib (experimental) arm or letrozole plus palbociclib 
(control) arm in a 1:1 ratio.  
The population will be stratified by: 
• De-novo metastatic disease (Yes or No). 
• Postmenopausal women (Yes or No). 
• Visceral metastasis defined by at least 1 liver, lung, brain metastasis, pleural, or peritoneal 
involvement (Yes or No). 
1066 participants will be randomly assigned to study intervention with a balanced randomization 
ratio (533 participants randomized per treatment arm). 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine whether amcenestrant in 
combination with palbociclib improves 
progression free survival (PFS) when compared 
with letrozole in combination with palbociclib in 
participants with ER+, HER2- advanced breast 
cancer who have not received prior systemic 
anticancer therapies for advanced disease 
• 
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 local radiologist/investigator or death 
(due to any cause), whichever comes first. 
Secondary 
Key secondary objective: 
Key secondary endpoint: 
• 
To compare the overall survival (OS) in both 
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). 
Other Secondary objectives: 
Other Secondary endpoints: 
• 
To evaluate the objective response rate (ORR) 
in both treatment arms 
• 
Objective response rate is defined as the proportion of participants 
who have a complete response (CR) or partial response (PR), as 
best overall response determined as per RECIST 1.1, from the date 
of randomization until disease progression, death, cutoff date, 
initiation of post-treatment anti-cancer therapy, whichever occurs 
first. 
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Objectives 
Endpoints 
• 
To evaluate the duration of response (DOR) in 
both treatment arms 
• 
Duration of response is defined as the time from first documented 
evidence of CR or PR until progressive disease (PD) as determined 
as per RECIST 1.1 or death from any cause, whichever occurs first. 
• 
To evaluate the clinical benefit rate (CBR) in 
both treatment arms 
• 
Clinical benefit rate is defined as the proportion of participants who 
have a confirmed CR, PR, or stable disease (SD) for at least 24 
weeks determined as per RECIST 1.1, from the date of 
randomization until disease progression, death, cutoff date, initiation 
of post-treatment anti-cancer therapy, whichever occurs first. 
• 
To evaluate progression-free survival on next 
line of therapy (PFS2) 
• 
The PFS2 is defined as the time from the date of randomization to 
the date of first documentation of PD on the next systemic anti-
cancer therapy according to investigator or death due to any cause 
in the absence of documented PD on the next systemic anti-cancer 
therapy, whichever occurs first. 
• 
To evaluate the pharmacokinetics (PK) of 
amcenestrant, and palbociclib 
• 
Plasma concentrations of amcenestrant, palbociclib 
 
• 
To evaluate health-related quality of life (HRQL) 
in both treatment arms 
• 
Symptoms and function related to HRQL as measured by EORTC 
QLQ-C30, breast cancer specific module (QLQ-BR23/BR45) and 
EQ-5D-5L  
Disease-specific and generic HRQL, disease and treatment-related 
symptoms, the impact of symptoms and treatment, health state 
utility, and health status will be evaluated using the European 
Organization for Research and Treatment of Cancer (EORTC) core 
quality of life questionnaire (QLQ-C30), the EORTC-QLQ breast 
cancer specific module (QLQ-BR23/BR45) 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 study 
treatment 
• 
To evaluate the time to first chemotherapy in 
both treatment arms 
• 
Time to chemotherapy is defined as the time interval from the date 
of randomization to the start date of the first chemotherapy after 
study treatment discontinuation 
• 
To evaluate safety in both treatment arms 
• 
Adverse events (AEs)/serious adverse events (SAEs) and 
laboratory abnormalities 
Tertiary/exploratory 
• 
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). 
• 
Tumor ER, Ki67, Bcl-2, and PgR protein, and RNA gene expression 
profiles in paired biopsies at Cycle 1 Day 1 (pre-treatment) and 
optional at end of treatment for participants who discontinued 
treatment due to disease progression  
• 
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. 
• 
The gene mutation profile of the tumor by cfDNA analysis over time 
(Cycle 1 Day 1 [pre-treatment], at Cycle 4 Day 1 predose (tumor 
assessment), and upon disease progression on treatment or EOT 
whichever comes first) 
• 
To evaluate exposure/response relationship of 
amcenestrant and palbociclib 
• 
PK of amcenestrant will be correlated with safety and/or efficacy 
• 
To evaluate the PK of goserelin 
• 
Plasma concentrations of goserelin 
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Objectives 
Endpoints 
• 
To evaluate PFS in participants expressing 
PIK3CA and ESR1 mutation in both treatment 
arms 
• 
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 local radiologist/investigator or death 
(due to any cause), whichever comes first. 
1.2.1 Estimands  
Primary estimands defined for the primary endpoint and key secondary endpoint are summarized 
in below Table 3. More details are provided in Section 4. For both estimands, the comparison of 
interest will be the comparison of amcenestrant in combination with palbociclib versus letrozole 
in combination with palbociclib. The analysis population corresponds to all participants from the 
intent-to-treat population.       
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Table 3 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
Population-level summary 
(Analysis and missing data handling) 
Primary objective: to determine whether amcenestrant in combination with palbociclib improves the progression free survival (PFS) when compared to letrozole in combination 
with palbociclib. 
Primary endpoint 
(Estimand 1) 
PFS 
ITT 
- Interruption/discontinuation of study intervention: PFS will be 
analyzed based on events irrespective of study intervention 
interruption/discontinuation (treatment policy strategy). 
- Start of new anti-cancer therapy prior to PFS event: PFS will 
be censored at the last evaluable tumor assessment prior to a 
new anti-cancer therapy is initiated (hypothetical strategy). 
- PFS event documented after two or more non-evaluable tumor 
assessments: PFS will be censored at the last evaluable tumor 
assessment prior to the event (hypothetical strategy). 
 
One-sided log-rank test stratified by 
randomization stratification factors, as entered in 
the IRT system. 
Hazard ratio (HR) and corresponding 95% CI 
estimated using stratified Cox proportional hazard 
model. 
The Kaplan Meier estimate of PFS at specified 
time points, PFS quartiles and corresponding 
95% CI from Kaplan Meier method. 
Primary endpoint 
Sensitivity analysis #1 
(Estimand 1 – SA#1) 
PFS 
ITT 
- Interruption/discontinuation of study intervention: PFS will be 
analyzed based on events irrespective of study intervention 
interruption/discontinuation (treatment policy strategy). 
- Start of new anti-cancer therapy prior to PFS event: PFS will 
be analyzed based on events irrespective of start of new anti-
cancer therapy (treatment policy strategy). 
- PFS event documented after two or more non-evaluable tumor 
assessments: PFS will be analyzed based on events 
irrespective of time interval between an event and the last 
evaluable tumor assessment prior to the event (treatment policy 
strategy) 
One-sided log-rank test stratified by 
randomization stratification factors, as entered in 
the IRT system. 
Hazard ratio (HR) and corresponding 95% CI 
estimated using stratified Cox proportional hazard 
model. 
The Kaplan Meier estimate of PFS at specified 
time points, PFS quartiles and corresponding 
95% CI from Kaplan Meier method. 
 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
Population-level summary 
(Analysis and missing data handling) 
Key secondary objective: to compare overall survival between two treatment arms. 
Key secondary 
endpoint 
(Estimand 2) 
OS 
ITT 
- Interruption/discontinuation of study intervention: OS will be 
analyzed based on events irrespective of study intervention 
interruption/discontinuation (treatment policy strategy). 
- Start of new anti-cancer therapy prior to death: OS will be 
analyzed based on events irrespective of start of new anti-
cancer therapy (treatment policy strategy). 
 
 
 
One-sided log-rank test stratified by 
randomization stratification factors, as entered in 
the IRT system. 
Hazard ratio (HR) and corresponding 95% CI 
estimated using stratified Cox proportional hazard 
model. 
The Kaplan Meier estimate of OS at specified 
time points, OS quartiles and corresponding 95% 
CI from Kaplan Meier method. 
 
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2 
SAMPLE SIZE DETERMINATION  
Global population 
For PFS, a total of 516 PFS events assessed by local radiologist/investigator will be needed to 
reject the null hypothesis using a logrank test at the one-sided level of 2.5% and a 90% power 
under the assumption of a HR of 0.75. Assuming proportional hazards under an exponential 
model and based on an anticipated median PFS of 24.8 months in the letrozole + palbociclib arm, 
this is expected to correspond to a median PFS of 33.1 months in the SAR439859 + palbociclib 
arm. Based on an expected accrual duration of 18 months (15% of total accrual in the first 
4.5 months and 40% of total accrual in the first 9 months), a PFS analysis cut-off date (COD) 
40 months after the first participant randomized and an annual dropout rate of 5%, a total of 
1066 participants are expected to be randomized in a 1:1 ratio into the SAR439859 + palbociclib 
and letrozole + palbociclib arms. The power calculation accounts for two interim analyses at 40% 
and 70% of the planned number of events. 
For OS, a total of 632 deaths will be needed to reject the null hypothesis using a logrank test at the 
one-sided level of 2.5% and a 80% power under the assumption of a HR of 0.80. Assuming 
proportional hazards under an exponential model and based on an anticipated median OS of 
46 months in the letrozole + palbociclib arm, this is expected to correspond to a median OS of 
57.5 months in the SAR439859 + palbociclib arm. OS COD is expected 80 months after the first 
participant randomized (assuming an annual dropout rate of 1%). The power calculation accounts 
for two interim analyses at the time of the PFS primary analysis and at 75% of the planned 
number of OS events. 
Calculations were made using East 6.5 software. 
 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 4 - Populations for analyses  
Population 
Description 
Screened  
All participants who signed the ICF. 
Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by IRT regardless of whether the intervention was received or not. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the treatment 
arm assigned at randomization. 
Safety 
All randomized participants and who took at least 1 dose of study intervention. 
Participants will be analyzed according to the treatment arm they actually received. 
Pharmacokinetic (amcenestrant) 
All participants from the safety population who receive at least 1 dose of 
amcenestrant and with at least 1 evaluable plasma concentration of amcenestrant 
posttreatment.  
Pharmacokinetic (palbociclib) 
All participants from the safety population who receive at least 1 dose of palbociclib 
and with at least 1 evaluable plasma concentration of palbociclib posttreatment.  
Pharmacokinetic (goserelin) 
All participants from the safety population who receive at least 1 dose of goserelin 
and with at least 1 evaluable plasma concentration of goserelin posttreatment. 
Population without trial impact 
(disruption) due to Covid-19 
All randomized participants: 
• 
without any critical or major deviation related to Covid-19  
• 
and who did not permanently discontinue full treatment due to Covid-19  
• 
and who did not permanently discontinue study due to Covid-19. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety 
experience of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population.  The safety experience associated with any 
later randomization will be reported separately. 
For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be the as-randomized intervention group if the participant has 
received at least one administration of the as-randomized intervention. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
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.  
Unless otherwise specified, analyses will be performed by intervention group (and overall for 
baseline and demographics characteristics). 
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to first IMP administration.  
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days.  
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. Reasons for exclusion from the population without trial impact (disruption) due to 
Covid-19 will be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
Regarding intervention discontinuation, the following definitions will be used: 
• Permanent partial intervention discontinuation of palbociclib is defined as the 
discontinuation of palbociclib but amcenestrant/letrozole is continued.  
• Permanent full intervention discontinuation is defined as the discontinuation of all the 
study drugs. 
The number (%) of participants in the following categories will be provided:  
• Randomized participants. 
• Randomized but not exposed participants. 
• Randomized and exposed participants. 
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• Participants who discontinued all the study drugs and main reason for permanent full 
intervention discontinuation.  
• Participants who discontinued palbociclib but amcenestrant/letrozole is continued, and 
main reason for permanent partial discontinuation of palbociclib. 
• Participants still on treatment. 
• Status at the cut-off date (Alive/Death). 
• Participants with date of last contact obtained before the cutoff date and duration from last 
contact to cut-off date (0-4 weeks, 4-8 weeks, 8-12 weeks, >12 weeks). 
Reasons for permanent study intervention “adverse event” and “other reasons” will be split as 
related versus not related to Covid-19, if applicable. 
The number (%) of exposed and not randomized participants will also be summarized.  
In addition, the number (%) of participants screened, screened-failed, randomized, with 
permanent full intervention discontinuation will be provided by country and site/geographical 
region. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population as well as displayed separately as related versus not related to Covid-19 if 
applicable. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint Progression-Free Survival (PFS) 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 local radiologist/investigator or 
death (due to any cause), whichever comes first. 
4.3.2 Main analytical approach  
Primary efficacy analysis will consist of PFS according to local radiologist’s/investigator’s 
assessment comparison between the amcenestrant + palbociclib arm and the letrozole + 
palbociclib arm through a logrank test procedure stratified by the stratification factors as entered 
in the IRT (ie, de-novo metastatic disease, postmenopausal women and visceral metastasis defined 
by at least 1 liver, lung, brain metastasis, pleural, or peritoneal involvement). A onesided 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 
experimental arm is lower than or equal to the SDF of the control arm. 
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- 
H0: SDF (Experimental) ≤ SDF (Control) 
versus 
• The alternative hypothesis that the SDF for the PFS of the experimental arm is superior to 
the SDF of the control arm. 
- 
H1: SDF (Experimental) > SDF (Control) 
The cut-off date for the analysis of PFS is the actual date when the 516 PFS events (first 
occurrence of either documented progression assessed by local radiologist/investigator or death 
due to any cause) have been observed according to the primary PFS analysis. It is approximately 
estimated 40 months after first randomized participant assuming an accrual duration of 18 months 
(15% of total accrual in the first 4.5 months and 40% of total accrual in the first 9 months), an 
annual dropout rate of 5%, and a median PFS of 24.8 months in the control arm and a hazard ratio 
of 0.75.  
The primary efficacy analyses on PFS will be performed on the ITT population, based on local 
radiologist’s/Investigator’s assessment of tumor burden. Analysis based on blinded Independent 
Review Committee (BIRC) assessment will also be performed but considered as supportive 
analyses.  
PFS will be analyzed with Estimand 1 introduced in Section 1.2.1 and defined according to the 
following attributes: 
• Intercurrent events: 
- 
The IMP discontinuation IE will be handled with the treatment policy strategy: PFS 
will be assessed based on tumor assessments and death irrespective of IMP 
discontinuation, 
- 
The new anticancer therapy IE will be handled with the hypothetical strategy: PFS 
will be censored at last evaluable tumor assessments prior to a new anti-cancer 
therapy, 
- 
Events documented after two or more non-evaluable tumor assessment will be handled 
with the hypothetical strategy: PFS will be censored at last evaluable tumor 
assessment if the event is documented after two or more non-evaluable tumor 
assessment. 
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 different 
timepoints (for example, at least 3, 6, 9, 12, 15, 18, 21, 24, 30, 36 and 39 months) with 
95% CIs will be estimated for each treatment group using the Kaplan-Meier method 
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and a log-log approach based on a normal approximation following the Greenwood’s 
formula, 
- 
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. 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. 
• Median follow-up time (months) for the overall population will be estimated by treatment 
group using the reverse Kaplan-Meier method, where censored data are treated as events 
and events are treated as censored data. 
• Time to tumor assessment may be summarized for the two treatment arms using 
descriptive statistics. 
4.3.3 Sensitivity analysis  
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 and considering events (documented progression or 
death) occurring after two or more non-evaluable tumor assessment as event. 
• Considering events (documented progression or death) occurring after exactly one or two 
or more non-evaluable tumor assessment as event and back-dated to the next scheduled 
assessment. 
Additional details are provided in Section 5.9. 
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Sensitivity analysis #1 (PFS considering events occurring after two or more non-evaluable tumor 
assessment as event and ignoring further anti-cancer therapy) 
PFS endpoint will be analyzed based on local radiologist’s/Investigator’s assessment, with 
Estimand 1-SA#1 introduced in Section 1.2.1. Events (documented progression or death) 
occurring after two or more non-evaluable tumor assessment and events (documented progression 
or death) occurring after the start of any further ani-cancer therapy will be included. The date of 
progression (or death) will be used for date of outcome. 
Sensitivity analysis #2 (PFS considering events occurring after two or more non-evaluable tumor 
assessment as event and back-dating at the next scheduled assessment) 
If more than 10% patients have two or more consecutive non-evaluable assessments prior to PFS 
event, PFS endpoint will be analyzed based on local radiologist’s/Investigator’s assessment, 
including events (documented progression or death) occurring after two or more non-evaluable 
tumor assessment as event. The date of the next scheduled assessment will be used for date of 
outcome. 
Stratification factors 
The same statistical methods used in the primary analysis will be applied using different 
stratification rules as defined below.  
Sensitivity analysis #3 (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 endpoint will be analyzed based on local 
radiologist’s/Investigator’s 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 is not valid, Restricted Mean Survival Time (RMST) method (1) 
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 progression-free time between randomization and a common timepoint denoted by 
τ. The timepoint τ should be limited to the largest uncensored time to event in the data: 
• 𝜏𝑚𝑎𝑥 = minimum of (largest observed PFS event time for experimental arm, largest 
observed PFS event time for control arm). 
The treatment effect will be estimated based on the difference in RMST between the two 
treatment arms. The associated 95% CI for the difference in means RMST as a function of τ will 
be generated and the associated treatment effect between the two treatment arms will be plotted 
against time τ. 
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4.3.4 Supplementary analyses  
A supplementary analysis will be performed considering the clinical/non-radiological progression 
as event, with the date of clinical/non-radiological progression as date of outcome. In addition 
sensitivity analyses could be performed using different censoring and event rules or stratification 
rules as defined in Section 4.3.3, if relevant. 
4.3.5 Evaluation of BIRC data  
A random sample-audit BIRC approach will be used as an auditing tool to support the primary 
findings on PFS based on the local radiologist’s/investigator’s assessment (denoted by LE-PFS). 
Approximately 50% of the randomized participants will be randomly selected and the BIRC will 
assess the tumor progression of these participants based on the review of tumor assessments.  
The audit size calculation approach will be based on the method proposed by Dodd, et al (2). 
Assuming local radiologist’s/investigator’s and BIRC assessments are similar and the estimated 
log of investigator-based HR is -0.2877 (ie, HR=0.75), the audit size of 50% will ensure that the 
upper bound of a one-sided 95% CI for BIRC-based log-hazard ratio has 83% probability of being 
below 0 (ie, HR <1) if the correlation between local radiologist’s/investigator’s assessment and 
BIRC assessment is 0.65. If the correlation based on the LE-PFS and BIRC-PFS is greater than 
our assumption, the power of the sample-audit will increase. 
Two methods will be used to summarize the data from the sample-based BIRC assessment of 
PFS.  
Robustness of LE-PFS treatment effect 
Robustness of PFS treatment effect will be evaluated with the NCI (National Cancer Institute) 
method (2), which uses an auxiliary variable estimator of the log-hazard ratio that combines 
information from participant level local radiologist’s/investigator’s assessment from all 
participants and the BIRC assessment of participants randomly selected for central review. If the 
upper bound of the one-sided 95% CI of the auxiliary estimator is below 0, then the BIRC audit is 
considered to have confirmed findings based on local evaluations; otherwise, a full BIRC may be 
triggered.  
The auxiliary variable estimates and its one-sided 95% CI will be calculated as follows: 
• 𝛿 =
𝑚
𝑁 , the ratio of sample-audit BIRC size (m) on the trial size (N). 
• 𝛳̂𝐿𝐸; 𝑉̂𝐿𝐸, the estimate of the log-hazard ratio and associated variance of the LE-PFS based 
on all patients. 
• 𝛳̂𝐿𝐸1; 𝑉̂𝐿𝐸1, the estimate of the log-hazard ratio and associated variance of the LE-PFS for 
the patients not selected based on the sample-audit BIRC. 
• 𝛳̂𝐿𝐸2; 𝑉̂𝐿𝐸2, the estimate of the log-hazard ratio and associated variance of the LE-PFS for 
the patients selected based on the sample-audit BIRC. 
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• 𝛳̂𝐵𝐼𝑅𝐶; 𝑉̂𝐵𝐼𝑅𝐶, the estimate of the log-hazard ratio and associated variance of the 
BIRC-PFS for the patients selected based on the sample-audit BIRC. 
• 𝜌̂, a bootstrap estimator of the correlation between 𝛳̂𝐵𝐼𝑅𝐶 and 𝛳̂𝐿𝐸2.  
Specifically, within the randomly selected sample (of size m) for BICR audit, a bootstrap sample 
of m participants will be sampled with replacement. The two sample-based log-hazard ratio 
estimates (LE-based vs. BICR-based) will be estimated with the bootstrap sample. The procedure 
will be repeated 10000 times, and 10000 pairs of sample estimates of log (HR) (LE-based versus 
BICR-based) will be calculated. The sample correlation coefficient between the LE-based 
log(HR) estimates and BICR-based log(HR) estimates denoted 𝜌̂ will be obtained based on the 
Pearson correlation coefficient, which will be used in the calculation of the auxiliary estimator 
and the corresponding one-sided 95% CI. 
The auxiliary estimator, 𝛳 ̃, will be calculated as 
𝛳  
̃ = 𝛳̂𝐵𝐼𝑅𝐶+ 𝜌̂√𝛿(1−δ)√
𝑉̂𝐵𝐼𝑅𝐶
𝑉̂𝐿𝐸 (𝛳̂𝐿𝐸2 −𝛳̂𝐿𝐸1) 
The estimate of variance of  𝛳  
̃will be calculated as  
𝑉  ̃ = 𝑉̂𝐵𝐼𝑅𝐶{1 − 𝜌̂2(1 −𝛿)} 
Assuming asymptotic normality of 𝛳  
̃, the upper bound of one-sided 95% CI of this estimator will 
be calculated as 𝛳  
̃ + 𝑍1−0.05√𝑉  ̃, where 𝑍1−0.05 is the 95% quantile of a standard normal 
distribution. Then the associated upper bound of the confidence interval for the BIRC-PFS HR is 
obtained with 𝑒𝛳  
̃+𝑍1−0.05√𝑉  ̃ . 
The criteria for determining the robustness of the LE-PFS treatment effect will be based on the 
comparison of this upper bound of the 95% one-sided confidence interval with a clinically 
irrelevant threshold corresponding to no treatment effect, ie, an HR of 1. If the upper bound of the 
95% one-sided confidence interval is below 1, robustness of the LE-PFS treatment effect will be 
considered as a similar outcome is observed between the BIRC and LE assessment. Indeed, in this 
situation, the upper bound of the confidence interval associated with the estimate of the true LE-
PFS and the true BIRC-PFS treatment effects both exclude the threshold of no treatment effect. 
Otherwise, if the upper bound of the 95% one-sided confidence interval is greater than 1, one 
cannot conclude that the sample-audit BIRC is supportive of the LE findings and a full BIRC may 
be triggered to support the primary findings based on the LE-PFS treatment effect. 
Differential discordance on PD events 
The differential discordance between the BIRC and the investigator assessment of documented 
progression will be assessed using the Pharmaceutical Research and Manufacturers of America 
(PhRMA) method (3). The early discrepancy rate (EDR) and late discrepancy rate (LDR) 
differences between the two treatment arms will be calculated as follows: 
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Table 5 - Cross-tabulation of ICR and investigator assessments of documented PD  
Investigator/local radiologist 
BIRC 
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 BIRC 
a3: number of times investigator declares documented PD earlier than BIRC 
If full BIRC is not triggered, the calculation will be based on participants who were randomly 
selected for central review. Otherwise, the calculation will be based on all participants. 
The timing of investigator/local radiologist and BIRC (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 + palbociclib arm 
minus the rate on the letrozole + palbociclib 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. 
Concordance of PFS outcome 
A comparison of PFS outcome (ie, "Documented progression", "Death", "Censored") and timing 
(ie, "Same time", "ICR after INV", "ICR before INV") between the ICR and the investigator 
assessments will be summarized for each treatment group.  
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If full BIRC is not triggered, the calculation will be based on participants who were randomly 
selected for central review. Otherwise, the calculation will be based on all participants. 
Table 6 - Cross-tabulation of ICR and investigator assessments of PFS outcome  
Investigator/local 
radiologist 
ICR 
Documented PD 
Death 
Censored 
Documented PD 
n11 
n12 
n13 
Death 
n21 
n22 
n23 
Censored 
n31 
n32 
n33 
The PFS Outcome Discrepancy Rate (PFS ODR) will be calculated for each treatment arm as 
follow. 
PFS ODR = 𝑛13 + 𝑛23 + 𝑛31 + 𝑛32
∑𝑛𝑖𝑗
𝑖𝑗
 
4.3.6 Subgroup analyses  
Evaluation of treatment effect 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 7. 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 25th, 50th and 75th percentiles and their associated 
95% CIs 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 7 - Subgroups analyses: covariates investigated  
Subgroup 
Description 
De-novo metastatic disease as per IRT 
Yes or No 
Postmenopausal women as per IRT 
Yes or No 
Visceral metastasis as per IRT 
Yes or No 
ECOG 
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 
Prior chemotherapy 
Yes or No 
PgR status 
PgR+ or PgR- 
PIK3CA mutational status 
Wild type or mutated 
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Subgroup 
Description 
ESR1 mutational status 
Wild type or mutated 
Number of metastatic sites 
<3 or ≥3 
Measurable disease status 
Measurable or Non-measurable 
Treatment-free interval 
<2 years v.s. >=2 years 
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 7, PFS will be analyzed using an unstratified Cox 
proportional hazards model with terms for the factor, treatment and their interaction. The p-value 
of the test of interaction will be provided. 
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 7 using a stepwise selection procedure with a 15% significance level for removing effects. 
For significant prognostic factors identified in the multivariate model, the balance between 
treatment groups will be assessed. 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. 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are overall survival (OS), objective response rate 
(ORR), clinical benefit rate (CBR), duration of response (DOR), time to first chemotherapy 
(TT1C) and progression-free survival on the next systemic anti-cancer therapy (PFS2). Other 
secondary endpoints analyses are defined in Section 4.7.2 (AE, SAE), Section 4.7.3 (laboratory 
abnormalities), Section 4.8.1 (PK) and Section 4.8.2 (quality of life).   
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
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 at the last date the 
participant is known to be alive or at the OS cut-off date, whichever occurs first.  
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4.4.1.2 Main analytical approach  
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 the amcenestrant + 
palbociclib arm and the letrozole + palbociclib arm 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 
experimental arm is lower than or equal to the SDF of the control arm. 
- 
H0: SDF (Experimental) ≤ SDF (Control) 
versus 
• The alternative hypothesis that the SDF for the OS of the experimental arm is superior to 
the SDF of the control arm. 
- 
H1: SDF (Experimental) > 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 632 death events have been observed.  
OS will be analyzed on the ITT population, with Estimand 2 introduced in Section 1.2.1. 
Intercurrent events will be handled with the treatment policy strategy: OS will be assessed based 
on overall survival data irrespective of IMP interruption/discontinuation and irrespective of start 
of new anti-cancer therapy. The same estimates will be provided as for PFS defined in  
Section 4.3.2, with the exception that the follow-up of OS will be defined as the time interval 
from the date of randomization to the date of last contact with the patient. Patients who have died 
will be censored on their date of death.  
4.4.1.3 Sensitivity analysis  
Sensitivity analyses adjusting OS for switch to subsequent anti-cancer treatment could be 
performed at interim and/or final analyses, eg, using inverse probability of censoring weighting 
(IPCW) method (4) and rank preserving structural failure time model (RPSFTM) (5). 
4.4.2 Supportive secondary endpoint(s)  
4.4.2.1 Definition of endpoint(s)  
Objective response rate 
The Best Overall Response observed from the date of randomization until documented disease 
progression, death, start of an anti-cancer therapy, or analysis cut-off date (COD), whichever 
occurs first, will be determined according to RECIST v1.1. Confirmation of responses (CR or PR) 
is necessary.  
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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 Investigator, 
according to RECIST 1.1) by the number of participants from the analysis population of the 
respective treatment arm.  
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.   
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) or COD, whichever comes first.  
DOR is determined only for patients who have achieved a BOR of PR or better. 
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 investigator 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. Only 
tumor assessments performed before documented disease progression, death, start of an anti-
cancer therapy, or analysis cut-off date, whichever occurs first, will be used for the derivation of 
the CBR. 
Progression-free survival on next line of therapy (PFS2) 
The PFS2 is defined as the time from the date of randomization to the date of first documentation 
of PD on the next systemic anti-cancer therapy according to investigator or death due to any 
cause, whichever occurs first. Documentation of progression on the next systemic anti-cancer 
therapy is based on investigator assessment of PD as captured in the follow-up CRF page.  
Time to first Chemotherapy (TT1C) 
The time to first use of chemotherapy after disease progression is defined as the time from date of 
randomization to start of the first use of chemotherapy. In the absence of chemotherapy after 
study treatment discontinuation, TT1C will be censored at the last contact date or the cutoff date, 
whichever occurs first. 
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4.4.2.2 Main analytical approach  
Analysis of response-based endpoints (ie, ORR, DOR and CBR) will be performed primarily on 
the ITT population and supported by the analyses based on the ITT population with measurable 
disease at study entry. The other secondary analyses will be performed on ITT population only.  
Response-based endpoints 
ORR and CBR according to investigator assessments 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. 
Of note, the BOR for each participant will also be summarized according to Investigator 
assessments. 
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 using Kaplan-Meier methods and displayed graphically, if appropriate. 25th, 50th 
and 75th percentiles of DOR and associated 95% CI will be provided. The 95% CIs will be 
estimated for each treatment group using the Kaplan-Meier method and a loglog approach based 
on a normal approximation following the Greenwood’s formula. 
Exploratory analyses of response-based endpoints may be provided according to subgroups of 
interest (Table 7). 
Waterfall plots will be used to display the best relative change from baseline in tumor size 
observed for each patient.  It will be sorted within each arm by decreasing order of best relative 
change from baseline in patients with measurable disease at baseline. BOR will be displayed. 
Only patients with post-baseline target lesions measurement will be included in the plot. 
Progression-free survival on next line of therapy (PFS2) 
The PFS2 will be assessed with the following censoring and event scheme: 
• Alive patients who have not yet initiated a next systemic anticancer therapy will be 
censored at the last contact date, or COD, whichever comes first.  
• Patients who have died prior to initiation of the next systemic anticancer therapy will be 
considered as having an event with death date as event date in the PFS2 analysis.  
• Patients without PFS2 event who have initiated a first next systemic anticancer therapy but 
not a second next systemic anticancer therapy will be censored at the last contact date or 
COD, whichever comes first.  
• Patients without PFS2 event who have initiated a first next systemic anticancer therapy 
and a second next systemic anticancer therapy without event will be censored at the start 
date of their second next systemic anticancer therapy or COD, whichever comes first. 
The same statistical methods as for PFS will be used with the exception that no statistical test will 
be made. 
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Time to first Chemotherapy (TT1C) 
The TT1C will be assessed with the following censoring scheme: 
• Alive patients who have not yet initiated a new chemotherapy will be censored at the last 
contact date, or COD, whichever comes first.  
• Patients who have died prior to initiation of a new chemotherapy will be censored at the 
death date, or COD, whichever comes first.  
The same statistical methods as for PFS will be used with the exception that no statistical test will 
be made. 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
Tertiary endpoints analyses are defined in Section 4.8.1 (PK), Section 4.8.3 (Biomarker) and 
Section 4.8.4 (Exposure/response relationship).   
4.6 
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. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 3, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized within the safety population. In addition, summaries may be provided by trial impact 
(disruption) due to Covid-19. 
Duration of IMP exposure 
Duration of IMP exposure will be summarized quantitatively and categorically: Less than 
24 weeks, 24 to 48 weeks, 48 to 72 weeks, 72 to 96 weeks, 96 to 120 weeks, 120 to 144 weeks 
and >144 weeks. 
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Treatment compliance 
Percentage of treatment compliance for a participant will be evaluated by relative dose intensity 
for each IMP, as defined in Section 4.7.1.2 and Section 4.7.1.3.  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least one 
dose of any study interventions is administered. 
• Duration of IMP exposure (in weeks) is defined as (last day of exposure – first day of 
exposure + 1)/7. 
• The first day of exposure is defined as the first administration date with non-zero dose for 
at least one of the IMP amcenestrant/letrozole, matching placebo, palbociclib. The last day 
of exposure is the last day of study treatment administration plus appropriate carryover 
days, defined as the maximum between: 
- 
The last administration date of amcenestrant/letrozole, 
- 
Minimum of (date of death, the last administration date of Palbociclib + 7. 
The total number of cycles started, number of cycles started by participants will be summarized as 
a quantitative variable and by category (number (%) of participants receiving at least 4 cycles, at 
least 8 cycles, etc.). The duration of overall exposure will be summarized quantitatively.  
The following variable will be computed to describe overall dose modification (cycle delay): 
• Cycle delay: A cycle is deemed as delayed if the start date of the current cycle – start date 
of the previous cycle is >31 days. Cycle delay is not defined for the first cycle. 
Cycle delay will be analyzed at the participant (with number of participants used as denominator) 
and cycle (with number of cycles used as denominator) levels, as follows: 
• Number (%) of participants with a least 1 cycle delayed 
- 
Number (%) of participants with a cycle delayed between 4 and 7 days (using 
maximum delay across all cycles),  
- 
Number (%) of participants with a cycle delayed between 8 and 14 days (using 
maximum delay across all cycles),  
- 
Number (%) of participants with a cycle delayed >14 days (using maximum delay 
across all cycles). 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 4 and 7 days, 
- 
Number (%) of cycles delayed between 8 and 14 days, 
- 
Number (%) of cycles delayed >14 days. 
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4.7.1.2 Amcenestrant/Letrozole exposure  
The dose information will be assessed by the following: 
• Duration of amcenestrant/letrozole exposure (in weeks) is defined by (date of last 
administration of amcenestrant/letrozole – date of first administration of 
amcenestrant/letrozole+1) /7. 
• Cumulative dose (mg): the cumulative dose is the sum of all actual doses of 
amcenestrant/letrozole, given from first to last administration.  
• Actual dose intensity (ADI in mg/day) for amcenestrant/letrozole: defined as the 
cumulative dose divided by the duration of amcenestrant/letrozole exposure (in weeks×7) 
ADI=
Cumulative Dose (mg)
Duration of treatment in weeks ×7 
• Planned dose intensity (PDI in mg/day): planned dose of amcenestrant/letrozole on C1D1. 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/day)
PDI (mg/day) 
The total number of doses, total number of cycles started, number of cycles started by participant 
will be summarized as a quantitative variable and by category (number [%] of participants 
receiving at least 1 cycle, at least 2 cycles, etc.). Duration of amcenestrant/letrozole exposure, 
cumulative dose, ADI and RDI will be summarized quantitatively. RDI will also be summarized 
according to the following categories: 0-80%, 80-100%, >100%. 
The following variables will be derived to describe dose modifications:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent amcenestrant/letrozole administrations, a dose is deemed to have 
been reduced if the daily dose taken by a patient is lower than the daily dose taken on the 
previous day or the day before dose(s) omitted. 
• Dose omission is defined as a dose not taken or equal to 0 mg/day but administered 
afterwards. Several consecutive dose omissions will be counted as one episode of 
omission.  
Dose modifications will be analyzed by participant and dose as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification (dose reduction or dose 
omission), 
- 
Number (%) of participants with at least 1 dose reduction, 
- 
Number (%) of participants with at least 1 dose omission, 
- 
Number of participants with at least 7 consecutive days of dose omission, 
- 
Number of dose reductions by patient according to the following categories: 0, 1, >1, 
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- 
Number of dose omissions by patient according to the following categories: 0, 1-2, 
3-4, 5-6, >6, 
- 
Number of participants (respectively cycles) with at least one cycle delay. 
• Dose (number of doses administered will be used as denominator)  
- 
Number (%) of dose reductions, 
- 
Number (%) of dose omissions. 
In addition, time to first dose reduction and time to first episode of dose omission will be 
calculated and summarized. Time to first dose reduction is defined as the time interval from 
randomization to the date of first dose reduction. Time to first episode of dose omission is defined 
as the time interval from randomization to the first day of dose omission. 
4.7.1.3 Palbociclib exposure  
The dose information will be assessed by the following: 
• Duration of palbociclib exposure (in weeks) is defined by [min(date of death, date of last 
cycle last palbociclib intake + 7) – date of first cycle first palbociclib intake + 1]/7. 
• Cumulative dose (mg): the cumulative dose is the sum of all actual doses of palbociclib, 
given from first to last administration.   
• Actual dose intensity (ADI in mg/week/cycle) for palbociclib: defined as the cumulative 
dose divided by the duration of palbociclib exposure (in weeks×7)  
ADI=
Cumulative Dose (mg)
Actual number of weeks on-treatment for palbociclib 
• Planned dose intensity (PDI in mg/week/cycle) for palbociclib:  
PDI = 
125 𝑥 7 𝑥 3
4
= 656.25 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/week/cycle)
PDI (mg/week/cycle) 
The total number of doses, total number of cycles started, number of cycles started by participant 
will be summarized as a quantitative variable and by category (number [%] of participants 
receiving at least 1 cycle, at least 2 cycles, etc.). Duration of palbociclib exposure, cumulative 
dose, ADI and RDI will be summarized quantitatively. RDI will also be summarized according to 
the following categories: 0-80%, 80-100%, >100%. 
The following variables will be derived to describe dose modifications:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent palbociclib administrations, a dose is deemed to have been reduced 
if the daily dose taken by a patient is lower than the daily dose taken on the previous day 
or the day before dose(s) omitted. 
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• Dose omission is defined as a dose not taken or equal to 0 mg/day between two non-zero 
doses, except for the planned 7 days off according to the palbociclib regimen as per 
protocol. Several consecutive dose omissions will be counted as one episode of omission.  
Dose modifications will be analyzed by participant, cycle and dose as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification (dose reduction or dose 
omission), 
- 
Number (%) of participants with at least 1 dose reduction,  
- 
Number (%) of patients with at least one dose reduction to 100 mg, 
- 
Number (%) of patients with at least one dose reduction to 75 mg, 
- 
Number (%) of participants with at least 1 dose omission, 
- 
Number of participants with at least 7 consecutive days of dose omission, 
- 
Number of dose reductions by patient according to the following categories: 0, 1, >1, 
- 
Number of dose omissions by patient according to the following categories: 0, 1, >1, 
- 
Number of participants (respectively cycles) with at least one cycle delay. 
• Dose (number of doses administered will be used as denominator) 
- 
Number (%) of dose reductions (including reduced to 100mg, 75mg), 
- 
Number (%) of dose omissions. 
In addition, time to first dose reduction and time to first episode of dose omission will be 
calculated and summarized. Time to first dose reduction is defined as the time interval from 
randomization to the date of first dose reduction. Time to first episode of dose omission is defined 
as the time interval from randomization to the first day of dose omission. 
4.7.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to National cancer institute common terminology for adverse 
events (NCI-CTCAE version 5.0) 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 Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock.   
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period. 
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• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period. 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a 
pre-treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the grade is missing for 1 of the treatment-emergent occurrences of an AE, the 
grade will be summarized with the maximal grade of the other occurrences. If the grade is missing 
for all the occurrences, the grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. Summaries 
will be provided for all grades combined and for grade ≥3 (including grade 5). Missing grades, if 
any, will be included in the “all grades” category.  
The AE tables will be sorted as indicated in Table 8. 
Table 8 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the SAR439859 intervention group. 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE.  
• Any grade ≥3 TEAE.   
• Any treatment emergent SAE. 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period). 
• Any TEAE related to amcenestrant/letrozole. 
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• Any TEAE related to Palbociclib. 
• Any grade ≥3 TEAE related to amcenestrant/letrozole. 
• Any grade ≥3 TEAE related to palcociclib. 
• Any treatment emergent SAE related to amcenestrant/letrozole. 
• Any treatment emergent SAE related to Palbociclib. 
• Any TEAE leading to permanent partial discontinuation of palbociclib. 
• Any TEAE leading to permanent full intervention discontinuation.  
The AE summaries of Table 9 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3. The all 
TEAE summary by Primary SOC and PT (and other safety summaries (eg, SAEs, deaths), if 
deemed needed after TEAE evaluation) may be performed by trial impact (disruption) due to 
Covid-19.  
Table 9 - Analyses of adverse events  
Type of AE 
MedDRA levels 
TEAE 
 
All TEAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
Common TEAE (≥5% in any treatment arm)  
Primary SOC and PT 
TEAE related to amcenestrant/letrozole as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to palbociclib as per Investigator’s judgment 
Primary SOC and PT 
SAE 
 
Treatment emergent SAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
Treatment emergent SAE related to amcenestrant/letrozole as per 
Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to palbociclib as per Investigator’s 
judgment 
Primary SOC and PT 
TEAE leading to treatment discontinuation or modification 
 
TEAE leading to permanent full intervention discontinuation 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of palbociclib 
Primary SOC and PT 
TEAE leading to dose modification (including dose reduction and dose 
omission) of amcenestrant/letrozole 
Primary SOC and PT 
TEAE leading to dose modification (including dose reduction and dose 
omission) of palbociclib 
Primary SOC and PT 
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Type of AE 
MedDRA levels 
Death 
 
TEAE leading to deatha 
Primary SOC and PT 
AE leading to deatha 
• 
In context of disease progressionb 
• 
In context other than disease progressionc 
Primary SOC and PT  
a death as an outcome of the AE as reported by the Investigator in the AE page  
b death within 30 days from last study treatment administration and the cause of death is disease progression 
c 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 
Analysis of deaths 
In addition to the analyses of deaths included in Table 9, the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by reason for death. 
• Deaths in non-randomized participants or randomized but not treated participants. 
An 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). 
In addition, a listing of all deaths during the study will be provided. 
Analysis of adverse events of special interest (AESIs)  
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 10. 
Number (%) of participants experiencing at least one event will be provided for each event of 
interest. Tables will be sorted as indicated in Table 8.  
Table 10 - Selections for AESIs  
AESIs 
Selection 
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/NIMP 
e-CRF specific tick box on the AE page 
Symptomatic overdose (serious or nonserious) with IMP/NIMP 
 
e-CRF specific tick box on the AE page 
Increase in alanine transaminase (ALT) ≥Grade 3 
e-CRF specific tick box on the AE page 
Photosensitivity 
e-CRF specific tick box on the AE page 
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4.7.3 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• 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, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, albumin, 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphate, magnesium, 
- 
Renal function: creatinine, eGFR (as collected in the eCRF, blood urea nitrogen, urea, 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, lactate dehydrogenase, total and conjugated bilirubin, gamma-
glutamyltransferase (GGT). 
• Urinalysis: 
- 
Urinalysis for qualitative analysis: pH, proteins, glucose, ketones, leukocytes, 
erythrocytes.   
• Vital signs: heart rate, systolic and diastolic blood pressure, weight and ECOG PS (0, 1, 2, 
3, 4). 
• ECG variables: ECG assessments will be described as normal/missing or abnormal. ECG 
parameters collected at baseline will be summarized quantitatively. 
For hematological parameters and some selected biochemistry parameters, Sanofi sponsor generic 
ranges (LLN, ULN) are defined and will be used for grading. For other biochemistry parameters, 
grading will be derived using local laboratory normal ranges.  
Quantitative analyses 
For blood pressure, a table will be provided with the baseline value and worst value during the on-
treatment period.  
Analyses according to PCSA and NCI grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version as defined in the protocol. In addition, for laboratory variables for which NCI-CTCAE 
scale is not applicable and vital signs, PCSA analyses will be performed and PCSA values are 
defined as abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on literature review (Section 5.5). 
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Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For hematology/clinical chemistry toxicities (except for liver function) and ECOG PS, shift tables 
showing the number of patients in each grade at baseline by worst grade during the on-treatment 
period will be provided.  
For laboratory variables graded by NCI-CTCAE, 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.   
• The number (%) of participants with abnormal laboratory tests during the treatment-
emergent period will be summarized by grade.  When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided.  
For ECG, the incidence of participants with at least one abnormal ECG during the treatment-
emergent period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
• Normal/missing. 
• Abnormal.  
4.8 
OTHER ANALYSES  
4.8.1 PK analyses  
Plasma concentrations will be summarized for amcenestrant, palbociclib and goserelin by 
treatment arm for each time point using descriptive statistics (such as the number of observations, 
arithmetic and geometric mean, median, standard deviation (SD), standard error (SE), coefficient 
of variation (CV)%, minimum, and maximum). A summary of predose concentrations over time 
will be presented graphically by treatment arm. These analyses will be performed by specific 
subgroups (eg, gender, BMI, age) if appropriate. 
Amcenestrant and palbociclib plasma concentrations will be included in the descriptive statistics 
if actual sampling occurs in the following time windows: [2-4h] for samples at 3h post dose on 
Day 1 Cycle 1 and Cycle 2; within 2 hours before administration for predose samples. 
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All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics excepted for the geometric mean and associated coefficient of variation for 
which they will be considered as missing.  
In case of exposure response analysis (See Section 4.8.4) using PK estimates is conducted, 
corresponding descriptive statistics of PK parameters of interest will be presented.  
4.8.2 Quality of life analyses  
Health-related quality of life (HRQL) 
Symptoms and function related to health-related quality of life (HRQL) will be assessed using: 
• The European Organisation for Research and Treatment of Cancer Core Quality of Life 
Questionnaire with 30 items (EORTC QLQ-C30) (version 3.0) (6, 7, 8).  
• The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Breast cancer module with 23 items (EORTC QLQ-BR23) or with 
45 items (EORTC QLQ-BR45) (9, 10). 
• The EuroQol measure with 5-dimensions and 5-levels per dimension (EQ-5D-5L) (11). 
EORTC-QLQ-C30 
The EORTC QLQ-C30 (version 3.0) is a 30-item cancer-specific patient-reported outcome 
measure of health-related quality of life (HRQL) in patients with cancer (6, 7, 8). The QLQC30 
assesses disease-related symptoms, treatment-related symptoms, and functioning relevant to 
patients with cancer. 
The QLQ-C30 is composed of both multi-item scales and single-item scales, including: five 
functional scales (physical functioning (5 items), role functioning (2 items), emotional functioning 
(4 items), cognitive functioning (2 items), and social functioning (2 items)); eight symptom scales 
(fatigue (3 items), nausea and vomiting (2 items), pain (2 items), dyspnoea (1 item), insomnia 
(1 item), appetite loss (1 item), constipation (1 item), diarrhoea (1 item)); a financial difficulties 
scale (1 item); and a global health status (GHS)/quality of life (QOL) scale (2 items). Items in the 
functional, symptom, and financial difficulties scales have a 4-point verbal rating scale ranging 
from “not at all” (1) to “very much” (4). Items in the GHS/QOL scale each have a 7-point 
numeric rating scale ranging from “very poor” (1) to “excellent” (7). The recall period for each 
scale is one week. 
Each QLQ-C30 scale is scored according to the validated scoring algorithms available in the 
QLQ-C30 scoring manual, which standardize and transform the raw scores to a 0-100 range (8). 
Each scale is scored such that higher scores indicate higher levels of each construct. Higher scores 
on the functional scales indicates higher levels of functioning. Higher scores on the GHS/QOL 
scale indicates higher levels of GHS/QOL. High scores on the symptom and financial difficulties 
scales indicate higher levels of symptoms and financial difficulties, respectively.  
Missing data will be handled in accordance with the scale developer’s rules (Section 5.10), (8). 
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EORTC QLQ-BR23 
The EORTC QLQ breast cancer module (QLQBR23) is a 23-item disease-specific patient-
reported outcome measure of disease-related symptoms, treatment-related symptoms, and 
functioning relevant to patients with breast cancer in patients with breast cancer. The QLQ-BR23 
is used in conjunction with the QLQC30. The QLQBR23 assesses.  
The QLQ-BR23 is composed of both multi-item scales and single-item scales, including: four 
functional scales (body image (4 items), sexual functioning (2 items), sexual enjoyment (1 item), 
and future perspective (1 item)); and four symptom scales (systemic therapy side effects (7 items), 
breast symptoms (4 items), arm symptoms (3 items), upset by hair loss (1 item)).  
Each QLQ-BR23 scale is scored according to the validated scoring algorithms available in the 
QLQ-BR23 scoring manual, which standardize and transform the raw scores to a 0-100 range (8). 
Each scale is scored such that higher scores indicate higher levels of each construct. Higher scores 
on the functional scales indicates higher levels of functioning. High scores on the symptom scales 
indicate higher symptom levels.  
Missing data will be handled in accordance with the scale developer’s rules (Section 5.10), (8). 
EORTC QLQ-BR45 
The EORTC QLQ breast cancer module (QLQBR45) is a 45-item disease-specific patient-
reported outcome measure of disease-related symptoms, treatment-related symptoms, and 
functioning relevant to patients with breast cancer (10). The QLQ-BR45 includes all 23 items 
from the QLQ-BR23 plus an additional 22 items assessing endocrine therapy symptoms (10 
items), endocrine sexual symptoms (4 items), breast satisfaction (2 items), and skin/mucosis 
symptoms (6 items) (10). In countries where the translated and validated EORTC QLQ-BR45 
questionnaire is not available, study participants can use EORTC QLQ-BR23 questionnaire until 
the availability of translated and validated EORTC QLQ-BR45 questionnaire. 
Each QLQ-BR45 scale is scored according to the validated scoring algorithms available in the 
QLQ-BR45 scoring manual, which standardize and transform the raw scores to a 0-100 range 
(Section 5.10), (8, 10). Each scale is scored such that higher scores indicate higher levels of each 
construct. Higher scores on the functional scales indicates higher levels of functioning. High 
scores on the symptom scales indicate higher symptom levels.  
Missing data will be handled in accordance with the scale developer’s rules (Section 5.10), (8). 
EQ-5D-5L 
The EuroQoL questionnaire with 5 dimensions and 5 levels per dimension (EQ5D-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 
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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 selfcompletion 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 (11). 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. 
Statistical analyses 
For each of the PRO/HRQL and health utility instruments (EORTC QLQ-C30, QLQ-BR45/QLQ-
BR23, and EQ-5D-5L), patient reported outcomes endpoints 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). A questionnaire is considered received if a 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. For multi-item scales, a scale is defined as complete 
when at least half of the scale items have responses (8). For single item scales, a scale is defined 
as complete when the item has a response (8). Reasons for non-completion will be summarized on 
the safety population. 
For the QLQC30 (15 total scales), QLQ-BR45 (12 scales, 8 of which are QLQ-BR23 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 EOT, and at the first post-treatment follow up visit.  
For each scale within each instrument, statistical 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. The variables in the model will be treatment, time, treatment-by-time, with the 
baseline value and stratification factors used as covariates. 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 differences in least square means between treatment and control 
group, and the corresponding 2-sided 95% CI at selected time points will be presented. No 
adjustments for multiple comparisons will be made. A graphical display of mean changes from 
baseline over time will also be provided for each scale of each instrument. 
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4.8.3  Biomarker analyses   
4.8.3.1 Tumor biopsy biomarkers  
Tumor biopsy tissue will be collected pre-treatment (or archival) and at EOT/progression. The 
expression of several proteins [eg, ER, progesterone receptor (PgR), B-Cell Lymphoma 2 
(BCL2)] assessed by IHC will be described at baseline by considering the percentage of positive 
cells and/or the derived H-score. The relationship between baseline protein expression and 
efficacy endpoint (such as ORR, CBR or PFS) may be explored to assess potential prognostic 
and/or predictive effects. 
The change from baseline to EOT/progression will be summarized per treatment arm. 
Ribonucleic acid (RNA) may be also isolated from these tumor biopsies for additional exploratory 
analyses. Differential gene expression analyses may be performed, and some tumor gene 
signatures (such as the ER activation signature and other gene signature of interest) may be also 
derived and described. 
4.8.3.2 cfDNA tumor and germline mutation analysis  
cfDNA samples will be collected at baseline, Cycle 4 Day 1 predose and EOT/progression. From 
these samples, genomic aberrations from targeted gene panel will be identified (eg, single 
nucleotide variants, copy number variants, indels or fusion genes). For each gene, the prevalence 
of aberrations will be provided overall and possibly according to some baseline characteristics. 
For some genes of interest, the detail of the detected mutations will be provided. Descriptive 
statistics will be also used to describe the mutant allele frequency and concentration for single 
nucleotide variants and indels. The evolution of the genomic aberrations overtime (baseline, 
Cycle 4 Day 1 predose and EOT/progression) will be summarized per treatment arm. 
Germline mutations from baseline normal tissue reference will be subtracted from mutations 
identified through cfDNA to identify somatic mutations.  
The association between efficacy endpoints (such as ORR, CBR or PFS) and the mutation status 
at baseline for some key genes (such as ESR1 or PIK3CA, by comparing mutant versus wild-type) 
will be evaluated to assess potential prognostic and/or predictive effects.  
4.8.3.3 Estradiol  
Descriptive statistics of the circulating level of estradiol (such as the number of observations, 
arithmetic and geometric mean, median, standard deviation (SD), standard error (SE), coefficient 
of variation (CV)%, minimum, and maximum).will be provided at baseline and at Cycle 3 Day 1 
for each treatment arm. The number of values below the limit of quantification (BLQ) will be 
summarized and imputed at the value LOQ/2 for descriptive statistics. 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. 
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4.8.3.4 Genotyping analysis  
The number of participants with available data for DMET genotyping will be reported. The 
frequencies of the different genotypes and phenotype will be tabulated by genes for UGT1A1 and 
UGT1A4. 
4.8.4 Exposure response analysis  
PK estimates may also be used to conduct the exploratory exposure-response analyses for safety 
(eg, incidence of AEs) and efficacy (eg, PFS, BOR, CBR, DOR). This analysis will be described 
in a separate analysis plan and reported in a stand-alone report. 
4.8.5  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. 
4.9 
INTERIM ANALYSES  
4.9.1 Interim analyses for PFS  
Two interim analyses are planned based on the primary PFS endpoint at 40% (non-binding futility 
only) and 70% (efficacy only) of the planned total number of events expected. The stopping 
boundary for futility is based on the observed HR based on stratified Cox proportional hazard 
model, ie, an HR>1.1. The stopping boundary for efficacy will be derived based on the O’Brien 
and Fleming α-spending function and depend on the actual number of PFS events observed at the 
time of the interim analysis.  
A summary of the PFS analyses is provided in Table 11. At IA 1 for futility, 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. At IA2 for efficacy, 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 efficacy boundary. 
Demographics and baseline characteristics, prior or concomitant medication, extent of IMP 
exposure and compliance, AEs (TEAE, death, SAE, related TEAE, TEAE leading to 
discontinuation, TEAE leading to dose modification, 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 endpoints, 
PK, and biomarker. 
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Table 11 - PFS analyses  
Analysis 
Months 
after FPI 
(approx. 
under 
PFS 
HR=0.75) 
Planned 
accrual 
Number 
of 
events  
Information 
fraction 
Cumulative 
Power 
(under PFS 
HR=0.75) 
Futility 
boundary 
Efficacy 
boundary 
PFS IA 1 
(futility 
only) 
19.5 
1066 
206 
40% 
 
HR >1.1 
NA 
PFS IA 2 
(efficacy) 
28 
1066 
361 
70% 
62% 
NA 
p ≤0.0074 
(HRa ≤0.7736) 
PFS Final 
analysis 
40 
1066 
516 
100% 
90% 
p >0.0228 
(HRa >0.8386) 
p ≤0.0228 
(HRa ≤0.8386) 
a 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. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; PFS = progression-free survival 
In case of positive results at interim analysis, disease assessments data will continue to be 
collected according to the protocol until the final PFS analysis cut-off date (defined as the date 
when 516 PFS events assessed by radiologist/investigator are observed) and PFS results will be 
updated (non-inferential analysis only). 
4.9.2 Interim analyses for OS  
Comparison between arms on the OS will be performed only if the primary analysis of the PFS is 
statistically significant. Therefore, a maximum of three analyses are planned for OS, at the time of 
the primary analysis of PFS, at 75% of the planned number of OS events and at the final OS 
analysis. 
A gamma error spending function (γ=-10) independent from the O’Brien and Fleming α-spending 
function for PFS will be used, along with the hierarchical testing strategy in order 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 (12).  
A summary of the OS analyses is provided in Table 12. 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 
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Table 12 - OS analyses  
Analysis 
Months 
after FPI 
(approx.) 
Planned 
accrual 
Number 
of 
deaths 
(approx.) 
Information 
fraction 
Cumulative 
Powera 
(under 
HR=0.80) 
Futility 
boundary 
Efficacy 
boundary 
Scenario 1: PFS is statistically significant at the PFS IA 2 
OS IA 1 (at 
PFS IA 2) 
28 
1066 
228 
36.1% 
1.2% 
NA 
p ≤4.07×10-5 
(HRb ≤0.5934) 
OS IA 2  
55 
1066 
474 
75% 
32.9% 
NA 
p ≤0.0020 
(HRb ≤0.7680) 
Final 
analysis 
80 
1066 
632 
100% 
80% 
p >0.0248 
(HRb >0.8554) 
p ≤0.0248 
(HRb ≤0.8554) 
Scenario 2: PFS is statistically significant at the PFS final analysis 
OS IA 1 (at 
PFS final 
analysis) 
40 
1066 
348 
55.1% 
8.5% 
NA 
p ≤2.78×10-4 
(HRb ≤0.6408) 
OS IA 2  
55 
1066 
474 
75% 
32.7% 
NA 
p ≤0.0020 
(HRb ≤0.7673) 
Final 
analysis 
80 
1066 
632 
100% 
80% 
p >0.0248 
(HRb >0.8554) 
p ≤0.0248 
(HRb ≤0.8554) 
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 an annual dropout rate of 1%. 
FPI = first participant in; HR = hazard ratio; IA = interim analysis; NA = not applicable; OS = overall survival.  
4.9.3 Data Monitoring Committee (DMC)  
This study will use an independent DMC. The first DMC meeting will be set up to review early 
safety results (eg, after approximately 50 participants have completed at least 2 cycles, or after 
6 months after first participant randomized), and then periodically. In addition to review of safety 
results, DMC will also evaluate efficacy at the interim analyses and make a recommendation 
regarding study continuation based on observed results of the study. 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 4.9.1. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
AI: 
aromatase inhibitor 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
BIRC: 
blinded Independent Review Committee 
BMI: 
body mass index 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
cfDNA: 
cell-free deoxyribonucleic acid 
CI: 
confidence interval 
COD: 
cut-off date 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EDR: 
early discrepancy rate 
EORTC: 
European Organization 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 positive 
ESR1: 
estrogen receptor 1 gene 
FWER: 
family wise error rate 
GGT: 
gamma-glutamyltransferase 
GHS: 
global health status 
HGLT: 
high level group term 
HR: 
hazard ratio 
IA: 
interim analysis 
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-CTCAE: 
National cancer institute common terminology for adverse events 
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NIMP: 
noninvestigational medicinal product 
ODR: 
outcome discrepancy rate 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PD: 
progressive disease 
PDI: 
planned dose intensity, planned dose intensity 
PFS: 
progression free survival 
PgR: 
progesterone receptor 
PIK3CA: 
gene which encodes the p110alpha catalytic subunit of PI3K 
PK: 
pharmacokinetic 
PS: 
performance status 
QLQ: 
quality of life questionnaire 
RDI: 
relative dose intensity, relative dose intensity 
RNA: 
ribonucleic acid 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SDF: 
survival distribution function, survival distribution function 
SERD: 
selective estrogen receptor down-regulator 
SERM: 
selective estrogen receptor modulator 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
VAS: 
visual analogue scale 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Table 13 - Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
01 
27-Jul-2020 
Pharmacodynamics analyses were 
removed, and genetics analyses were 
added 
Pharmacodynamics analyses are not planned 
in study, and genetic analyses were missing. 
02 
30-Sep-2020 
Updated the censoring rules for PFS 
analysis 
The censoring rules have been detailed 
based on feedback from regulatory 
authorities. 
02 
30-Sep-2020 
PFS assessed by the BIRC will be 
considered as supportive analysis of the 
primary PFS analysis even if a full BIRC is 
triggered 
The strategy has been updated based on the 
feedback from regulatory authorities. 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
03 
16-Dec-2020 
Modification of statistical assumptions; 
modification of the study sample size from 
708 to 1066 patients; addition of second 
interim analysis for OS; and change in 
study duration & estimated cut-off dates for 
PFS and OS analyses. 
Revised PFS HR assumption used to power 
this endpoint, revised futility analysis strategy 
at interim analyses and revised dropout 
assumption due to change in PFS censoring 
scheme. 
Revised OS HR assumption used to power 
this endpoint. 
03 
16-Dec-2020 
Addition of PFS2 as secondary endpoint 
and description of how the PFS2 will be 
assessed. 
To assess the PFS after next line of therapy. 
PFS2 is a useful endpoint to assess any 
benefit beyond initial disease progression. 
03 
16-Dec-2020 
Removed descriptions for China extension 
study including objective, population and 
sample size consideration. 
In Nov 2020, an enrollment plan for China 
was adopted that targeted the completion of 
enrollment at the same time as global 
population. It is possible that an extension 
study is no longer needed. Therefore, 
relevant descriptions for sub-study are 
removed and flexible statement regarding the 
enrollment plan has been added. 
Consideration on patient number was also 
removed as all study participants from China 
may be treated within the global study. 
Specific sample size consideration will be 
provided in separate regulatory packages 
submitted to China National Medical Products 
Administration -  
Center for Drug Evaluation (NMPA-CDE). 
 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the randomized 
population. 
Demographic and baseline characteristics  
• Age in years as quantitative variable and in categories (<65, 65 to <84, ≥85).  
• Gender (Male, Female). 
• 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, Unknown). 
• Weight (kg). 
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• Eastern cooperative oncology group (ECOG) performance status. 
• Menopausal status for females. 
Baseline safety parameters (apart from those listed above) will be presented along with the safety 
summaries.  
Medical (or surgical) history includes relevant history of previous or associated pathologies other 
than the tumor. Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and 
associated primary SOC using the MedDRA version currently in effect at Sanofi at the time of 
database lock. 
Specific disease history at initial diagnosis includes time from initial diagnosis of breast cancer to 
randomization date (in years), histology, disease location and laterality, histopathology type and 
stage of the disease.  
Specific disease status at study entry includes extent of the disease, number of organs involved, 
disease status, type of organ(s) involved, visceral metastasis or not, HER2 status, ER status, PgR 
status, disease status, ESR1 mutation status, PIK3CA mutation status. 
Prior or concomitant medications 
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 participant used prior to first IMP intake. Prior medications 
can be discontinued before first administration or can be ongoing during treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to any IMP(s) from the first administration of IMP to the last IMP intake +30 days.  
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication. If it cannot be determined whether a given medication was taken prior or 
concomitantly or post, it will be considered as prior and concomitant medication. 
The prior and concomitant medications will be summarized for the randomized population, by 
anatomic and therapeutic level. The summaries will be sorted by decreasing frequency of 
anatomic category (ATC) based on overall incidence across treatment groups for prior 
medications, and incidence in the SAR439859 group for concomitant medications. In case of 
equal frequency, alphabetical order will be used. Participants will be counted once in each ATC 
category (anatomic or therapeutic) linked to the medication.  
Anticancer therapies  
Prior anticancer therapies include chemotherapy, hormonotherapy, immunotherapy, targeted 
therapy, surgery and radiotherapy.  
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The following variables will be collected/derived: 
• Intent of prior anti-cancer therapy according to the following categories: neoadjuvant only, 
adjuvant only, both neoadjuvant and adjuvant, no prior treatment. 
• Time from last relapse to randomization (in months). 
• Intent of the last prior anti-cancer therapy according to the following categories: 
neoadjuvant only, adjuvant only, both neoadjuvant and adjuvant, no prior treatment. 
• 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). 
• Time from start of adjuvant therapy to relapse in adjuvant setting (in years). 
• Time from end of adjuvant therapy to relapse in adjuvant setting (in years). 
• Duration of adjuvant therapy (in 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.  
• Among prior hormonotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, both neoadjuvant and 
adjuvant, 
- 
Type of prior hormonotherapy in neoadjuvant or adjuvant settings:  
- 
Aromatase inhibitors (AIs) 
- 
SERM (eg, Tamoxifen) 
- 
SERD (eg, Fulvestrant) 
• Among prior chemotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, both neoadjuvant and 
adjuvant, 
- 
Type of prior chemotherapy in neoadjuvant or adjuvant settings: 
- 
Anthracyclins 
- 
Taxanes 
- 
Capecitabine 
- 
5-fluorouracile 
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- 
Other 
• Among prior targeted therapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, both neoadjuvant and 
adjuvant, 
- 
Type of prior targeted therapy in neoadjuvant or adjuvant settings: 
- 
Anti-HER2 
- 
CDK4/6 inhibitors 
- 
Other 
• Among prior immunotherapy: 
- 
Number of patients with intent: neoadjuvant only, adjuvant only, both neoadjuvant and 
adjuvant, 
- 
Type of prior immunotherapy in neoadjuvant or adjuvant settings: 
- 
Anti PD-1 
- 
Anti PD-L1 
- 
Other 
- 
Prior anti-cancer therapies in combination with endocrine therapy, 
- 
Type of prior endocrine-based combinations in neoadjuvant or adjuvant settings: 
- 
CDK4/6 inhibitors + AIs 
- 
AIs + SERM 
- 
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. 
Further therapies after discontinuation of intervention will be summarized based on WHO-DD 
coding. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
5.4.1 General conventions  
The following formulas will be used for computation of parameters. 
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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 
5.4.2 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.  
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. 
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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 next theoretical tumor assessment per 
protocol after the last evaluable tumor 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. 
5.4.3 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 (up to 
documented progression, death, further anticancer therapy or COD, whichever occurs first) 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. 
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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.  
5.4.4 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-
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. 
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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 further anti-cancer treatments, if the medication start date is missing, it will be imputed as 
follows: 
• If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date + 1. 
• If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 
• If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start date will be set to the treatment end 
date + 1. 
• If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
• If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
• If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set 
to 01. 
• If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date + 1. 
Handling of 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 first day of the month. 
• 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 end day of the 
month. 
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• 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 end day of the month. 
• If the day and month of the end date of the prior radiotherapy are missing, no imputation 
will be done. 
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 grade 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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5.4.5 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. 
5.4.6 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
5.4.7 Statistical technical issues  
Not applicable. 
5.5 
APPENDIX 5 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) 
 
 
 
 
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5.6 
APPENDIX 6 SUMMARY OF STATISTICAL ANALYSES  
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Sensitivity analysis 
Supportive analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
PFS according to 
investigator 
ITT 
Stratified Log-
rank test 
Kaplan-Meier 
Cox proportional 
hazards model 
 
#1 PFS considering events 
occurring after two or more non-
evaluable tumor assessment as 
event and ignoring further anti-
cancer therapy 
#2 PFS considering events 
occurring after two or more non-
evaluable tumor assessment as 
event and back-dating at the 
next scheduled assessment 
#3 PFS analysis using stratification 
factors derived from eCRF data 
- Robustness of LE-PFS 
treatment effect, evaluated 
with the NCI (National Cancer 
Institute) method with BIRC 
data 
- PFS according to BIRC 
assessments  
-  PFS considering the 
clinical/non-radiological 
progression as event, and 
same rules as the sensitivity 
analyses if relevant) 
- Concordance of PFS outcome 
(PFS ODR) 
- Differential discordance on PD 
events (EDR and LDR) 
- RMST if proportional hazard 
assumption is not fulfilled 
Yes  
- Multivariate Cox 
proportional hazards 
model 
 
- PFS considering 
clinical/non-
radiological 
progression as event 
 
Secondary endpoints 
OS 
ITT 
Stratified Log-
rank test 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
IPCW and RPSFTM to account 
for informative censoring due to 
further anti-cancer therapy, if 
relevant  
Yes 
Multivariate Cox 
proportional hazards 
model 
ORR according to 
investigator 
ITT 
ITT measurable 
Descriptive 
statistics 
Clopper-Pearson 
95% CI 
No  
 
 
Yes if relevant based 
on subgroups of 
primary endpoint 
- Best Overall 
Response 
- Best relative change 
from baseline in 
tumor size (waterfall 
plot) 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Sensitivity analysis 
Supportive analysis 
Subgroup 
analysis 
Other 
analyses 
DOR according to 
investigator 
ITT (responders) 
ITT measurable 
(responders) 
Kaplan-Meier 
No 
 
Yes if relevant based 
on subgroups of 
primary endpoint 
 
CBR according to 
investigator 
ITT 
ITT measurable 
Descriptive 
statistics 
Clopper-Pearson 
95% CI  
 
No 
 
Yes if relevant based 
on subgroups of 
primary endpoint  
 
PFS2 according to 
investigator 
ITT 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
 
Yes if relevant based 
on subgroups of 
primary endpoint 
 
Pharmacokinetics of 
SAR439859 and 
Palbociclib 
Pharmacokinetic-
evaluable 
population 
Descriptive 
statistics 
No 
No 
Yes if relevant 
Safety/efficacy 
endpoints according 
to PK parameters 
Time to first use of 
chemotherapy  
ITT 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
No 
No 
 
Tertiary/exploratory endpoints 
Tumor biomarkers 
ITT 
Descriptive 
statistics 
 
 
 
 
Mutation profile 
ITT 
Descriptive 
statistics 
 
 
 
Relationship between 
the mutation status 
and clinical response 
PFS according to 
PIK3CA and ESR1 
mutation status at 
baseline based on 
investigator 
assessment 
ITT 
Kaplan-Meier 
Cox proportional 
hazards model 
No 
PFS according to PIK3CA and 
ESR1 mutation status at 
baseline based on BIRC 
assessment, if full BIRC is 
triggered 
No 
 
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 
No 
Deaths 
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm  
No 
Laboratory  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm  
No 
Vital signs  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm  
No 
ECG  
Safety 
Descriptive statistics by treatment group 
Descriptive statistics by treatment arm 
No 
Health-related quality of life 
(HRQL): EORTC QLQ-
C30, EORTC QLQ-
BR23/EORTC-BR45, EQ-
5D-5L 
Safety population who 
have completed the 
baseline and at least 
1 postbaseline 
assessment 
Descriptive statistics 
Mixed effects model on the change from baseline for 
each of the scales of each instrument 
No 
No 
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5.7 
APPENDIX 7 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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5.8 
APPENDIX 8 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1)  
Details provided in bibliographic reference (13). 
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 [13]). 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.  
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• 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 
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.  
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• 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 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 14 - 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 15 - 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 16) 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 17 is to be used. 
Table 16 - 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 17 - A summary of overall response status for non-measurable disease 
Non-target lesions 
New lesions 
Overall response 
CR 
Non-CR/non-PD 
No 
No 
CR 
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 18 - 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 63 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 18. 
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5.9 
APPENDIX 9 DESCRIPTION OF CENSORING AND EVENT RULES FOR PRIMARY 
AND SENSITIVITY ANALYSES OF PFS  
Table 19 - PFS Primary analysis 
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assesmentb 
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 25 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 26 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 26 weeks corresponds to twice the time between two disease assessments per protocol (every 2*12 weeks), plus 
the 7-day window before and after. 
 
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Table 20 - PFS sensitivity analysis #1 (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 26 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 26 weeks corresponds to twice the time between two disease assessments per protocol (every 2*12 weeks), plus 
the 7-day window before and after. 
 
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Table 21 - PFS sensitivity analysis #2 (PFS considering events occurring after two or more non-
evaluable tumor assessment as event and back-dating at the next scheduled assessment)  
 
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 scheduled 
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 scheduled 
assessment 
Event 
Documented progression (or Death 
without documented progression) 
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 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 26 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 26 weeks corresponds to twice the time between two disease assessments per protocol (every 2*12 weeks), plus the 
7-day window before and after. 
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Table 22 - PFS supplementary 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 25 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 26 weeks (excluded) after the last evaluable tumor assessment, documenting no progression or randomization 
date, whichever is last. 26 weeks corresponds to twice the time between two disease assessments per protocol (every 2*12 weeks), plus the 
7-day window before and after. 
 
 
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5.10 APPENDIX 10 EORTC QLQ-C30, QLQ-BR23, AND QLQ-BR45 ITEMS, SCALES 
AND SCORES  
For QLQ-C30: 
 
 
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For QLQ-BR23 
The scoring approach for the QLQ-BR23 is identical in principle to that for the function and 
symptom scales / single items of the QLQ-C30† 
 
 
BRSEE, sexual enjoyment, is not applicable if item 15 is “not at all.” 
BRHL, upset by hair loss, is not applicable if item 4 is “not at all.” 
 
 
 
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For QLQ-BR45 
 
 
 
SE, sexual enjoyment, is not applicable if item 45 is “not at all”. 
HU, upset by hair loss, is not applicable if item 34 is “not at all”. 
Problems with weight gain (item 69) is not applicable if item 68 is “not at all”. 
 
Principle for Scoring: 
Take into account that the scoring of questions 44, 45, 46, 74, and 75 must be reversed prior to 
statistical analysis. 
 
 
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Handling of Missing items for QLQ-C30, QLQ-BR23, and QLQ-BR45: 
• Multi-item Scales 
Have at least half of the items from a given scale been answered?  
- 
If Yes, use all the items that were completed, and apply the standard equations given 
above for calculating the scale scores; ignore any items with missing values when 
making the calculations.  
- 
If No, set scale score to missing.  
• Single-item Scales: 
Set to missing if no response.  
 
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6 
REFERENCES  
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13. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
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47. 
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