A Phase 1/2 Study for the Safety, Efficacy, Pharmacokinetic and Pharmacodynamics Evaluation of Amcenestrant (SAR439859), Administered Orally as Monotherapy, Then in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor-positive Advanced Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Sanofi

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According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016)
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AMENDED CLINICAL TRIAL PROTOCOL 10 
COMPOUND: amcenestrant (SAR439859) 
A Phase 1/2 study for the safety, efficacy, pharmacokinetic and 
pharmacodynamics evaluation of amcenestrant (SAR439859), administered orally 
as monotherapy, then in combination with other anti-cancer therapies in 
postmenopausal women with estrogen receptor-positive advanced breast cancer 
STUDY NUMBER: TED14856 
VERSION DATE/STATUS: 08 December 2021 / Approved 
Study name: AMEERA-1 
Version Number: 
1 
EudraCT  
2017-000690-36 
IND Number(s) 
133204 
WHO universal trial number: 
U1111-1189-4896 
Date: 
08-Dec-2021
Total number of pages: 
230 
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NCT number: NCT03284957

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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
Company: 
Address: 
 
 
 
Tel: 
Fax: 
Sanofi-Aventis Recherche & Developpement 
1 Avenue Pierre Brossolette 
91380 Chilly-Mazarin 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document  
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 10 
All 
08 December 2021, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 09 
All 
23 March 2021, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 08 
All 
30 October 2020, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 07 
All 
03 April 2020, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 06 
All 
02 October 2019, version 1 (electronic 7.0)  
Amended Clinical Trial Protocol 05 
All 
02 August 2019, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 04 
All 
29 January 2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 03 
All 
27 July 2018, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
23 July 2018, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
15 June 2017, version 1 (electronic 1.0) 
Original Clinical Trial Protocol 
 
30 March 2017, version 1 (electronic 5.0) 
AMENDED PROTOCOL 10 (Date 08 December, 2021) 
This Amended Protocol 10 (Amendment 10) 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 
1. Change the recommendation for amcenestrant 200 mg to only be taken with food in the 
combination cohorts  
2. Clarification of the inclusion criteria I 06 language  
3. Modification of exclusion criteria E13 to allow fulvestrant as a prior therapy in dose 
escalation study parts 
4. Removal of the exclusion criteria E20: treatment with drugs that are P-gp sensitive 
substrate, BCRP sensitive substrate, and UGT inhibitors are no more prohibited following 
recent clinical data. 
5. Modification of the exclusion criteria E21: extension of the exclusion criteria E21b to 
Arm#5 patients under full PK sampling as they will also have 4βOH cholesterol 
assessment. 
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6. Addition of the exclusion criteria E40 to prohibit use of medicines which are 
OATP1B1/1B3 substrate sensitive 
7. Modification of 8.6 Concomitant Therapy (1/ PgP and BCRP sensitive substrate, UGT 
inhibitors, anti-acids, H2 antagonists, Proton Pump Inhibitors are no more prohibited. 
2/ sensitive substrates of OATP1B1/1B3 are prohibited) 
8. Adding the language concerning the avoidance of concomitant use of QT prolonging drugs 
for patients in Arm#3 (Parts F and G) per Canadian Health Authorities request 
9. Modification of the Arm#2 cut-off date (COD). The PFS in Arm#2 was expected to be 
mature at LPI+12 months based on the available data from the literature and patients’ 
population. However, observed Arm#2 PFS data were not mature at LPI+12 months, and 
the COD for this Arm has been changed to LPI+20 months. That way, mature PFS data 
will be collected for ongoing Arm#2 patients.  
10. Addition of the Benefit/Risk Assessment sub-section to reflect the latest benefits and risks 
for amcenestrant as mentioned in other AMEERA protocols, and all anti-cancer agents 
used in the study combinations, as well as benefit-risk in the context of the COVID-19 
pandemic 
11. Correction of any typo and inconsistencies 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Food conditions for all 
amcenestrant combinations was 
updated  
Updated to reflect new PK food study findings 
and recommendation for amcenestrant 
administration in combination cohorts  
Global 
“moderate fat breakfast” was 
replaced with “standard meal” 
Updated to reflect FDA’s guideline definitions 
Title page 
“Amcenestrant” was added to title 
page and the sponsor company 
address was updated 
The compound official name was added and the 
correct company address 
Clinical trial summary and Section 5.1 
Primary Objectives 
Objectives were reorganized 
Objectives were reorganized for clarity 
Clinical trial summary and Section 5.2 
Secondary Objectives 
Participants from Arm#5 Parts J 
and K with full PK sampling were 
added 
Objectives were updated for the assesment of 
potential induction/inhibition effects of 
amcenestrant on CYP450 
Clinical trial summary and Section 5.3 
Exploratory Objectives 
Arm#3 was added to sections on 
confirming the ER degradation 
with re-biopsy of the tumor.  
Error correction to reflect biopsies for new 
combinations. 
Clinical trial summary and Section 
6.10 Study Committees 
Revised the description of the 
Study Committee and their roles 
in the study 
To improve the clarity of the contributors and 
their functions 
Clinical trial summary and Section 7.2 
Inclusion Criteria  
I 06 was revised 
To improve recruitment 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary and Section 
7.3.2 Exclusion criteria related to the 
disease  
E 13, 20, 21, 22, 24, 25, and 39 
were modified. E 40 was newly 
added 
Exclusion criteria were modified to allow 
fulvestrant as a prior therapy in dose escalation 
study parts, to reflect new DDI risk information, 
to add back information mistakenly removed in 
amended protocol 09, and to provide clarity of 
language 
Clinical trial summary and Section 
8.1.1.3 Alpelisib 
Removed “150 mg” 
Updated to reflect actual drug supply  
Clinical trial summary (secondary 
endpoint) 
Secondary endpoint was modified 
to include “Part J, Part K), or 
Cycle 2 Day 28 versus Day 1 
Cycle 1 (Part J, Part K)” 
To update and improve the clarity of the 
secondary objective/endpoint 
Clinical trial summary (exploratory 
endpoint) 
Updated the ER degradation 
exploratory endpoint 
To improve clarity of the language and to reflect 
the updated study arms and parts involved 
Clinical trial summary and 
Section 13.9.5.1 Analyses of 
pharmacokinetic variables 
Added “4β-hydroxy/total 
cholesterol concentration ratio 
(Cycle2/Cycle1) will be estimated 
with 90% CI.” 
To update statistical considerations involved for 
Arm #5 Part J 
Clinical trial summary and Section 
6.8.1 Duration of the study 
participation for each patient 
Modification of COD. Also, “After 
the final COD” was replaced with 
“After each study Arm COD” 
COD was modified to allow mature PFS data 
collection for ongoing Arm#2 participants. Texts 
were modified for improved clarity 
Section 1.2 Graphical study design – 
study scheduling 
Graphical study design figure was 
replaced 
Correction to show the missing information prior 
to the screening period and to update the 
product code with the product name 
Section 1.3 Study Flowchart 
Removed “for F and G only” for 
Molecular profiling in cfDNA 
(NGS, plasma) on D28 (±2). 
Added footnote jj. Footnotes b, g, 
i, l, x, y, z, and gg were modified 
Footnotes and table were updated to reflect the 
food effects of amcenestrant and to provide 
further clarity of the study 
Section 1.4.3.1 Part F and G 
Removed: “The Sponsor will 
evaluate if the patient has a 
mutation of interest by cfDNA 
analysis during the screening 
period.” 
Correction, since this sentence refers to cfDNA 
and not to biopsy 
Section 1.4.3.1.1 Full PK sampling 
(Parts F and G) 
An “X” was placed under the 24 h 
column 
Updated to reflect amcenestrant administration 
start at Day 3 T24h 
Section 1.4.4.1 Parts H and I 
Footer a was modified 
Updated to reflect food effects for amcenestrant 
combinations 
Section 1.4.5.1.1 Parts J and K, full 
PK sampling 
Footer a was modified. Also, P02 
was moved to column for day 28 
Footer updated to reflect food effects for 
amcenestrant combinations and table modified 
to allow PK collection on C2D28 
Section 4.1.1 Benefit/Risk 
Assessment 
Benefit/risk assessment section 
was added. Subsequent tables 
were renumbered. 
 
This section was added to reflect the latest 
benefits and risks of amcenestrant and the anti-
cancer agents used in the study combinations, 
as well as the risks in the context of the COVID-
19, and to align with other AMEERA studies 
which also have this section in their protocols 
Section 4.2 Description of 
Amcenestrant 
Updated description of 
amcenestrant 
Updated to reflect the MOA agreed by the study 
team and for clarity of language 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.3.1 Preclinical data 
Modified text in metabolism and 
preclinical pharmacokinetics 
Updated to reflect in vitro data 
Section 4.4.3.2 Part G (Dose 
Expansion, Combination with 
alpelisib) 
Replaced v4 with v4.03 
Updated to reflect correct NCI-CTCAE version 
Section 6.6 Expansion Cohorts to 
Confirm the Maximum Tolerated 
Dose 
Added “In Part I, approximately 
12 patients are planned to be 
treated. In Part K, approximately 
20 patients are planned to be 
treated.” 
Updated to include information on patients 
planned to be treated with everolimus and 
abemaciclib combinations 
Section 8.5.1 Treatment 
accountability and compliance 
Added everolimus and 
abemaciclib after “amcenestrant 
and/or palbociclib/alpelisib” as 
potential combinations with 
amcenestrant, modified arms for 
amcenestrant, and the text 
regarding patient diary logs was 
modified 
Updated to reflect amcenestrant combinations 
involved in the study and to improve clarity 
Section 8.6 Concomitant Treatment 
Content regarding concomitant 
medications in treatment arms 
were updated. Also, added 
“Arm#5 Part J and K (for patients 
with full PK sampling” 
Content was updated to reflect the amcenestrant 
drug-drug interaction risk and per Canadian 
Health Authority request. Text was also updated 
to provide clarity. 
Section 9.2.2 Pharmacokinetic 
sample handling procedure  
In table 33, “The remaining liquid 
blood will be diluted (v/v) with 
water” was replaced with “The 
remaining liquid blood samples 
are guard samples. They must 
remain stored in the BA lab until 
the end of the analysis of the 
DBS samples.”  
Updated to reflect the most up to date 
recommendations of the handling procedures 
Section 9.2.3 Bioanalytical method 
In tables 36 and 37, changed 
names of sites of bioanalysis from 
Covance to LabCorp for 
everolimus and for all other sites, 
names were replaced with Pyxant 
Updated to reflect the correct names of sites for 
this study 
Section 9.3.1 Optional drug 
metabolizing enzymes and 
transporters DNA sample 
Replaced patients who signed the 
optional pharmacogenetic ICF 
with “patients who select to do the 
optional pharmacogentic 
assessment in the Main ICF” 
Correction, to clarify that there is no separate 
pharmacogentic ICF a patient will sign  
Section 9.6 Future Use of Samples 
Rephrased the sentence 
regarding leftovers from used 
samples and their potential uses 
of research 
To improve clarity of language 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 13.9.2 Extent of 
investigational medicinal product 
exposure 
Removed: “in the expansion parts 
of the study (dose expansion 
Arms #1, #2, #3, #4, and #5 
[Parts B, D, G, I and K])”, added 
in Arm#3, and removed 
specifications of Arm#5 parts 
involved 
Correction to improve clarity, as this section is 
not just limited to expansion parts. Also, updates 
were made to reflect the arms involved in cycle 
delays 
Section 13.9.4.2 Analyses of adverse 
events 
Added version number (v4.03) to 
NCI-CTCAE version 
Updated to reflect correct NCI-CTCAE version 
Section 13.10 Interim Analysis 
Removed a paragraph regarding 
Arm #1 Part B, mentioning the 
planning of an interim analysis 
when 29 patients are treated 
This paragraph was removed in order to fix an 
error from the previous amended protocol 
Section 14.2 Informed Consent 
Modified the informed consent 
section 
Updated to improve clarity on the different ICFs 
involved and to clarify the information on 
pharmacogenetic ICF, as there is no separate 
pharmacogenetic ICF 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical error corrections) were 
implemented throughout the protocol. 
 
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CLINICAL TRIAL SUMMARY  
 
COMPOUND: SAR439859 
STUDY No: TED14856 AMEERA-1 
TITLE 
A Phase 1/2 study for the safety, efficacy, pharmacokinetic and 
pharmacodynamics evaluation of amcenestrant, administered orally as 
monotherapy, then in combination with other anti-cancer therapies in 
postmenopausal women with estrogen receptor-positive advanced breast cancer 
INVESTIGATOR/TRIAL LOCATION Worldwide 
PHASE OF DEVELOPMENT 
1/2 
STUDY OBJECTIVES 
Primary objective 
DOSE ESCALATION:  
Monotherapy Arm #1 – PART A (amcenestrant monotherapy); Combination 
Arm #2 – PART C (amcenestrant in combination with palbociclib); 
Combination Arm#4 - PART H (combination of amcenestrant with 
everolimus); Combination Arm #5 - PART J (combination of amcenestrant 
with abemaciclib) 
• 
To assess the incidence rate of dose-limiting toxicity (DLT) and to 
determine the maximum tolerated dose (MTD) as well as the 
recommended dose (RD) of amcenestrant administered as 
monotherapy (Part A), then in combination with palbociclib (Part C), in 
postmenopausal women with estrogen receptor (ER) positive and 
human epidermal growth factor receptor 2 (HER2)-negative advanced 
breast cancer. 
• 
To assess the incidence rate of dose-limiting toxicity (DLT) and 
determine the recommended dose (RD) of everolimus (Part H) or 
abemaciclib (Part J) administered in combination with the selected 
amcenestrant dose for the combination therapy  
SAFETY RUN-IN Phase:  
Combination Arm #3 – PART F (combination of amcenestrant with 
alpelisib) 
• 
To confirm the recommended dose (RD) of amcenestrant in 
combination with alpelisib in postmenopausal women with ER positive, 
HER2 negative and PIK3CA-mutated advanced breast cancer. 
DOSE EXPANSION:  
Monotherapy Arm #1 – PART B (amcenestrant monotherapy) 
• 
To assess antitumor activity using objective response rate (ORR) 
according to response evaluation criteria in solid tumors (RECIST) 
v1.1 determined by an Independent Central Review (ICR) at the 
amcenestrant RD administered as monotherapy (Part B) in 
postmenopausal women with ER-positive and HER2-negative 
advanced breast cancer. 
Combination Arm #2 – PART D (combination of amcenestrant with 
palbociclib); Combination Arm #3 – PART G (combination of amcenestrant 
with alpelisib); Combination Arm #4 – PART I (combination of 
amcenestrant with everolimus); Combination Arm #5 – PART K 
(combination of amcenestrant with abemaciclib) 
• 
To characterize the overall safety profile of amcenestrant administered 
in combination with palbociclib (Part D), in combination with alpelisib 
(Part G), in combination with everolimus (Part I), and in combination 
with abemaciclib (Part K) 
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Secondary objectives 
• 
To characterize the overall safety profile of amcenestrant administered 
as monotherapy (Arm #1 Parts A and B), in combination with 
palbociclib (Arm #2 Part C) and in combination with alpelisib (Arm #3 
Part F), everolimus (Arm #4 Part H) and abemaciclib (Arm #5 Part J). 
• 
To characterize the PK profile of amcenestrant administered as 
monotherapy (Arm#1), or in combination in each study Arms, as well 
as the PK profile of palbociclib, alpelisib, everolimus and abemaciclib in 
the appropriate treatment arm.  
• 
To evaluate the antitumor activity using ORR according to RECIST 
v1.1 of amcenestrant  administered as monotherapy (Arm #1 Part A), 
in combination with palbociclib (Arm #2 Part C and D), in combination 
with alpelisib (Arm #3 Part F and G), in combination with everolimus 
(Arm #4 Parts H and I), and in combination with abemaciclib (Arm #5 
Parts J and K), the clinical benefit rate (CBR) defined as complete 
response [CR], partial response [PR] and stable disease [SD] 
≥24 weeks, and progression-free survival (PFS) in each treatment arm. 
• 
To evaluate the ORR and CBR (CR, PR and SD ≥24 weeks) in dose 
expansion of each study treatment arm according to the estrogen 
receptor 1 (ESR1) gene mutational status (mutant and wild type) at 
baseline and during treatment. 
• 
To evaluate the time to first tumor response (CR or PR) in dose 
expansion of each study treatment arm.  
• 
To evaluate residual ER availability with positron emission tomography 
(PET) scan [(18)F] fluoroestradiol (18F-FES) uptake with increasing 
doses of amcenestrant (Arm #1 Part A).  
• 
To assess the food effect on PK of amcenestrant (Arm #1 Part A). 
• 
To assess potential induction/inhibition effect of amcenestrant on 
cytochrome P450 (CYP) 3A using 4b-OH cholesterol (ie, full PK 
sampling for Arm #1 Parts A and B, Arm#5 Parts J and K)  
Exploratory objectives 
• 
To evaluate PK/pharmacodynamic (PD) relationships.  
• 
To evaluate target engagement: confirm the ER degradation with re-
biopsy of the tumor at recommended dose in Arms #1 (Part B), #3 
(Parts F,G), #4 (Parts H,I), and #5 (Parts  J, K). 
• 
To evaluate other breast cancer biomarkers in tumor over time such as 
Ki67, Bcl-2, PgR, ER and tumor gene expression profiles in Arms #1 
(Parts A, B), #3 (Parts F, G), #4 (Parts H, I), and #5 (Parts J, K). In Arm 
#5 (Parts J, K), Cyclin D1 protein expression will be evaluated too, at 
baseline and over time. Results will be correlated with patients' clinical 
parameters. 
• 
To assess the extent of metastases with FDG PET/CT during dose 
escalation (Arm #1 Part A BID). 
• 
To evaluate change of cfDNA alterations from screening to progression 
of disease during Arm #1 (Part B), #2, #3, #4, and #5. The percentage 
of patients with cfDNA alterations will be provided over time to 
characterize the biological evolution of the disease in each patient. The 
association of these alterations with clinical outcomes will also be 
provided. 
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STUDY DESIGN 
This is an open-label, non-comparative, dose escalation and dose expansion, 
safety, efficacy, PK, and PD evaluation study of amcenestrant administered 
orally as monotherapy (Parts A and B) and in the following combinations: with 
palbociclib (Parts C and D), alpelisib (Parts F and G), everolimus (Parts H and I) 
and abemaciclib (Parts J and K).  
This study will be performed in 10 parts (5 Arms), in postmenopausal women 
with ER-positive and HER2-negative advanced breast cancer: 
Arm #1 Part A 
Dose escalation study to evaluate the safety, PK and PD of amcenestrant 
administered as monotherapy, including pilot food effect sub-study. 
Arm #1 Part B 
Dose expansion study to evaluate the efficacy, safety, PK and PD of 
amcenestrant administered at the RD (from Part A). 
Arm #2 Part C 
Dose escalation study to evaluate the safety, PK and PD of amcenestrant 
administered in combination with the recommended standard dosage of 
palbociclib. 
Arm #2 Part D 
Dose expansion study to characterize the overall safety, anti-tumor activity 
PK and PD of amcenestrant administered at the selected dose(s) (from 
Part C) in combination with palbociclib. 
Arm #3 Part F  
Safety run-in phase to evaluate the safety, PK and PD of amcenestrant 
administered in combination with the recommended standard dosage of 
alpelisib. 
Arm #3 Part G 
Dose expansion study to characterize the overall safety, anti-tumor activity 
PK and PD of amcenestrant administered at the RD dose (from Part F) in 
combination with alpelisib 
Arm #4 Part H  
Dose escalation study to evaluate the safety, PK and PD of amcenestrant 
administered in combination with everolimus. 
Arm #4 Part I 
Dose expansion study to characterize the overall safety, anti-tumor activity 
PK and PD of amcenestrant administered at the confirmed RD dose (from 
Part H) in combination with everolimus.  
Arm #5 Part J  
Dose escalation study to evaluate the safety, PK and PD of amcenestrant 
administered in combination with abemaciclib. 
Arm #5 Part K 
Dose expansion study to characterize the overall safety, anti-tumor activity 
PK and PD of amcenestrant administered at the confirmed RD dose (from 
Part J) in combination with abemaciclib. 
 
A Study Committee will be set up, which will include the investigators (or 
designee) who participate in dose escalation study parts, Sponsor 
representatives, and, if needed, the ad-hoc experts (eg, FES PET expert). The 
Study Committee will meet regularly during the dose escalation/safety run-in 
study parts. The Study Committee will review available clinical data including PK 
and safety data (especially DLTs) as well as FES-PET scan results for Arm#1 
Part A of each individual patient who are treated in dose escalation study parts in 
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order to adjust the number of enrolled patients at each dose level, as well as to 
decide the further dose escalation, if appropriate. Decisions regarding final dose 
selection will be made at the Dose Selection meeting which will be documented 
and shared with sites. 
 
Arm #1 
A) Dose escalation of amcenestrant monotherapy (Part A) 
Dose escalation will be initiated with a once daily (QD)  schedule with a starting 
dose of 20 mg/day. Dose escalation is expected to proceed according to the 
table below. Intra-patient dose escalation or re-escalation will not be permitted. 
Amcenestrant dose levels in Part A 
Dose level (DL)a 
Amcenestrant (mg)  
DL(-1) QD 
10 once daily 
DL1 QD 
20 once daily 
DL1bis QD 
50 once daily 
DL2 QD 
100 once daily 
DL2bis QD 
150 once daily 
DL3 QD 
200 once daily 
DL4 QD 
400 once daily 
DL4bis BIDb 
200 twice daily 
DL5 QD 
600 once daily 
DL5bis BIDb 
300 twice daily 
a Additional intermediate or higher dose levels can be tested after agreement 
between Sponsor and Investigators (Study Committee) 
b A BID schedule of administration may be added during the study, the starting dose 
will be a DL of the same dose intensity as the highest cleared DL with QD 
Schedule. Other schedules of administration may be added during the study. 
Part A of this study is designed using the 3 + 3 concept; 3 to 6 patients will be 
treated at each dose level depending on DLTs observed in the first 3 patients. If 
one of the first 3 evaluable patients experiences DLTs during Cycle 1, this cohort 
will be expanded with a total of up to 6 patients. If less than 1 out of 3 patients or 
less than 2 out of 6 patients experienced DLTs at a given dose level, the dose 
escalation will proceed to the next dose level.  
In addition, 18F-FES-PET scan results should be available for all DLT evaluable 
patients in Part A  and depending on results at DL1 and DL2, the intermediate 
dose levels (DL1bis and DL2bis) could be explored (see Section 6.2.1). From 
these two dose levels DL1bis and DL2bis, the next dose levels (DL2 and DL3 
respectively) should not be skipped. 
At subsequent dose levels (≥DL3), other intermediate or higher dose levels may 
be tested based on safety, 18F-FES-PET scan results (if all patients have >90% 
of inhibition of the target) and PK parameters upon recommendation from the 
Study Committee. 
The second and third patients of a given cohort can only be enrolled when the 
first patient will have received at least 1 week of amcenestrant without DLT. The 
enrollment at the next dose level may not proceed before at least 3 patients 
treated at the current dose level have been followed for at least 1 cycle duration 
(ie, 28 days) and are evaluable for DLT assessment. 
Patients who discontinue study treatment prematurely before the end of DLT 
observation period for any reason other than DLT must be replaced. 
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As a rule, the dose escalation part will stop when the maximum administered 
dose (MAD) is reached, MAD being defined as the dose at which ≥33% 
(2 patients out of up to 6) of evaluable patients have experienced a DLT at 
Cycle 1. 
The MTD is defined as the highest dose level at which no more than 1 patient of 
a maximum of 6 patients experienced a DLT. Usually, the MTD is one dose level 
below the MAD or the highest dose tested if the MAD is not reached. 
Although dose escalation process is guided by the safety evaluation during 
Cycle 1 of treatment, cumulative or irreversible toxicities observed after 
subsequent administrations should also be considered for the dose escalation 
and the dose selection decisions (ie, expansion of a given dose level, 
intermediate dose levels), as well as any other relevant information, upon 
recommendation from the Study Committee. 
The RD for the expansion cohorts will be primarily based on safety data, but also 
on target saturation, PK and PK/PD data. If the MTD cannot be determined in the 
absence of DLTs at the MAD, the following will also be taken into account for the 
RD selection and the decision to expand the study to other dose expansion study 
parts: PK after repeated administration, level of inhibition of target occupancy 
measured by 18F-FES-PET imaging, PK/PD on ER occupancy and any other 
relevant information. The RD should be potentially at least 2 dose levels above 
the dose level showing >90% of inhibition of the target on 18F-FES-PET scan at 
this dose level, unless there are DLTs at this dose, in which case the RD could 
be any dose where >90% inhibition was reached. 
The twice a day (BID) regimen will be explored on 6 DLT-evaluable patients at 
the dose level providing the same dose intensity as the highest cleared QD dose 
level (600 mg): 300 mg taken two times a day 12 hours apart (ie, 2 x 300 mg 
±1 hour). Other doses such as 200 mg taken two times a day 12 hours apart 
may be explored. In that case, 6 DLT-evaluable patients will be enrolled at this 
dose level.  
Pilot food effect: A pilot food effect will be assessed by PK sampling after drug 
administration with a standard meal on Day 3 of Cycle 1 in all patients treated in 
Part A. All other dosing in Part A will be taken in fasted condition. If results from 
the QD dosing regimen allow conclusions to be drawn, this will not be 
implemented for other dosing regimens (eg, BID) that are explored. 
 
B) Dose Expansion of amcenestrant monotherapy (Part B) 
When the dose escalation phase ends for the QD regimen, the RD will be 
proposed by the Study Committee for the expansion cohort (Part B) and a total of 
78 patients will be treated at this RD. Intra-patient dose escalation or re-
escalation is not allowed. An interim analysis based on ORR (by RECIST v1.1) is 
planned when 45 patients are treated in order to decide, based on preset criteria, 
if the recruitment of planned additional patients is justified (see statistical 
considerations). If results in Part A with the BID dosing regimen are of interest in 
terms of safety, PK, exposure, preliminary efficacy and any other relevant 
information such as data from patients treated with the QD regimen, and 
warrants further investigation, a BID regimen could be tested in an additional 
expansion subpart with a total of 56 patients treated at the recommended BID 
regimen from Part A. In that case, an interim analysis based on ORR (by 
RECIST v1.1) would be planned when 29 patients are treated in order to decide, 
based on preset criteria, if the recruitment of planned total patients is justified.  
 
 
 
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Arm #2 – amcenestrant in combination with palbociclib 
C) Dose Escalation (Part C) 
It is expected to assess 2 amcenestrant dose levels schedule starting from one 
dose level below the RD fixed in Part A (RD[A-1]) and then amcenestrant 
(RD[A]), using the 3 + 3 standard dose escalation design with palbociclib given at 
fixed dose. The Study Committee will decide on whether to escalate (or not) to 
the next amcenestrant dose level in combination with palbociclib during Study 
Committee meetings on the basis of their knowledge of the whole safety profile, 
and PK results. 
Amcenestrant dose levels in Part C 
Dose levels (DL)a 
Amcenestrant  
Palbociclibb 
DL1 QD 
DL RD(A-QD)-1 
125 mg 
DL2 QD 
RD(A-QD) 
125 mg 
DL3 BID 
RD(A-BID) 
125 mg 
a Lower dose, intermediate dose levels and a BID dose regimen can be tested after 
agreement between Sponsor and Investigators (Study Committee) 
b Oral route once daily with food for 21 days followed by 7 days off therapy to 
comprise a complete cycle of 28 days. Lower dose (eg, 100 mg, 75 mg) can be 
proposed depending on tolerance 
Three to 6 evaluable patients will be treated at each dose level, and dose 
escalation decision will be based on DLT observed for at least 1 cycle duration 
(ie, 28 days) of the first 3 evaluable patients. If one of the first 3 evaluable 
patients experiences DLT during Cycle 1, this cohort will be expanded with 
a total of 6 patients. If none of the first 3 patients or less than 2 out of 6 patients 
experienced a DLT, the dose escalation will proceed to the next dose level. The 
second and third patients of a given cohort can only be enrolled when the 
first patient will have received 1 week of amcenestrant and palbociclib without 
DLT. The enrollment at the next dose level may not proceed before at least 
3 patients treated at the current dose level have been followed for at least 1 cycle 
duration (ie, 28 days) and are evaluable for DLT assessment. 
Patients who discontinue study treatment prematurely before the end of DLT 
observation period for any reason other than DLT must be replaced. 
As a rule, the dose escalation will stop when the MAD, dose at which ≥33% 
(2 patients out of up to 6) of evaluable patients have experienced a DLT at 
Cycle 1, is reached. The MTD is defined as the highest dose level at which no 
more than 1 patient of a maximum of 6 evaluable patients experienced a DLT. 
The MTD is one dose level below the MAD or the highest dose tested if MAD is 
not reached. Intra-patient dose escalation or re-escalation of any study drug is 
not allowed. 
Although the dose escalation process is guided by the safety evaluation during 
Cycle 1 of treatment, cumulative or irreversible toxicities observed after 
subsequent administrations will also be considered for the dose escalation and 
the dose selection decisions (ie, expansion of a given dose level, intermediate 
dose levels), as well as any relevant information, upon recommendation from the 
Study Committee. 
 
D) Dose Expansion (Part D) 
When the dose escalation phase (Part C) ends, at least one RD will be proposed 
by the Study Committee for the expansion cohort (Part D) and approximately 
28 patients will be treated at each selected RD (from Part C). Intra-patient dose 
escalation or re-escalation of any study drug is not allowed. The Study 
Committee will review preliminary data (eg, safety, efficacy and PK) of each 
selected RD.  
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Arm #3 – amcenestrant in combination with alpelisib 
E) Safety Run-In (Part F)  
Amcenestrant 200 mg QD dose level will be assessed in combination with 
alpelisib at a fixed (standard) dose of 300 mg per alpelisib label according to 
incidence of DLTs and PK results.  Additional dose levels of amcenestrant 
(eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 200 mg BID etc.) with 
alpelisib could be explored if needed based on the safety and PK results from the 
200 mg dose level testing with 300 mg alpelisib. Lower dose of alpelisib 
(eg, 250 mg or 200 mg) could be explored from Cycle 1 Day 1 based on the PK 
results and safety profile from the initial combination of amcenestrant 200 mg 
and alpelisib 300 mg on the first 3 to 6 patients in Part F.  
Based on the preliminary safety profile as well as PK and preliminary antitumor 
activity data, the Study Committee will decide whether to test additional 
amcenestrant dose levels in the safety run-in part and expand the alpelisib 
combination to Part G, or not. 
Amcenestrant and alpelisib dose levels in Part Fa 
Dose levels 
(DL)b  
Amcenestrant  
Alpelisib 
Standard dosec 
Alpelisib 
(reduced dose)d 
DL1 QD 
200 mg  
300 mg 
 
DL2 QD 
200 mg 
 
250 mg 
DL3 QD 
200 mg 
 
200 mg 
a In Part F (and G), Cycle 1 is defined as a 28-day cycle with 3 days of pretreatment 
with alpelisib single-agent for PK assessment followed by a 25-day treatment cycle 
with amcenestrant and alpelisib. Following cycles will also continue to be 28 days.   
b Lower or higher doses QD, and BID dose regimen can be tested after agreement 
between Sponsor and the Study Committee 
c Oral route, once daily with food.  
d Lower dose (eg, 250 mg, 200 mg) can be proposed depending on tolerance  
Up to 6 DLT-evaluable patients could be treated at the already established 
amcenestrant dose of 200 mg when given in combination with other drugs, in 
order to confirm this dose when administered in combination with alpelisib. Lower 
dose levels of alpelisib and/or other dose levels of amcenestrant could be 
considered for testing in Part F if this established dose is not confirmed. 
A decision to continue to dose expansion study part (Part G) will be based on 
DLTs observed for at least 1 cycle duration of all evaluable patients, and PK 
results from Part F combination. Intra-patient dose escalation or re-escalation of 
any study drug is not allowed 
1) If none or one of the first 3 evaluable patients experiences DLT(s) 
during Cycle 1, the cohort will be expanded to include an additional 
3 patients for a total of 6 patients.  
a) In the second set of 3 patients (ie, 6 patients altogether), if none 
or one DLT is experienced among the 6 patients (ie, 0/6 or 1/6), 
the doses of the combination are adequate for further testing in 
Part G. 
b) In the second set of 3 patients (ie, 6 patients altogether), if two or 
more DLTs are experienced among the 6 patients (ie, ≥2/6), the 
doses of the combination are NOT adequate for further testing in 
Part G. In this case, other dose levels of alpelisib and/or 
amcenestrant could be considered in Part F, or Part F can be 
stopped. 
2) If 2 or more of the first 3 evaluable patients experience DLT(s), lower 
dose of alpelisib dose and/or other dose levels of amcenestrant will be 
considered or a decision to stop Part F can be made.  
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Although the confirmation of amcenestrant dose when given in combination with 
alpelisib will be guided by safety evaluation during Cycle 1, cumulative or 
irreversible toxicities observed after subsequent administrations will also be 
considered for dose selection/confirmation decision (ie, expansion of a given 
dose level), as well as any relevant information such as PK and anti-tumor 
activity data that may need additional patients, upon recommendation from the 
Study Committee. 
F) Dose Expansion (Part G) 
When the safety run-in (Part F) completes, based on safety, PK and efficacy 
data, RD of amcenestrant for the combination therapy will be confirmed by Study 
Committee for expansion cohort (Part G), and approximately 34 patients will be 
treated at the amcenestrant confirmed RD from Part F agreed by the Study 
Committee. Intra-patient dose escalation or re-escalation of any study drug is not 
allowed. 
 
Arm #4 – amcenestrant in combination with everolimus 
G)  Dose escalation (Part H)  
Amcenestrant 200 mg QD dose level will be assessed in combination with 
everolimus two dose levels: 5 mg QD and 10 mg QD based on the incidence of 
DLT(s) and PK results.  In this dose escalation part, additional dose levels of 
amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 200 mg BID 
etc.) with everolimus could also be explored if needed, based on the safety and 
PK results of everolimus in this dose escalation study.  
Based on the preliminary safety profile, PK and antitumor activity data, Study 
Committee will determine the recommended dose (RD) of everolimus in 
combination with amcenestrant 200 mg QD, and/or expand this combination to 
Part I, or not. 
Amcenestrant and everolimus dose levels in Part Ha 
Dose levels  
(DL)  
Amcenestrantb 
Everolimusc  
(QD)  
DL1 QD 
200 mg  
5 mg 
DL2 QD 
200 mg 
10 mgd 
a In Part H, Cycle 1 is defined as a 28-day treatment cycle of amcenestrant and 
everolimus. Following cycles will also continue to be 28 days.   
b Lower or higher doses QD, and BID dose regimen can be tested after agreement 
between Sponsor and Study Committee  
c Oral route, once daily (QD) with food.  
d Lower dose of everolimus, (5 mg QOD (every other day) can be explored 
depending on tolerance 
Six (6) to 12 evaluable patients will be treated with already established RP2D of 
amcenestrant dose of 200 mg QD when given in combination with 2 dose levels 
of everolimus: 5 mg QD and 10 mg QD. Dose escalation decision will be based 
on DLT(s) observed for at least 1 cycle duration (ie, 28 days) in a following way:  
• 
If 1 of the first 3 evaluable patients who were treated with 
amcenestrant 200 mg QD and everolimus 5 mg QD experienced 
DLT(s) during Cycle 1, this cohort will be expanded with 3 additional 
patients at the same dose level of everolimus and amcenestrant to the 
total of 6 patients.  
• 
If 0 of the first 3 patients or less than 2 out of 6 patients treated at 
amcenestrant 200 mg QD with 5 mg everolimus QD experienced 
DLT(s), dose escalation will proceed to the next dose level of 
everolimus (ie,10 mg QD) and amcenestrant 200 mg QD by adding 
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3 patients at this new combination dose level, to the total of 6 or 
9 patients. 
• 
If 1 of the first 3 evaluable patients treated with amcenestrant 200 mg 
QD and everolimus 10 mg QD experienced DLT(s) during Cycle 1, this 
cohort will be expanded with 3 additional patents to total of 9 or 
12 patients in dose escalation study. 
The second and third patients of a given cohort can only be enrolled when the 
first patient will have received 1 week of amcenestrant and everolimus without 
experiencing DLT(s).  
The enrollment at the next dose level of everolimus may not proceed to 10 mg 
QD dose level before at least 3 patients treated with amcenestrant 200 mg QD 
and everolimus initial dose level (5 mg QD) have been followed for at least 
1 cycle duration (ie, 28 days) and are evaluable for DLTs’ assessment. 
Patients who discontinue study treatment prematurely before the end of DLT 
observation period for any reason other than DLT(s) must be replaced. 
As a rule, the dose escalation will stop when the MAD, dose at which ≥33% 
(2 patients out of up to 6) of evaluable patients have experienced a DLT at 
Cycle 1, is reached. The MTD is defined as the highest dose level at which no 
more than 1 patient of a maximum of 6 evaluable patients experienced DLT(s). 
The MTD is one dose level below the MAD or the highest dose tested if MAD is 
not reached. Intra-patient dose escalation or re-escalation of any study drug is 
not allowed. 
Although the dose escalation process is guided by the safety evaluation during 
Cycle 1 of treatment, cumulative or irreversible toxicities observed after 
subsequent administrations will also be considered for dose escalation, dose 
selection decisions (ie, expansion of a given dose level, intermediate dose 
levels), as well as any relevant information, upon recommendation from the 
Study Committee. 
H) Expansion cohort (Part I) 
When the dose escalation study (Part H) completes, based on safety, PK and 
preliminary antitumor activity data, RD of everolimus for the combination therapy 
will be proposed by Study Committee for expansion cohort (Part I); 
approximately 12 patients will be treated at the RD from Part H selected by the 
Study Committee. Intra-patient dose escalation or re-escalation of any study drug 
is not allowed. 
 
Arm #5 – amcenestrant in combination with abemaciclib 
I) 
Dose Escalation (Part J)  
Amcenestrant 200 mg QD dose level will be assessed in combination with 
abemaciclib two dose levels: 100 mg BID and 150 mg BID according to 
incidence of DLT(s) and PK results.  Additional dose levels of amcenestrant 
(eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 200 mg BID etc.) with 
abemaciclib could be explored if needed based on the safety and PK results from 
this dose escalation study.  
Based on the preliminary safety profile, PK and preliminary antitumor activity 
data, the Study Committee will determine the recommended dose (RD) of 
abemaciclib in combination with amcenestrant 200 mg QD, and/or expand this 
combination to Part K, or not. 
 
 
 
 
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Amcenestrant and abemaciclib dose levels in Part Ja 
Dose levels 
(DL)  
Amcenestrantb 
 
Abemaciclibc 
(BID) 
DL1 QD 
200 mg QD  
100 mg BIDd 
DL2 QD 
200 mg QD 
150 mg BID 
a In Part J, Cycle 1 is defined as a 28-day treatment cycle of amcenestrant and 
abemaciclib. Following cycles will also continue to be 28 days.   
b Lower or higher doses QD and BID dose regimen can be tested after agreement 
between Sponsor and Study Committee  
c Oral route, twice daily (BID) with food.  
d Lower doses of abemaciclib, 50 mg BID can be used depending on tolerance 
Six (6) to 12 evaluable patients will be treated with already established RP2D of 
amcenestrant dose of 200 mg QD when given in combination with 2 dose levels 
of abemaciclib: 100 mg BID and 150 mg BID. Dose escalation decision will be 
based on DLT(s) observed for at least 1 cycle duration (ie, 28 days) in a following 
way:  
• 
If 1 of the first 3 evaluable patients who were treated with 
amcenestrant 200 mg QD and abemaciclib 100 mg BID experienced 
DLT(s) during Cycle 1, this cohort will be expanded with 3 additional 
patients at the same dose level of abemaciclib and amcenestrant to the 
total of 6 patients.  
• 
If 0 of the first 3 patients or less than 2 out of 6 patients treated at 
amcenestrant 200 mg QD with abemaciclib 100 mg BID experienced 
DLT(s), dose escalation will proceed to the next dose level of 
abemaciclib (ie,150 mg BID) and amcenestrant 200 mg QD by adding 
3 patients at this new combination dose level, to the total of 6 or 
9 patients 
• 
If 1 of the first 3 evaluable patients treated with amcenestrant 200 mg 
QD and abemaciclib 150 mg BID experienced DLT(s) during Cycle 1, 
this cohort will be expanded with 3 additional patents to total of 9 or 
12 patients in dose escalation study. 
The second and third patients of a given cohort can only be enrolled when the 
first patient will have received 1 week of amcenestrant and abemaciclib without 
experiencing DLT(s).  
The enrollment at the next dose level of abemaciclib may not proceed to 150 mg 
BID dose level before at least 3 patients treated with amcenestrant 200 mg QD 
and abemaciclib initial dose level (100 mg BID) have been followed for at least 
1 cycle duration (ie, 28 days) and are evaluable for DLTs’ assessment. 
Patients who discontinue study treatment prematurely before the end of DLT 
observation period for any reason other than DLT(s) must be replaced. 
As a rule, the dose escalation will stop when the MAD, dose at which ≥33% 
(2 patients out of up to 6) of evaluable patients have experienced a DLT at 
Cycle 1, is reached. The MTD is defined as the highest dose level at which no 
more than 1 patient of a maximum of 6 evaluable patients experienced DLT(s). 
The MTD is one dose level below the MAD or the highest dose tested if MAD is 
not reached. Intra-patient dose escalation or re-escalation of any study drug is 
not allowed. 
Although the dose escalation process is guided by the safety evaluation during 
Cycle 1 of treatment, cumulative or irreversible toxicities observed after 
subsequent administrations will also be considered for dose escalation, dose 
selection decisions (ie, expansion of a given dose level, intermediate dose 
levels), as well as any relevant information, upon recommendation from the 
Study Committee. 
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J) Dose expansion (Part K) 
When the dose escalation study (Part J) completes, based on safety, PK and 
preliminary antitumor activity data, RD of abemaciclib for the combination 
therapy will be proposed by Study Committee for expansion cohort (Part K); 
approximately 20 patients will be treated at the RD from Part J selected by the 
Study Committee. Intra-patient dose escalation or re-escalation of any study drug 
is not allowed. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria:  
I 01. 
Patients must be postmenopausal women as defined by one of the 
following: 
a) 
Women >60 years 
b) 
Women ≤60 years: 
- 
With spontaneous cessation of menses >12 months prior to 
registration in the absence of chemotherapy, tamoxifen and 
toremifene. 
- 
Or with cessation of menses of duration ≤12 months or secondary 
to hysterectomy AND have follicle stimulating hormone (FSH) 
level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L if institutional range is not available) prior 
to registration. 
- 
Or who have received hormonal replacement therapy but who 
have discontinued this treatment AND have FSH level in the 
postmenopausal range according to institutional standards (or 
>34.4 IU/L if institutional range is not available) prior to 
registration. 
- 
Or with status post bilateral surgical oophorectomy. 
- 
Or are premenopausal women on a gonadotropin-releasing 
hormone (GnRH) analog for at least 6 months (to be continued 
during study treatment) and have a negative pregnancy test prior 
to initiation of study treatment and at monthly intervals during 
treatment. In Arm #3 (Parts F and G) only, patients and their male 
partners must agree to use non-oral contraception if sexually 
active during the treatment and 1 week after the last dose. In Arm 
#4 (Parts H and I) only, patients and their male partners must 
agree to use non-oral contraception if sexually active during the 
treatment and 8 weeks after the last dose. In Arm #5 (Parts J and 
K) only, patients and their male partners must agree to use non-
oral contraception if sexually active during the treatment and 
3 weeks after the last dose. 
I 02. 
Patients with histological or cytological proven diagnosis of the breast 
adenocarcinoma with evidence of either locally advanced not amenable 
to radiation therapy or surgery in a curative intent, inoperable and/or 
metastatic disease. 
I 03. 
Either the primary tumor or any metastatic site must be positive for ER 
(>1% tumor cell staining by immunohistochemistry (IHC). 
I 04. 
Either the primary tumor or any metastatic site must be HER2 non-
overexpressing by IHC (0, 1+) or in situ hybridization-negative based 
on single-probe average HER2 copy number <4.0 signals/cell or dual-
probe HER2/ centromeric probe for chromosome 17 (CEP17) ratio 
<2 with an average HER2 copy number <4.0 signals/cell as per the 
American Society of Clinical Oncology guidelines. 
 
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I 05. 
Prior chemotherapy for advanced disease is allowed. Prior 
chemotherapy for advanced disease is not allowed in dose 
expansion of Arms #3, #4, and #5 (Part G, I and K respectively). 
(Note: Antibody drug conjugates [ADCs] are considered as 
chemotherapy in the study): 
- 
Patients must have received no more than 3 prior 
chemotherapeutic regimens in Arm #1 Part A (dose escalation, 
monotherapy). 
- 
Patients must have received no more than 1 prior 
chemotherapeutic regimen in Arms #1, #2, #3, #4, and #5 
(Parts B, C, D, F, H and J respectively) 
I 06. 
Patients must have received at least 6 months of prior endocrine 
therapy for advanced breast cancer.  
Dose Escalation study parts: 
Arm #3: - Part F: up to 2 prior lines of either single endocrine therapy 
and/or endocrine-based therapy 
Arm #4:  - Part H: up to 2 prior lines of either single endocrine therapy 
and/or endocrine-based therapy (exemestane not allowed) 
Arm #5: - Part J: up to 2 prior lines of either single endocrine therapy 
and/or endocrine-based therapy 
Dose Expansion study parts: 
Arm #2: - Part D: no more than 2 prior lines of advanced endocrine 
therapy for advanced disease are allowed 
Arm #3: - Part G: patients must have received and progressed on the 
combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the 
first line (1L) treatment for advanced disease 
Arm#4:  - Part I: patients must have received and progressed on the 
combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first 
line (1L) treatment for advanced disease (exemestane not allowed) 
Arm#5:  - Part K: up to 1 prior line of a single endocrine therapy for 
advanced disease 
Note:     Additional patients who relapsed while on previous adjuvant 
endocrine therapy that was initiated ≥24 months ago, OR relapsed 
<12 months after completion of adjuvant endocrine therapy are also 
allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J and K) 
I 07. 
Age ≥18 years old. 
I 08. 
Measurable lesion by RECIST v1.1. 
I 09. 
The patient is capable of understanding the informed consent and 
complying with the protocol and has signed the informed consent form 
(ICF) before any study (specific screening procedures or evaluations). 
 
Arm #1 Part A only 
I 10. 
Patient entering Part A must agree to undergo:  
c) 
Two 18F-FES-PET/computerized tomography (CT) imaging scans, 
one at baseline and one between Day 11 and Day 15 of study 
treatment intake, and  
d) 
Two FDG PET/CT for Part A BID, one at baseline and one 
between Day 11 and Day 15 of study treatment intake before  
18F-FES-PET (patients whose baseline FDG PET/CT results are 
negative for tumors will not be eligible), and 
e) 
Paired biopsies (before treatment and during treatment): For 
baseline samples, formalin-fixed and paraffin-embedded (FFPE) 
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archived biopsy samples (within past 3 months prior initiation of 
study treatment) can be used, but preferably fresh biopsies from 
primary tumor or recurrence or metastasis, will be collected. It is 
recommended that the end of Cycle 2 on-treatment biopsy be 
collected at the same location as the baseline biopsy, whenever 
the tumor is accessible for a biopsy during treatment. 
 
Arm #1 Part B  
I 11. 
For patients who consent to paired biopsies (before treatment and 
during treatment): for baseline samples, FFPE archived biopsy samples 
can be used (within past 3 months prior to initiation of study treatment), 
but preferably fresh biopsies from primary tumor or recurrence or 
metastasis will be collected. It is recommended that the end of Cycle 2 
on-treatment biopsy be collected at the same location as the baseline 
biopsy, whenever the tumor is accessible for a biopsy during treatment.  
 
Arm #3 Part F and G only 
I 12. 
In Parts F and G, patient must have confirmed/detected PIK3CA 
mutations determined in tumor tissue and/or plasma cfDNA. The 
PIK3CA testing should be performed locally. 
 
General exclusion criteria related to study methodology 
E 01. 
Eastern Cooperative Oncology Group (ECOG) performance status ≥2. 
E 02. 
Significant concomitant illness, including psychiatric condition that, in 
the opinion of the Investigator or Sponsor, would adversely affect the 
patient’s participation in the study. 
E 03. 
Medical history or ongoing gastrointestinal disorders potentially 
affecting the absorption of oral IMPs. Patients unable to swallow 
normally and to take capsules. Predictable poor compliance to oral 
treatment. 
E 04. 
Any malignancy related to human immunodeficiency virus (HIV); or 
unresolved viral hepatitis. 
E 05. 
Patients with a life expectancy less than 3 months. 
E 06. 
Patient not suitable for participation, whatever the reason, as judged by 
the Investigator, including medical or clinical conditions, or patients 
potentially at risk of noncompliance to the study procedures 
(ie, unwillingness and inability to comply with scheduled visits, drug 
administration plan, laboratory tests, other study procedures, and study 
restrictions). 
E 07. 
Major surgery within 4 weeks prior to first study treatment 
administration. 
E 08. 
Patient with any other cancer. However, adequately treated basal cell 
or squamous cell skin cancer or in situ cervical cancer or any other 
cancer from which the patient has been disease free for >3 years are 
allowed. 
E 09. 
Patient is the Investigator or any sub-investigator, research assistant, 
pharmacist, study coordinator, or other staff or relative thereof directly 
involved in the conduct of the protocol. 
Arm #1 Part A only 
E 10. 
Patient with liver metastases only. 
 
 
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Exclusion criteria related to the disease 
E 11. 
Patients with known brain metastases, leptomeningeal carcinomatosis 
or/and spinal cord compression. Patients with brain metastases that 
have been previously totally resected or irradiated are eligible provided 
no progression or relapse is observed within 4 weeks of the treatment 
E 12. 
Treatment with anticancer agents (including investigational drugs) less 
than 2 weeks before first study treatment administration (less than 
4 weeks if the anticancer agents were antibodies). 
E 13. 
Prior treatment with another selective ER down-regulator (SERD): 
- 
Dose Escalation study parts (Parts F, H and J): SERDs are not 
allowed except for fulvestrant which will need a washout of at 
least 6 weeks prior to the first study drug administration. 
- 
Dose Expansion study parts (Parts G, I and K): prior (last) 
treatment with any SERD including fulvestrant will not be allowed. 
E 14. 
Inadequate hematological function including neutrophils <1.5 x 109/L; 
platelet count <100 x 109/L. 
E 15. 
Prothrombin time: International normalized ratio(INR)  >1.5 times the 
upper limit of normal (ULN) or out of therapeutic range if receiving 
anticoagulation that would affect the PT/INR. 
E 16. 
Inadequate renal function with serum creatinine ≥1.5 x ULN or, if 
between 1.0 and 1.5 x ULN with eGFR <60 mL/min/1.73 m2 as 
estimated using the abbreviated Modification of Diet in Renal Disease 
formula (Appendix I).  
E 17. 
Liver function: aspartate aminotransferase (AST) >3 x ULN, or alanine 
aminotransferase (ALT) >3 x ULN. Alkaline phosphatase (ALP) up to 
Grade 2 (2.5 to 5 X ULN), gamma glutamyl transferase (GGT)  up to 
Grade 2 (2.5 to 5 X ULN) would be acceptable only if related to the 
presence of bone and/or liver metastases as judged by the Investigator. 
Total bilirubin >1.5 x ULN. 
E 18. 
Patients with Gilbert disease. 
E 19. 
Non-resolution of any prior treatment related toxicity to < Grade 2, 
except for alopecia according to National Cancer Institute Common 
Terminology Criteria for adverse events (NCI-CTCAE) v4.03  
(Appendix B). 
E 20. 
E20 criterion removed per amendment 10 
E 21. 
a. All study parts, treatment with strong CYP3A inducers within 2 weeks 
before first study treatment administration or 5 elimination half-lives 
whichever is longest (see Appendix E).  
b.  For Arm#1 (Part A and B) and Arm#5 (Part J and K, full PK 
sampling only), in patients with 4βOH cholesterol assessment: 
Treatment with strong and moderate CYP3A inhibitors within 2 weeks 
before first study treatment administration or 5 elimination half-lives 
whichever is longest (see Appendix E).  
E 22. 
More than 1 prior advanced CDK4/6 inhibitor-based therapy in Arm #1, 
Arm #2 (Part C), Arm #3 (Parts F and G), and Arm#4 (Part H). 
E 23. 
Treatment with strong CYP3A inhibitors within 2 weeks before 
first study treatment administration or 5 elimination half-lives whichever 
is longest in Arm#2 (Parts C and D) only according to palbociclib 
labeling (see Appendix E). 
 
 
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E 24. 
Medical conditions requiring concomitant administration of medications 
with a narrow therapeutic window metabolized by CYP3A and for which 
a dose reduction cannot be considered in Arm #2 (Part C and D) 
according to palbociclib labeling (see Appendix F). 
E 25. 
Arm #2 (Part D) and Arm #5 (Parts J, and K) only: Prior therapy with 
targeted therapy for advanced disease (ie, CDK 4/6 inhibitors, PI3K 
inhibitors, mTOR inhibitors and AKT inhibitor). 
 
Part E (Canceled per Amendement 08) 
The following exclusion criteria are specfic for patients enrolled in the drug-drug 
interaction sub-study 
E 26. 
E26 criterion removed per Amendment 08. 
E 27. 
E27 criterion removed per Amendment 08. 
E 28. 
E28 criterion removed per Amendment 08. 
E 29. 
E29 criterion removed per Amendment 08. 
E 30. 
Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: Patients 
with concurrent or history of pneumonitis 
E 31. 
Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment 
therapies that target the PI3K axis (mTOR inhibitors, AKT inhibitors, 
PI3K inhibitors)  
E 32. 
Arm #3 and #4 (Parts F, G, H and I) only: Patients with Diabetes 
Mellitus type-I or uncontrolled Diabetes Mellitus type-II: ie, fasting 
plasma glucose ≥140 mg/dL (7.7 mmol/L) or HbA1C >6.2% 
E 33. 
Arm #3 and #4 (Parts F, G, H and I) only: History of severe cutaneous 
reaction (eg.  Stevens-Johnson syndrome [SJS], erythema multiforme 
[EM), Toxic epidermal necrolysis (TEN), and Drug reaction with 
eosinophilia and systemic symptoms [DRESS]. 
E 34. 
Arm #3 (Parts F and G) only: Ongoing osteonecrosis of jaw 
 
New Exclusion Criteria added in Amendment 09  
E 35. 
Arm #4 (Parts H and I) only: Any active, untreated or uncontrolled 
infection (eg, viral, bacterial, fungal etc.) 
E 36. 
Arm #4 (Parts H and I) only: Patients with active and uncontrolled 
Stomatitis, Angioedema due to concomitant treatment with ACE 
Inhibitors, impaired wounds 
E 37. 
Arm #4 (Parts H and I) only: Uncontrolled Hypercholesterolemia, 
Hypertriglyceridemia and Hyperglycemia in non-diabetic patients 
E 38. 
Arm #4 (Parts H and I) only: Treatment with strong or moderate 
CYP3A4 inhibitors, strong CYP3A4 inducers and/or P-gp inhibitors 
within 2 weeks before the first study treatment administration or 
5 elimination half-lives, whichever is the longest 
E 39. 
Arm #5 (Parts J and K) only: History or current (controlled/not 
controlled) Venous Thromboembolism (ie, Deep Vein Thrombosis 
(DVT), Pulmonary Embolism (PE), Cerebral Venous Sinus Thrombosis 
(CVST) 
New Exclusion Criterion added in Amendment 10 
E 40. 
Treatment with drugs that are sensitive substrate of OATP1B1/1B3 
(eg, asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, 
glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, 
rosuvastatin and simvastatin acid) within 5 days before first study 
treatment administration or 5 half-lives whichever is longer, and in 
which this drug cannot be replaced. 
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Total expected number of patients Up to approximately 251 patients (see statistical considerations) 
Expected number of sites: 
Approximately 40 sites overall  
STUDY TREATMENT(s) 
 
Investigational medicinal product 
Amcenestrant (SAR439859) 
Formulation 
100 mg capsules  
Route of administration 
Oral route 
Dose regimen 
In Arm #1 Part A, amcenestrant will be administered at assigned dose levels, 
within a 28-day cycle. For the QD regimen, during Cycle 1, one dose will be 
taken on Day 1 in fasting condition, no dose on Day 2 and repeated 
administration will start from Day 3. On Day 3 only, the dose will be taken in fed 
condition for a food effect evaluation, and then all subsequent administrations will 
be taken in fasted condition, and at approximately the same time each day 
(±3 hours). From the conclusions drawn with the initial QD dose regimen, 
patients treated with other dose regimens will be allowed to take amcenestrant in 
fasted or fed condition. For the BID regimen, the 600 mg dose will be split in 
two drug administrations: 300 mg taken two times a day 12 hours apart  
(ie, 2 x 300 mg) ±1 hour with or without food (with one dose only taken in the 
morning on Day 1, no dose on Day 2 and then repeated BID dosing from Day 3).  
In Arm #1, Part B, amcenestrant will be taken QD from Day 1 (without omission 
on Day 2) at the RD fixed in Part A, within a 28-day cycle, either in a fasting or 
fed condition; and at approximately the same time each day (±3 hours). A BID 
regimen (without omission on Day 2) may also be explored if found to be 
needed. 
In Arm #2, Parts C and D, amcenestrant will be administered from Day 1 
(without omission on Day 2) at assigned dose levels, within a 28-day cycle in fed 
condition, and at approximately the same time each day (±3 hours). 
Amcenestrant and palbociclib must be taken together, 5 minutes apart. Both 
IMPs must be taken with food, regardless of the order of intake.  
In Arm #3, Parts F and G, amcenestrant will be taken in fed condition QD from 
Cycle 1 Day 4 at 200 mg (or other amcenestrant doses) together with alpelisib 
300 mg QD (or lower alpelisib doses) at approximately the same time each day 
(±3 hours) within a 28-day cycle. The days of PK assessment (ie, on C1D3 and 
C1D22) the drugs will have to be taken with a standard breakfast. 
In Arm #4, Parts H and I, amcenestrant will be taken in fed condition QD from 
Cycle 1 Day 1 at 200 mg (or other amcenestrant doses) together with everolimus 
10 mg QD (or lower doses) at approximately the same time each day (±3 hours) 
within a 28-day cycle. The days of PK assessment (ie, on C1D1 and C1D22) the 
drugs will have to be taken together with a standard breakfast.  
In Arm #5, Parts J and K, amcenestrant will be administered QD and 
abemaciclib BID, both from Cycle 1 Day 1 at assigned dose levels, within a 
28-day cycle in fed condition, and at approximately the same time each day 
(±3 hours). Amcenestrant and abemaciclib will be administered together during 
the morning. The days of PK assessment (ie, on C1D1 and C1D22) the drugs 
will have to be taken together with a standard breakfast. 
If a dose is vomited or omitted, the patient should not take the dose later or 
2 doses at the next planned dose, and this information has to be recorded in the 
diary. Amcenestrant dose omission or reduction could occur in case of toxicity, 
as well as cycle delay in Arms #2, #3, #4, and #5 (see Section 6.5). 
Advise to avoid sun exposure and wear protective clothing, sunscreen, and lip 
balm with high sun protection (eg, SPF ≥30) when outdoors during study 
treatment and 5 days after the last amcenestrant administration. 
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Investigational medicinal product  
 
Formulation 
Route of administration 
Dose regimen 
Palbociclib (Ibrance®) 
125 mg, 100 mg and 75 mg capsules  
Oral route 
The RD of palbociclib is a 125 mg capsule taken once daily for 21 consecutive 
days followed by 7 days off treatment to comprise a complete cycle of 28 days. 
Palbociclib should be taken with food at approximately the same time each day. 
Dose omission or reduction could occur in case of toxicity, (see Section 6.5). 
If a dose is vomited or omitted the patient should not take the dose later or 
2 doses at the next planned dosing, and this information has to be recorded in 
the diary. 
Investigational medicinal product  
 
Formulation 
Route of administration 
Dose regimen 
Alpelisib  
50 mg and 200 mg 
Oral route 
The RD of alpelisib is 300 mg. In both study parts, Part F (refer to the dose per 
pharmacy manual) and in Part G (refer to the dose per pharmacy manual) tablets 
should be taken orally once daily with food at approximately the same time each 
day. Dose omission or reduction could occur in case of toxicity (see Section 6.5). 
If a dose is vomited or omitted the patient should not take the dose later or 
2 doses at the next planned dosing, and this information has to be recorded in 
the diary. 
Investigational medicinal product  
 
Formulation 
Route of administration 
Dose regimen 
Everolimus  
5 mg  
Oral route 
The RD of everolimus is 10 mg taken orally, once a day as 2x5 mg with food at 
approximately the same time each day. Dose omission or reduction could occur 
in case of toxicity, (see Section 6.5). 
If a dose is vomited or omitted the patient should not take the dose later or 
2 doses at the next planned dosing, and this information has to be recorded in 
the diary. 
Investigational medicinal product  
 
Formulation 
Route of administration 
Dose regimen 
Abemaciclib  
50 mg, 100 mg, and 150 mg tablet  
Oral route 
Abemaciclib will be taken orally, twice a day as 2x100 mg and/or 2x150 mg with 
food at approximately the same time each day. Dose omission or reduction could 
occur in case of toxicity, (see Section 6.5). 
If a dose is vomited or omitted the patient should not take the dose later or 
2 doses at the next planned dosing, and this information has to be recorded in 
the diary. 
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ENDPOINT(S) 
 
Primary endpoint 
Arms #1, #2, #3, #4, and #5 (Part A, C, F, H and J) 
Incidence of study treatment related DLTs at Cycle 1 (Day 1 to Day 28). DLT will 
be defined as the occurrence of any of the following treatment-emergent adverse 
events (TEAEs) related to the study therapy using NCI-CTCAE (v4.03): 
• 
Any Grade ≥3 non-hematological toxicity, except: 
- 
Grade 3 nausea and vomiting resolving to Grade ≤1 within 
48 hours, with or without adequate antiemetic treatment (all study 
arms) 
- 
Grade 3 diarrhea, if controlled with adequate antidiarrheal therapy 
and lasting less than 48 hours (all study arms) 
- 
Grade 3 hyperglycemia resolving to Grade ≤1 within 48 hours, 
with or without adequate treatment (Arm #4 Part H only)  
• 
Any Grade ≥3 hematological toxicity in all study arms, except: 
- 
Grade 3 anemia 
- 
Grade 4 neutropenia <7 days 
- 
Grade 3 neutropenia without fever or infection* 
- 
Grade 3 thrombocytopenia without bleeding. 
• 
Any elevated total serum bilirubin >2 x ULN in all study arms, except 
Part F 
• 
In addition, in Arm#3 (Parts F) only: 
- 
Grade 3 hyperglycemia (confirmed with a repeat FPG within 
24 hours) not resolving to Grade ≤2 within 7 days after initiation of 
oral antidiabetic treatment, provided hyperglycemia did not lead to 
diabetic keto-acidosis, hospitalization for intravenous insulin 
infusion, or non-ketonic coma 
- 
Grade 2 hyperglycemia (confirmed with a repeat FPG within 
24 hours) not resolving to Grade ≤1 within 21 consecutive days 
(after initiation of oral antidiabetic treatment) 
- 
Grade 2 ALT increase in conjunction with total blood bilirubin 
Grade ≥2 of any duration in the absence of liver metastases. 
- 
Grade ≥3 ALT and/or AST increase for more than 4 consecutive 
days 
- 
Grade 3 Rash and Maculopapular Rash not resolving to Grade ≤1 
within 7 days, with or without adequate treatment (including 
systemic steroid use as per protocol) 
• 
Any toxicity related to study treatment, resulting in omission of the 
study treatment for 7 days or more during Cycle 1, or in Cycle 2 delay 
of more than 2 weeks in Parts C. 
• 
A TEAE that in the opinion of the Study Committee is possibly or 
probably study treatment-related and is of potential clinical significance 
such that further dose escalation would expose patients to 
unacceptable risk. 
These TEAEs will be considered as study treatment-related in the absence of 
evidence to the contrary and if not related to disease progression. If multiple 
toxicities are seen, the presence of DLTs will be based on the most severe 
experienced toxicity. 
At the end of Cycle 1, each patient must be assessed by the Investigator as to 
whether or not the patient experienced DLTs, and this information must be 
recorded within the appropriate screen of the electronic case report forms 
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(eCRFs) and an electronic DLT notification (either DLT or not) will be sent to the 
Sponsor. 
Patients could continue the treatment after resolution (≤ Grade 1) of the adverse 
event (AE)  or to their baseline status.  
Patients need to complete at least 75% of the intended doses at Cycle 1 to be 
evaluable, and in Part A  only, should also have 18F-FES-PET scans evaluable at 
baseline and between Day 11 and Day 15 to be evaluable for DLTs 
(see Section 13.8).  
The non-evaluable for DLT patients will be replaced, and additional patients 
could be treated if testing of other amcenestrant doses alone or with the current 
or other dose of palbociclib/alpelisib/everolimus/abemaciclib are needed upon 
agreement with the Study Committee.  
* G-CSF may be used to treat patients who have developed dose-limiting 
neutropenia, as per institutional guidelines (for Arm#3, alpelisib should be 
discontinued as per dose modification recommendations). 
 
Arm #1 Part B  
ORR: antitumor activity as documented by tumor response (CR or PR) defined 
by RECIST v1.1 determined by Independent Central Review (ICR). 
Arms #2, #3, #4, and #5 (Parts D, G, I, and K) 
Safety and tolerability: type, frequency, severity, relationship to study therapy 
and seriousness of adverse events (AE) or laboratory abnormalities according to 
NCI-CTCAE v4.03. 
 
Of note: the specific AESIs are ALT ≥ Grade 3 and photosensitivity. 
 
Secondary endpoints 
• 
Overall safety profile of amcenestrant, and characterization in terms of 
the type, frequency, severity, and relationship to study therapy of any 
AEs or abnormalities of physical findings, laboratory tests, or 
electrocardiograms (ECGs); drug discontinuation/omission/reduction 
and cycle delay due to AEs; or serious adverse events (SAEs) in all 
treatment arms. 
• 
ORR as per RECIST v1.1 (Parts A, B, C, D, F, G, H, I, J and K) 
assessed by investigators/local radiologists. 
• 
ORR and CBR in patients based on their ESR1 status (mutated or wild 
type) analyzed by multiplex droplet digital polymerase chain reaction 
(ddPCR) after extraction of plasma circulating DNA in Arms #1, #2, #3, 
#4, and #5 (all study parts). ORR assessed by investigators/local 
radiologists, and for Part B also by ICR. 
• 
Clinical benefit (CR+PR+SD ≥24 weeks) as per RECIST v1.1 
assessed by investigators/local radiologists (Part A, B, C, D, F, G, H, I, 
J and K) and in Part B also determined by ICR  
• 
Duration of response assessed by investigators/local radiologists (in all 
treatment arms) and in Part B also determined by ICR 
• 
PFS in all treatment arms defined as the time interval from the date of 
the first IMP intake to the date of the first tumor progression assessed 
by investigators/local radiologists (and by IRC in Part B) per Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1), or death (due to any 
cause), whichever comes first  
• 
Time to first tumor response (CR or PR) in Arms #1, #2, #3, #4, and #5 
(in all study parts) will be defined as the time interval from the date of 
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first administration of the study treatment to the date of the first 
occurrence of CR or PR, assessed by investigators/local radiologists 
and in Part B also determined by ICR.  
• 
To correlate the changes observed in 18F-FES-PET scan with the 
changes in glucose metabolism seen on FDG PET/CT in Part A BID 
• 
PK parameters for amcenestrant during Cycle 1:  
- 
After a single dose (on Day 1 Part A fasted state, B (fast or fed), 
C, D,H, I, J and K and Day 3 Part A (fed state)): at least tlag, tmax, 
Cmax, AUC0-24, or AUC0-12 and if possible for Part A Day 1, AUC, 
t1/2z and CL/F 
- 
After repeated administration (all treatment arms: fasting in Part 
A, fasting or fed in Part B, fed in Part C, D, F, G, H, I, J, and K) at 
least tmax, Cmax, AUC0-24 or AUC0-12.  
- 
Ctrough (T=0 h ie, before daily administration) will be also obtained 
over Cycle 1.  
• 
Urine excretion of amcenestrant will be estimated during the 
monotherapy expansion phase (Part B). 
• 
PK parameters of palbociclib (fed): after first dose (Day 1) and after 
repeated once daily administrations (Day 21) during Cycle 1 (Parts C 
and D): at least tmax, Cmax, AUC0-24. 
• 
PK parameters of alpelisib (fed): after repeated administration alone or 
in combination with amcenestrant (Part F and G): at least tmax, Cmax, 
AUC0-24 
• 
PK parameters of everolimus (fed): after first dose (Day 1) and after 
repeated administration in combination with amcenestrant (Part H and 
I): at least tmax, Cmax, AUC0-24 
• 
PK parameters of abemaciclib and its metabolites M2, M18 and M20 
(fed): after first dose (Day 1) and repeated administration in 
combination with amcenestrant (Part J and K): at least tmax, Cmax, 
AUC0-12 
• 
Potential for CYP3A enzyme induction and inhibition by amcenestrant: 
plasma 4β-hydroxy/total cholesterol concentration ratios on Day 22 
versus Day 1 (Part B) or Cycle 2 Day 1 versus Day 1 Cycle 1 (Part A, 
Part J, Part K), or Cycle 2 Day 28 versus Day 1 Cycle 1 (Part J, Part 
K). 
• 
Inhibition of ER occupancy at 18F-FES-PET imaging (signal extinction). 
All patients in Part A will have an 18F-FES-PET/CT scan imaging 
performed at baseline and on treatment in addition to an FDG PET/CT 
which will be done in Part A BID at baseline and on treatment. For 
patients on a QD regimen, the second 18FES PET scan will be 
performed after at least 8 continuous days of treatment (ie, between 
Day 11 and Day 15) and between 16 to 24 hours after the previous 
administration of the study drug, with a time window of 2 hours around 
24 hour theoretical time. For patients on a BID regimen, the second 
scan for both 18F-FES-PET and FDG PET/CT will be performed after at 
least 8 days of continuous treatment (ie, between Day 11 and Day 15 
post first study treatment dose) and between 7 to 12 hours after the 
previous administration of the drug. The signal extinction between 
baseline and on study treatment 18F-FES-PET scans will constitute the 
PD readout of the ER engagement.  
• 
18F-FES-PET or FDG PET/CT imaging will be performed in Part A only 
and Part A BID respectively only. 
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Exploratory endpoints 
• 
ER degradation:  In all patients in Arm#1 (Part A ), and, in Arm#1 
(Part B), Arm#3 (Parts F, G), Arm#4 (Parts H, I)  and Arm#5 
(Parts J,K), in patients who consented to, the paired biopsies will be 
asked for whether as the most recent archived biopsy (within past 
3 months prior to initiation of study treatment) or, preferably, the fresh 
tumor biopsy which will be performed at baseline and at the end of 
Cycle 2. A total of 9 FFPE slides (5 micron each for IHC analysis) and 
3 FFPE slides (10-µm each for RNA analysis, if possible) will be 
collected for each biopsy. The presence of ER will be determined by 
central IHC and the ER results at baseline and on treatment will be 
compared to assess ER degradation. 
• 
ESR1 mutation status: Twelve independent mutations of ESR1 gene 
will be determined in all patients at baseline and at end of Cycle 2 
(Day 15 to Day 28) by digital droplet (ddPCR) PCR from plasma 
extracted cfDNA. For Arm#3 (Parts F, G), Arm#4 (Parts H, I) Arm#5 
(Parts J, K), ESR1 mutation status will only be determined by broad 
mutational profile NGS and not limited to C2 on treatment evaluation.  
- 
The clinical responses will also be assessed in the ESR1 wild 
type and the ESR1 mutated population separately in Arm#1 
(Part B). For Arm#3 (Parts F, G),Arm#4 (Parts H, I), Arm#5 (Parts 
J, K), CfDNA for ESR1 gene mutation status (by ddPCR) will not 
be collected but instead, the information of the ESR1 gene 
mutation status will be retrieved only from the CfDNA collected for 
mutational profile (NGS, multi-gene panel). 
• 
Broad Mutational profile (NGS): In all patients, plasma will be 
collected during the screening process and at the EOT and cfDNA will 
be extracted.                                                                                        
For Arms #3 (Parts F, G), Arm #4 (Parts H, I), and Arm#5 (Parts J, K), 
additional plasma samples for cfDNA analysis by NGS will be collected 
at end of Cycle 2 and Cycle 4 (at tumor assessment). The mutation 
status of a limited number of cancer genes (including, but not limited to 
ESR1, PIK3CA) will be determined by the Next Generation Sequencing 
(NGS) and the potential link between specific mutation and clinical 
outcomes will be investigated to understand intrinsic or acquired 
resistance to the amcenestrant treatment. Germline mutations in saliva 
will be used as reference. 
• 
To evaluate PK/PD relationships of amcenestrant with ER occupancy, 
PD and/or efficacy endpoints and/or other breast cancer biomarkers 
such as Ki67, Bcl-2 and PgR. 
• 
To evaluate FDG SUV uptake before and during treatment with 
amcenestrant (Part A BID). 
• 
To correlate the changes observed in 18F-FES-PET scan with the 
changes in glucose metabolism seen on FDG PET/CT in Part A 
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STATISTICAL CONSIDERATIONS 
 
Sample size justification 
It is anticipated that up to approximately 251 patients will be enrolled into the 
study. The actual sample size will vary depending on DLTs observed, number of 
dose levels actually explored and the other potential schedules to be tested. 
According to different simulated scenarios, it is anticipated that approximately 
25 DLT-evaluable patients will enter into the monotherapy dose escalation phase 
(Part A) of the study in QD regimen and 12 DLT-evaluable patients may enter the 
monotherapy dose escalation phase (Part A) in BID regimen.  
For Arm #1 Part B, it is anticipated that approximately 78 patients will enter into 
the dose expansion cohort of the study.  
For Arm #2 Part C, it is anticipated that approximately 12 DLT-evaluable 
patients will be required to establish the MTD and preliminary RD of SAR43859 
when administered in combination with palbociclib. Additionally, a BID regimen 
could be explored in Part C. 
For Arm #2 Part D, it is anticipated that approximately 28 patients will be treated 
in an expansion phase at the selected RD (as per Study Committee 
recommendation) of amcenestrant with palbociclib in order to further assess the 
safety, tolerability and PK profiles of each RD and to explore preliminary 
antitumoral activity. 
For Arm #3 Part F, it is anticipated that approximately up to 6 DLT-evaluable 
patients will be required to establish RD of amcenestrant when administered in 
combination with alpelisib. 
For Arm #3 Part G, it is anticipated that approximately 34 patients will be treated 
in the expansion phase at the amcenestrant confirmed RD from Part F with 
alpelisib as per Study Committee agreement in order to further assess: safety, 
tolerability, PK profile and preliminary anti-tumoral activity of the confirmed 
amcenestrant RD and alpelisib combination therapy. 
For Arm #4 Part H, it is anticipated that approximately up to 12 DLT-evaluable 
patients will be required to establish RD of amcenestrant when administered in 
combination with everolimus. 
For Arm #4 Part I, it is anticipated that approximately 12 patients will be treated 
in an expansion phase at the selected RD (as per Study Committee 
recommendation) of amcenestrant with everolimus. 
For Arm #5 Part J, it is anticipated that approximately to 12 DLT-evaluable 
patients will be required to establish RD of amcenestrant when administered in 
combination with abemaciclib. 
For Arm #5 Part K, it is anticipated that approximately 20 patients will be treated 
in an expansion phase at the selected RD (as per Study Committee 
recommendation) of amcenestrant with abemaciclib. 
 
General statistical approach 
Populations 
DLT-evaluable population in dose escalation phase and dose safety run-in phase 
includes all patients who have received a first complete cycle (28-day, oral 
administration), taking at least 75% of the intended dosing, unless the patient 
discontinued the study treatment before Cycle 1 completion for a DLT, and in 
Part A, have an evaluable 18F-FES-PET scans at baseline and between Day 11 
and Day 15 of the first cycle. Any patient who develops a DLT in Part A despite 
the absence of evaluable 18F-FES-PET scan will be included in the DLT 
population. A patient not evaluable who will discontinue the study treatment 
before the end of Cycle 1 for any reason other than DLT will be replaced. 
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Safety population includes all patients exposed to at least one dose of the study 
treatment. 
Response evaluable patients are defined as treated patients with measurable 
disease at study entry who had at least one postbaseline evaluable tumor 
assessment. Patients with an early progression as per RECIST v1.1 or who died 
from disease progression will be evaluable for response. 
PK evaluation will be performed on all patients without any major deviations 
related to study treatment administration (eg, early vomiting just after drug 
administration), and for whom any PK parameters are available. 
Arm #1 Part A (Dose Escalation Monotherapy) 
Study treatment-related DLTs occurring during Cycle 1 will be assessed and 
analyzed on the DLT-evaluable population. In addition, AEs meeting DLT criteria 
occurring in any additional cycle will be assessed and analyzed on the safety 
population.  
Safety and PK data will be descriptively summarized for each dose level on the 
safety population. 
Treatment emergent adverse events (TEAEs) will be analyzed according to 
current version of the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Laboratory abnormalities will be analyzed according to the NCI-
CTCAE v.4.03. Type, frequency, seriousness, severity and relatedness of study 
treatment TEAEs will be analyzed on the safety population for each dose level. 
Dose proportionality will be assessed on pooled data from Parts A and B, using 
a power model on Cmax, and AUC0-24 on Day 1 and Day 22.  
Accumulation ratio (Day 22/Day 1) for Cmax and AUC0-24 or AUC0-12 will be 
estimated with 90% confidence intervals (CI) using a linear fixed effects model 
on log transformed parameters. 
Within-subject and total standard deviations for log(Cmax) and log(AUC0-24 or 
AUC0-12 will be estimated (Parts A and B). 
The food effect will be assessed by comparing AUC0-24 and Cmax between 
Day 1/Cycle 1 and Day 3/Cycle 1 Part A. 
4β-hydroxy/total cholesterol concentration ratio (Cycle2/Cycle1) will be estimated 
with 90% CI. 
Preliminary efficacy will be descriptively presented on activity/efficacy population. 
Arm #1 Part B (Dose Expansion Monotherapy) 
It is assumed that the response rate is 10% under the null hypothesis according 
to literature with fulvestrant monotherapy in this population. It is expected that 
amcenestrant would induce a response rate of 20%. Under these hypotheses, 
with a one-sided 5% significance level with a power of 80%, it is anticipated that 
78 patients for efficacy will be entered into the dose expansion cohort of the 
study. 
An interim analysis of the response rate will be done after treatment of the 
first 45 response patients. It is expected to have at least 5 patients with response 
(CR or PR); other parameters are also to be taken into consideration such as the 
duration of response, the CBR (CR + PR + SD ≥24 weeks), the percentage of 
patients with SD and the duration of SD. 
If a BID regimen is tested in the expansion cohort, with a one-sided 
10% significance level with a power of 80%, it is anticipated that 56 patients 
could be entered into the dose expansion cohort of the study. 
Similar analyses as for the escalation phase will be performed.  
Response rate and other clinical outcomes will also be presented according to 
ESR1 status (mutation or wild type) for interim and final analysis. 
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4β-hydroxycholesterol concentration ratio (Day 22/Day 1) will be estimated with 
90% CI. 
Arm #2 Part C (Dose Escalation, combination with palbociclib) 
Similar statistical considerations as for Part A will be applied for Part C regarding 
safety and efficacy. 
Accumulation ratio (Day 21/Day 1) for Cmax and AUC0-24 will be estimated with 
90% CI using a linear fixed effects model on log transformed parameters for 
amcenestrant and palbociclib. 
Interaction ratio of amcenestrant on Cmax and AUC0-24 for effect of palbociclib on 
amcenestrant will be estimated. 
Arm #2 Part D (Dose Expansion, Combination with palbociclib) 
Similar analyses will be performed in the combination dose expansion phase as 
for the escalation phase (Part C). 
Arm #3 Part F (Safety Run-In Phase, with alpelisib) 
Similar statistical considerations as for Part A will be applied for Part F regarding 
safety and efficacy. 
Interaction ratio of amcenestrant on Cmax and AUC0-24 for effect of alpelisib on 
amcenestrant will be estimated using comparison with amcenestrant exposure in 
Part B (monotherapy). 
For alpelisib, the treatment effect of alpelisib in combination with amcenestrant 
versus alpelisib alone on log-transformed Cmax, AUC0-24 will be analyzed with a 
linear mixed effects model for each amcenestrant dose level. Treatment 
(amcenestrant + alpelisib/alpelisib alone) differences and 90% CIs will be 
computed by first taking the mean logarithmic differences within the mixed model 
framework, and then converting them to ratios of geometric means using the 
anti-logarithmic transformation. 
Arm #3 Part G (dose expansion, combination with alpelisib) 
Similar analyses will be performed in the combination dose expansion phase as 
in the safety run-in phase (Part F). 
Arm #4 Part H (Dose escalation, Combination with everolimus) 
Similar statistical considerations as for Part A will be applied for Part H regarding 
safety and efficacy. 
Accumulation ratio (Day 22/Day 1) for Cmax and AUC0-24 will be estimated with 
90% CI using a linear fixed effects model on log transformed parameters for 
amcenestrant and everolimus. 
Arm #4 Part I (Dose Expansion, Combination with everolimus) 
Similar analyses will be performed in the combination dose expansion phase as 
in the dose escalation (Part H). 
Arm #5 Part J (Dose Escalation Phase, with abemaciclib) 
Similar statistical considerations as for Part A will be applied for Part J regarding 
safety and efficacy. 
Accumulation ratio (Day 22/Day 1) for Cmax and AUC0-12 will be estimated with 
90% CI using a linear fixed effects model on log transformed parameters for 
amcenestrant and abemaciclib. 
4β-hydroxy/total cholesterol concentration ratio (Cycle2/Cycle1) will be estimated 
with 90% CI. 
Arm #5 Part K (Dose Expansion, Combination with abemaciclib) 
Similar analyses will be performed in the combination dose expansion phase as 
in the dose escalation (Part J). 
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DURATION OF THE STUDY 
PERIOD (per patient)  
Duration of the entire study per patient 
The duration of the study for an individual patient will include a period to assess 
eligibility (screening period) of up to 4 weeks (28 days), a treatment period of at 
least 1 cycle (28 days) of study treatment, and an EOT visit at least 22 to 
30 days (or until the patient receives another anticancer therapy, whichever is 
earlier) following the last administration of study treatment.  
Study treatment may continue until precluded by unacceptable toxicity, disease 
progression, or upon patient’s request.  
In Arms #2, #3, #4, and #5 (Parts C/D, F/G, H/I and J/K), 
palbociclib/alpelisib/everolimus/abemaciclib can be prematurely and permanently 
discontinued; in that case, amcenestrant can be continued as a single agent 
(monotherapy) until EOT criterion is met. The EOT visit in this case will be 
30 days after the date of last amcenestrant administration.  
Patients who discontinue the study treatment prior to documentation of PD will 
be followed every 2 months until disease progression or initiation of further anti-
cancer therapy, or cut-off date (COD), whichever comes first. Treatment may 
stop at any time if the study is terminated by the Sponsor. 
Duration of the entire study 
The expected enrolment period is approximately 60 months.  
There will be several cut off dates (COD) for this study: 
1. 
In each study Arm dose escalation (Parts A, C, F, H and J), the first 
COD will be done at the end of the first cycle of the last patient treated 
in the given cohort study part in order to have at least the first cycle 
evaluable for all patients for determination of the MTD and for the RD.  
2. 
The COD for each study Arm (dose escalation and dose expansion 
combined), for primary analysis, will be at each study Arm’s LPI 
+12mos, except for Arm#2, in which the COD will be at LPI+20 months 
3. 
The final study COD will be performed when the last study Arm will 
have reached its COD  
4. 
In addition, for all study parts, informal analyses could be performed on 
as needed basis during the study to support further development of the 
compound and regulatory requirements. 
After each study Arm COD, ongoing patients will receive study therapy until 
disease progression, occurrence of an unacceptable toxicities, whichever is 
earlier, and they will only be followed for study treatment administration, SAEs, 
study treatment-related AEs and AEs leading to study treatment discontinuation. 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN - DOSING SCHEME  
 
 
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1.2 
GRAPHICAL STUDY DESIGN - STUDY SCHEDULING  
 
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1.3 
STUDY FLOWCHART  
 
Evaluationa 
 
 
 
Pre-Screening 
Screening 
Treatment Cycle 1 
Subsequent cyclesd  
End-of-
treatment 
(EOT) 
D-28 to 
D1 
D1b 
D3 
D8 
(±1) 
D15 
(±2) 
D22c 
(±2) 
D1b 
(±2) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D28 
(±2) 
D22-D30 (after 
last 
administration 
of study 
treatment)bb  
Inclusion/exclusion criteria/informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and medical/disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status/body 
weight/heighte 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Vital signs, physical examination/signs and 
symptomsf 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood hematologyg 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulationh 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Blood chemistryi 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead electrocardiogram j   
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Urinalysisk 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Amcenestrant administrationl 
 
 
Continuous once or twice daily 
 
Palbociclib administration once daily (Arm #2 
Parts C and D)m  
 
 
Day 1 to 21 
 
Day 1 to 21 
 
 
 
Alpelisib administration once daily (Arm #3 
Parts F and G)dd  
 
 
Continuous once daily 
 
Everolimus administration once daily (Arm #4 
Parts H and I) gg 
 
 
Continuous once daily 
 
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Evaluationa 
 
 
 
Pre-Screening 
Screening 
Treatment Cycle 1 
Subsequent cyclesd  
End-of-
treatment 
(EOT) 
D-28 to 
D1 
D1b 
D3 
D8 
(±1) 
D15 
(±2) 
D22c 
(±2) 
D1b 
(±2) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D28 
(±2) 
D22-D30 (after 
last 
administration 
of study 
treatment)bb  
Abemaciclib administration twice daily (Arm 
#5 Parts J and K)gg 
 
 
Continuous twice daily 
 
Hospitalizationn 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
18F-FES-PET scan and FDG PET/CT (Part A 
Only)o  
 
X 
 
 
 
D11 
to 
D15 
 
 
 
 
 
 
 
Adverse events assessmentp 
 
Continuous throughout study assessment 
Concomitant medicationsq 
 
Continuous throughout study assessment 
Patient diary review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
RECIST v1.1, CT/MRIr  
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pharmacokinetics/pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amcenestrant PK assessments 
 
 
X 
Xt 
X 
X 
X 
Xu  
 
 
 
Xv 
 
Palbociclib PK assessmentw 
 
 
X 
 
X 
X 
X 
Xu 
 
 
 
 
 
Alpelisib PK assessment 
 
 
 
Xcc 
X 
X 
Xcc 
 
 
 
 
 
 
Everolimus PK assessmenthh  
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Abemaciclib PK assessmentii  
 
 
X 
 
 
 
X 
 
 
 
 
 
 
DMET genotypingx 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Evaluationa 
 
 
 
Pre-Screening 
Screening 
Treatment Cycle 1 
Subsequent cyclesd  
End-of-
treatment 
(EOT) 
D-28 to 
D1 
D1b 
D3 
D8 
(±1) 
D15 
(±2) 
D22c 
(±2) 
D1b 
(±2) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D28 
(±2) 
D22-D30 (after 
last 
administration 
of study 
treatment)bb  
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen/biopsyy 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
ESR1 status in cfDNA (ddPCR, plasma)z  
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Molecular profiling in cfDNA (NGS, 
plasma)aa 
 
X 
 
 
 
 
 
 
 
 
 
Xjj  
X 
Germline DNA reference (saliva) aa 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PIK3CA Testingee 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol (Serum) ff 
 
 
X 
(except 
for Part 
A, C, H, 
and J) 
 
 
 
 
 
 
 
 
X 
(except 
for Part 
A, C, H, 
and J) 
 
a Evaluation: Assessments should be performed when possible prior to administration of study treatment unless otherwise indicated. Every effort should be made to keep the schedule of assessments on time for 
each patient. All visits should be performed on the day specified, unless otherwise noted. Additional safety tests (eg, electrocardiogram) can be performed whenever clinically indicated. All the tests or procedures 
on Day 1 should be done at predose time unless otherwise stated. 
b Part A: Cycle 1 Day 1 refers to the day the patient receives the initial dose of study treatment which will be a single administration of amcenestrant, there will be no drug administration on Day 2; from Day 3, it will 
be once/twice daily administration (QD/BID) of amcenestrant in Part A.  
In Arms #1, #2, #4, and #5 (Parts B, C, D, H, I, J and K), amcenestrant is given QD from Day 1 Cycle 1 and from Day 4 for Arm#3 (Part F, G). Before Cycle 1, repeated evaluation of body weight, signs and 
symptoms, physical examination, electrocardiogram, hematology, coagulation tests, blood chemistry and urinalysis should occur within 2 days before the study treatment administration if abnormal or to be 
performed more than 7 days before study treatment administration. The Day 8-time window at Cycle 1 is ±1 day. The Day 15 and Day 22 time windows at Cycle 1 are ±2 days (see footnote c for the timing of this 
visit in Parts C and D). For subsequent cycles, Day 1, Day 8, Day 15 and Day 22 visit time windows are ±2 days. In the combination therapies, a visit/cycle will be delayed if start date of the current cycle minus 
start date of previous cycle >31 days (28 +3 days). In case when all screening procedures have been completed and the patient is confirmed to be eligible, the Screening visit, and Cycle 1 Day 1 could be 
performed on the same day.  
c In Parts C, D this visit must take place on Day 21 (instead of D22) to coincide with the last day of dosing of palbociclib. 
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d Weekly visits during Cycle 1 and 2; from Cycle 3 to Cycle 6 (inclusive), visits to be every 2 weeks, in subsequent cycles (ie, from Cycle 7 and onwards), visits to be once a month. Day 8 and Day 22 visits and 
associated exams are applicable only for Cycles 1 and 2. Day 28 of the previous cycle may overlap with Day 1 of the next cycle if all procedures planned for the new cycle are completed before amcenestrant 
administration. 
e Height: will be assessed at baseline. ECOG performance status and weight: will be assessed at baseline, on Day 1, Day 15 Cycle 1 to Cycle 6 (inclusive), Day 1 from Cycle 7 and onwards, and at the EOT.  
f 
Vital signs will be assessed at baseline, on Day 1, Day 8, Day 15, and Day 22 from Cycle 1 to Cycle 6 (inclusive), Day 1 from Cycle 7 and onwards, and at EOT; it will include body temperature, blood pressure, 
heart rate and respiratory rate which are to be measured after sitting for10-minutes in a supine position. Only clinically relevant signs and symptoms will be reported as AEs in the eCRF. 
g Hematology: Hemoglobin, white blood cell count with differential, platelet counts. If Grade 3 neutropenia, repeat complete blood count monitoring it within 1 week (or as per Investigators’ judgement). If Grade 4 
neutropenia, assess ANC every 2 to 3 days until ANC  ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L. Blood count will be performed weekly at Cycle 1 and 2, then every 2 weeks (Days 1 and 
15) from Cycle 3 to 6, and every 4 weeks (Day 1) in subsequent cycles from cycle 7. For Arm#5 (Parts J and K): Monitor white blood count with differential prior to start of abemaciclib treatment (screening period), 
every 2 weeks for the first 2 cycles (ie, C1D1 & D15 and C2D1 & D15), then every 4 weeks for the next 2 cycles (ie, C3D1 & C4D1), and afterwards as clinically indicated. 
h Coagulation: prothrombin time and INR. For Arm #3, Parts F and G, to add: activated Partial Thromboplastin Time (aPTT). It will be assessed at baseline, on Day 1 and Day 15 from Cycle 1 to Cycle 6 
(inclusive), Day 1 from Cycle 7 and onwards, and at EOT.  
i 
Blood chemistry: Liver function tests (LFTs): aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, conjugated bilirubin, alkaline phosphatase (ALP), gamma glutamyl transferase 
(GGT). Serum Albumin. Electrolytes: sodium, potassium, chloride, magnesium, calcium, phosphate, bicarbonate or BUN and creatinine. Additional tests will be performed when clinically appropriate. In case of 
Grade 3 or higher liver function abnormal tests; additional tests will be done every 2 to 3 days until recovery to baseline value. Blood chemistry will be performed in any study arms weekly at Cycles 1 and 2, then 
every 2 weeks (Days 1 and 15) from Cycle 3 to 6, and every 4 weeks (Day 1) in subsequent cycles from cycle 7. 
In Arm #3 and #4 (Part F, G, H, and I) only: Fasting Serum Glucose sample for safety assessment will be collected after 8-12 hours of an overnight fasting, prior to the light breakfast at the following 
timepoints: baseline (approximately 2 weeks before C1 Day 1), in C1 (Day 8 and Day 15), C2 (Day 1, Day 15 and Day 28), and monthly thereafter (ie, on Day 1 in subsequent cycles), and EOT. 
Additional measurements may be performed as clinically indicated.  
Hemoglobin A1C (HbA1C) will be assessed for safety after 8-12 hours of an overnight fasting, pre-dose prior to the light breakfast, at the following timepoints: baseline (approximately 2 weeks 
before C1 Day 1), Cycle 1 and Cycle 2 Day 1, Day 1 of every 3rd cycle (ie, C5D1, C8D1 etc.), EOT and when clinically indicated.  
In Arm #4 (Parts H and I): lipid panel, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and total cholesterol 
j 
12-lead electrocardiogram: at baseline, start of each cycle from Cycle 2 and EOT; to be repeated as clinically indicated.  
k Urinalysis: Dipstick or qualitative analysis for pH, glucose, ketones, blood, protein and leucocytes, will be assessed at baseline and on Day 1 and 15 of each cycle, at EOT and if clinically relevant. Patients with 
3+ or greater urine protein dipstick reading should undergo further assessment with a 24-hour urine collection for determination of proteinuria.  
l 
In Arm #1 dose escalation Part A, amcenestrant will be administered QD/BID within a 28-day cycle. In Part A, QD regimen, in Cycle 1, one dose is administered on Day 1 in fasted condition, none on Day◦2 and 
repeated once daily in fasted condition from Day◦3. On Day◦3 only, the dose is administered in fed condition. In Part B, amcenestrant will be administered in fasting or fed conditions. In Part C and D, 
amcenestrant and palbociclib will be taken together, with food, 5 minutes apart, regardless of the order of intake.Amcenestrant will be dispensed every 2 weeks.  
In Arm #5 Parts F and G, amcenestrant will be administered daily from Cycle 1 Day 4 at assigned dose levels, within a 28-day cycle together with alpelisib in fed condition, and at approximately the same time 
each day (±3 hours). In case of the alpelisib premature discontinuation, amcenestrant treatment can continue as a single therapy (monotherapy), and it must be taken with food, in cycles of the 28-days duration. 
The days of PK assessment (ie, on C1D3 and C1D22) the drugs will have to be taken together after a standard breakfast. 
In Arm #4 and #5 (Parts H and I / J and K), amcenestrant and everolimus / abemaciclib will be taken together at approximately the same time each day (±3 hours), with food, administered daily from Cycle 1 Day 
1 at assigned dose levels, within a 28-day cycle. The days of PK assessment (ie, C1D1 and C1D22) the combinations amcenestrant with everolimus for Parts H, I and amcenestrant with abemaciclib for Parts J, K 
will have to be taken together after a standard breakfast. 
m In Arm #2 (Parts C and D) (starting from Cycle 2 Day 1), palbociclib will be systematically administered during the meal for 21 consecutive days followed by 7 days off treatment within a 28-day cycle. Palbociclib 
will be dispensed every 4 weeks. 
n Hospitalization: if necessary, one day of hospitalization can be envisioned assuming that all planned exams could be performed within that period. Hospitalization would be recommended mainly on Day 22 due to 
the PK sampling schedule, and if needed, in Cycle 2 Day 1.  
o 
18F-FES-PET scan (Part A QD and BID) and FDG PET/CT (Part A BID only): will be performed in all patients of Part A at baseline (within 3 days or more prior to Day 1) and between Day 11 and Day 15 in 
Cycle 1.  
p Adverse event assessment: The period of observation for collection of AEs extends from informed consent signed, until at least 30 days after the last administration of study treatment. Ongoing SAEs and 
ongoing related AEs should be followed beyond EOT until resolution or stabilization. 
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q Concomitant medications: the period of collection of concomitant medications extends from the date of the informed consent signature until EOT and post EOT if associated with ongoing SAE or ongoing related 
AEs. 
r 
Tumor assessment: chest, abdomen, and pelvis CT scan or MRI scan and any other exams as clinically indicated to be performed to assess disease status at baseline. The same body parts’ (ie, chest  abdomen, 
and pelvis) CT or MRI scan (whichever was used at baseline) should be performed every 8 weeks from C1D1 with flexibility of +/- 7 days, approximately corresponding to the even-numbered cycles (eg, Cycles 2, 
4, 6, 8, etc) or when clinically indicated during treatment, whenever disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or CR, and at the end of study treatment (RECIST v1.1 for 
solid tumors see Appendix C). Tumor assessment should not be repeated at EOT if performed at immediate prior cycle. Date of disease progression or date of first further anticancer therapy (whichever is earlier) 
will be collected in follow up for patients who discontinue the study treatment prior to documentation of disease progression. Follow up will be performed approximately every 2 months. Imaging should be available 
for central review for Part B. 
s PK amcenestrant: see detailed PK/PD flowchart. 
t 
PK samples collected on Day 3 only in the QD regimen of Part A (not to be collected for the BID sampling regimen).  
u Pre-dose PK sampling Cycle 2 only. 
v Only for Parts B,  D and G sparse PK sampling (see Section 1.4.1.2.2, Section 1.4.2.1.2, and Section 1.4.3.1.2) 
w PK palbociclib: see detailed PK/PD flowchart (Section 1.4.2). 
x DMET genotyping: for patients who agreed to this in the informed consent form, one blood sample prior to study treatment initiation will be dedicated for DMET genotyping. 
y Tumor sampling: For all patients in Part A and for patients in Part B, Arm#3, #4 and #5 who consent to paired biopsies (before treatment and during treatment) and with tumor accessible: 1) preferably fresh 
biopsy or archived tumor tissues (within past 3 months prior to initiate of study treatment) will be collected and centrally analysed for IHC at Screening. 2) On-treatment biopsy should be performed at the end of 
Cycle 2 (between Day 15 and Day 28). (See detailed PK/PD flowchart).    
z ESR1 mutation by dd-PCR: One blood sample will be collected and processed for cfDNA analyses of ESR1 mutation status by droplet digital PCR (all patients) at baseline and at the end of Cycle 2 (between 
Day 15 and Day 28). This does not apply to Parts F, G, H, I, J and K. ESR1 mutation status in Parts F,G,H,I,J and K  will be provided by molecular profiling panel and not by ESR1 focused panel.  
aa Molecular profiling by NGS: two blood samples (plasma) will be collected at screening and at the EOT to determine mutation profiles by next generation sequencing in cfDNA (all patients). Molecular profiling will 
be performed by NGS. For Parts F, G, H, I, J and K, cfDNA will be collected at screening, end of Cycle 2 and Cycle 4 (at the time of tumor assessment), as well as EOT/Progression. Saliva germline mutation 
analysis: Saliva will be collected at baseline to extract germline DNA which will be used as reference for tumor mutational analysis. 
bb If further therapy is initiated before D22 after last IMP, investigator should contact the patient (either by phone call or visit) to obtain final collection of safety information (stabilization or recovery of TEAEs) within 
30 days after last IMP intake or in follow up visit in case of ongoing SAE or related AE. Patients who discontinue the study treatment prior to documentation of PD will be followed every 2 months until disease 
progression or initiation of further anticancer therapy, or cut-off date dates (COD), whichever comes first (see Section 6.8.1). 
cc PK alpelisib: see detailed PK/PD flowchart.  
dd Alpelisib will be administered daily with food within 28-day cycles starting from Cycle 1 Day 1 for Part F and G  
ee PIK3CA Testing: For Parts F and G only: Detected PIK3CA mutation(s) in solid biopsy or plasma is mandatory for patients’ eligibility. This PIK3CA testing must be performed locally. For patients not having prior 
access to PIK3CA testing, but willing to have it performed, in order to be eligible (if mutation detected), will have to sign the Pre-screening PIK3CA Testing ICF before the main consenting and screening process 
begins.  No fresh biopsy will be required from Sponsor for eligibility purposes. All PIK3CA reports regardless of the time of testing (recent/archival) are acceptable.   
ff Estradiol: samples collected on C1D1 and C2D28 see detailed PK/PD flowchart.  
gg Everolimus (Arm #4 Parts H, I) and abemaciclib (Arm #5 Parts J, K) will be administered with food during the study. On the days of PK assessment (ie, C1D1 and C1D22) where the combinations amcenestrant 
with everolimus for Parts H, I and amcenestrant with abemaciclib for Arm #5 Parts J and K will have to be taken together after a standard breakfast. 
hh PK everolimus: see detailed PK/PD flow chart 
ii PK abemaciclib: see detailed PK/PD flow chart 
jj For Arms #3, 4, and 5, samples should be collected at the end of C2, end of C4, and at EOT (but not at the end of other cycles). 
AE = adverse event; Blood Urea Nitrogen (BUN); aPTT = activated Partial Thromboplastin Time ;  cfDNA = circulating free DNA; COD = cut-off dates, CR = complete response; CT = computerized tomography;  
D = day; DMET = drug metabolizing enzymes and transporters; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; ER = estrogen receptor; ESR1 = estrogen 
receptor 1; 18F-FES-PET = (18)F-fluoroestradiol-positron emission tomography; (18FDG)  = fluorodésoxyglucose (18F); IHC = immunohistochemistry; INR = international normalized ratio; MRI = magnetic resonance 
imaging; NGS= next generation sequencing;    PCR = polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors; SAE = serious adverse 
event. 
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1.4 
PHARMACOKINETIC AND PHARMACODYNAMIC FLOW CHART  
1.4.1 Arm #1  
1.4.1.1 Part A  
 
Cycle 
  
PART A Cycle 1  
Day within cycle 
Day -3 
Day 1 
Day 2 
Relative Nominal Time 
  
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
36 h 
Time window 
  
[-10 min, 0 h] ±5 min ±10 min ±15 min ±15 min ±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
±1 h 
Indicative clock time 
  
08:00 
08:30 
09:00 
09:30 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
20:00 
Amcenestrant administrationa 
 
Once/twice Daily 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Amcenestrant pharmacokineticsj 
Plasma  
  
P00b, k 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P09 
P10 
P11 
Pharmacogenetics (DMET genotyping)  
DMET analysis 
  
B00b 
  
  
  
  
  
  
  
  
  
  
  
Pharmacodynamics 
  
  
Plasma (cfDNA-ESR1 by  
dd-PCR)c 
  
ER00 
  
  
  
  
  
  
  
  
  
  
  
18F-FES-PET and FDG imagingd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Plasma (cfDNA-NGS mutational 
profiling)e 
  
CF00 
  
  
  
  
  
  
  
  
  
  
  
Saliva (germline DNA)e 
  
SA00 
  
  
  
  
  
  
  
  
  
  
  
Tumor specimeni 
A0 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyi 
S0 
 
 
 
 
 
 
 
 
 
 
 
 
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Cycle 
PART A Cycle 1  
Day within cycle 
Day 3/4 
D8 
Between 
Day 11 
and 
Day 15 
Relative Nominal Time 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
0 h 
Time window 
[-10 min, 0 
h] 
±5 min ±10 min ±15 min ±15 min ±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
[-10 min, 0 h] 
  
Indicative clock time 
08:00 
08:30 
09:00 
09:30 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
08:00 
Amcenestrant administrationa   
Once/twice daily 
Xf 
  
  
  
  
  
  
  
  
  
X 
X 
Xh 
Amcenestrant pharmacokineticsj 
Plasma  
P12b 
P13 
P14 
P15 
P16 
P17 
P18 
P19 
P20 
P21 
P22b 
P23b 
P24g 
Pharmacodynamics 
18F-FES-PET and FDG imagingd 
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
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Cycle 
PART A Cycle 1 
Cycle 2 
EOT 
Day within cycle 
Day 22/23 
Day 1 
Day 28 Day 22-30 
Relative Nominal Time 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
 
  
Time window 
[-10 min, 
0 h] 
±5 min ±10 min ±15 min ±15 min ±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
[-10 min, 
0 h] 
 
  
Indicative clock time 
08:00 
08:30 
09:00 
09:30 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
 
  
Amcenestrant administrationa 
Once/twice daily 
X 
  
  
  
  
  
  
  
  
  
X 
X 
 
  
Amcenestrant pharmacokineticsj 
Plasma  
P25b 
P26  
P27 
P28 
P29 
P30 
P31 
P32 
P33 
P34 
P35b 
P36b, k 
 
  
Pharmacodynamics 
Plasma (cfDNA-ESR1 by dd-
PCR)c 
 
 
 
 
 
 
 
 
 
 
 
 
ER001 
 
Plasma (cfDNA-NGS mutational 
profiling)e 
 
 
 
 
 
 
 
 
 
 
 
 
 
CF01 
Saliva (germline DNA)e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyi 
  
  
  
  
  
  
  
  
  
  
  
  
T1 
 
a A single administration of amcenestrant on Day 1, no administration on Day 2 and once or twice daily administration of amcenestrant from Day 3. For the QD dosing regimen, all patients will receive amcenestrant   
doses in fasting condition in the morning (ie, the drug will be taken after an overnight fast of at least 10 hours and at least 3h before breakfast on D1 and D22 and 2 hours the other days). On Day 3, a full PK 
evaluation will be done in fed state for all patients, the drug will be taken after a standard meal. For the BID dosing regimen, pilot food effect will not be conducted on Day 3. Amcenestrant will be taken independent 
of the food conditions at approximately the same time each day. 
b Sample collected just before amcenestrant administration.  
c Plasma will be collected at baseline and at end of Cycle 2 (between Day 15 and Day 28) to determine the ESR1 mutation status in cfDNA by droplet digital PCR.  
d A first full body PET/CT scan imaging, after intravenous injection of 18F-radiolabelled estradiol to be done 3 days or more before the start of treatment and a second scan to be at least 8 days after once a day of 
continuous treatment (ie, between Day 11 and Day 15). For QD regimen, the 18F-FES-PET scan should be completed between 16 to 24 hours after the previous administration of the drug, with a time window of 
2 hours around the 24 hour theoretical time. For BID regimen, the 18F-FES-PET scan should be completed between 7 to 12 hours after the previous administration of the drug. Patients should be instructed to take 
the previous study treatment dose at the appropriate time in line with availability of the PET/CT scan at sites. If limited response is observed at that time, an earlier 18F-FES-PET time window may be considered. 
Additionally, an FDG will also be performed for Part A BID patients only.  
e Plasma will be collected in all patients to monitor mutational profiling of the tumor by NGS in cfDNA at baseline (CF00) and at the EOT (CF01). Saliva germline mutation analysis: Saliva will be collected at baseline 
to extract germline DNA which will be used as reference for tumor mutational analysis. 
f 
For QD regimen only: The food effect evaluation will be done on Day 3: all patients will receive amcenestrant doses in fed state in the morning (ie, after an overnight fast of at least 10 hours, a standard meal will 
be taken within 30 minutes and amcenestrant will be administered within 5 minutes after meal completion).  
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g PK sample taken the day of the 18F-FES-PET scan and FDG PET/CT just before 18F-radiolabelled estradiol administration. 
h The day of 18F-FES-PET scan and FDG PET/CT, the patient will receive the amcenestrant dose just after imaging procedures.  
i 
When patients consent for paired biopsies, a tumor sample is required at baseline: either the most recent FFPE tumor specimen (within past 3 months prior to initiation of study treatment, A0) should be provided or 
preferably a fresh biopsy (S0) can be performed but is not mandatory and collection of an on-treatment biopsy (T1) should be done in at least 10 patients at the recommended dose to assess centrally at least ER 
degradation by IHC. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28). Time of sampling in relation to dose administration should be noted. 
j 
For Part A BID dosing regimen, a twice a day drug administration will be planned over the 28-day cycle. The PK samples planned on Day 3, Day 4 and the 24 hour sample on Day 22/23 are not necessary. 
k Plasma 4β-OH and total cholesterol assessment to be done. 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; CT = computerized tomography; DMET = drug metabolizing enzymes and transporters; EOT = end of treatment; ESR1 = estrogen receptor 1; 18F-FES-PET = (18) F-fluoroestradiol-
positron emission tomography; NGS= Next Generation Sequencing; PCR = polymerase chain reaction; PK = pharmacokinetics. 
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1.4.1.2 Part B  
At least 12 patients will be sampled according to following PK/PD flow chart in Section 1 (full 
PK sampling). For the remaining patients of the cohort, a sparse sampling approach for PK with 3 
to 4 time points on Day 1, and 3 to 4 time points on Day 22 is presented in 
Section 1.4.1.2.2. 
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1.4.1.2.1 Part B Full PK Sampling  
 
Cycle 
  
PART B Cycle 1  
Day within cycle 
Day 1/2 
Day 8 
Day 15 
Relative Nominal Time 
  
0 h 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
0 h 
Time window 
  
[-10 min, 0 h] 
±5 min ±10 min ±15 min ±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
[-10 min, 0 h] 
[-10 min, 0 h] 
Indicative clock time 
  
08:00 
08:30 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
08:00 
Amcenestrant administrationa  
Once daily 
  
X 
  
  
  
  
  
  
  
  
X 
X 
X 
Amcenestrant pharmacokinetics 
 
Plasmab 
  
P00c, d 
P01 
P02 
P04 
P05 
P06 
P07 
P08 
P09 
P10c 
P11c 
P12c 
Urine  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pharmacogenetics (DMET genotyping) 
 
DMET analysis 
  
B00c 
  
  
  
  
  
  
  
  
  
  
  
Pharmacodynamics 
 
Tumor specimene 
A0 
  
  
  
  
  
  
  
  
  
  
  
-  
Tumor biopsye 
 S0 
  
  
  
  
  
  
  
  
  
  
  
 
Plasma (cfDNA – NGS mutational 
profiling)f  
  
CF00 
  
  
  
  
  
  
  
  
  
  
  
Saliva (germline DNA)g 
  
SA00 
  
  
  
  
  
  
  
  
  
  
  
Plasma (cfDNA - ESR1 by dd-PCR)h  
  
ER00 
  
  
  
  
  
  
  
  
  
  
  
 
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Cycle 
PART B Cycle 1 
 Cycle 2 
EOT 
Day within cycle 
Day 22/23 
Day 1 Day 28 
Day 
22-30 
Relative Nominal Time 
0 h 
0.5 h 
1 h 
Time window 
[-10 min, 0 h] 
±5 min 
±10 min 
±15 min 
Indicative clock time 
08:00 
08:30 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
 
  
Amcenestrant administrationa 
 
Once daily 
X 
  
  
  
  
  
  
  
  
X 
X 
 
  
Amcenestrant pharmacokinetics  
 
Plasmab 
P13c, d 
P14 
P15 
P17 
P18 
P19 
P20 
P21 
P22 
P23c 
P24c 
 
  
Urine  
 
------ 
---- 
------- 
------- 
U00 
------ 
------- 
------ 
→ 
  
 
Pharmacodynamics 
 
Plasma (cfDNA - ESR1 by dd-
PCR)h 
 
 
 
 
 
 
 
 
 
 
 
ER001 
 
Tumor biopsye 
  
  
  
  
  
  
  
  
  
  
  
T1 
 
Plasma (cfDNA-mutational 
profiling)f 
 
 
 
 
 
 
 
 
 
 
 
 
CF01 
Saliva (germline DNA)g 
 
 
 
 
 
 
 
 
 
 
 
 
 
a On the basis of preliminary PK information from the pilot food effect in Part A and safety information, amcenestrant can be taken with or without food. 
b Circulating amcenestrant metabolites will be explored.  
c Sample collected just before amcenestrant administration.  
d Amcenestrant plasma samples will be used also for 4β-hydroxycholesterol measurement.  
e When patients consent for paired biopsies, a tumor sample is required at baseline: either the most recent FFPE tumor specimen (within past 3 months prior to initiation of study treatment, A0) should be provided or 
preferably a fresh biopsy (S0) can be performed but is not mandatory and collection of an on-treatment biopsy (T1) should be done in at least 10 patients at the recommended dose to assess centrally at least ER 
degradation by IHC. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28). Time of sampling in relation to dose administration should be noted.  
f 
Plasma will be collected in all patients to monitor mutational profiling of the tumor in cfDNA by NGS at baseline (CF00) and at the EOT (CF01).  
g Saliva germline mutation analysis: Saliva will be collected at baseline (SA00) to extract germline DNA which will be used as a reference to determine tumor somatic mutations in CfDNA. 
h  Plasma (ER00) will be collected at baseline and (ER001) at end of Cycle 2 (between D15 to D28) to determine the ESR1 mutation status in cfDNA by droplet digital PCR. 
Note: For the comfort of patients, some PK samplings may be omitted during the course of the study if they are no longer deemed necessary by the Sanofi PK team 
CfDNA = circulating free DNA; DMET = drug metabolizing enzymes and transporters; EOT = end of treatment; ESR1 = estrogen receptor 1; FFPE = formalin-fixed paraffin-embedded; PCR = polymerase chain 
reaction; PK = pharmacokinetics. 
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1.4.1.2.2 Part B Sparse PK sampling  
 
Cycle 
  
PART B Cycle 1 
Cycle 2 
EOT 
Day within cycle 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 28 
Day 
22-30 
Time window 
  
  
[1 h - 2 h] [3 h - 5 h] [7 h - 9 h] [-10 min, 
0 h] 
[-10 min, 
0 h] 
[-10 min, 
0 h] 
[1 h- 2 h] [3 h - 5 h] [7 h - 9 h] [-10 min, 
0 h] 
  
  
Indicative clock time 
  
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
08:00 
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
  
  
Amcenestrant administrationa 
 
Once or twice daily 
  
X 
 
  
  
X 
X 
X 
 
  
  
X 
  
  
Amcenestrant pharmacokinetics  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Plasma 
  
  
P00 
P01 
P02 
P03b 
P04b 
P05b 
P06 
P07 
P08 
P09b 
P10g  
  
Pharmacogenetics (DMET genotyping) 
 
DMET analysis 
  
B00b 
 
  
  
  
  
  
  
  
  
  
  
  
Pharmacodynamics  
Tumor specimenc 
A0 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsyc 
 S0 
  
  
  
  
  
 
 _ 
 _ 
 _ 
 _ 
 _ 
T01 ➔ 
  
Plasma (cfDNA – NGS mutational 
profiling)d 
  
CF00 
  
  
  
  
  
  
  
  
  
  
  
CF01 
Saliva (germline DNA)e 
  
SA00 
  
  
  
  
  
  
  
  
  
  
  
  
Plasma (cfDNA - ESR1 by dd-PCR)f  
  
ER00 
  
  
  
  
  
  
  
  
  
  
ER001  
 
Serum (Estradiol) 
 
ES00 
 
 
 
 
 
 
 
 
 
 
ES01 
 
a On the basis of preliminary PK information from the pilot food effect in Part A and safety information, amcenestrant can be taken with or without food. 
b Sample collected just before amcenestrant administration. 
c When patients consent for paired biopsies, a tumor sample is required at baseline: either the most recent FFPE tumor specimen (within past 3 months prior to initiation of study treatment, A0) should be provided or 
preferably a fresh biopsy (S0) can be performed but is not mandatory and collection of an on-treatment biopsy (T1) should be done in at least 10 patients at the recommended dose to assess centrally ER 
degradation by IHC. Day of collection of biopsy under treatment should be at the end of Cycle 2 (D15 to D28) (→). Time of sampling in relation to dose administration should be noted.  
d Plasma will be collected in all patients to monitor mutational profiling of the tumor in cfDNA by NGS, at baseline (CF00) and at the EOT (CF01).  
e Saliva (germline DNA): Saliva will be collected at baseline (SA00) to extract germline DNA which will be used as a reference to determine tumor somatic mutations in CfDNA 
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f 
Plasma (ER00) will be collected at baseline and (ER001) at end of Cycle 2 (D15 to D28) to determine the ESR1 mutation status in cfDNA by droplet digital PCR.  
g One PK sample will be collected just after tumor assessment (CT/MRI scan) in Cycle 2 (P10), Cycle 4 (P11) and Cycle 6 (P12). No sample will be collected after Part B cut-off date. 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team 
CfDNA = circulating free DNA; DMET = drug metabolizing enzymes and transporters; EOT = end of treatment; ESR1 = estrogen receptor 1; FFPE = formalin-fixed paraffin-embedded; NGS=Next Generation 
Sequencing; PCR = polymerase chain reaction; PK = pharmacokinetics. 
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1.4.2 Arm #2  
1.4.2.1 Parts C and D  
Study treatment in Parts C and D, Cycle 1, Day 1 should not be initiated on a Monday.  
The following flow chart in Section 1.4.2.1.1 and Section 1.4.2.1.2 represents the option when 
amcenestrant is administered concomitantly with food and concomitantly with palbociclib.  
In Part D, selected dose(s) will be sampled according to the following full PK/PD flow chart in 
Section 1.4.2.1.1.  
The remaining patients of the cohort will be sampled according to a sparse PK/PD flow chart 
presented in Section 1.4.2.1.2. 
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1.4.2.1.1 Part C and D full PK sampling  
 
Cycle 
PARTS C and D Cycle 1 
Day within cycle 
Day 1/2 
Day 8 
Day 15 
Relative Nominal Time 
0 h 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
0 h 
Time window 
[-10 min, 0 h] 
±5 min 
±10 min 
±15 min 
±15 min 
±30 min 
±30 min 
±30 min 
±1 h 
±1 h 
[-10 min, 0 h] [-10 min, 0 h] 
Indicative clock time 
08:00 
08:30 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
08:00 
Amcenestrant administrationa 
Once or twice daily 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Palbociclib administration 
Once daily for 21 days 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Amcenestrant pharmacokineticsg 
Plasma 
P00b 
P01 
P02 
P04 
P05 
P06 
P07 
P08 
P09 
P10b 
P11b 
P12b 
Palbociclib pharmacokinetics 
Plasma 
PP00b 
PP01 
PP02 
PP04 
PP05 
PP06 
PP07 
PP08 
PP09 
PP10b 
PP11b 
PP12b 
Pharmacogenetics (DMET genotyping) 
DMET analysis 
B00b 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics 
Plasma (cfDNA-NGS mutational 
profiling)c 
CF00 
 
 
 
 
 
 
 
 
 
 
 
Saliva (germline DNA)e   
SA00 
 
 
 
 
 
 
 
 
 
 
 
Plasma (cfDNA-ESR1 by dd-PCR)d 
ER00 
 
 
 
 
 
 
 
 
 
 
 
Serum (Estradiol)h  
ES00 
 
 
 
 
 
 
 
 
 
 
 
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Cycle 
PARTS C and D Cycle 1 
Cycle 2 
EOT 
Day within cycle 
Day 21/22 
Day 1 
Day 15 to 
Day 28 
Day 30 
Relative Nominal Time 
0 h 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
 
 
Time window 
[-10 min, 0 h] ±5 min 
±10 min ±15 min ±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
[-10 min, 0 h] 
 
 
Indicative clock time 
08:00 
08:30 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
 
 
Amcenestrant administrationa 
Once or twice daily 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Palbociclib administration 
Once daily for 21 days 
X f 
 
 
 
 
 
 
 
 
 
X 
 
 
Amcenestrant pharmacokineticsg 
Plasma 
P13b 
P14 
P15 
P17 
P18 
P19 
P20 
P21 
P22 
P23b 
P24b 
 
Palbociclib pharmacokinetics 
Plasma 
PP13b 
PP14 
PP15 
PP17 
PP18 
PP19 
PP20 
PP21 
PP22 
PP23b 
PP24b 
 
 
Pharmacodynamics 
Plasma (cfDNA-ESR1)d  
 
 
 
 
 
 
 
 
 
 
 
ER001 
 
Plasma (cfDNA – NGS mutational 
profiling)c 
 
 
 
 
 
 
 
 
 
 
 
 
CF01 
Saliva germline (DNA)e  
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (Estradiol) h   
 
 
 
 
 
 
 
 
 
 
 
ES01 
 
a On basis of PK information from the pilot food effect in Part A and safety information, amcenestrant will be taken together with palbociclib, ie, with food, 5 minutes apart, regardless of the order of intake on Day 1 
and Day 21/22 (days with full PK sampling) in Cycle 1. Amcenestrant will be taken with food together with palbociclib, 5 minutes apart, regardless of the order of intake.  
b Sample collected just before amcenestrant and palbociclib administration. 
c Plasma will be collected in all patients to monitor the molecular profile of the tumor in cfDNA at baseline (CF00) and at the EOT (CF01).  
d Plasma will be collected at baseline and at end of Cycle 2 (D15 to D28) to determine the ESR1 mutation status in cfDNA by droplet digital PCR (ER00, ER001). 
e Saliva germline mutation analysis: Saliva will be collected at baseline (SA00) to extract germline DNA which will be used as a reference to determine tumor somatic mutations in CfDNA. 
f 
Last day of palbociclib administration for cycle 1. 
g In case of twice daily regimen, Day 1 24 h sample and Day 21/22 24 h sample are not mandatory. 
h Estradiol will be assessed in Part D only. 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics 
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1.4.2.1.2 Part D sparse PK sampling  
 
Cycle 
PARTS D Cycle 1 
Cycle 2 
EOT 
Day within cycle 
Day 1 
Day 8 
Day 15 
Day 21 
Day 1 
Day 28 Day 30 
Time window 
 
[1 h - 2 h] [3 h - 5 h] [7 h - 9 h] [-10 min, 0 h] [-10 min, 0 h] [-10 min, 0 h] [1 h - 2 h] [3 h - 5 h] [7 h - 9 h] [-10 min, 0 h] 
 
 
Indicative clock time 
08:00 [09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
08:00 
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
 
 
Amcenestrant administrationa 
Once or twice daily 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
Palbociclib administrationa 
Once daily for 21 days 
X 
 
 
 
X 
X 
Xe 
 
 
 
X 
 
 
Amcenestrant pharmacokinetics 
Plasma 
 
P00 
P01 
P02 
P03b 
P04b 
P05b 
P06 
P07 
P08 
P09b 
P10f 
 
Palbociclib pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
 
PP00 
PP01 
PP02 
PP03b 
PP04b 
PP05b 
PP06 
PP07 
PP08 
PP09b 
PP10 
 
Pharmacogenetics (DMET genotyping) 
DMET analysis 
B00b 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics 
Plasma (cfDNA-NGS mutation 
profiling)c 
CF00 
 
 
 
 
 
 
 
 
 
 
 
CF01 
Saliva (germline DNA)c 
SA00 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma (cfDNA-ESR1 by dd-PCR)d ER00 
 
 
 
 
 
 
 
 
 
 
ER001 
 
Serum (Estradiol) 
ES00 
 
 
 
 
 
 
 
 
 
 
ES01 
 
a Amcenestrant will be taken with palbociclib in fed condition, 5 minutes apart, regardless of the order of intake. 
b Sample collected just before amcenestrant and palbociclib administration. 
c Plasma will be collected in all patients to monitor molecular profile of the tumor in cfDNA at baseline (CF00) and at the EOT (CF01). Saliva will be collected at baseline (SA00) to extract germline DNA which will be 
used as a reference to determine tumor somatic mutations in CfDNA. 
d Plasma will be collected at baseline and at end of Cycle 2 (D15 to D28) Cycle 2 to determine the ESR1 mutation status in cfDNA by droplet digital PCR (ER00, ER001). 
e Last day of palbociclib administration for Cycle1. 
f 
One PK sample will be collected just after tumor assessment (CT/MRI scan) in Cycle 2 (P10), Cycle 4 (P11) and Cycle 6 (P12). No sample will be collected after Part D cut-off date. 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics. 
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1.4.3 Arm #3  
1.4.3.1 Part F and G  
Plasma (cfDNA – Next Generation Sequencing (NGS) mutational profiling) will be collected 
predose at screening, end of Cycle 2 and Cycle 4 (at tumor assessment) and at EOT/progression 
(whichever comes first). This NGS targeted panel measures genomic aberrations of PIK3CA, 
ESR1 and other tumor driver genes.  
ESR1 targeted digital droplet PCR panel from plasma cfDNA will not be collected or analyzed. 
ESR1 mutations will be analyzed by means of plasma cfDNA broader mutational profiling NGS 
panel.  
Biopsy: When patients consent for paired biopsies, a tumor sample is required in the screening 
period: either the most recent FFPE tumor specimen should be provided or preferably a fresh 
biopsy (S0) can be performed but is not mandatory. The day of collection of biopsy under 
treatment should be at the end of Cycle 2 (D15 to D28, at the tie of tumor assessment). The time 
of sampling in relation to dose administration should be noted 
All patients from the safety run-in will be sampled according to full PK sampling design  
(Section 1.4.3.1.1) for amcenestrant and alpelisib. At the RD in the expansion phase, additional 
patients will be sampled according to full PK sampling to reach a total (safety run-in + expansion) 
of approximately 18 evaluable patients. For the remaining patients of the expansion phase, a 
sparse sampling approach for PK of amcenestrant will be proposed as presented in 
Section 1.4.3.1.2.  
 
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1.4.3.1.1 Full PK sampling (Parts F and G)  
A total of 18 patients (including Part F and G) could undergo a full PK sampling schedule at the recommended dose(s) assessed in Part G. 
Adjustment of the number of patients needed will be done according to preliminary PK results.  
 
Cycle 
Screening 
PARTS F and G Cycle 1 
Day within cycle 
 
Day 3 (3rd administration of alpelisib’s first administration) 
Day 8 
Day 15 
Relative Nominal Time 
 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
0 h 
Time window 
 
[-10 min, 0 h] 
±10 min 
±15 min 
±15 min ±30 min ±30 min ±30 min 
±1 h 
±1 h 
[-10 min, 0 h] [-10 min, 0 h] 
Indicative clock time 
 
08:00 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
08:00 
Amcenestrant administrationa 
Once daily 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Alpelisib administration 
Once daily  
 
Xe 
 
 
 
 
 
 
 
X 
X 
X 
Amcenestrant pharmacokinetics 
Plasma 
 
 
 
 
 
 
 
 
 
 
P00b 
P01b 
Alpelisib pharmacokinetics 
Plasma 
 
P00b 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08b 
P09b 
P10b 
Pharmacogenetics (DMET genotyping) 
DMET analysis 
 
B00b 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics 
Plasma (cfDNA-NGS mutation 
profiling)c 
CF00 
 
 
 
 
 
 
 
 
 
 
 
Saliva (germline DNA)d  
 
SA00 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyf 
S0 
 
 
 
 
 
 
 
 
 
 
 
Serum (Estradiol) 
 
ES00 
 
 
 
 
 
 
 
 
 
 
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Cycle 
PARTS F and G Cycle 1 
Cycle 2 
Cycle 4 
EOT 
Day within cycle 
Day 22 +/- 2 
Day 1 
Day 15 to 
Day 28 
Day 28 
Day 30 
Relative Nominal Time 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
 
 
 
Time window 
[-10 min, 0 h] 
±10 min 
±15 min ±15 min ±30 min ±30 min 
±30 min 
±1 h 
±1 h 
[-10 min, 
0 h] 
 
 
 
Indicative clock time 
08:00 
09:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
08:00 
08:00 
 
 
 
Amcenestrant administrationa 
Once daily 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Alpelisib administration 
Once daily 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Amcenestrant pharmacokinetics 
Plasma 
P02b 
P03 
P04 
P05 
P06 
P07 
P08 
P09 
P10b 
P11 b 
 
 
Alpelisib pharmacokinetics 
Plasma 
P11b 
P12 
P13 
P14 
P15 
P16 
P17 
P18 
P19b 
P20b 
 
 
 
Pharmacodynamics 
Plasma (cfDNA -NGS mutational 
profiling)c  
CF01 
CF02 
CF03 
Saliva germline (DNA)d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyf 
 
 
 
 
 
 
 
 
 
 
 
T1 
 
 
Serum (Estradiol) 
 
 
 
 
 
 
 
 
 
 
 
ES01 
 
 
a Amcenestrant will be taken with alpelisib in fed condition, QD from C1D4. The days of PK assessment ie, C1D1 and C1D22, the drugs will have to be taken with a standard breakfast. 
b Sample collected just before amcenestrant and/or alpelisib administration. 
c Plasma will be collected in all patients to monitor the molecular profile of the tumor in cfDNA at Screening (CF00), end of Cycle 2 (CF01) and 4 (CF02) (at the time of tumor assessment) and at the 
EOT/progression (CF03). Analysis of mutational profiling will be done by Next Generation Sequencing (NGS) in reference to the sequence of germline DNA extracted from saliva (S00). 
d Saliva germline mutation: Saliva will be collected at baseline (SA00) to extract germline DNA which will be used as a reference to determine tumor somatic mutations in CfDNA. 
e Alpelisib will be administrated once daily alone,in fed condition, without amcenestrant for 3 days and then in combination with amcenestrant. 
f 
When patients consent for paired biopsies, a tumor sample is requested at screening: either the most recent FFPE tumor specimen (no time limitation, A0) should be provided or preferably a fresh biopsy (S0) can 
be performed but is not mandatory and collection of an on-treatment biopsy (T1) will be requested. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28 at tumor 
assessment). Time of sampling in relation to dose administration should be noted.  
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics; NGS= Next Generation Sequencing 
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1.4.3.1.2 Sparse PK sampling (Remaining patients in Part G)  
 
Cycle 
Screening 
Part G Cycle 1  
Cycle 2 
Cycle 4 EOT 
Day within cycle 
 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 28 28 day Day 30 
Time window 
 
 
[1 h - 2 h] [3 h - 
5 h] 
[7 h - 
9 h] 
[-10 min, 
0 h] 
[-10 min, 
0 h] 
[-10 min, 
0 h] 
[1 h - 
2 h] 
[3 h - 
5 h] 
[7 h - 
9 h] 
[-10 min, 
0 h] 
 
 
 
Indicative clock time 
 
08:00 [09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
08:00 
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
[15:00 - 
17:00] 
08:00 
 
 
 
Amcenestrant administrationa 
Once 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
Alpelisib administrationa 
Once  
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
Amcenestrant pharmacokinetics 
Plasmac 
 
 
 
 
 
P01b 
P02b 
P03b 
P04 
P05 
P06 
P07b 
P08c 
P09c 
 
Pharmacogenetics (DMET genotyping) 
DMET analysis 
 
B00b 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics 
Plasma (cfDNA-NGS mutational 
profiling)d  
CF00 
 
 
 
 
 
 
 
 
 
 
 
CF01 
CF02 
CF03 
Saliva (germline DNA)d  
 
SA00 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsye 
S0 
 
 
 
 
 
 
 
 
 
 
 
T1 
 
 
Serum (Estradiol) 
 
ES00 
 
 
 
 
 
 
 
 
 
 
ES01 
 
 
a Amcenestrant will be taken with alpelisib in fed condition.  
b Sample collected just before amcenestrant and alpelisib administration. 
c One PK sample will be collected just after tumor assessment (CT/MRI scan) in Cycle 2 (P08), Cycle 4 (P09) and Cycle 6 (P10). No sample will be collected after Part G cut-off date. 
d Plasma will be collected in all patients to monitor molecular profile of the tumor in cfDNA at screening (CF00), end of Cycle 2 (CF01) and Cycle 4 (CF02) (same day as tumor assessment) and at the 
EOT/progression (CF03). Analysis of mutational profiling will be done by NGS in reference to the sequence of germline DNA extracted from saliva (SA00). 
e When patients consent for paired biopsies, a tumor sample is requested at screening: either the most recent FFPE tumor specimen (no time limitation, A0) should be provided or preferably a fresh biopsy (S0) can 
be performed but is not mandatory and collection of an on-treatment biopsy (T1) will be requested. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28 at tumor 
assessment). Time of sampling in relation to dose administration should be noted.  
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics; NGS= Next Generation Sequencing, FFPE = formalin-fixed 
paraffine-embedded 
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1.4.4 Arm #4  
1.4.4.1 Parts H and I  
When the dose escalation study (Part H) completes, based on preliminary safety, PK and tumor response data, the Study Committee will decide or 
not to expand the combination to Part I with approximately 12 patients. 
 
Cycle 
Screening 
PARTS H and I, Cycle 1 
Day within cycle 
 
Day 1 
Relative Nominal Time 
 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
Time window 
 
[-10 min, 0 h] 
±10 min 
±15 min 
±15 min 
±30 min 
±30 min 
±30 min 
±1 h 
±1 h 
Indicative clock time 
 
8:00 
9:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
8:00 
IMP administration a 
 
Amcenestrant, QD 
 
X 
  
  
  
  
  
  
  
X 
Everolimus, QD 
 
X 
  
  
  
  
  
  
  
X 
Pharmacokinetics samples 
 
Amcenestrant, Plasma 
 
P00b 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08b 
Everolimus, Blood 
 
BE00b 
BE01 
BE02 
BE03 
BE04 
BE05 
BE06 
BE07 
BE08b 
Pharmacogenetics (DMET genotyping) 
 
DMET analysis 
 
B00b 
  
  
  
  
  
  
  
  
Pharmacodynamics  
Plasma (cfDNA -NGS mutational profiling)c 
CF00 
 
  
  
  
  
  
  
  
  
Saliva germline (DNA)d 
 
SA00 
  
  
  
  
  
  
  
  
Tumor biopsye 
S0 
 
  
  
  
  
  
  
  
  
Serum (Estradiol)f 
 
ES00 
 
 
 
 
 
 
 
 
 
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Cycle 
PARTS H and I, Cycle 1 
Cycle 2 
Cycle 4 
EOT 
Day within cycle 
Day 22 ± 2 
Day 1 
Day 28 
Day 28 
Day  
Relative Nominal Time 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
 
 
  
Time window 
[-10 min, 0 h] 
±10 min 
±15 min 
±15 min 
±30 min 
±30 min 
±30 min 
±1 h 
±1 h 
[-10 min, 0 h] 
 
 
  
Indicative clock time 
8:00 
9:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
8:00 
8:00 
 
 
  
IMP administration a 
Amcenestrant, QD 
X 
  
  
  
  
  
  
  
X 
X 
 
 
  
Everolimus, QD 
X 
  
  
  
  
  
  
  
X 
X 
 
 
  
Pharmacokinetics samples 
Amcenestrant, Plasma 
P09b 
P10 
P11 
P12 
P13 
P14 
P15 
P16 
P17b 
P18b 
 
 
  
Everolimus, Blood 
BE09b 
BE10 
BE11 
BE12 
BE13 
BE14 
BE15 
BE16 
BE17b 
BE18b 
 
 
  
Pharmacodynamics  
Plasma (cfDNA -NGS 
mutational profiling)c  
  
  
  
  
  
  
  
  
  
  
CF01 
CF02 
CF03 
Saliva germline (DNA)d 
 
  
  
  
  
  
  
  
  
  
 
 
 
Tumor biopsye 
  
  
  
  
  
  
  
  
  
  
T1 
 
 
Serum (Estradiol)f 
 
 
 
 
 
 
 
 
 
 
ES01 
 
 
a Amcenestrant and everolimus will be taken with food, once daily (QD), together, 5 minutes apart. The days of PK assessment ie, C1D1 and C1D22, the drugs will have to be taken with a standard breakfast. 
b Sample collected just before amcenestrant and everolimus administration 
c Plasma will be collected in all patients to monitor the molecular profile of the tumor in cfDNA at Screening (CF00), end of Cycle 2 (CF01) and 4 (CF02) (at the time of tumor assessment) and at the 
EOT/progression (CF03). Analysis of mutational profiling will be done by Next Generation Sequencing (NGS) in reference to the sequence of germline DNA extracted from saliva (S00). 
d Saliva germline mutation: Saliva will be collected at baseline (SA00). 
e When patients consent for paired biopsies, a tumor sample is requested at screening: either the most recent FFPE tumor specimen (no time limitation, A0) should be provided or preferably a fresh biopsy (S0) can 
be performed but is not mandatory and collection of an on-treatment biopsy (T1) will be requested. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28 at tumor 
assessment). Time of sampling in relation to dose administration should be noted.  
f 
Estradiol will be assessed in Part I only 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics; NGS= Next Generation Sequencing 
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1.4.5 Arm #5  
1.4.5.1 Parts J and K  
When the dose escalation study (Part J) completes, based on preliminary safety, PK and efficacy 
data, the Study Committee will decide or not to expand the combination to Part K with 
approximately 20 patients. In Part K, up to 12 patients could undergo a full PK sampling  
(Section 1) to allow a total of 15 evaluable patients under a full PK sampling, overall Part J and 
Part K. The remaining patients of Part K, will undergo a sparse PK sampling approach  
(Section 1.4.5.1.2). 
 
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1.4.5.1.1 Parts J and K, full PK sampling  
 
Cycle 
Screening 
PARTS J and K, Cycle 1 
Day within cycle 
 
Day 1 
Relative Nominal Time 
 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
Time window 
 
[-10 min, 0 h] 
±10 min 
±15 min 
±15 min 
±30 min 
±30 min 
±30 min 
±1 h 
±1 h 
Indicative clock time 
 
8:00 
9:00 
10:00 
11:00 
12:00 
14:00 
16:00 
18:00 
8:00 
IMP administrationa 
 
Amcenestrant, QD 
 
X 
  
  
  
  
  
  
  
X 
Abemaciclib, BID 
 
X 
  
  
  
  
  
  
  
X 
Pharmacokinetics samples 
Amcenestrant, Plasma 
 
P00b 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08b 
Abemaciclib and metabolites, Plasma 
 
P00b 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08b 
4β-hydroxycholesterol /total cholesterol 
 
P00b 
 
 
 
 
 
 
 
 
Pharmacogenetics (DMETgenotyping) 
 
DMET analysis 
 
B00b 
  
  
  
  
  
  
  
  
Pharmacodynamics 
 
 Plasma (cfDNA -NGS mutational 
profiling)c  
CF00 
  
  
  
  
  
  
  
  
  
Saliva germline (DNA)d  
 
SA00  
  
  
  
  
  
  
  
  
Tumor biopsye 
S0 
  
  
  
  
  
  
  
  
  
Serum (Estradiol)f 
 
ES00 
 
 
 
 
 
 
 
 
 
 
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Cycle 
PARTS J and K, Cycle 1 
 
Cycle 2 
Cycle 3 
Cycle 4 
EOT 
Day within cycle 
Day 22 ± 2 
Day 1 
Day 28 
Day 1 
Day 28 
Day  
Relative Nominal Time 
0 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
24 h 
0 h 
4 h 
 
0 h 
 
  
Time window 
[-10 min, 
0 h] 
±10 
min 
±15 
min 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±1 h 
±1 h 
[-10 min, 
0 h] 
±30 min 
 
[-10 min, 0 h] 
 
  
Indicative clock time 
8:00 
9:00 
10:0
0 
11:0
0 
12:0
0 
14:0
0 
16:0
0 
18:0
0 
8:00 
8:00 
12:00 
 
8:00 
 
  
IMP administrationa  
Amcenestrant, QD 
X 
  
  
  
  
  
  
  
X 
X 
 
 
X 
 
  
Abemaciclib, BID 
X 
  
  
  
  
  
  
  
X 
X 
 
 
X 
 
  
Pharmacokinetics samples  
Amcenestrant, Plasma 
P09b 
P10 
P11 
P12 
P13 
P14 
P15 
P16 
P17b 
P18b 
P19 
 
 
 
  
Abemaciclib and metabolites, 
Plasma 
P09b 
P10 
P11 
P12 
P13 
P14 
P15 
P16 
P17b 
P18b 
P19 
 
 
 
  
4β-hydroxycholesterol /total 
cholesterol 
 
 
 
 
 
 
 
 
 
P01b 
 
P02b 
 
 
 
Pharmacodynamics  
Plasma (cfDNA -NGS 
mutational profiling)c 
 
 
 
 
 
 
 
 
 
 
 
CF01 
 
CF02 
CF03 
 Saliva germline (DNA)d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tumor biopsye 
 
 
 
 
 
 
 
 
 
 
 
T1 
 
 
 
Serum (Estradiol)f 
 
 
 
 
 
 
 
 
 
 
 
ES01 
 
 
 
a Amcenestrant will be taken once daily, and abemaciclib twice daily (BID), both taken with food during the study. The days of PK assessment (ie, C1D1 and C1D22) the drugs will have to be taken after a standard 
breakfast   
b Sample collected just before amcenestrant and abemaciclib administration 
c Plasma will be collected in all patients to monitor the molecular profile of the tumor in cfDNA at Screening (CF00), end of Cycle 2 (CF01) and 4 (CF02) (at the time of tumor assessment) and at the 
EOT/progression (CF03). Analysis of mutational profiling will be done by Next Generation Sequencing (NGS) in reference to the sequence of germline DNA extracted from saliva (SA00). 
d Saliva germline mutation: Saliva will be collected at screening (SA00) to extract germline DNA which will be used as a reference to determine tumor somatic mutations in CfDNA. 
e When patients consent for paired biopsies, a tumor sample is requested at screening: either the most recent FFPE tumor specimen (no time limitation, A0) should be provided or preferably a fresh biopsy (S0) can 
be performed but is not mandatory and collection of an on-treatment biopsy (T1) will be requested. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28 at tumor 
assessment). Time of sampling in relation to dose administration should be noted.  
f 
Estradiol will be assayed in Part K only 
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics; NGS= Next Generation Sequence 
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1.4.5.1.2 Part K, sparse PK sampling  
 
Cycle 
Screening 
Part K Cycle 1 
Cycle 2 
Cycle 4 
EOT 
Day within cycle 
  
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 28 
  
Day 30 
Time window 
  
  
[1 h - 2 h] 
[3 h - 5 h] [-10 min, 
0 h] 
[-10 min, 
0 h] 
[-10 min, 
0 h] 
[1 h - 
2 h] 
[3 h - 
5 h] 
[-10 min, 
0 h] 
[7 h - 
9 h] 
  
  
  
Indicative clock time 
  
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
08:00 
08:00 
08:00 
[09:00 - 
10:00] 
[11:00 - 
13:00] 
08:00 
[15:00 - 
17:00] 
  
  
  
IMP administrationa 
Amcenestrant, QD 
  
X 
  
  
X 
X 
X 
  
  
X 
  
  
  
  
Abemaciclib, BID  
  
X 
  
  
X 
X 
X 
  
  
X 
  
  
  
  
Pharmacokinetics samples 
 
Amcenestrant, Plasma 
  
  
P00 
P01 
P02b 
P03b 
P04b 
P05 
P06 
P07b 
P08 
P09c 
  
  
Abemaciclib, Plasma 
  
  
P00 
P01 
P02b 
P03b 
P04b 
P05 
P06 
P07b 
P08 
P09c 
  
  
Pharmacogenetics  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DMET analysis 
  
B00b 
  
  
  
  
  
  
  
  
  
  
  
  
Pharmacodynamics  
Plasma (cfDNA-NGS 
mutational profiling)d 
CF00 
  
  
  
  
  
  
  
  
  
  
CF01 
CF02 
CF03 
Saliva (germline DNA)d 
  
SA00 
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsye 
S0 
  
  
  
  
  
  
  
  
  
  
T1 
  
  
Serum (Estradiol) 
  
ES00 
  
  
  
  
  
  
  
  
  
ES01 
  
  
a Amcenestrant will be taken once daily (QD), and abemaciclib twice daily (BID), both taken with food The days of PK assessment (ie, C1D1 and C1D22) the drugs will have to be taken after a standard breakfast. 
b Sample collected just before amcenestrant and abemaciclib administration. 
c One PK sample will be collected just after tumor assessment (CT/MRI scan) in Cycle 2, Cycle 4 and Cycle 6. No sample will be collected after Part K cut-off date. 
d Plasma will be collected in all patients to monitor molecular profile of the tumor in cfDNA at screening (CF00), end of Cycle 2 (CF01) and Cycle 4 (CF02) (same day as tumor assessment) and at the 
EOT/progression (CF03). Analysis of mutational profiling will be done by NGS in reference to the sequence of germline DNA extracted from saliva (SA00). 
e When patients consent for paired biopsies, a tumor sample is requested at screening: either the most recent FFPE tumor specimen (no time limitation, A0) should be provided or preferably a fresh biopsy (S0) can 
be performed but is not mandatory and collection of an on-treatment biopsy (T1) will be requested. Day of collection of biopsy under treatment should be at the end of Cycle 2 (between D15 to D28 at tumor 
assessment). Time of sampling in relation to dose administration should be noted.  
Note: For the comfort of patients, some PK samplings may be deleted during the course of the study if they are no longer deemed necessary by the Sanofi PK team. 
CfDNA = circulating free DNA; EOT = end of treatment; ESR1 = estrogen receptor 1; PCR = polymerase chain reaction; PK = pharmacokinetics; NGS= Next Generation Sequencing, FFPE = formalin-fixed 
paraffine-embedded 
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2 
TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 10 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS ............................................................................................................................. 33 
1.1 
GRAPHICAL STUDY DESIGN - DOSING SCHEME .................................................................... 33 
1.2 
GRAPHICAL STUDY DESIGN - STUDY SCHEDULING .............................................................. 34 
1.3 
STUDY FLOWCHART ................................................................................................................... 35 
1.4 
PHARMACOKINETIC AND PHARMACODYNAMIC FLOW CHART ............................................ 40 
1.4.1 
Arm #1 ............................................................................................................................................ 40 
1.4.1.1 
Part A ............................................................................................................................................. 40 
1.4.1.2 
Part B ............................................................................................................................................. 44 
1.4.2 
Arm #2 ............................................................................................................................................ 49 
1.4.2.1 
Parts C and D ................................................................................................................................. 49 
1.4.3 
Arm #3 ............................................................................................................................................ 53 
1.4.3.1 
Part F and G ................................................................................................................................... 53 
1.4.4 
Arm #4 ............................................................................................................................................ 57 
1.4.4.1 
Parts H and I .................................................................................................................................. 57 
1.4.5 
Arm #5 ............................................................................................................................................ 59 
1.4.5.1 
Parts J and K .................................................................................................................................. 59 
2 
TABLE OF CONTENTS ................................................................................................................ 63 
2.1 
LIST OF TABLES ........................................................................................................................... 71 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 73 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 75 
4.1 
INTRODUCTION ............................................................................................................................ 75 
4.1.1 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 77 
4.1.1.1 
Benefit Assessment ....................................................................................................................... 77 
4.1.1.2 
Risk Assessment ............................................................................................................................ 78 
4.1.1.3 
Risks in the Context of COVID-19 ................................................................................................. 80 
4.1.1.4 
Overall Benefit/Risk Conclusion ..................................................................................................... 80 
4.2 
DESCRIPTION OF AMCENESTRANT .......................................................................................... 81 
4.3 
BACKGROUND INFORMATION OF AMCENESTRANT .............................................................. 81 
4.3.1 
Preclinical data ............................................................................................................................... 81 
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4.4 
RATIONALE FOR THE STUDY ..................................................................................................... 83 
4.4.1 
Arm #1 ............................................................................................................................................ 83 
4.4.1.1 
Part A (Dose Escalation, Monotherapy amcenestrant) .................................................................. 83 
4.4.1.2 
Part B (Dose Expansion, Monotherapy amcenestrant) ................................................................. 84 
4.4.2 
Arm #2 ............................................................................................................................................ 85 
4.4.2.1 
Part C (Dose Escalation, Combination with palbociclib) ................................................................ 85 
4.4.2.2 
Part D (Dose Expansion, Combination with palbociclib) ................................................................ 85 
4.4.3 
Arm #3 ............................................................................................................................................ 86 
4.4.3.1 
Part F (Safety Run-In Phase with alpelisib) ................................................................................... 86 
4.4.3.2 
Part G (Dose Expansion, Combination with alpelisib) ................................................................... 87 
4.4.4 
Arm #4 ............................................................................................................................................ 87 
4.4.4.1 
Part H (Dose Escalation with everolimus)...................................................................................... 87 
4.4.4.2 
Part I (Dose Expansion, Combination with everolimus)................................................................. 88 
4.4.5 
Arm #5 ............................................................................................................................................ 88 
4.4.5.1 
Part J (Dose Escalation Phase with abemaciclib) ......................................................................... 88 
4.4.5.2 
Part K (Dose Expansion, Combination with abemaciclib).............................................................. 89 
5 
STUDY OBJECTIVES ................................................................................................................... 90 
5.1 
PRIMARY OBJECTIVES ............................................................................................................... 90 
5.2 
SECONDARY OBJECTIVES ......................................................................................................... 90 
5.3 
EXPLORATORY OBJECTIVES ..................................................................................................... 91 
6 
STUDY DESIGN ............................................................................................................................ 92 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 92 
6.2 
STARTING DOSE AND DOSE ESCALATION DESIGN ............................................................... 92 
6.2.1 
Starting dose and dose levels ........................................................................................................ 92 
6.2.2 
Dose Escalation Arms #1, #2, #4 and #5 (Parts A, C, H and J) and Safety Run-In Arm #3 
(Part F) strategy ............................................................................................................................. 96 
6.3 
MAXIMUM ADMINISTERED DOSE/MAXIMUM TOLERATED DOSE .......................................... 98 
6.4 
RETREATMENT OF PATIENTS ................................................................................................... 99 
6.5 
DOSE DELAYS/MODIFICATIONS ................................................................................................ 99 
6.5.1 
Arm #2 Parts C and D .................................................................................................................. 100 
6.5.2 
Arm #3 Dose modification in Parts F and G ................................................................................ 101 
6.5.3 
Arm #4 Dose modification in Parts H and I .................................................................................. 106 
6.5.4 
Arm #5 Dose modification in Parts J and K ................................................................................. 108 
6.6 
EXPANSION COHORTS TO CONFIRM THE MAXIMUM TOLERATED DOSE ........................ 109 
6.7 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS .................................................... 110 
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6.8 
DURATION OF STUDY PARTICIPATION .................................................................................. 110 
6.8.1 
Duration of study participation for each patient ........................................................................... 110 
6.8.2 
Determination of end of clinical trial (all patients) ........................................................................ 111 
6.9 
INTERIM ANALYSIS .................................................................................................................... 111 
6.10 
STUDY COMMITTEES ................................................................................................................ 111 
7 
SELECTION OF PATIENTS ........................................................................................................ 112 
7.1 
NUMBER OF PATIENTS ............................................................................................................. 112 
7.2 
INCLUSION CRITERIA ................................................................................................................ 112 
7.3 
EXCLUSION CRITERIA .............................................................................................................. 114 
7.3.1 
Exclusion criteria related to study methodology .......................................................................... 114 
7.3.2 
Exclusion criteria related to the disease ...................................................................................... 115 
8 
STUDY TREATMENTS ............................................................................................................... 118 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................. 118 
8.1.1 
Pharmaceutical form .................................................................................................................... 118 
8.1.1.1 
Amcenestrant ............................................................................................................................... 118 
8.1.1.2 
Palbociclib .................................................................................................................................... 118 
8.1.1.3 
Alpelisib ........................................................................................................................................ 118 
8.1.1.4 
Everolimus ................................................................................................................................... 118 
8.1.1.5 
Abemaciclib .................................................................................................................................. 118 
8.1.2 
Dose of drug per administration ................................................................................................... 118 
8.1.2.1 
Amcenestrant ............................................................................................................................... 118 
8.1.2.2 
Palbociclib .................................................................................................................................... 121 
8.1.2.3 
Alpelisib ........................................................................................................................................ 121 
8.1.2.4 
Everolimus ................................................................................................................................... 121 
8.1.2.5 
Abemaciclib .................................................................................................................................. 121 
8.2 
NON INVESTIGATIONAL MEDICINAL PRODUCT .................................................................... 122 
8.3 
PACKAGING AND LABELING .................................................................................................... 122 
8.4 
STORAGE CONDITIONS AND SHELF LIFE .............................................................................. 122 
8.5 
RESPONSIBILITIES .................................................................................................................... 122 
8.5.1 
Treatment accountability and compliance.................................................................................... 123 
8.5.2 
Return and/or destruction of treatments ...................................................................................... 123 
8.6 
CONCOMITANT TREATMENT ................................................................................................... 124 
8.7 
POST INVESTIGATIONAL PRODUCT ....................................................................................... 127 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ............................................ 128 
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9.1 
SAFETY ....................................................................................................................................... 128 
9.1.1 
Dose-limiting toxicities.................................................................................................................. 128 
9.1.2 
Adverse events ............................................................................................................................ 129 
9.1.3 
Laboratory safety variables .......................................................................................................... 130 
9.1.4 
Clinical examinations ................................................................................................................... 130 
9.1.5 
Other safety endpoints ................................................................................................................. 130 
9.2 
PHARMACOKINETIC EVALUATION .......................................................................................... 130 
9.2.1 
Sampling time and sample blood volume .................................................................................... 130 
9.2.2 
Pharmacokinetic sample handling procedure .............................................................................. 132 
9.2.3 
Bioanalytical method .................................................................................................................... 135 
9.2.4 
Urine sampling times and handling procedures ........................................................................... 135 
9.2.5 
Pharmacokinetic parameters ....................................................................................................... 136 
9.3 
PHARMACOGENETIC ASSESSMENT ....................................................................................... 138 
9.3.1 
Optional drug metabolizing enzymes and transporters DNA sample .......................................... 138 
9.4 
PHARMACODYNAMIC ASSESSMENTS.................................................................................... 138 
9.4.1 
18 fluorestradiol-positron emission tomography and 18 fluorodesoxyglucose scans (Part A 
only) ............................................................................................................................................. 138 
9.4.2 
Estrogen receptor 1 gene mutation status in circulating free DNA .............................................. 139 
9.4.3 
Mutational profiling in circulating free DNA .................................................................................. 139 
9.4.4 
Tumor biopsy to assess estrogen receptor degradation (Arm #1, #3, #4, and #5 [Part A 
BID, Parts B, F G, H, I, J, and K]) ................................................................................................ 140 
9.4.5 
Estradiol ....................................................................................................................................... 140 
9.5 
SAMPLED BLOOD VOLUME ...................................................................................................... 140 
9.6 
FUTURE USE OF SAMPLES ...................................................................................................... 142 
9.7 
EFFICACY (ALL STUDY PARTS) ............................................................................................... 142 
9.7.1 
Criteria for response (antitumoral activity) ................................................................................... 142 
10 
PATIENT SAFETY (ALL STUDY PARTS).................................................................................. 143 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ................................................................... 143 
10.2 
SAFETY INSTRUCTIONS ........................................................................................................... 143 
10.3 
ADVERSE EVENTS MONITORING ............................................................................................ 143 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT ................................ 143 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 144 
10.5.1 
Adverse events ............................................................................................................................ 144 
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10.5.2 
Serious adverse events ............................................................................................................... 144 
10.5.3 
Follow-up ...................................................................................................................................... 145 
10.5.4 
Treatment discontinuation due to nonserious adverse event ...................................................... 145 
10.5.5 
Adverse event of special interest ................................................................................................. 145 
10.5.6 
Laboratory abnormalities ............................................................................................................. 146 
10.6 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 147 
11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION .................................... 148 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) ............................................................................................................................... 148 
11.1.1 
List of criteria for permanent treatment discontinuation ............................................................... 148 
11.1.2 
Handling of patients after permanent treatment discontinuation ................................................. 149 
11.2 
REPLACEMENT OF PATIENTS ................................................................................................. 149 
11.3 
CRITERIA FOR TEMPORARILY DELAYING ............................................................................. 149 
12 
STUDY PROCEDURES .............................................................................................................. 150 
12.1 
VISIT SCHEDULE ........................................................................................................................ 150 
12.2 
BASELINE EVALUATION ............................................................................................................ 150 
12.3 
BEFORE THE FIRST INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
(WITHIN 2 DAYS BEFORE) IF NOT PERFORMED WITHIN THE 7 PREVIOUS DAYS ........... 152 
12.4 
DURING THE TREATMENT PERIOD AT CYCLE 1 ................................................................... 152 
12.4.1 
Cycle 1, Day 1 .............................................................................................................................. 152 
12.4.2 
Cycle 1, Day 3 .............................................................................................................................. 152 
12.4.3 
Cycle 1, Day 8 (±1 day)................................................................................................................ 153 
12.4.4 
Cycle 1, between Day 11 and Day 15 (Arm #1 Part A only) ........................................................ 153 
12.4.5 
Cycle 1, Day 15 (±2 days) ............................................................................................................ 153 
12.4.6 
Cycle 1, Day 22 (±2 days) ............................................................................................................ 153 
12.5 
DURING SUBSEQUENT CYCLES .............................................................................................. 154 
12.5.1 
Subsequent cycles, Day 1 (±2 days) ........................................................................................... 154 
12.5.2 
Cycle 2, Day 8 (±2 days) .............................................................................................................. 154 
12.5.3 
Cycle 2, Day 15 (±2 days) ............................................................................................................ 154 
12.5.4 
Cycle 2, Day 22 (±2 days) ............................................................................................................ 154 
12.5.5 
Subsequent cycles (up to and including C6), Day 15 (±2 days) .................................................. 155 
12.5.6 
Subsequent cycles (starting from C7 and onwards), Day 1 (±2 days) ........................................ 155 
12.5.6.1 Every 8 weeks .............................................................................................................................. 155 
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12.5.6.2 Additional Tests for Arms #3 and #4 (Parts F, G, H, and I) ......................................................... 156 
12.6 
END OF TREATMENT VISIT (TO BE PERFORMED BETWEEN 22 AND 30 DAYS AFTER 
THE LAST ADMINISTRATION OF THE STUDY TREATMENT) ................................................ 156 
12.7 
PERIOD POST END OF TREATMENT ....................................................................................... 157 
12.8 
POST STUDY CUT-OFF PERIOD .............................................................................................. 157 
13 
STATISTICAL CONSIDERATIONS ............................................................................................ 158 
13.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 158 
13.2 
ARM #1 ........................................................................................................................................ 158 
13.2.1 
Sample size of the escalation phase for amcenestrant as monotherapy (Part A) ....................... 158 
13.2.2 
Sample size of the expansion phase for amcenestrant as monotherapy (Part B) ...................... 158 
13.3 
ARM #2 ........................................................................................................................................ 158 
13.3.1 
Sample size of the escalation phase for amcenestrant in combination with palbociclib 
(Part C) ......................................................................................................................................... 158 
13.3.2 
Sample size of the expansion phase for amcenestrant in combination with palbociclib 
(Part D) ......................................................................................................................................... 159 
13.4 
ARM #3 ........................................................................................................................................ 159 
13.4.1 
Sample size of the safety run-in part for amcenestrant in combination with alpelisib (Part F) .... 159 
13.4.2 
Sample size of the expansion phase for amcenestrant in combination with alpelisib (Part 
G) ................................................................................................................................................. 159 
13.5 
ARM #4 ........................................................................................................................................ 160 
13.5.1 
Sample size of the dose escalation part for amcenestrant in combination with everolimus 
(Part H) ......................................................................................................................................... 160 
13.5.2 
Sample size of the expansion phase for amcenestrant in combination with everolimus 
(Part I) .......................................................................................................................................... 160 
13.6 
ARM #5 ........................................................................................................................................ 161 
13.6.1 
Sample size of the dose escalation part for amcenestrant in combination with abemaciclib 
(Part J) ......................................................................................................................................... 161 
13.6.2 
Sample size of the expansion phase for amcenestrant in combination with abemaciclib 
(Part K) ......................................................................................................................................... 161 
13.7 
PATIENT DESCRIPTION ............................................................................................................ 161 
13.7.1 
Disposition of patients .................................................................................................................. 162 
13.7.2 
Protocol deviations ....................................................................................................................... 162 
13.8 
ANALYSIS POPULATIONS ......................................................................................................... 162 
13.8.1 
All-treated/safety population ........................................................................................................ 162 
13.8.2 
Patients evaluable for DLT assessment ...................................................................................... 162 
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13.8.3 
Pharmacokinetic population ......................................................................................................... 163 
13.8.4 
Activity/efficacy population ........................................................................................................... 163 
13.8.5 
Pharmacodynamic population ...................................................................................................... 163 
13.9 
STATISTICAL METHODS ........................................................................................................... 163 
13.9.1 
Demographics and baseline characteristics ................................................................................ 163 
13.9.2 
Extent of investigational medicinal product exposure .................................................................. 164 
13.9.3 
Prior/concomitant medication/therapy.......................................................................................... 164 
13.9.4 
Analyses of safety data ................................................................................................................ 165 
13.9.4.1 Dose-limiting toxicities.................................................................................................................. 165 
13.9.4.2 Analyses of adverse events ......................................................................................................... 165 
13.9.4.3 Deaths .......................................................................................................................................... 166 
13.9.4.4 Clinical laboratory evaluations ..................................................................................................... 166 
13.9.4.5 Vital signs ..................................................................................................................................... 166 
13.9.4.6 Analyses of other safety variables ............................................................................................... 166 
13.9.5 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................. 167 
13.9.5.1 Analyses of pharmacokinetic variables ........................................................................................ 167 
13.9.5.2 Analyses of pharmacodynamic variables..................................................................................... 168 
13.9.6 
Analyses of antitumor activity/efficacy variables .......................................................................... 168 
13.10 
INTERIM ANALYSIS .................................................................................................................... 168 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 169 
14.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 169 
14.2 
INFORMED CONSENT ............................................................................................................... 169 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 169 
15 
STUDY MONITORING................................................................................................................. 171 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 171 
15.2 
RESPONSIBILITIES OF SPONSOR ........................................................................................... 171 
15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 171 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS ......... 172 
15.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 172 
15.6 
DATA QUALITY ASSURANCE .................................................................................................... 172 
16 
ADDITIONAL REQUIREMENTS ................................................................................................. 173 
16.1 
CURRICULUM VITAE.................................................................................................................. 173 
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16.2 
RECORD RETENTION IN STUDY SITES(S) ............................................................................. 173 
16.3 
CONFIDENTIALITY ..................................................................................................................... 173 
16.4 
PROPERTY RIGHTS ................................................................................................................... 174 
16.5 
DATA PROTECTION ................................................................................................................... 174 
16.6 
INSURANCE COMPENSATION .................................................................................................. 174 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 175 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 175 
16.8.1 
By the Sponsor ............................................................................................................................. 175 
16.8.2 
By the Investigator ....................................................................................................................... 176 
16.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 176 
16.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 176 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 177 
18 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 178 
19 
APPENDICES .............................................................................................................................. 182 
APPENDIX A 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
SCALE ......................................................................................................................................... 183 
APPENDIX B 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 184 
APPENDIX C 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1) ................................................................................................................................ 185 
APPENDIX D 
STANDARD MEAL EXAMPLE .......................................................................................... 190 
APPENDIX E 
LIST OF CYP3A4 PROHIBITED MODULATORS ............................................................. 191 
APPENDIX F 
LIST OF CYP SUBSTRATE WITH A NARROW THERAPEUTIC RANGE AND LIST 
OF SUBSTRATES MAINLY METABOLIZED BY CYP3A/2B/2C/UGT ........................................ 194 
APPENDIX G 
LIST OF BCRP INHIBITORS, CYP2C9 SUBSTRATES AND P-GP, BCRP AND 
OAT3 SUBSTRATES ................................................................................................................... 197 
APPENDIX H 
IN VIVO INHIBITORS OF P-GP PROBES ........................................................................ 199 
APPENDIX I 
ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE FORMULA ................... 203 
APPENDIX J 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY .......................................................... 204 
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APPENDIX K 
PROTOCOL AMENDMENT HISTORY ............................................................................. 206 
 
2.1 
LIST OF TABLES  
Table 1 - Amcenestrant Risks ....................................................................................................................... 78 
Table 2 - Part A dose escalation ................................................................................................................... 93 
Table 3 - Amcenestrant dose levels in Part C ............................................................................................... 93 
Table 4 - Amcenestrant and alpelisib dose levels in Part Fa......................................................................... 94 
Table 5 - Amcenestrant and everolimus dose levels in Part Ha .................................................................... 96 
Table 6 - Amcenestrant and abemaciclib dose levels in Part Ja ................................................................... 96 
Table 7 - Classical dose escalation phase .................................................................................................... 97 
Table 8 - Dose levels for palbociclib and alpelisib dose reduction .............................................................. 100 
Table 9 - Dose levels for everolimus and abemaciclib dose reduction ....................................................... 100 
Table 10 - Dose modification and management: hematologic toxicities ..................................................... 100 
Table 11 - Dose modification and management: non-hematologic toxicities .............................................. 101 
Table 12 - Dose modification and management - ILD/Pneumonitis ............................................................ 101 
Table 13 - Dose modification for alpelisib ................................................................................................... 102 
Table 14 - Everolimus dose modification and management: hematologic toxicities ................................... 106 
Table 15 - Everolimus Dose modification and management: non-hematologic toxicities ........................... 106 
Table 16 - Abemaciclib Dose modification and management: hematologic toxicitiesa ............................... 108 
Table 17 - Abemaciclib Dose modification and management: non-hematologic toxicities ......................... 108 
Table 18 - Fasting condition ........................................................................................................................ 119 
Table 19 - Fed condition .............................................................................................................................. 119 
Table 20 - Blood sample volume collected per patient during study Arm #1 Part A ................................... 130 
Table 21 - Blood sample volume collected per patient during study Arm #1 Part A, BID regimen ............. 130 
Table 22 - Blood sample volume collected per patient during study Arm #1 Part B ................................... 131 
Table 23 - Blood sample volume collected per patient during study Arm #2 Part C ................................... 131 
Table 24 - Blood sample volume collected per patient during study Arm #2 Part D ................................... 131 
Table 25 - Blood sample volume collected per patient during study Arm #3 (Part F and G) ...................... 131 
Table 26 - Blood sample volume collected per patient during study Arm #4 (Part H and I) ....................... 131 
Table 27 - Blood sample volume collected per patient during study Arm #5 (Part J and K) ....................... 131 
Table 28 - Summary of blood sample handling procedures for amcenestrant (Arm #1 Part A) ................. 132 
Table 29 - Summary of blood sample handling procedures for amcenestrant and metabolic profiling 
(Arm #1 Part B) ............................................................................................................................................ 132 
Table 30 - Summary of blood sample handling procedures for amcenestrant and palbociclib (Arm #2 
[Parts C and D]) ........................................................................................................................................... 133 
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Table 31 - Summary of blood sample handling procedures for amcenestrant (Arm #3, #4, and #5 
[Parts F to Part K]) ....................................................................................................................................... 133 
Table 32 - Summary of blood sample handling procedures for alpelisib (Arm #3 [Parts F and G]) ........... 133 
Table 33 - Summary of blood sample handling procedures for everolimus (Arm #4 [Parts H and I]) ........ 134 
Table 34 - Summary of blood sample handling procedures for abemaciclib and its metabolites M2, 
M18, M20 (Arm #5 [Parts J and K]) ............................................................................................................. 134 
Table 35 - Summary of blood sample handling procedures for 4β-OH cholesterol and total 
cholesterol (Arm #5 [Parts J to Part K]) ....................................................................................................... 134 
Table 36 - Bioanalytical method for amcenestrant, palbociclib, alpelisib, 4β-hydroxycholesterol and 
total cholesterol in plasma ........................................................................................................................... 135 
Table 37 - Bioanalytical method for everolimus, abemaciclib and its metabolites ...................................... 135 
Table 38 - Urine sampling times .................................................................................................................. 135 
Table 39 - Urine handling procedure ........................................................................................................... 136 
Table 40 - List of pharmacokinetic parameters and definitions ................................................................... 136 
Table 41 - Sampled blood volume during the study .................................................................................... 141 
 
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3 
LIST OF ABBREVIATIONS  
 
18FDG: 
18fluorodesoxyglucose (18F) 
18F-FES: 
18F-fluorestradiol 
ADME: 
absorption, distribution, metabolism, excretion 
AE: 
adverse events 
AIs: 
aromatase inhibitors 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutraphil count, absolute neutraphil count 
aPTT: 
activated partial thromboplatin time 
AST: 
aspartate aminotransferase 
ATC: 
anatomical, therapeutic, and chemical 
AUC0-24: 
area under the plasma concentration versus time curve from time zero to 24 
hours 
BID: 
twice daily 
BUN: 
blood urea nitrogen 
CDK: 
cyclin dependent kinase 
cfDNA: 
circulating free DNA 
COD: 
cut-off date 
CR: 
complete response 
CSR: 
clinical study report 
CT: 
computerized tomography 
Ctrough: 
plasma concentration observed before treatment administration 
CYP: 
cytochrome P450 
ddPCR: 
droplet digital polymerase chain reaction 
DLT: 
dose-limiting toxicity 
DMET: 
drug metabolizing enzyme and transporters 
DRESS: 
drug reaction with eosinophilia and systemic symptoms 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EM: 
erythema multiforme 
EOT: 
end of treatment 
ER: 
estrogen receptor 
ERα: 
estrogen receptor alpha 
ESR1: 
estrogen receptor 1 
F%: 
oral bioavailability 
FFPE: 
formalin-fixed paraffine-embedded 
FSH: 
follicle stimulating hormone 
GCP: 
Good Clinical Practice 
GGT: 
gamma glutamyl transferase 
GLP: 
Good Laboratory Practice 
GnRH: 
gonadotrophin-releasing hormone 
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HER2: 
human epidermal growth factor receptor 2 
HIV: 
human immunodeficiency virus 
HNSTD: 
higher non-severely toxic dose 
HR: 
hazard ratio 
ICF: 
informed consent form 
ICR: 
independent central review 
IEC: 
Institutional Ethics Committee 
IHC: 
immunohistochemistry 
ILD: 
interstitial lung disease 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
LLN: 
lower limit of normal, lower limit of normal 
MAD: 
maximum administered dose 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS: 
next generation sequencing 
NOAEL: 
no observed adverse effect limit 
ORR: 
objective response rate 
PCR: 
polymerase chain reaction 
PD: 
pharmacodynamics 
PET: 
positron emission tomography 
PFS: 
progression-free survival 
PI3K: 
phosphoinositide 3-kinase 
PK: 
pharmacokinetic 
PR: 
partial response 
QD: 
once daily 
RD: 
recommended dose 
RECIST: 
response evaluation criteria in solid tumors 
SD: 
stable disease 
SERD: 
selective estrogen receptor down-regulator 
SERM: 
selective estrogen receptor modulator 
SJS: 
Stevens-Johnson syndrome 
STD10: 
severely toxic dose in 10% of the animals 
SUV: 
standardized uptake value 
TEAE: 
treatment-emergent adverse event 
TEN: 
toxic epidermal necrolysis 
tmax: 
time to maximum plasma concentration 
UGT: 
UDP-glucuronosyltransferase 
ULN: 
upper limit of normal 
US: 
United States 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
Breast cancer is the most commonly diagnosed cancer and the second leading cause of death in 
women (1). In the United States (US) in 2015 it was estimated 231 840 new cases of invasive 
breast cancer as well as 60 290 additional cases of in situ breast cancer would be reported. 
Approximately 40 290 women were expected to die (2015) from breast cancer (2). 
Both endogenous and exogenous steroid hormones such as estrogen and progesterone have been 
implicated in the pathogenesis of breast cancer. Clinical treatment decisions are driven by the 
expression of estrogen receptors (ERs), progesterone receptors and human epidermal growth 
factor receptor 2 (HER2) receptor status into HER2+, ER+/HER2- and triple negative clinical 
subtypes. About 75% of breast cancers express estrogen receptor alpha (ERα) which is a hormone 
regulator transcription factor (3). ER-positive breast cancers respond well to therapy targeting ER 
signaling either through competitive binding of ER antagonists such as tamoxifen or by blocking 
the production of estrogen by aromatase inhibitors (AIs) (4). 
According to guidelines, sequential hormonal therapy (alone or in combination) is the standard of 
care in the metastatic breast cancer setting for ER-positive, HER2-negative patients without 
rapidly progressing visceral or symptomatic metastases. Common classes of drugs used for this 
purpose include selective estrogen receptor modulator (SERM) such as tamoxifen, AIs like 
letrozole, anastrozole or exemestane, selective estrogen receptor down-regulators (SERD) 
represented by fulvestrant and luteinizing hormone releasing hormone agonists like buserelin and 
goserelin. 
Unfortunately, not all patients respond to first-line hormonal therapy as they present with primary 
or de novo resistance, and some patients who initially respond subsequently have breast cancer 
progression (acquired resistance). Resistance to endocrine therapies is frequent but relapsed 
tumors remain dependent on ER, which is highlighted by patient responses to second and 
third line endocrine therapies after failure of an earlier line of hormonal therapy. Estrogen receptor 
alpha signaling reactivation can occur due to change in ligand sensitivity and specificity or by 
new mutations of the estrogen receptor 1 (ESR1) (5). Estrogen receptor 1 gene mutation was 
recently evaluated in clinical studies with a high prevalence (25% to 40%) in relapse patients after 
AI therapy (6); with a limited benefit with current monotherapy. The continued dependence of 
breast cancer tumors on ER provides a strong rationale to continue to target ER in both first line 
and relapsed/advanced settings. 
Selective ER down-regulators are competitive ER antagonists that also induce conformational 
changes that lead to the degradation of ER via an ubiquitin-proteasome system (7). 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. The clinical 
effect of fulvestrant as a treatment for recurrent endocrine-resistant disease supports this matter. 
Although fulvestrant has served as an important proof of concept for the SERD approach, this 
therapy is limited by its poor pharmaceutical properties which necessitate intramuscular 
administration and limits the applied dose, exposure and receptor engagement (8, 9). 
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The fulvestrant 500 mg regimen (500 mg on Days 1, 14, 28; monthly thereafter) exhibited 
improvement in progression free survival and overall survival over the initially marketed 250 mg 
dose (10). However the 500 mg dose of fulvestrant does not fully saturate ER binding in patients 
as inhibition of 18F-fluorestradiol (18F-FES) positron emission tomography (PET) scan uptake 
was incomplete in 38% (6/16) of patients. This lack of receptor occupancy was associated with 
lack of clinical benefit (9, 11).  
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 SERDs with optimized characteristics: improved route of administration 
(oral versus intramuscular route), bioavailability and maintenance of ER receptor blockade 
combined with a strong antitumor activity. 
There is strong efficacy data to support the addition of targeted therapy, including the cyclin 
dependent kinase (CDK) 4/6 inhibitor or phosphoinositide 3-kinase (PI3K) inhibitor to endocrine 
therapy for the treatment of ER+/HER2- advanced/metastatic breast cancer. A recent series of 
studies have evaluated combinations of CDK4/6 inhibitor (palbociclib, abemaciclib, ribociclib), 
with endocrine therapy and demonstrated significant improvement in both progression-free 
survival (PFS) and overall survival (OS) compared to endocrine monotherapy in the first and 
second line settings (12, 13, 14). Abemaciclib was approved in combination with an aromatase 
inhibitor as initial endocrine based therapy for advanced or metastatic breast cancer and in 
combination with fulvestrant for advanced or metastatic breast cancer with disease progression 
following endocrine therapy (15). It was also approved as monotherapy for advanced or metastatic 
breast cancer with disease progression following endocrine therapy and prior chemotherapy in the 
metastatic setting. 
Advances in treating metastatic BC have focused on improving the efficacy of endocrine therapy 
by adding agents that target specific molecular pathways of breast cancer cell growth and survival. 
The combination of the aromatase inhibitor exemestane and the mammalian target of rapamycin 
inhibitor(mTOR) everolimus, more than doubled PFS compared with exemestane alone. Results 
according to investigator review: showed median PFS of  7.8 vs 3.2 months, respectively; hazard 
ratio 0.45 [95% CI: 0.38–0.54]; log rank P <0.0001) in the BOLERO-2 study (14) in 
724 postmenopausal women with HR+, HER2- locally advanced or metastatic breast cancer that 
had recurred or progressed on prior nonsteroidal aromatase inhibitor therapy. According to central 
review the median PFS was 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% 
CI: 0.31–0.48); log-rank P<0.0001] in the overall population and in all prospectively defined 
subgroups, including patients with visceral metastases, patients with recurrence during or within 
12 months of completion of adjuvant therapy, and irrespective of age. In addition, everolimus plus 
exemestane was associated with a manageable safety profile. The results of BOLERO-2 led to 
regulatory approval of everolimus plus exemestane. Everolimus was approved in treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer 
in combination with exemestane after failure of treatment with letrozole or anastrozole. 
More recently, alpelisib was approved by the FDA based on results from the SOLAR-1 study 
(16). In this Phase 3 randomized and placebo-controlled study, patients with HR-positive, HER2-
negative advanced or metastatic breast cancer who had experienced disease recurrence or 
progression following the use of an aromatase inhibitor were stratified by the presence or absence 
of a PIK3CA mutation and randomized to receive alpelisib with fulvestrant or placebo with 
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fulvestrant. The prespecified primary endpoint of SOLAR-1 was locally assessed progression-free 
survival in the cohort with PIK3CA-mutated breast cancer. To note, only 20 of the 341 mutated 
patients had prior exposure to CDK4/6 inhibitors. In the cohort with PIK3CA-mutated breast 
cancer patients the PFS was 11.0 months in the alpelisib with fulvestrant group compared to 
5.7 months in the placebo with fulvestrant group and this difference was statistically significant 
(hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001). In regards to disease 
response rate, among patients with measurable disease in the cohort with PIK3CA-mutated cancer 
the overall response rate was 35.7% in the alpelisib with fulvestrant group compared to 16.2% in 
the placebo with fulvestrant group. In addition to SOLAR-1, preliminary data from the Phase 2 
BYLieve study (17), conducted in patients who had experienced disease progression with the use 
of CDK4/6 inhibitors, indicated a lower ORR (15%) compared to the ORR observed in SOLAR-1 
(26.6%).  
The ability to measure pharmacodynamics (PD) of endocrine therapy in breast cancer patients has 
been limited, and mechanisms of resistance are incompletely understood. One tool that holds 
promise for measuring drug effects in cancer patients is molecular imaging. 18F-FES-PET/CT has 
been validated as an accurate method for localizing ER-expressing tumors (18, 19) and as a 
predictive assay for breast cancer endocrine therapy (18, 20, 21). In breast cancer, the uptake of 
18F-FES, as measured by standardized uptake value (SUV) on PET, has been shown to correlate 
with ER expression in biopsy material assayed by in vitro radioligand binding and by 
immunohistochemistry (IHC) (22), providing evidence of the value of 18F-FES SUV to measure 
specific binding to ER. 18F-FES uptake in breast cancer metastases declines after therapy with ER 
blocking agents such as tamoxifen and fulvestrant as well as estrogen-depleting agents such as 
AIs (23, 24). These studies suggest a role for 18F-FES-PET as a key PD biomarker for breast 
cancer which can help determine the dosage of ER targeted therapies needed for maximal ER 
occupancy and/or downregulation (25). 
4.1.1 BENEFIT/RISK ASSESSMENT  
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of amcenestrant may be found in the Investigator’s Brochure (IB). 
Refer to Summary of Product Characteristics or approved label of IBRANCE® (palbociclib), 
PIQRAY® (alpelisib), AFINITOR® (everolimus) and VERZENIO® (abemaciclib) for more 
information on additional benefit /risk when the above drugs are being used in combination within 
the protocol. 
4.1.1.1 Benefit Assessment  
Amcenestrant, as a new generation SERD with an expected and almost full inhibition of the ER 
target, may represent a new therapeutic option with a better benefit/risk ratio than approved 
endocrine-based treatments. Moreover, preclinical findings and clinical pharmacodynamics show 
a very high saturation of the ER at the tumor level. 
Amcenestrant could provide meaningful benefit to participants with advanced breast cancer who 
progressed on previous advanced therapeutic options or expressed secondary resistance to the 
adjuvant endocrine treatment. 
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4.1.1.2 Risk Assessment  
To date, the efficacy and safety data from ongoing studies of amcenestrant support continued 
clinical development of amcenestrant.  Based on non-clinical toxicity study results, completed or 
ongoing clinical studies in patients and in healthy post-menopausal participants, there have been 
no important identified risks confirmed so far. The important potential risks as per non-clinical 
toxicity and in vitro assessments include the following: gastrointestinal (GI) toxicity and 
complications; hepatotoxicity; photosensitivity; drug-drug Interaction; rash; osteoporosis and 
fertility impairment. Routine Pharmacovigilance (PV) activities are being conducted to monitor 
these potential risks associated with amcenestrant.  Potential risks are summarized in Table 1. 
Table 1 - Amcenestrant Risks  
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention: Amcenestrant (SAR439859) 
Gastrointestinal 
toxicity 
AMEERA-1 Arm#1 (Parts A and B): A total of 22 out of 62 
patients who received amcenestrant monotherapy (>20 mg 
QD) developed various GI toxicities considered to be related to 
amcenestrant, none of them were of Grade ≥3. 
AMEERA-1 Arm#2 (Parts C and D): A total of 19 out of 39 
patients who received 200 mg amcenestrant and palbociclib 
developed GI toxicities considered to be associated to 
amcenestrant, none of them were of Grade ≥3. 
In studies conducted in healthy subjects, there were few single 
occurrences of GI events considered related to amcenestrant. 
None of them were of Grade ≥3 
Events ≥ Grade 3 are to be closely 
monitored. 
Preventive or corrective treatment(s): 
antiemetics, antidiarrheal. 
Hepatotoxicity 
Preclinical safety data have shown evidence of hepatotoxicity 
in repeat dose toxicity study at 100 mg/kg/day in dogs. 
AMEERA-1 Arm#1 (Parts A and B) / Arm#2 (Parts C and D): 
No event of hepatotoxicity considered to be related to 
amcenestrant has been reported. 
Studies in healthy subjects: In completed or ongoing studies in 
healthy subjects, 3 subjects developed asymptomatic transient 
ALT increase ≥ 2 × ULN with amcenestrant 300 mg SD alone 
or in combination with rifampicin. All occurrences were Grade 
1. All events of ALT increase were non serious and 
spontaneously resolutive. 
Monitor LFT in cases of increase of 
Grade≥3 ALT, listed as AESI in the 
study. 
Monitor patients with symptoms/signs 
suggestive of hepatotoxicity: jaundice, 
increase of liver function tests (LFT) 
(ALT, AST, GGT, ALP and bilirubin). 
Patients with impaired liver function 
should not be included in the study 
(Exclusion criteria # 17). 
Phototoxicity 
A phototoxicity risk for amcenestrant was identified based on 
the absorption spectrum of the compound and in an in vitro 
phototoxicity study in 3T3 cells which was confirmed in a 
repeat dose in vivo mouse phototoxicity study. 
Within the amcenestrant development program which includes 
the sun protection measures, cumulatively Grade 1 sunburns 
were observed only in 2 patients out of an estimated 700 
participants exposed so far to amcenestrant doses (from 20 to 
1200 mg). The first patient received amcenestrant 150 mg QD 
and experienced G1 sunburn while being exposed to sun 
without sun protection and the second patient developed G1 
sunburn after amcenestrant 400 mg QD. 
Limitation of exposure to sunlight or 
artificial sunlight is recommended 
along with the requirement for sun 
protection measures (wear protective 
clothing, use a broad-spectrum 
sunscreen to cover ultra-violet A (UVA) 
and ultra-violet B (UVB) light exposure 
when outdoors with frequent re-
application as necessary, along with lip 
balm (sun protection factor [SPF] ≥30). 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Rash 
In Ameera 2, 1 Grade 2 rash and 1 serious Grade 3 rash 
maculo-papular were reported in Japanese patients 
(respectively at 400 mg QD and 300 mg BID). The last event 
was declared as a DLT. 
Grade 1 rashes have been reported in global population. 
Closely monitor if further risk 
mitigation/management is required 
Osteoporosis 
Due to mechanism of action of amcenestrant, there is a 
theoretical risk of osteoporosis when patients are exposed 
long-term to amcenestrant. 
No case of osteoporosis has been reported in amcenestrant 
program. 
No long-term observation has been performed. 
Monitor DEXA at baseline and follow 
up every 2 years. 
Monitor bone markers CTX and P1NP 
at baseline and every 2 years. 
DDI 
 
Amcenestrant effect on other drugs: Amcenestrant is 
• 
A moderate inducer of CYP3A based on a midazolam 
clinical study. 
• 
A potential CYP2B6, CYP2Cs and UGTs inducer 
• 
A potential inhibitor of OATP1B1/1B3 transporters 
Effect of other drugs on amcenestrant: 
• 
In vitro amcenestrant biotransformation occurs mainly 
through non-CYP enzymes (around 80% of hepatic 
clearance) involving UGT1A1 and 1A4. CYP2C8 and 
CYP3A are involved to less than 20%.  
• 
CYP3A clearance was confirmed to be minimal based on 
an itraconazole interaction clinical study. Atazanavir, a 
UGT1A1 inhibitor increases amcenestrant exposure by 
59 to 74%. 
• 
Strong metabolism enzyme inducers (Rifampicin) 
decrease amcenestrant exposure by 30% 
No adverse event related to DDI has been reported in clinical 
studies as of 29 May 2021. 
Drugs which are sensitive substrates of 
CYP3A, CYP2B6, CYP2Cs, and/or 
UGT should be closely monitored for 
efficacy. 
Treatment with drugs that are sensitive 
substrates of OATP1B1/1B3 
(asunaprevir, batorvastatin, bosentan, 
danoprevir, fexofenadine, glyburide, 
nateglinide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin and 
simvastatin acid) should not be 
administered with amcenestrant. 
Drugs that are UGT inhibitors (ie, 
probenecid, atazanavir) should be 
used with caution with amcenestrant 
highest dose (400mg QD). 
Drugs that are strong inducers of 
CYP3A should not be administered 
with amcenestrant. 
Patients with concomitant medications 
that are considered to interact with 
amcenestrant should be excluded 
(Exclusion criteria # 21) 
Study 
procedures 
 
 
Biopsies 
It is normal practice to biopsy possible recurrence of breast 
cancer to (a) confirm diagnosis and (b) check for change of 
subtype. 
When required, biopsies should be 
done only when tumor is accessible, 
limiting the risk of Infection or bleeding 
at the biopsy site. 
Special caution is needed for patients 
on anticoagulants, with INR increased, 
or with thrombocytopenia. 
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4.1.1.3 Risks in the Context of COVID-19  
Cancer patients are at increased risk of contracting SARS-CoV-2 infection and running more 
severe disease course (26). Cancer encompasses a heterogeneous group of subtypes and stages 
and the patient’s risk profile should therefore be individualized taking into consideration primary 
tumor type and stage as well as age and sex. The benefit and risk balance of anti-tumor treatments 
should be also tailored considering the overall treatment goal. For cancer in the curative setting, 
this risk/benefit balance favors maintaining systemic treatments. 
The investigators should always exercise their medical judgement to individualize clinical 
decisions and adhere to local and institutional guidelines for SARS-CoV-2 infection prevention 
and vaccine administration.  
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 6.5. 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) (27) 
• European Society for Medical Oncology (ESMO) (28) 
Refer to the contingency measures for a regional or national emergency that is declared by a 
governmental agency detailed in Section 19 (Appendix J) 
• It is important to minimize the risk of exposure of patients to COVID-19. In addition to 
the contingency measures described in Section 19 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. 
4.1.1.4 Overall Benefit/Risk Conclusion  
The benefit-to-risk assessment in patients with advanced breast cancer is still deemed to be 
acceptable within the context of the AMEERA-1 study, including during the COVID-19 
pandemic. This is based on the amcenestrant experience and the observed safety profile in this and 
other ongoing AMEERA studies, as well as the safety precautions that have been established to 
safeguard the wellbeing of the participants. Sponsor will continue to evaluate benefit-risk during 
the study period. 
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Refer to Summary of Product Characteristics or approved label of IBRANCE® (palbociclib), 
PIQRAY® (alpelisib), AFINITOR® (everolimus) and VERZENIO® (abemaciclib) for more 
information on additional benefit /risk information. 
4.2 
DESCRIPTION OF AMCENESTRANT   
Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with dual activity 
which antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. 
These dual properties translate into a deeper inhibition of ER pathways and more effective 
antiproliferative activity in ER dependent breast cancer cell lines driven by mutant or wild type 
ER compared to fulvestrant. 
4.3 
BACKGROUND INFORMATION OF AMCENESTRANT   
Please refer to the Investigator Brochure for more detailed information. 
4.3.1 Preclinical data  
In vitro pharmacology 
Amcenestrant inhibits the activity of both ER wild type and ER mutants (Y537S, D538G). 
Amcenestrant demonstrates potent antiproliferative activity in ER-positive dependent breast 
cancer cell lines with IC50 of 0.4 nM in MCF7 cells and in mutated MCF7 cells (Y537S=10 nM, 
D538G=1 nM). Amcenestrant antagonizes the binding of estradiol to ER but also induces receptor 
degradation (98%) in MCF7 cells (IC50=0.2 nM). 
The ER degrading activity of amcenestrant was compared to its direct competitors and reference 
compounds such as fulvestrant in a panel of 13 breast cancer cell lines. Amcenestrant shows 
strong ER degradation activity that is comparable to fulvestrant but superior to the SERD 
competitors, ARN810, AZD9496, and RAD1901. 
In vivo pharmacology 
At a large range of tolerated doses, amcenestrant demonstrated in vivo tumor regression of 
ER-positive breast cancer xenograft models including: hormone sensitive (MCF7), ER mutant 
driven (MCF7- ERY537S) and ET resistant PDX models (HCI 013). 
Initial preclinical experiments on ER-positive breast cancer tumor model MCF7 expressing the 
mutant ER Y537S have demonstrated that 18F-FES-PET imaging is a quantitative assay. 
Extinction of standard uptake values signal in 18F-FES-PET was shown to match ER degradation 
as detected with classical ER IHC. 
Amcenestrant was evaluated in combination efficacy with CDK4/6 inhibitor palbociclib in 
MCF7-Y537S xenograft tumor model in nude mice. Either amcenestrant at 5 mg/kg twice a day 
or palbociclib 100 mg/kg once a day orally as a monotherapy treatment achieved minimal or 
moderate effect on the tumor growth (%∆T/∆C: 59 and 27 respectively), but when combined both 
together the combination effect demonstrated strong antitumor efficacy and induced tumor 
regression (%∆T/∆C: -32). 
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Toxicology 
Amcenestrant was tested in a variety of in vitro and in vivo studies to identify potential safety 
issues, determine the safe threshold of exposure in rat and dog as well as target organs of toxicity. 
Genotoxicity and safety pharmacology liabilities were not identified for amcenestrant. 
A phototoxicity liability has been determined for amcenestrant. The no observed adverse effect 
limit (NOAEL) for phototoxicity was 10 mg/kg/day in a repeat dose study in mice. 
Amcenestrant has been tested in repeat dose toxicity studies in rat and dog. A NOAEL could not 
be established in the 4-week toxicity studies in rat and dog with 4-week recovery. Findings 
<30 mg/kg/day in both species can be attributed to the antiestrogenic mechanism of action of 
amcenestrant. The severely toxic dose in 10% of the animals (STD10) in the rat 4-week repeat 
dose toxicity study with 4-week recovery was >100 mg/kg/day. Target organs of toxicity were 
ovary, pituitary gland, adrenal gland, and bone. 
The higher non-severely toxic dose (HNSTD) in the 4 week repeat dose toxicity study in dogs 
with 4-week recovery was 30 mg/kg/day in the female. The HNSTD could not be determined in 
male dogs due to the incomplete recovery of the findings in the testis and epididymis. Target 
organs of toxicity in the dog were liver, kidney, stomach, ovary and testis/epididymis. 
Metabolism and preclinical pharmacokinetics 
In animals, amcenestrant generally showed a rapid oral absorption (time to maximum plasma 
concentration [tmax] ~2 to 4 hours) which was longer (up to 24 hours) at higher doses 
(>100 mg/kg). The oral bioavailability (F% ) in mice, rats and dogs was high to moderate with 
62%, 76% and 44%, respectively. Following single administration from 3 to 100 mg/kg/day in 
rats and dogs, area under the plasma concentration versus time curve from time zero to 24 hours 
(AUC0-24) increased about 2-times more than expected by dose proportionality. After 14-day or 
1-month repeated daily administrations in the 3 to 300 mg/kg dose range, no accumulation, nor 
sex effect were observed. 
Amcenestrant was highly bound to plasma proteins and no significant inter-species differences in 
plasma free fraction were evidenced, including human. The blood over plasma ratio showed no 
specific affinity to blood in animals or human. The compound showed a moderate volume of 
distribution in rats (0.8 L/kg) and dogs (0.5 L/kg) but a large volume of distribution in mice 
(6.1 L/kg).  
Amcenestrant inter-species in vitro metabolic profiling in mouse, rat, dog and human hepatocytes 
revealed a high biotransformation rate of amcenestrant in human, moderate in rat and low in 
mouse and dog. Phase II glucuronide metabolite formation was the main route of metabolism in 
vitro, including a direct acyl-glucuronide observed in all species and a N-glucuronide in human. 
Plasma clearance after single intravenous administration was found to be low to moderate in 
mouse, rat and dog corresponding to 37%, 5% and 1.2% of hepatic blood flow, respectively. The 
terminal plasma elimination half-life was long in mice and rats, and very long in dogs. 
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In vitro, amcenestrant showed very high intrinsic clearance using cryopreserved human. The 
biotransformation of amcenestrant was shown to be mainly non-cytochrome P450 (CYP) 
dependent (around 80% of clearance involve UDP-glucuronosyltransferase [UGT] 1A1 and 1A4) 
leading to direct glucuro-conjugation of amcenestrant. CYP2C8 and CYP3A are involved in 
amcenestrant oxidative metabolism. Therefore, there is a potential risk of interaction identified 
with UGTs, CYP2C8 and/or CYP3A inhibitors and inducers.  
Based on in vitro data, there is no risk of inhibition of metabolizing enzymes by amcenestrant at 
clinically relevant concentrations. Amcenestrant showed in vitro a potential for induction on 
CYP2B6, CYP3A4, CYP2Cs, and UGT1A1 and 1A4.  In vitro, amcenestrant was shown to be an 
potential inhibitor of P-gp and BCRP at absorption level, and of OATP1B1/B3 at systemic level. 
4.4 
RATIONALE FOR THE STUDY  
TED14856 is an open-label, non-comparative, Phase 1/2 study which goals are to evaluate the 
safety profile, the efficacy, the pharmacokinetics (PK), and the PD of escalating doses of 
amcenestrant administered as a monotherapy, then in combination with the approved doses of 
palbociclib or other anti-cancer agents (alpelisib, everolimus and abemaciclib). 
4.4.1 Arm #1  
4.4.1.1 Part A (Dose Escalation, Monotherapy amcenestrant)  
To assess the incidence rate of dose-limiting toxicity (DLT) and to determine the maximum 
tolerated dose (MTD) as well as the recommended dose of amcenestrant administered as 
monotherapy to postmenopausal women with advanced ER-positive and HER2-negative breast 
cancer. 
The proposed starting dose and dose escalation scheme in the clinic is based on the results of the 
4-week Good Laboratory Practice (GLP) toxicity studies conducted in two species dogs (females 
and males) and rat (females and males). The HNSTD was identified in the female dog at 
30 mg/kg/day. The HNSTD or STD10 was not identified in the rat. Therefore, the starting dose 
was calculated based on the HNSTD in female dog as this was the most sensitive species in the 
GLP toxicity studies. The dose of 30 mg/kg/day in the dog corresponds to a dose of 160 mg/day 
in human and is the maximum allowable starting dose in patients according to International 
Conference on Harmonization guidelines in oncology patients (29). 
In parallel to the toxicity studies, PK/PD correlations based on in vivo studies in mice and 
physiologically-based PK modelling prediction in human allowed to predict potential dose that 
inhibits the target (ER) occupancy in humans (IHC on mice tumor). The results of this simulation 
anticipate a daily dose of 20 mg to significantly inhibit the target on an 18F-FES-PET basis (at 
least 90%). Therefore, it is envisaged to start this first in human study at 20 mg once a day, and, 
depending on the results of the 18F-FES-PET scans (% of inhibition of the target) obtained, to 
increase the dose until reaching at least 90% of inhibition in all patients. Due to the limited 
availability of the 18F-FES-PET scan technology, Part A will only be conducted in certain selected 
sites in US and France.  
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In addition, a twice daily (BID)  dosing regimen will be assessed. A BID administration will allow 
modification of the PK behavior of the drug by increasing Ctrough and decreasing Cmax for a same 
dose intensity as once-daily regimen. It is expected that this regimen will allow a better and more 
constant coverage for ER inhibition. 
Together with the DLT assessment, PK after repeated administration and level of inhibition of 
target occupancy measured by 18F-FES-PET imaging (at baseline and during treatment) will also 
be taken into account for the decision to expand the study to Parts B and C.  
4.4.1.2 Part B (Dose Expansion, Monotherapy amcenestrant)  
When the dose escalation phase ends, a preliminary RD for Phase 2 will be proposed by the Study 
Committee for an expansion cohort (Part B), primarily based on safety, PD, and PK data. The 
primary endpoint will be the objective response rate (ORR) according to response evaluation 
criteria in solid tumors (RECIST v1.1) in postmenopausal advanced breast cancer patients. 
Testing on ESR1 mutation status will be done as part of the general characterization of the tumor. 
Exploring the activity of amcenestrant in ESR1 mutated patients may be of interest as when 
patients relapsed after AI therapy (but not after tamoxifen) ESR1 mutations is observed in 25% to 
39% of women (30). Patients with ESR1 mutation had significantly improved PFS after taking 
fulvestrant monotherapy compared with exemestane (hazard ratio [HR]=0.52) (31) and after 
taking fulvestrant combined with palbociclib versus fulvestrant alone (HR=0.43) (13). In addition, 
an effort will be made to collect fresh biopsy of primary tumor or any metastatic site to evaluate 
the ER protein level by IHC and evaluate the ER degradation by comparing ER protein level 
determined by IHC in the most recently collected tumor. 
The Part B expansion cohort will include approximately 78 patients. An interim analysis will be 
performed after 45 patients are treated in order to assess the efficacy: it is expected to have at least 
5 patients with response (complete response [CR] or partial response [PR]); other parameters 
should also have to be taken into consideration such as the duration of response, clinical benefit 
rate (CBR, CR+PR+stable disease [SD] ≥24 weeks), the percentage of patients with SD, and the 
duration of SD. 
If results in Part A with the BID dosing regimen are of interest in terms of safety, PK, exposure, 
preliminary efficacy and any other relevant information such as data from patients treated with the 
QD regimen, and warrants further investigation, a BID regimen could be tested in an additional 
expansion subpart with approximately 56 patients. In that case, an interim analysis will be 
performed after 29 patients are treated in order to assess the efficacy: it is expected to have at least 
3 patients with response (complete response [CR] or partial response [PR]); other parameters 
should also have to be taken into consideration such as the duration of response, clinical benefit 
rate (CBR, CR + PR + stable disease [SD] ≥24 weeks), the percentage of patients with SD, and 
the duration of SD. 
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4.4.2 Arm #2  
4.4.2.1 Part C (Dose Escalation, Combination with palbociclib)  
Three recent studies in ER-positive postmenopausal breast cancer patients showed about 
50% improvement on PFS with the combination of palbociclib, a CDK4/6 inhibitor, with 
hormone therapy versus hormone therapy alone. The phase 2 study PALOMA-1 (n=165 women) 
(12), and the confirmatory Phase 3 study PALOMA-2 (n=666 women) (32) assessed letrozole 
+ palbociclib versus letrozole alone (or letrozole+placebo, respectively) in first line treatment 
achieving a PFS of 20.2 months with combination versus 10.2 months (HR=0.49; p=0.0004) and 
of 24.8 months with combination versus 14.5 months (HR=0.58; p <0.000001), respectively. The 
patient population was postmenopausal women with ER+, HER- advanced breast cancer and no 
prior systemic therapy.  
The Phase 3 study PALOMA-3 (n=521 women) evaluated fulvestrant+palbociclib (patients with 
HR+, HER- metastatic breast cancer, progressive disease after endocrine therapy, and 
≤1 chemotherapy for advanced breast cancer) versus fulvestrant+placebo achieving a PFS of 
9.5 months with combination versus 4.6 months (HR=0.46; p <0.0001) (13). 
Palbociclib is indicated for the treatment of ER-positive, HER2-negative advanced or metastatic 
breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal 
women, or with fulvestrant in women with disease progression following endocrine therapy. 
The combination of amcenestrant with palbociclib in this study aims to assess the incidence rate 
of DLT and to determine the MTD as well as the RD of amcenestrant in combination with the 
recommended standard dosage of palbociclib administered to postmenopausal women with 
ER-positive and HER2-negative advanced breast cancer. It is intended to test 2 doses of 
amcenestrant QD (1 dose below amcenestrant RD and amcenestrant RD) with 1 fixed dose of 
palbociclib. Additionally, a BID regimen could be explored. Mutation profiling of circulating free 
DNA (cfDNA) will be determined at baseline and end of treatment (EOT) in order to explore 
a possible link between lack of response and the presence of specific tumor mutation. 
Based on amcenestrant PK predictions in human, the risk of interaction of amcenestrant over the 
dose range planned (20 to 600 mg) on the PK of palbociclib at the RD (125 mg) is unlikely. In 
addition the PK of palbociclib in combination with amcenestrant will be characterized in this part 
of the study. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg 
dosing to steady state in humans, consequently low or no risk of interaction of palbociclib on PK 
of amcenestrant is predicted. The first dose of amcenestrant will be one dose level below RD for 
monotherapy, and PK of amcenestrant in combination with palbociclib will be characterized in 
this part of the study. Due to the limited sample size, Part C will be conducted in the same sites 
which enrolled patients in Part A.  
4.4.2.2 Part D (Dose Expansion, Combination with palbociclib)  
When dose escalation of the combination phase in Part C ends, at least one dose for the expansion 
cohort (Part D) will be proposed by the Study Committee. More than 1 DL may be selected to be 
evaluated in this cohort. Approximately 28 patients will be treated at each selected dose from 
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Part C with approximately 56 patients enrolled if 2 dose levels are selected. Intra-patient dose 
escalation or re-escalation of any study drug is not allowed. The Study Committee will review the 
preliminary data (eg, safety, efficacy and PK), of each selected RD. 
4.4.3 Arm #3  
4.4.3.1 Part F (Safety Run-In Phase with alpelisib)  
Amcenestrant 200 mg QD dose level will be assessed in combination with alpelisib at a fixed 
(standard) dose of 300 mg per alpelisib label according to incidence of DLTs and PK results. 
Additional dose levels of amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 
200 mg BID etc.) with alpelisib could be explored if needed based on the safety and PK results 
from the 200 mg dose level testing with 300 mg alpelisib. Lower dose of alpelisib (eg, 250 mg or 
200 mg) could be explored from Cycle 1 Day 1 based on PK results and safety profile from the 
initial combination of amcenestrant 200 mg and alpelisib 300 mg on the first 3 to 6 patients in 
Part F. 
A Phase 1b study conducted in 87 women with the combination of alpelisib and fulvestrant 
(sharing the same mechanism of action as amcenestrant) showed a manageable safety profile and 
suggested that the combination could have greater clinical activity in PIK3CA-mutated breast 
cancer compared to patients with PIK3CA wild-type tumors.  
This was confirmed in a Phase 3 randomized and placebo-controlled SOLAR-1 study (16). In this 
study, patients with HR-positive, HER2-negative advanced or metastatic breast cancer who had 
experienced disease recurrence or progression following the use of an aromatase inhibitor were 
stratified by the presence or absence of a PIK3CA mutation and randomized to receive alpelisib 
with fulvestrant or placebo with fulvestrant. To note, only 20 of the 341 mutated patients had prior 
exposure to CDK4/6 inhibitors. The prespecified primary endpoint of SOLAR-1 was locally 
assessed progression-free survival in the cohort with PIK3CA-mutated breast cancer. In this 
cohort the PFS was 11.0 months in the alpelisib with fulvestrant group compared to 5.7 months in 
the placebo with fulvestrant group and this difference was highly statistically significant (hazard 
ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001). Regarding disease response 
rate, among patients with measurable disease in the cohort with PIK3CA-mutated cancer the 
overall response rate was 35.7% in the alpelisib with fulvestrant group compared to 16.2% in the 
placebo with fulvestrant group.  
Regarding toxicity and tolerance, the most frequent grade 3-4 adverse events in SOLAR-1 among 
the alpelisib with fulvestrant group were hyperglycemia (36.6%), rash (9.9%) and diarrhea 
(6.7%). A significant proportion of patients (25%) discontinued alpelisib due to adverse events, 
most commonly hyperglycemia (6.3%) and rash (3.2%). Dose reductions of alpelisib were 
permitted in SOLAR-1 with starting dose of 300 mg daily and reductions to 250 mg then 200 mg. 
The median relative dose intensity of alpelisib was 82.7% with dose reductions occurring in 
63.9% of patients and dose interruptions in 74% of patients. In cohort A of the BYLieve study 
(17), 127 patients who had received a CDKi with an AI as immediate prior therapy were treated 
with alpelisib and fulvestrant. In this cohort, the most frequent grade 3-4 adverse were 
hyperglycemia (28.3%), rash (9.4%) and diarrhea (5.5%). Of note, 20.5% of these patients 
discontinued alpelisib due to adverse events, compared to 25% of patients in SOLAR-1, and there 
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were also fewer discontinuations related to hyperglycemia in BYLieve (33) compared to  
SOLAR-1 (1.6% and 6.3%, respectively). 
Based on the PK properties of both drugs, amcenestrant could potentially increase alpelisib 
exposure through BCRP inhibition. Conversely, due to the potential induction effect of alpelisib 
on metabolizing enzymes (CYP2B6 and CYP2C9), alpelisib could decrease amcenestrant 
exposure (since CYP2Cs inducers may also induce the UGTs which is the main metabolic 
pathway for amcenestrant). Considering this uncertain risk of drug-drug interaction, PK of 
amcenestrant and alpelisib will be assessed in the safety run-in and expansion study parts.   
4.4.3.2 Part G (Dose Expansion, Combination with alpelisib)  
After the completion of the safety run-in (Part F), a recommended dose for Phase 2 will be 
proposed/confirmed by the Study Committee for an expansion cohort (Part G), primarily based on 
safety, PD, and PK data in Part F. Approximately 34 patients will be treated at the confirmed dose 
from Part F. Intra-patient dose escalation or re-escalation of any study drug is not allowed. 
The primary endpoint will be safety and tolerability per type, frequency, severity, relationship to 
study therapy and seriousness of adverse events (AE) or laboratory abnormalities according to 
NCI-CTCAE v4.03.  
4.4.4 Arm #4  
4.4.4.1 Part H (Dose Escalation with everolimus)  
Amcenestrant 200 mg QD dose level will be assessed in combination with everolimus two dose 
levels: 5 mg QD and 10 mg QD based on the incidence of DLT(s) and PK results.  Additional 
dose levels of amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 200 mg BID etc.) 
with everolimus could also be explored if needed, based on the safety and PK results from this 
dose escalation study.  
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP (34). 
Therefore, absorption and further elimination of everolimus may be influenced by amcenestrant 
which is a moderate CYP3A inducer and PgP inhibitor. In vitro, everolimus was reported as a 
potential UGT1A1 inhibitor (34), which may influence elimination of amcenestrant, mainly 
metabolized by UGT.  
Pharmacokinetic assessment of both amcenestrant and everolimus will be conducted during dose 
escalation to anticipate any major interaction. 
The BOLERO-2 study (14), which was conducted on 724 patients with HR+ advanced breast 
cancer who had recurrence or progression while on previous adjuvant  treatment with Aromatase 
Inhibitor (letrozole or anastrozole) or other hormonal therapy (tamoxifen or fulvestrant) or 
chemotherapy, showed that the addition of everolimus to exemestane significantly improved 
progression-free survival, with observed medians of 11 months versus 4.1 months  exemestane 
single agent.  
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4.4.4.2 Part I (Dose Expansion, Combination with everolimus)  
After the completion of dose escalation study (Part H), based on safety, PK and preliminary 
antitumor activity data, RD of everolimus for the combination therapy will be proposed by Study 
Committee for expansion cohort (Part I); approximately 12 patients will be treated at the RD from 
Part H selected by the Study Committee. Intra-patient dose escalation or re-escalation of any 
study drug is not allowed. 
The primary endpoint will be safety and tolerability: type, frequency, severity, relationship to 
study therapy and seriousness of adverse events (AE) or laboratory abnormalities according to 
NCI-CTCAE v4.03.  
4.4.5 Arm #5  
4.4.5.1 Part J (Dose Escalation Phase with abemaciclib)  
Amcenestrant 200 mg QD dose level will be assessed in combination with abemaciclib two dose 
levels: 100 mg BID and 150 mg BID based on the incidence of DLT(s) and PK results.  
Additional dose levels of amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 
200 mg BID etc.) with abemaciclib could also be explored if needed based on the safety and PK 
results from this dose escalation study.  
The MONARCH 1 (35) study demonstrated that abemaciclib administered as a single agent on a 
continuous schedule had anti-tumor activity and manageable toxicities in patients with 
HR+/HER2- metastatic breast cancer who had previously progressed on or after endocrine 
therapy, and received 1-2 lines of chemotherapy in the metastatic setting. This was confirmed in 
the nextMONARCH (36) study that was conducted in the CDK4/6-naive patients who were also 
heavily pretreated.   
In the MONARCH 2 (37), Phase 3 study, treatment with abemaciclib plus fulvestrant resulted in a 
statistically significant and clinically meaningful median OS improvement of 9.3 months for 
patients with HR+, HER2- advanced breast cancer who progressed after prior endocrine therapy 
regardless of menopausal status.  
In the MONARCH 3 (38), Phase 3 study, treatment with abemaciclib plus letrozole resulted in a 
significantly longer median PFS than the placebo Arm (28.18 vs. 14.76 months; hazard ratio 
[95% confidence interval],0.540 [0.418–0.698]; p = .000002). 
Abemaciclib is a primarily metabolized by CYP3A to several metabolites including three 
equipotent metabolites to abemaciclib (M2, M18 and M20). Elimination of abemaciclib, and 
possibly its metabolites, may be influenced by amcenestrant which is a potential CYP3A inducer. 
In addition, abemaciclib is a substrate of PgP and BCRP and its absorption may be influenced by 
amcenestrant which is a potential PgP inhibitor/inducer and BCRP inhibitor. It is not anticipated 
that abemaciclib will influence pharmacokinetics of amcenestrant. Pharmacokinetic assessment of 
both amcenestrant and abemaciclib will be conducted during dose escalation phase to anticipate 
any major interaction 
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4.4.5.2 Part K (Dose Expansion, Combination with abemaciclib)  
After the completion of dose escalation study (Part J), a recommended dose of abemaciclib will be 
proposed for Phase 2 by the Study Committee for an expansion cohort (Part K), primarily based 
on safety, PD, and PK data in Part J. Approximately 20 patients will be treated at the confirmed 
dose from Part J. Intra-patient dose escalation or re-escalation of any study drug is not allowed. 
The primary endpoint will be safety and tolerability: type, frequency, severity, relationship to 
study therapy and seriousness of adverse events (AE) or laboratory abnormalities according to 
NCI-CTCAE v4.03. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY OBJECTIVES  
DOSE ESCALATION:  
Monotherapy Arm #1 - Part A (amcenestrant monotherapy); Combination Arm #2 - Part C 
(amcenestrant in combination with palbociclib); Combination Arm #4 - Part H (combination of 
amcenestrant with everolimus); Combination Arm #5 - Part J (combination of amcenestrant with 
abemaciclib) 
• To assess the incidence rate of DLT and to determine the MTD as well as the RD of 
amcenestrant administered as monotherapy (Part A), then in combination with palbociclib 
(Part C), in postmenopausal women with ER-positive and HER2-negative advanced breast 
cancer. 
• To assess the incidence rate of dose-limiting toxicity (DLT) and determine the 
recommended dose (RD) of everolimus (part H) or abemaciclib (part J) administered in 
combination with the selected amcenestrant dose for the combination therapy 
SAFETY RUN-IN Phase:  
Combination Arm #3 - Part F amcenestrant in combination with alpelisib) 
• To confirm the RD (Recommended Dose) of amcenestrant in combination with alpelisib in 
postmenopausal women with ER positive, HER2 negative and PIK3CA-mutated advanced 
breast cancer. 
DOSE EXPANSION:  
Monotherapy Arm #1 - Part B (amcenestrant monotherapy) 
• To assess the antitumor activity using ORR according to RECIST v1.1 determined by an 
Independent Central Review (ICR) at the amcenestrant RD administered as monotherapy 
in postmenopausal women with ER-positive and HER2-negative advanced breast cancer. 
Combination Arm #2 - Part D (amcenestrant in combination with palbociclib); Combination Arm 
#3 – Part G (combination of amcenestrant with alpelisib); Combination Arm #4 – Part I 
(combination of amcenestrant with everolimus); Combination Arm #5 – Part K (combination of 
amcenestrant with abemaciclib) 
• To characterize the overall safety profile of amcenestrant administered in combination 
with palbociclib (Part D), in combination with alpelisib (Part G), in combination with 
everolimus (Part H), and in combination with abemaciclib (Part K) 
5.2 
SECONDARY OBJECTIVES  
• To characterize the overall safety profiles of amcenestrant administered as monotherapy 
(Arm #1 Parts A and B), in combination with palbociclib (Arm #2 Part C), and in 
combination with alpelisib (Arm #3 Part F), everolimus (Arm #4 Part H) and abemaciclib 
(Arm #5 Part J). 
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• To characterize the PK profile of amcenestrant administered as monotherapy (Arm#1), or 
in combination in each study Arms, as well as the PK profile of palbociclib, alpelisib, 
everolimus and abemaciclib in the appropriate treatment arm.  
• To evaluate the antitumor activity using ORR according to RECIST v1.1 of amcenestrant 
administered as monotherapy (Arm #1 Part A), in combination with palbociclib (Arm #2 
Parts C and D), in combination with alpelisib (Arm #3 Part F and G), in combination with 
everolimus (Arm #4 Parts H and I), and in combination with abemaciclib (Arm #5 Parts J 
and K),the clinical benefit rate (CBR) defined as complete response [CR], partial response 
[PR] and stable disease [SD] ≥24 weeks, and progression-free survival (PFS) in each 
treatment arm. 
• To evaluate the ORR and CBR (CR, PR and SD ≥24 weeks) in dose expansion of each 
study treatment arm according to the ESR1 gene mutational status (mutant and wild type) 
at baseline and during treatment. 
• To evaluate the time to first response (CR or PR) in dose expansion of each study 
treatment arm. 
• To evaluate residual ER availability with PET scan 18F-FES uptake with increasing doses 
of amcenestrant (Arm #1 Part A). 
• To assess the food effect on PK of amcenestrant (Arm #1 Part A). 
• To assess potential induction/inhibition effect of amcenestrant on cytochrome P450 
(CYP) 3A using 4b-OH cholesterol (ie, full PK sampling for Arm #1 Parts A and B, 
Arm#5 Parts J and K). 
5.3 
EXPLORATORY OBJECTIVES  
• To evaluate PK/PD relationships. 
• To evaluate target engagement: confirm the ER degradation with re-biopsy of the tumor at 
recommended dose in Arms #1 (Part B), #3 (Parts F,G), #4 (Parts H,I), and #5 (Parts  J, 
K). 
• To evaluate other breast cancer biomarkers in tumor over time such as Ki67, Bcl-2, PgR, 
ER and tumor gene expression profiles in Arms #1 (Part A, B), #3 (Parts F, G), #4 (Parts 
H, I), and #5 (Parts J, K). In Arm #5 (Parts J, K), Cyclin D1 protein expression will be 
evaluated too, at baseline and over time. Results will be correlated with patients’ clinical 
parameters. 
• To assess the extent of metastases with FDG PET/CT during dose escalation (Arm #1 
Part A BID). 
• To evaluate change of cfDNA alterations from screening to progression of disease during 
Arm #1 (Part B), #2, #3, #4, and #5. The percentage of patients with cfDNA alterations 
will be provided over time to characterize the biological evolution of the disease in each 
patient. The association of these alterations with clinical outcomes will also be provided. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is an open-label, non-comparative, dose escalation and dose expansion, safety, efficacy, PK, 
and PD evaluation study of amcenestrant administered orally as monotherapy (Parts A and B) and 
in the following combinations: with palbociclib (Parts C and D), alpelisib (Parts F and G), 
everolimus (Parts H and I) and abemaciclib (Parts J and K). Amcenestrant is given daily to 
postmenopausal women with ER-positive advanced breast cancer. 
The study will be performed in 10 parts (5 Arms): the escalation phase with amcenestrant as 
monotherapy (Arm #1 Part A), an expansion phase with amcenestrant as monotherapy (Arm #1 
Part B), an escalation phase with amcenestrant in combination with palbociclib (Arm #2 Part C), 
an expansion phase with amcenestrant in combination with palbociclib (Arm #2 Part D), safety 
run-in phase of amcenestrant with alpelisib (Arm #3 Part F), escalation phase with amcenestrant 
in combination with everolimus (Arm #4 Part H) and abemaciclib (Arm #5 Part J), and an 
expansion phase with amcenestrant in combination with alpelisib (Arm #3 Part G), everolimus 
(Arm #4 Part I) or abemaciclib (Arm #5 Part K). 
Enrollment of patients in dose expansion Arms #1, #2, #3, #4, and #5 (Parts B, D, G, I and K) will 
be initiated after completion of dose escalation and safety run-in in Parts A, C, F, H and J, and 
identification of MTD/RD, and can be conducted in parallel. Patients’ entry criteria in Parts B, D, 
G, I and K are slightly different with regards to prior anticancer therapy. Patients who are eligible 
to participate in other study parts, will not be able to participate in Parts F and G if they do not 
meet an additional inclusion criterion for these two study parts (F and G), ie, to have positive 
PIK3CA mutational status. 
6.2 
STARTING DOSE AND DOSE ESCALATION DESIGN  
The rationale for selecting the starting dose is described in Section 4. 
6.2.1 Starting dose and dose levels  
Arm #1 
Part A (monotherapy) 
Dose escalation will be initiated with a QD schedule with a starting dose of 20 mg/day. 
Dose escalation is expected to proceed according to Table 2. Intra-patient dose escalation or  
re-escalation will not be permitted. 
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Table 2 - Part A dose escalation  
Dose level 
(DL)a 
Dose of amcenestrant 
(mg)  
DL(-1) QD 
10 once daily 
DL1 QD 
20 once daily 
DL1bis QD 
50 once daily 
DL2 QD 
100 once daily 
DL2bis QD 
150 once daily 
DL3 QD 
200 once daily 
DL4 QD 
400 once daily 
DL4bis BIDb 
200 twice daily 
DL5 QD 
600 once daily 
DL5bis BIDb 
300 twice daily 
a Additional intermediate or higher dose levels could be tested, after agreement between Sponsor and Investigators (Study Committee). 
b A BID schedule of administration may be added during the study, the starting dose will be a DL of the same dose intensity as the highest 
cleared DL with QD Schedule. Other schedules of administration may be added during the study. 
The BID dosing regimen will be explored in 6 DLT-evaluable patients at the dose level providing 
the same dose intensity as the highest cleared QD dose level (600 mg): 300 mg taken two times 
a day 12 hours apart (ie, 2 x 300 mg) ±1 hour (DL5bis BID). Other doses such as 100 mg and/or 
200 mg taken two times a day 12 hours apart could also be explored if needed. In that case, 
6 DLT-evaluable patients will be enrolled at each of these dose levels. 
Arm #2 – amcenestrant in combination with palbociclib 
Part C (combination) 
Enrolment in the Part C dose escalation phase can be initiated once the amcenestrant RD 
monotherapy has been determined at the end of Part A. Dose escalation is expected to proceed 
according to Table 3. The starting dose of amcenestrant will be one dose level below the RD as 
monotherapy. Palbociclib will be given at the recommended standard dosage of 125 mg orally 
once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle 
of 28 days. Intra-patient dose escalation or re-escalation of any study drug is not allowed. 
Table 3 - Amcenestrant dose levels in Part C  
Dose levels (DL)a 
Amcenestrant 
Palbociclibb 
DL1 QD 
DL RD(A-QD)-1 
125 mg 
DL2 QD 
RD(A-QD) 
125 mg 
DL3 BID 
RD(A-BID) 
125 mg 
a Lower dose, intermediate dose levels and a BID dose regimen can be tested after agreement between Sponsor and Investigators (Study 
Committee) 
b Oral route once daily with food for 21 days followed by 7 days off therapy to comprise a complete cycle of 28 days. Lower dose 
(eg, 100 mg, 75 mg) can be proposed depending on tolerance 
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Arm #3 amcenestrant in combination with alpelisib 
Part F 
In Part F, safety run-in will be explored for amcenestrant given at one dose level below the RD as 
monotherapy (ie, 200 mg QD) and alpelisib given at the recommended standard dosage of 300 mg 
orally once daily for a complete cycle of 28 days (except in Cycle 1 where alpelisib will be taken 
alone for 3 days prior to amcenestrant administration [can be taken for 3 days in a 7 day window], 
followed by amcenestrant administration in combination with alpelisib for 25 days).  An 
additional BID dose could be tested in Part F based on factors including safety profile and PK and 
guided by the Study Committee's recommendations. 
Table 4 - Amcenestrant and alpelisib dose levels in Part Fa  
Dose levels (DL)a 
Amcenestrant 
Alpelisib (Standard dose)b 
Alpelisib (reduced dose)c 
DL1 QD 
200 mg  
300 mg 
 
DL2 QD 
200 mg 
 
250 mg 
DL3 QD 
200 mg 
 
200 mg 
a In Part F (and G), Cycle 1 is defined as a 28-day cycle with 3 days of pretreatment with alpelisib single-agent for PK assessment followed 
by a 25-day treatment cycle with amcenestrant and alpelisib. Following cycles will also continue to be 28 days.   
a Lower or higher doses QD and a BID dose regimen can be tested after agreement between Sponsor and Investigators (Study Committee) 
b Oral route, once daily with food.  
c Lower dose (eg, 250 mg, 200 mg) can be proposed depending on tolerance  
Up to 6 DLT-evaluable patients could be treated at the already established amcenestrant dose of 
200 mg when given in combination with other drugs, in order to confirm this dose when 
administered in combination with alpelisib. Lower dose levels of alpelisib and/or other dose levels 
of amcenestrant could be considered for testing in Part F if this established dose is not confirmed. 
A decision to continue to dose expansion study part (Part G) will be based on DLTs observed for 
at least 1 cycle duration of all evaluable patients, and PK results from Part F combination. Intra-
patient dose escalation or re-escalation of any study drug is not allowed. 
1. If none or one of the first 3 evaluable patients experiences DLT(s) during Cycle 1, the 
cohort will be expanded to include an additional 3 patients for a total of 6 patients.  
a) In the second set of 3 patients (ie, 6 patients altogether), if none or one DLT is 
experienced among the 6 patients (ie, 0/6 or 1/6), the doses of the combination are 
adequate for further testing in Part G. 
b) In the second set of 3 patients (ie, 6 patients altogether), if two or more DLTs are 
experienced among the 6 patients (ie, ≥2/6), the doses of the combination are NOT 
adequate for further testing in Part G. In this case, other dose levels of alpelisib and/or 
amcenestrant could be considered in Part F, or Part F can be stopped. 
2. If 2 or more of the first 3 evaluable patients experience DLT(s), lower dose of alpelisib 
dose and/or other dose levels of amcenestrant will be considered or a decision to stop 
Part F can be made.  
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Although the confirmation of amcenestrant dose when given in combination with alpelisib will be 
guided by safety evaluation during Cycle 1, cumulative or irreversible toxicities observed after 
subsequent administrations will also be considered for dose selection/confirmation decision 
(ie, expansion of a given dose level), as well as any relevant information such as PK and anti-
tumor activity data that may need additional patients, upon recommendation from the Study 
Committee. 
 
Arm #4 amcenestrant in combination with everolimus 
Part H 
Amcenestrant 200 mg QD dose level will be assessed in combination with everolimus two dose 
levels: 5 mg QD and 10 mg QD based on the incidence of DLT(s) and PK results.  In this dose 
escalation part, additional dose levels of amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg 
BID, or 200 mg BID etc.) with everolimus could also be explored if needed, based on the safety 
and PK results of everolimus in this dose escalation study.  
Based on the preliminary safety profile, PK and antitumor activity data, Study Committee will 
determine the recommended dose (RD) of everolimus in combination with amcenestrant 200 mg 
QD, and/or expand this combination to Part I, or not. 
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Table 5 - Amcenestrant and everolimus dose levels in Part Ha  
Dose levels  
(DL) 
Amcenestrantb 
Everolimusc 
(QD) 
DL1 QD 
200 mg  
5 mg 
DL2 QD 
200 mg 
10 mgd 
a In Part H, Cycle 1 is defined as a 28-day treatment cycle of amcenestrant and everolimus. Following cycles will also continue to be 28 
days. 
b Lower or higher doses QD and BID dose regimen can be tested after agreement between Sponsor and Study Committee  
c Oral route, once daily (QD) with food.  
d Lower dose of everolimus, (5mg QOD (every other day) can be explored depending on tolerance 
Arm #5 amcenestrant in combination with abemaciclib 
Part J 
Amcenestrant 200 mg QD dose level will be assessed in combination with abemaciclib two dose 
levels: 100 mg BID and 150 mg BID according to incidence of DLT(s) and PK results.  
Additional dose levels of amcenestrant (eg, 300 mg QD, or 400 mg QD, or 100 mg BID, or 
200 mg BID etc.) with abemaciclib could be explored if needed based on the safety and PK results 
from this dose escalation study.  
Based on the preliminary safety profile, PK and preliminary antitumor activity data, the Study 
Committee will determine the recommended dose (RD) of abemaciclib in combination with 
amcenestrant 200 mg QD, and/or expand this combination to Part K, or not. 
Table 6 - Amcenestrant and abemaciclib dose levels in Part Ja  
Dose levels  
(DL)  
Amcenestrantb 
 
Abemaciclibc 
(BID) 
DL1 QD 
200 mg QD  
100 mg BIDd 
DL2 QD 
200 mg QD 
150 mg BID 
a In Part J, Cycle 1 is defined as a 28-day treatment cycle of amcenestrant and abemaciclib. Following cycles will also continue to be 28 
days.   
b Lower or higher doses QD and BID dose regimen can be tested after agreement between Sponsor and Study Committee  
c Oral route, twice daily (BID) with food.  
d Lower doses of abemaciclib, 50 mg BID can be used depending on tolerance 
6.2.2 Dose Escalation Arms #1, #2, #4 and #5 (Parts A, C, H and J) and Safety Run-In 
Arm #3 (Part F) strategy  
The dose escalation decision will be based on the DLTs observed during Cycle 1. Before 
escalating the amcenestrant dose to the next level, the safety profile, PK profile, and 18F-FES-PET 
results (Part A only) will be reviewed by the Study Committee. Cumulative or irreversible 
toxicities observed after subsequent administrations should also be considered for the dose 
escalation and the dose selection decision, upon recommendation from the Study Committee. 
The Study Committee role is described in Section 6.10. 
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The definition of DLTs is provided in Section 9.1.1. 
The classical dose escalation will be followed based on safety and PD evaluation. The first patient 
treated at each new dose level will be followed for a minimum of 1 week prior to enrolling and 
treating 2 additional patients at this dose level. 
The following events will determine the total number of patients registered per dose level during 
the classical phase: 
• If none of the 3 patients experience a DLT, the next cohort starts 1 dose level higher. 
• If 1 of the 3 patients experiences a DLT, up to 3 additional patients are treated at this dose 
level. 
• If 2 or more patients experience a DLT, the maximum administered dose (MAD) is 
reached. 
The above plan is summarized hereafter: 
Table 7 - Classical dose escalation phase  
DLT observed at Cycle 1, in the first 3 patients: 
DLT observed in the whole cohort: 
DLT in 0/3 → escalate to the next dose level 
- 
DLT in 1/3 → add 3 more patients at the same level  
• 
1 DLT/6 patients → escalate to the next level 
• 
2 DLTs/6 patients → define MAD  
DLT in 2/3 → no additional patients  
Defines MAD 
DLT = dose limiting toxicity; MAD = maximum administered dose; implementation of prophylactic/curative therapies when appropriate 
In addition, 18F-FES-PET scan results should be available for all DLT-evaluable patients in Part A 
and depending on results at DL1 and 2, intermediate dose levels could be explored. The following 
rules regarding 18F-FES-PET scan findings and dose levels to be tested will apply: 
• If all patients treated at DL1 have 100% of inhibition of the target as shown on  
18F-FES-PET scan, DL(-1) will be explored.  
• If all patients treated at DL1 have >70% inhibition of the target as shown on 18F-FES-PET 
scan results, DL1bis will be explored.  
• If at least one patient at DL1 has inhibition of the target as shown on 18F-FES-PET scan 
results, between 30% and 70%, dose escalation will continue as planned and DL2 will be 
explored. 
• If at least one patient at DL1 has ≤30% inhibition of the target as shown on 18F-FES-PET 
scan results, DL2bis will be explored. 
• If all patients treated at DL2 have >85% inhibition of the target as shown on 18F-FES-PET 
scan results, DL2bis will be explored.  
• If at least one patient at DL2 has ≤85% inhibition of the target as shown on 18F-FES-PET 
scan results, dose escalation will continue as planned and DL3 will be explored. 
From the 2 dose levels DL1bis and DL2bis, the next dose levels (DL2 and DL3 etc. respectively) 
should not be skipped. 
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Considering the exploratory context of 18F-FES-PET scan, this strategy can be revised and 
adapted depending on the results. 
At subsequent dose levels (≥DL3), other intermediate dose levels may be tested based on safety, 
18F-FES-PET scan results (if all patients have >90% of inhibition of the target) and PK 
parameters, upon recommendation from the Study Committee. 
In Arms #1, #2, #3, #4, and #5, (Parts A, C, F, H and J) the second and third patients of a given 
dose level can only be enrolled when the first patient has received a minimum of 1 week of study 
treatment without DLT. The enrollment at the next dose level may not proceed before at least 
3 patients treated at the current dose level have been followed for the duration of at least the 
first cycle (ie, 28 days) and are evaluable for DLT assessment. 
In Arms #3, #4, and #5 (Parts F, H and J), it is planned to enroll approximately up to 12 evaluable 
patients (depending on the study part): 3 initial patients at the established amcenestrant dose of 
200 mg in combination with alpelisib, everolimus or abemaciclib and upon the DLT assessment, 
3 additional patients may be enrolled at the same dose level (Section 6.2.1). When Cycle 1 of 
other 3 treated patients is completed, and all patients are evaluable for DLT, the Study Committee 
will review safety and PK data in order to confirm recommended doses (RD) dose expansion.   
6.3 
MAXIMUM ADMINISTERED DOSE/MAXIMUM TOLERATED DOSE  
As a rule, the dose escalation will stop when the MAD is reached, MAD being defined as the dose 
at which ≥33% (4 patients out of up to 12) of evaluable patients have experienced a DLT at 
Cycle 1. 
In Arm #1 Part A, the MTD is defined as the highest dose level at which no more than 1 patient of 
a maximum of 6 patients experiences a DLT. Usually, the MTD is one dose level below the 
MAD, or the highest dose tested if the MAD is not reached. 
The RD for the expansion cohort will be primarily based on safety data. However, especially if 
the MTD cannot be determined in the absence of DLTs at the MAD in Part A, PK after repeated 
administration, PD and target engagement results (level of ER occupancy measured by 
18F-FES-PET imaging) as well as any other relevant information could support the determination 
of the RD to expand the study to Part B. The RD should potentially be at least 2 dose levels above 
the dose level showing >90% of inhibition of the target on 18F-FES-PET scan at this dose level, 
unless there are DLTs at this dose, in which case the RD could be any dose where >90% 
inhibition was reached. 
In Arm #2, #4, and #5 (Part C, H, and J), the MTD is 1 dose level below the MAD or the highest 
dose tested if MAD is not reached. 
Although the dose escalation process is guided by the safety evaluation during Cycle 1 treatment, 
cumulative and irreversible toxicities observed after subsequent administrations will also be 
considered for the dose escalation and dose selection decisions (ie, smaller increases in dose, 
expansion of a given dose level, intermediate dose level), upon agreement between the participant 
institutions and the Sponsor. Therefore, MAD/MTD will be defined/decided by the Study 
Committee, considering overall safety profile at all cycles. 
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6.4 
RETREATMENT OF PATIENTS  
The patient must have recovered to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) Grade ≤1 or to their baseline status before institution of the 
next cycle at the same dose level. In those cases of clear clinical benefit, a patient can continue the 
study treatment until disease progression, unacceptable toxicity, or patient’s decision. 
In case of DLT, study treatment may continue upon resolution of DLT or recovery to Grade ≤1 or 
to their baseline status. 
6.5 
DOSE DELAYS/MODIFICATIONS  
If a dose of any study drug is vomited or omitted the patient should not take the dose later or 
2 doses at the next planned dose and this information has to be recorded in the diary. 
Intra-patient dose escalation or re-escalation of any study drug is not allowed. 
Amcenestrant should be taken continuously in all study parts and dose omission is allowed only in 
case of severe toxicity and the reason should be documented in the electronic case report form 
(eCRF).  
In all study parts, if amcenestrant treatment is omitted for 2 consecutive weeks without resolution 
of the toxicity to Grade ≤1, the patient will be permanently discontinued from the study treatment 
unless a clear benefit is observed and this will be discussed on a case by case basis with the 
Sponsor. If the study treatment can be resumed within 2 weeks, dose decrease to the lower 
planned or intermediate dose level will be allowed depending on the type of toxicity. 
There should be no amcenestrant dose reduction or omission for Grade 1 toxicities. 
Grade 2: In the event of Grade 2 toxicities that are possibly related to amcenestrant, investigators 
should use their discretion in deciding whether to continue treatment. Patients experiencing 
Grade 2 non-hematologic AEs that are not easily managed or corrected and are not tolerable to the 
patient, or AEs that are not acceptable in the Investigator’s judgment, should have study treatment 
omission until the AE resolves to Grade ≤1 or baseline. 
Grade ≥3: In the event of Grade ≥3 toxicities (or DLTs), further treatment should be omitted until 
the toxicity is resolved to Grade 1 or baseline. If amcenestrant is permanently discontinued, study 
treatment will be stopped, ie, palbociclib, alpelisib, everolimus, and abemaciclib in the 
combination cohorts will also be discontinued. 
For combination study drugs, the recommended dose modifications for palbociclib, alpelisib, 
everolimus and abemaciclib in case of adverse reactions are listed in Table 8, Table 10 and 
Table 11.  
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Table 8 - Dose levels for palbociclib and alpelisib dose reduction  
 
Palbociclib Dose 
Alpelisib Dose 
Recommended/starting dose 
125 mg/day 
300 mg/day 
First dose reduction 
100 mg/day 
250 mg/day 
Second dose reduction 
75 mg/daya 
200 mg/daya 
a If further dose reduction below 75 mg/day (palbociclib) or 200 mg/day (alpelisib) is required, palbociclib/alpelisib respectively, will be 
permanently discontinued 
Table 9 - Dose levels for everolimus and abemaciclib dose reduction  
 
Everolimus Dose 
Abemaciclib Dose 
Starting dose 
5 mg/day or 
10 mg/day 
100 mg/twice daily or 
150 mg/twice daily 
Dose reduction* 
5 mg/every other daya or  
5 mg/every daya 
50 mg/twice dailyb or 
100 mg/twice dailyb 
a If further dose reduction below 5 mg/every day is needed, dose can be reduced to 5 mg/every other day; if additional dose reduction is 
needed (ie, below 5 mg/every other day), everolimus will be permanently discontinued. 
b If further dose reduction of abemaciclib (below 50 mg twice a day) is needed, they will be permanently discontinued. 
6.5.1 Arm #2 Parts C and D  
Table 10 - Dose modification and management: hematologic toxicities  
CTCAE Grade 
Dose modifications  
Grade 1 or 2  
No dose adjustment is required.  
Grade 3  
Day 1 of cycle: continue amcenestrant at the same dose, omit palboclib dosing, repeat complete 
blood count monitoring within 1 week (or as per Investigators’ judgement). When recovered to 
Grade ≤2, restart palbociclib at the same dose. 
Days 8 and 15 of first 2 cycles: continue amcenestrant at the same dose, 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 subsequent cycles and maintain amcenestrant at the same dose.   
Grade 3 and 4 
neutropeniaa with fever 
≥38.5ºC and/or infection or 
Grade 4b 
Day 1 of a cycle: continue amcenestrant at the same dose, omit palboclib dosing, repeat 
complete blood count monitoring within 1 week (or as per Investigators’ judgement). When 
recovered to Grade ≤2, restart palbociclib at the next lower dose. Restart could be either within 
the current cycle if recovery occurs before D21 of the cycle (and administration is up to D21 of 
the cycle) or at D1 of the next planned cycle. 
Within a cycle: continue amcenestrant at the same dose, omit palboclib dosing if applicable (ie, 
within D1 to D21 period of a given cycle), repeat complete blood count monitoring within 1 week 
(or as per Investigators’ judgement). When recovered to Grade ≤2, restart palbociclib at the 
same dose. Restart could be either within the current cycle if recovery occurs before Day 21 of 
the cycle (and administration is up to D21 of the cycle) or at D1 of the next planned cycle 
Note: Table applies to all hematologic abnormalities except lymphopenia (unless associated with clinical events, eg, opportunistic infections).  
a Absolute neutrophil count (ANC): Grade 1: ANC <LLN -1500/mm3; Grade 2: ANC 1000 -<1500/mm3; Grade 3: ANC 500 -<1000/mm3; 
b Grade 4: ANC 500/mm3 
Grading according to CTCAE 4.03.  
CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.  
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Table 11 - Dose modification and management: non-hematologic toxicities  
CTCAE grade 
Dose modifications  
Grade 1 or 2  
Continue amcenestrant and palbociclib as planned. No dose adjustment is required.  
Grade ≥3 nonhematologic toxicity 
attributed to palbociclib (if persisting 
despite optimal medical treatment)  
At any time: continue amcenestrant at the same dose, omit palboclib dosing, repeat 
complete blood count monitoring within 1 week. When recovered to Grade ≤2, restart 
palbociclib at the next lower dose. 
Palbociclib should always be taken for 3 weeks regardless of the cycle. 
CTCAE = Common Terminology Criteria for Adverse Events 
In study Parts C or D, patients should be monitored for any new or worsening of respiratory 
symptoms and be advised to report such symptoms promptly. If patients 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. 
If patients are diagnosed with ILD/Pneumonitis, palbociclib should be prematurely or 
permanently discontinued (Table 12).  
Table 12 - Dose modification and management - ILD/Pneumonitis  
CTCAE Gradea 
Dose Modifications  
Grade 1 (asymptomatic or 
suspected pneumonitis) or Grade 2 
(symptomatic new or worsening 
respiratory symptoms) 
At any time: continue amcenestrant at the same dose and omit palbociclib if applicable 
(ie, within D1 to D21 period of a given cycle); evaluate the patient until pneumonitis is 
diagnosed when palbociclib must be prematurely permanently discontinued.   
Grade 3 & 4 attributed to palbociclib 
Any day of a cycle: continue amcenestrant at the same dose and permanently 
discontinue palbociclib  
a Grading according to CTCAE 4.03.  
CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.  
6.5.2 Arm #3 Dose modification in Parts F and G  
For severe hypersensitivity, which is manifested by, but not limited to symptoms such as dyspnea, 
flushing, rash, fever, or tachycardia, alpelisib should be discontinued permanently. An appropriate 
treatment should be promptly initiated.                                                                                                            
If a patient requires a dose omission of amcenestrant >14 days from the intended day of the next 
scheduled dose, the patient should be discontinued from the study treatment. 
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Table 13 - Dose modification for alpelisib  
CTCAE Gradea  
Dose Modifications  
Severe cutaneous reactions (SJS, TEN, EM, DRESS)b, c  
Grade 3 and 4 
Permanently discontinue both, amcenestrant and alpelisib treatments. 
Rashd 
 
Grade 1 (<10% body surface area 
(BSA) with active skin toxicitye ) and   
Grade 2 (10-30% BSA with active 
skin toxicitye) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is requiredf. 
Grade 3 (>30% BSA with active skin 
toxicitye) 
Omit both, amcenestrant and alpelisib until symptoms recover to Grade ≤1; if 
symptoms recover to Grade ≤1, resume amcenestrant at the same dose level and 
alpelisib either at the same dose level for the first occurrence of rash, or at the next 
lower dose level in case of second occurrencef. 
Grade 4 (any % BSA associated with 
extensive superinfection, with IV 
antibiotics indicated: life-threatening 
consequences) 
Permanently discontinue both amcenestrant and alpelisib treatments. Consult a 
dermatologist. Treatment may follow guidelines for Grade 3 with the exception of 
restart of alpelisibf. Additional measures may be taken as per local treatment guidance. 
Hyperglycemiag 
Grade 1  
(FPG >ULN-160 mg/dL or  
>ULN-8.9 mmol/L 
For patients with baseline values 
between >ULN – 140 mg/dL  
(ULN – 7.7 mmol/L) this applies only 
for values >140 mg/dL (7.7 mmol/L) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required.  
Initiate or intensify oral anti-diabetic treatmenth, and remind patient on lifestyle 
changesi. 
 
 
Grade 2  
(FPG>160-250 mg/dL or  
>8.9-13.9 mmol/L) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Remind patient on lifestyle changesi. 
Initiate or intensify oral anti-diabetic treatmenth, j, k. 
Repeat FPG within 24 hours, then twice a week until FPG resolves to ≤ Grade 1, and 
as clinically indicated. 
If FPG does not decreased to ≤160 mg/dL or 8.9 mmol/L within 21 days under 
appropriate anti-diabetic treatment, reduce alpelisib dose by 1 dose level, continue 
amcenestrant at the same dose and follow FPG value specific recommendations: 
continue with anti-diabetic treatment and check FPG levels at least weekly for 8 weeks, 
then continue checking at least every 2 weeks; alert treating physician if FPG >250 
mg/dL. 
Grade 3  
(FPG>250-500 mg/dL  
or >13.9-27.8 mmol/L) 
Continue amcenestrant at the same dose level and omit alpelisib until symptoms 
recover to Grade ≤1. Repeat FPG within 24 hours, then twice a week until FPG 
resolves to ≤ Grade 1, and as clinically indicated. 
Initiate or intensify oral anti-diabetic treatmenth, j and consider additional anti-diabetic 
medications (insulin) for 1-2 days until hyperglycemia improves.  
Administer intravenous hydration and consider appropriate treatment (eg, intervention 
for electrolyte/ketoacidosis/hyperosmolar disturbances). 
If FPG decreased to ≤160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate 
anti-diabetic treatment, resume alpelisib at 1 lower dose level. A second and third oral 
hypoglycemic agent may be initiated concomitantly, if needed, in consultation with a 
diabetologist. Check FPG at least weekly for 8 weeks and then continue checking at 
least every 2 weeks; alert treating physician if FPG >250 mg/dL. 
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CTCAE Gradea  
Dose Modifications  
 
If FPG does not decrease to ≤160 mg/dL or 8.9 mmol/L within 3 to 5 days while off of 
alpelisib and under appropriate anti-diabetic treatment (eg, with metformin), 
consultation with expertise in the treatment of hyperglycemia is recommended and do 
not resume alpelisib. 
If FPG does not decrease to ≤160 mg/dL or 8.9 mmol/L within 21 days following 
appropriate anti-diabetic treatment in cooperation with diabetologist and exclusion of 
confounding factors eg, urinary tract infection, prematurely discontinue alpelisib 
treatment and continue amcenestrant at the same dose. 
Grade 4  
(FPG >500 mg/dL or ≥27.8 mmol/L) 
Continue amcenestrant at the same dose level and omit alpelisib until symptoms 
recover Grade ≤1. Re-check FPG within 24 hours and as clinically indicated. 
Initiate or intensify appropriate anti-diabetic treatmenth; administer intravenous 
hydration and consider appropriate treatment (eg, intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances), re-check FPG within 24 hours. 
If FPG decreases to ≤500 mg/dL or 27.8 mmol/L, follow FPG value specific 
recommendations for Grade 3.  
If FPG is confirmed at >500 mg/dL or 27.8 mmol/L, prematurely discontinue alpelisib 
treatment. 
ILD/Pneumonitisl 
Grade 1 (asymptomatic or suspected 
pneumonitis) or Grade 2 
(symptomatic new or worsening 
respiratory symptoms) 
Continue amcenestrant at the same dose and omit alpelisib; after ruling out infectious 
etiology and upon making a diagnosis of pneumonitis, prematurely discontinue alpelisib 
and promptly initiate appropriate treatment and supportive measures. If Pneumonitis is 
not diagnosed, restart alpelisib at the next lower dose when symptoms recover to the 
baseline level 
Grade 3 or 4 
Continue amcenestrant at the same dose and prematurely discontinue alpelisib 
treatment. 
Diarrhea (frequent and watery bowel movements) 
Grade 1  
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Initiate appropriate medical therapy and monitor as clinically indicated. 
Grade 2  
Continue amcenestrant at the same dose and omit alpelisib dose until symptoms 
recover to Grade ≤1, then resume alpelisib at the same dose level.  
In case of the second episode, omit alpelisib dose until resolved to ≤ Grade 1, then 
decrease one dose level. 
Initiate appropriate medical therapy and monitor as clinically indicated.   
Grade 3 
 
 
  
Grade 4  
Omit both, amcenestrant and alpelisib until symptoms recover to Grade ≤1; if 
symptoms recover to Grade ≤1, resume amcenestrant at the same dose and alpelisib 
at the next lower dose level. Initiate appropriate medical therapy and monitor as 
clinically indicatedm.   
Permanently discontinue both, alpelisib and amcenestrant treatment. 
Manage according to local standard of care medical management as clinically 
indicatedm.  
Isolated Total Bilirubin Elevation  
Grade 1 (>ULN - 1.5 x ULN) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Initiate appropriate medical therapy and monitor as clinically indicated. 
Grade 2 (>1.5 - 3.0 x ULN) 
Omit both, amcenestrant and alpelisib doses until recovery to Grade ≤1 and resume 
both study drugs  at the same dose if resolved in ≤14 days, or resume amcenestrant at 
the same dose and alpelisib at the next lower dose level if resolved in >14 days. 
Grade 3 (>3.0 - 10.0 x ULN) 
Omit both, amcenestrant and alpelisib dose until recovery to Grade ≤1, then resume 
amcenestrant at the same dose and alpelisib at the next lower dose level. 
Grade 4 (>10.0 x ULN) 
Permanently discontinue both, amcenestrant and alpelisib treatment. 
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CTCAE Gradea  
Dose Modifications  
Isolated ALT or AST Elevation 
Grade 1 (>ULN - 3.0 x ULN) & 
Grade 2 (>3.0 - 5.0 x ULN) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Initiate appropriate medical therapy and monitor as clinically indicated. 
Grade 3 (>5.0 - 20.0 x ULN) 
Omit both, amcenestrant and alpelisib until recovery to Grade ≤1. Repeat LFTs within 
2-3 days. If ALT or AST levels do not recover, monitor LFTs weekly (or more 
frequently, if clinically indicated) until recovery to Grade ≤1 or baseline. On recovery, 
restart amcenestrant at the same dose and alpelisib at the next lower dose. 
In case of the first recurrence of the same Grade 3 event, administer amcenestrant at 
the same dose and alpelisib at the next lower dose if restart is possible. If further dose 
reduction below 200 mg/day is needed, prematurely discontinue alpelisib. 
In case of the second recurrence of the same Grade 3 event, permanently discontinue 
both, amcenestrant and alpelisib. 
Grade 4 (>20.0 x ULN) 
Permanently discontinue both, amcenestrant and alpelisib treatment. 
Asymptomatic Amylase and/or Lipase Elevation 
Grade 1 (>ULN - 1.5 x ULN) & 
Grade 2 (>1.5 - 2.0 x ULN) 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Grade ≥3 (>2.0 x ULN) 
Omit both, amcenestrant and alpelisib dose until resolved to Grade ≤1 or baseline; if 
resolved in ≤14 days, resume both study drugs at the same dose. If resolved in >14 
days, resume amcenestrant at the same dose and alpelisib at the next lower dose level  
Note: In cases of isolated amylase elevations only, alpelisib dosing may be maintained 
provided amylase fractionation demonstrates that pancreatic amylase is ≤ Grade 1. 
Monitor total amylase and continue to assess fractionated amylaseo 
Other toxicitiesn, p, q 
 
Grade 1 and 2 
Continue amcenestrant and alpelisib as planned. No dose adjustment is required. 
Initiate appropriate medical therapy and monitor as clinically indicated. 
Grade 3 attributed to alpelisib 
Continue amcenestrant at the same dose and omit alpelisib dose until symptoms 
recover to Grade ≤1, then resume alpelisib at the next lower dose level. Initiate 
appropriate medical therapy and monitor as clinically indicated.   
Grade 4 attributed to alpelisib 
Permanently discontinue both, alpelisib and amcenestrant treatmentsn 
a Grading according to CTCAE 4.03 (CTCAE = Common Terminology Criteria for Adverse Events) 
b Severe Cutaneous Reactions (SCR): Stevens-Johnson Syndrome [SJS], Erythema Multiforme [EM], Toxic epidermal necrolysis [TEN], and 
Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]. If signs or symptoms of (non) confirmed/diagnosed Severe Cutaneous 
Reactions are present, omit alpelisib and amcenestrant until symptoms recover to Grade ≤1; if symptoms recover to Grade ≤1, resume 
amcenestrant at the same dose level and permanently discontinue alpelisib. Consultation with dermatologist is mandated for SCR, DRESS 
and all serious cutaneous reactions that fulfil serious criteria for AE reporting. 
c For all grades of severe cutaneous reaction, consider consultation with dermatologist.  
d Please refer to Section 8.6 (Concomitant Medications) for premedication and treatment recommendations. 
e “Active” skin toxicities:  If there are no new lesions or new areas of involvement developing, and if lesion appearance is changing color from 
red to pale or light brown, it is likely the skin toxicity has begun to fade and is not to be considered “active” any longer. A topical corticosteroid 
treatment can be reduced in these areas. The appearance of skin toxicity may fade slowly, over 10 days or more but not requiring ongoing 
therapy.  
f 
Initiate (Grade 1 & 3) / intensify (Grade 2) topical corticosteroids 3-4 x daily (preferred compounds to use are triamcinolone or betamethasone 
for up to 28 days, as long as skin toxicity is active). If active rash is not resolved within 28 days of appropriate treatment, add low dose 
systemic corticosteroid (20-40 mg/d), such as prednisone 10 mg 3x daily. For patients with symptoms like burning and/or pruritus add a non-
sedating antihistamine such as cetirizine once daily during daytime and a sedating antihistamine such as diphenhydramine once daily at 
night. If Grades 2 & 3 improve to ≤ Grade 1 within 10 days systemic corticosteroid may be discontinued. For Grade 3, antihistamine regimen 
should be continued for a minimum of 28 days after re-challenge with alpelisib. If rash/skin toxicity still active in up to 10% BSA (ie, Grade 1) 
after more than 14 days, continue oral corticosteroid for at least 48 hours upon re-challenge with alpelisib; if rash and/or pruritus do not 
reoccur within 48 hours after re-challenge with alpelisib, systemic corticosteroid may be discontinued. 
g FPG/Blood Glucose/Grade levels reflect hyperglycemia grading according to CTCAE v.4.03.  
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h Initiate applicable anti-diabetic medications: 1) Metformin 500 mg orally once daily with dinner.  If no gastrointestinal (GI) intolerance after 
several days, increase to 500 mg bid, with breakfast and dinner. If tolerated, increase to 500 mg with breakfast, and 1000 mg with dinner. If 
tolerated, 1000 mg bid with breakfast and dinner. If not tolerated, reduce to prior tolerated dose. Titrate metformin to the MTD over a period 
of 3 weeks. 2) Alternatively, consider starting an SGLT2 inhibitor (Sodium-Glucose Transport Protein 2) alone or in combination with 
metformin, especially in patients at risk for developing severe hyperglycemia. Starting dose and titration should be in accordance with the 
local prescribing information and consistent with local practice. 3) Monitor FPG levels as clinically indicated and at least twice weekly for 
8 weeks, then continue checking at least weekly until FPG is within baseline values.  
i 
Alpelisib, like other PI3K inhibitors, may affect glucose homeostasis which could result in increases of plasma glucose and insulin resistance. 
Alpelisib induced hyperglycemia is generally manageable with adequate anti-diabetic treatment. Alpelisib induced hyperglycemia typically 
occurs within the first month of treatment. Patients with pre-diabetes (ie, FPG 100 – 125 mg/dL; 5.6 - 6.9 mmol/L) and those with an 
established diagnosis of type 2 diabetes mellitus should be monitored carefully, thus allowing an early detection and prompt management of 
increases in fasting glucose while on alpelisib. The treatment includes early administration of metformin or a sodium-glucose cotransporter 2 
(SGLT2) inhibitor (alone or in combination with metformin). Fasting plasma glucose testing may be performed at site for rapid availability for 
safety evaluation and management guidance. Special attention should be paid to the risk of hypoglycemia in patients interrupting alpelisib 
treatment and concomitantly receiving insulin and/or sulfonylureas. Due to the short half-life of alpelisib, all glucose lowering medications 
should be discontinued when alpelisib is stopped. If metformin or an anti-diabetic agent is interrupted for radiologic assessments or another 
reason, then alternative hyperglycemia management should be considered for those days to ensure optimal hyperglycemia management. 
Consultation with a diabetologist or healthcare provider experienced in the management of hyperglycemia is highly recommended for better 
assessment and management of alpelisib-induced hyperglycemia.  
j 
 Exclude confounding factors like eg, urinary tract infection and consider consultation with a healthcare expert experienced in hyperglycemia 
management or a diabetologist. 
k Additional oral anti-diabetic agents may be initiated, if needed (especially in patients at risk for developing severe hyperglycemia). If FPG 
levels are still rising on MTD of metformin or persistently >160 mg/dL (>8.9 mmol/L), add an SGLT2 inhibitor if available, eg, empagliflozin up 
to 25 mg (max. dose) with metformin or alternatively start an SGLT2 inhibitor alone or in combination with metformin.  
l 
Symptoms of pneumonitis may include hypoxia, cough, dyspnea, interstitial infiltrates on radiologic exams (high resolution CT scan) broncho-
alveolar lavage (BAL); biopsy should be considered if clinically appropriate. Infectious causes of interstitial lung disease should be ruled out 
(infectious, neoplastic, and other causes by means of appropriate investigation). The institutional practice for management of pneumonitis 
should be followed which generally includes treatment with high dose corticosteroids (antibiotic therapy should be administered concurrently 
if infectious causes are suspected). Consultation with a pulmonologist is highly recommended for any pneumonitis case during the study 
treatment. 
m  Electrolyte monitoring, administration of antiemetics and antidiarrheal medicinal products and/or fluid replacement and electrolyte 
supplements 
n Omit both, amcenestrant and alpelisib dose for vomiting Grade ≥3 or nausea Grade 3 only if the vomiting or nausea cannot be controlled with 
optimal antiemetic (as per local practice). 
o Grade 3 must be tested weekly (or more frequently if clinically indicated) until ≤ Grade 1 (or baseline). After dosing is resumed, continue to 
test weekly for one additional cycle. If no reoccurrence of ≥ Grade 2 event, continue monitoring every cycle. An exception to these follow-up 
guidelines will be made for cases of isolated amylase elevations in which amylase fractionation demonstrates that pancreatic amylase is 
≤Grade 1. In such cases, total amylase and fractionated amylase should be monitored weekly (or more frequently if clinically indicated) for 
4 weeks. If pancreatic amylase remains ≤ Grade 1, subsequent monitoring must be performed at least every 4 weeks (or more frequently if 
clinically indicated). 
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly (or more frequently if clinically indicated) until 
the event resolves to ≤ Grade 1 or stabilization occurs (no CTCAE v4.03 grade change over 4 weeks). If amylase and/or lipase elevations 
are accompanied by new or progressive unexplained abdominal symptoms such as severe pain or vomiting, omission of study treatment, 
then perform diagnostic procedures (eg, abdominal CT scan or ultrasound) to exclude pancreatic pathology. 
p Toxicities excluding Hyperglycemia, Severe Cutaneous Reaction, Rash, Pneumonitis, and Diarrhea  
q  For Grade 2 and 3 pancreatitis, omit amcenestrant and alpelisib dose until recovery to Grade ≤1; resume amcenestrant at the same dose 
and alpelisib at the next lower dose level.  Only one dose reduction is permitted. If toxicity reoccurs, permanently discontinue alpelisib 
treatment. 
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6.5.3 Arm #4 Dose modification in Parts H and I  
Table 14 - Everolimus dose modification and management: hematologic toxicities  
Adverse events 
CTCAE Grade 
Dose modification 
Thrombocytopenia 
Grade 1 
 
Grade 2 
Continue amcenestrant and everolimus as planned. No dose adjustment is 
required. 
Day 1 of the cycle: continue amcenestrant at the same dose, omit everolimus 
until improvement to Grade 0 or 1. Resume everolimus at the same dose. 
Grade 3 or 4 
Days 8 and 15 of the first 2 cycles: continue amcenestrant at the same dose, 
omit everolimus until improvement to Grade 0 or1. Resume everolimus at 50% 
of previous dose; change to every other day dosing if the reduced dose is lower 
than the lowest available strength. 
Neutropeniaa 
Grade 1 or 2 
 
Grade 3 
Continue amcenestrant and everolimus as planned. No dose adjustment is 
required. 
Day 1 of the cycle: continue amcenestrant at the same dose, omit everolimus 
until improvement to Grade 0, 1, or 2. Resume everolimus at the same dose. 
Grade 4 
Continue amcenestrant and permanently discontinue everolimus. 
Febrile neutropeniab 
Grade 3 
Day 1 of the cycle: continue amcenestrant at the same dose, omit everolimus 
until improvement to Grade 0, 1, or 2, and no fever. Resume everolimus at 50% 
of previous dose; change to every other day dosing if the reduced dose is lower 
than the lowest available strength. 
Grade 4 
Continue amcenestrant and permanently discontinue everolimus. 
a Absolute neutrophil count (ANC): Grade 1: ANC <LLN -1500/mm3; Grade 2: ANC 1000 -<1500/mm3; Grade 3: ANC 500 -<1000/mm3 
b Grade 4: ANC 500/mm3 
Grading according to CTCAE 4.03.  
CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal. 
Table 15 - Everolimus Dose modification and management: non-hematologic toxicities  
Adverse events 
CTCAE Grade 
Dose modification 
Non-infectious pneumonitis 
Grade 1  
 
Grade 2 
Continue amcenestrant and everolimus as planned. No dose 
adjustment is required. 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0 or 1. Resume everolimus at 
50% of previous dose; change to every other day dosing if the 
reduced dose is lower than the lowest available strength. 
Permanently discontinue if toxicity does not resolve or improve to 
Grade 1 within 4 weeks. 
Grade 3  
 
 
 
 
Grade 4 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0 or 1. Resume everolimus at 
50% of previous dose; change to every other day dosing if the 
reduced dose is lower than the lowest available strength. 
If toxicity reoccurs at Grade 3, permanently discontinue. 
Continue amcenestrant and permanently discontinue everolimus. 
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Adverse events 
CTCAE Grade 
Dose modification 
Stomatitisa 
Grade 1 
 
Grade 2 
Continue amcenestrant and everolimus as planned. No dose 
adjustment is required. 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0 or 1. Resume everolimus at 
same dose. Resume at 50% of previous dose; change to every other 
day dosing if the reduced dose is lower than the lowest available 
strength. 
Grade 3 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0 or 1. Resume everolimus at 
50% of previous dose; change to every other day dosing if the 
reduced dose is lower than the lowest available strength. 
Grade 4 
Continue amcenestrant and permanently discontinue everolimus. 
Metabolic events 
(eg, hyperglycemia, dyslipidemia) 
Grade 1 or 2 
 
Grade 3 
Continue amcenestrant and everolimus as planned. No dose 
adjustment is required. 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0, 1, or 2. Resume 
everolimus at 50% of previous dose; change to every other day 
dosing if the reduced dose is lower than the lowest available 
strength. 
Grade 4 
Continue amcenestrant and permanently discontinue everolimus. 
Other non-hematologic toxicities 
Grade 1 
 
Grade 2 
. 
Continue amcenestrant and everolimus as planned. No dose 
adjustment is required. 
At any time: continue amcenestrant at the same dose, omit 
everolimus until improvement to Grade 0 or 1. Resume everolimus at 
50% of previous dose; change to every other day dosing if the 
reduced dose is lower than the lowest available strength. If toxicity 
becomes intolerable, omit everolimus until improvement to Grade 0 
or 1. Resume it at the same dose. 
Grade 3  
 
At any time: omit amcenestrant and everolimus until improvement to 
Grade 0 or 1. Once recovered, resume amcenestrant at the same 
dose and consider resuming everolimus at 50% of previous dose; 
change to every other day dosing if the reduced dose is lower than 
the lowest available strength. If recurs at Grade 3, permanently 
discontinue.  
Grade 4 
Continue amcenestrant if considered not related, otherwise 
permanently discontinue both amcenestrant and everolimus. 
a As a preventative measure of Stomatitis, initiate dexamethasone alcohol-free mouthwash when starting treatment as per label 
instructions. 
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6.5.4 Arm #5 Dose modification in Parts J and K  
Discontinue abemaciclib if patients are unable to tolerate 50 mg twice daily. 
Table 16 - Abemaciclib Dose modification and management: hematologic toxicitiesa  
CTCAE Grade 
Dose modification 
Grade 1 or 2 
Continue amcenestrant and abemaciclib as planned. No dose modification is required. 
Grade 3 
At any time: continue amcenestrant at the same dose, omit abemaciclib until toxicity 
resolves to ≤Grade 2. Dose reduction is not required. 
Grade 3 recurrent or Grade 4 
At any time: continue amcenestrant at the same dose, omit abemaciclib until toxicity 
resolves to ≤Grade 2. Resume at the next lower dose 
a If blood cell growth factors are required, omit abemaciclib dose for at least 48 hours after the last dose of blood cell growth factor and until 
toxicity resolves to ≤Grade 2. Resume at the next lower dose unless already performed for the toxicity that led to the use of the growth 
factor. Growth factor use as per current treatment guidelines. 
Table 17 - Abemaciclib Dose modification and management: non-hematologic toxicities  
CTCAE Grade 
Dose modification 
Diarrheaa 
 
Grade 1 
Continue amcenestrant and abemaciclib as planned. No dose modification is required. 
Grade 2 
At any time: continue amcenestrant at the same dose. If toxicity does not resolve within 
24 hours to ≤ Grade 1, omit abemaciclib dose until resolution. No dose reduction is 
required. 
Grade 2 that persists or recurs after 
resuming the same dose despite 
maximal supportive measures 
At any time: continue amcenestrant at the same dose, omit abemaciclib dose until 
toxicity resolves to ≤ Grade 1. Resume at the next lower dose. 
Grade 3  
 
 
At any time: omit both, amcenestrant and abemaciclib until toxicity resolves to ≤Grade 
1. Once resolved, resume amcenestrant at the same dose and abemaciclib at the next 
lower dose.  
Grade 4 or hospitalization  
Continue amcenestrant if considered not related, otherwise permanently discontinue 
both amcenestrant and abemaciclib. 
Hepatoxicityb 
 
Grade 1 (>ULN-3.0 x ULN) Grade 2 
(>3.0-5.0 x ULN), WITHOUT 
increase in total bilirubin above  
2 x ULN 
Continue amcenestrant and abemaciclib as planned. No dose modification is required. 
Persistent or Recurrent Grade 2, or 
Grade 3 (>5.020.0 x ULN), 
WITHOUT increase in total bilirubin 
above 2 x ULN 
At any time: continue amcenestrant at the same dose, omit abemaciclib dose until 
toxicity resolves to baseline or Grade 1. Resume at the next lower dose. 
Elevation in AST and/or  
ALT >3 x ULN WITH total bilirubin 
>2 x ULN, in the absence of 
cholestasis  
At any time: omit amcenestrant until recovery to Grade ≤1. Repeat LFTs within 2-3 
days. If ALT or AST levels do not recover, monitor LFTs weekly (or more frequently, if 
clinically indicated) until recovery to Grade ≤1 or baseline. On recovery, restart 
amcenestrant at the same dose and permanently discontinue abemaciclib. 
Grade 4 (>20.0 x ULN) 
Permanently discontinue both, amcenestrant and abemaciclib treatment. 
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CTCAE Grade 
Dose modification 
Other toxicities  
 
Grade 1 or 2 
Continue amcenestrant and abemaciclib as planned. No dose modification is required. 
Persistent or recurrent Grade 2 
toxicity that does not resolve with 
maximal supportive measures 
within 7 days to baseline or Grade 1 
At any time: continue amcenestrant at the same dose, omit abemaciclib dose until 
toxicity resolves to baseline or ≤Grade 1. Resume at the next lower dose. 
Grade 3  
At any time: continue omit both, amcenestrant at the same dose, omit and abemaciclib 
dose until toxicity resolves to ≤Grade 1. Once resolved, Resume both amcenestrant at 
the same dose and abemaciclib at the next lower dose.  
Grade 4 
Continue amcenestrant if considered not related, otherwise permanently discontinue 
both amcenestrant and abemaciclib. 
a At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.  
b Monitor ALT, AST, and serum bilirubin prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 
months, and as clinically indicated. 
Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. With concomitant use of 
other strong CYP3A inhibitors, in patients with recommended starting doses of 200 mg twice 
daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who 
have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the 
abemaciclib dose to 50 mg twice daily. If a patient taking abemaciclib discontinues a strong 
CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose 
that was used before starting the strong inhibitor. 
6.6 
EXPANSION COHORTS TO CONFIRM THE MAXIMUM TOLERATED DOSE  
In Arm #1 Part B, approximately 78 patients will be treated at the RD of amcenestrant in QD to 
collect safety, PK, and efficacy data. If results in Part A with the BID dosing regimen are of 
interest in terms of safety, PK, exposure, preliminary efficacy and any other relevant information 
such as data from patients treated with the QD regimen, and warrants further investigation, 
approximately 56 patients could be treated at the RD of amcenestrant after analysis of the  
Part A- BID to collect safety, PK and efficacy data. In Part D, approximately 28 patients will be 
treated at the selected RD(s). In Part G, approximately 34 patients are planned to be treated. In 
Part I, approximately 12 patients are planned to be treated. In Part K, approximately 20 patients 
are planned to be treated.  
In cases where the risk of additional or unexpected toxicities is judged as being too high by the 
Study Committee, the continuation of the study at a dose below the predefined MTD, with or 
without corrective measures, could be decided by the Study Committee. 
The occurrence of cumulative toxicity, and toxicities meeting the DLT criteria observed after 
Cycle 1, if any, will also be assessed. 
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6.7 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS  
This is a first-in-human study, therefore, so far, only limited clinical data are available for 
amcenestrant (eg, phototoxicity, gastrointestinal toxicities, changes in liver function, changes in 
hematological values). Based on preclinical data and clinical data from SERD, 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. Each treatment intervention should be clearly documented. 
Investigators are encouraged to exercise their medical judgment in the management of the 
toxicities (see Section 6.5). 
Because toxicity studies indicate a potential risk for phototoxicity, the patient should avoid direct 
exposure to natural or artificial sunlight during study treatment. It is recommended to advise to 
wear protective clothing, sunscreen, and lip balm with a high sun protection factor (eg, ≥30) to 
cover UVA and UVB when outdoors during treatment and until 5 days after treatment is 
completed. 
6.8 
DURATION OF STUDY PARTICIPATION  
6.8.1 Duration of study participation for each patient  
The patient will be considered in the study from informed consent signature until 30 days after 
last study treatment administration. 
For Arm #3 parts F and G only: Testing for PIK3CA status for patients who have never 
undergone PIK3CA testing will be done locally prior to the main consenting process and 
beginning of the screening procedures. Only patients with a documented PIK3CA mutation, 
whether previously detected/confirmed by an old test or established by the PIK3CA testing in the 
pre-screening period, will be allowed to consent for study participation.  
The duration of the study for an individual patient will include a period to assess eligibility 
(screening or baseline period) of up to 4 weeks (28 days), a treatment period of at least 1 cycle 
(28 days) of study treatment, and an EOT visit within 22 to 30 days following the last 
administration of study treatment (or until the patient receives another anticancer therapy, 
whichever is earlier). If further therapy is initiated before D22 after last IMP, investigator should 
contact the patient (either by phone call or visit) to obtain final collection of safety information 
(stabilization or recovery of TEAEs) within 30 days after last IMP intake or in follow up visit in 
case of ongoing SAE or related AE. Study treatment may continue until precluded by 
unacceptable toxicity, disease progression, or upon patient’s request.  
In Arms #2, #3, #4, and #5 (Parts C/D, F/G, H/I and J/K), if palbociclib/alpelisib/everolimus/ 
abemaciclib are prematurely permanently discontinued, amcenestrant can be continued until an 
EOT criterion is met. The end of study treatment visit in this case will be 30 days after the date of 
last amcenestrant administration.  
Patients who discontinue the study treatment prior to documentation of PD will be followed every 
2 months until disease progression or initiation of further anticancer therapy, or cut-off date 
(COD), whichever comes first. 
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The expected enrollment period is approximately 60 months. 
There will be several cut-off-dates (COD) for this study: 
1. In each study Arm dose escalation (Parts A, C, F, H and J), the first COD will be done at 
the end of the first cycle of the last patient treated in the given cohort study part in order to 
have at least the first cycle evaluable for all patients for determination of the MTD and for 
the RD.  
2. The COD primary analysis, for each study Arm (ie, combined dose escalation and dose 
expansion), will be at each study Arm's LPI+12 months, except for Arm#2 which COD 
will be at LPI+20 months. 
3. The final study COD will be performed when the last study Arm will have reached its 
COD. 
4. In addition, for all study parts, informal analyses could be performed on as needed basis 
during the study to support further development of the compound and regulatory 
requirements. 
After each study Arm COD, ongoing patients will receive study therapy until disease progression, 
occurrence of unacceptable toxicities, whichever is earlier, and they will only be followed for 
study treatment administration, SAEs, study treatment-related AEs and AEs leading to study 
treatment discontinuation. 
6.8.2 Determination of end of clinical trial (all patients)  
The end of study will occur when all patients have had the opportunity to complete the EOT visit 
30 days after the last study treatment administration. 
6.9 
INTERIM ANALYSIS  
Interim analyses of ORR (by RECIST v1.1) will be performed in Arm #1 Part B when 45 patients 
in the QD regimen. The procedure and criteria for undertaking an interim analysis are described in 
Section 13.10. 
6.10 
STUDY COMMITTEES  
A Study Committee will be set up, which will include the investigators (or designee) who 
participate in dose escalation study parts, Sponsor representatives, and, if needed, the ad-hoc 
experts (eg, FES PET expert). The Study Committee will meet regularly during the dose 
escalation/safety run-in study parts. The Study Committee will review available clinical data 
including PK and safety data (especially DLTs) as well as FES-PET scan results for Arm#1 Part 
A of each individual patient who are treated in dose escalation study parts in order to adjust the 
number of enrolled patients at each dose level, as well as to decide the further dose escalation, if 
appropriate. Decisions regarding final dose selection will be made at the Dose Selection meeting 
which will be documented and shared with sites. 
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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
Refer to Section 13.1. 
7.2 
INCLUSION CRITERIA  
I 01. Patients must be postmenopausal women as defined by one of the following: 
a) Women >60 years 
b) Women ≤60 years: 
- 
With spontaneous cessation of menses >12 months prior to registration in the absence 
of chemotherapy, tamoxifen and toremifene. 
- 
Or with cessation of menses of duration ≤12 months or secondary to hysterectomy 
AND have follicle stimulating hormone (FSH) level in the postmenopausal range 
according to institutional standards (or >34.4 IU/L if institutional range is not 
available) prior to registration. 
- 
Or who have received hormonal replacement therapy but have discontinued this 
treatment AND have FSH level in the postmenopausal range according to institutional 
standards (or >34.4 IU/L if institutional range is not available) prior to registration. 
- 
Or with status post bilateral surgical oophorectomy. 
- 
Or are premenopausal women on a gonadotropin-releasing hormone (GnRH) analog 
for at least 6 months (to be continued during study treatment) and have a negative 
pregnancy test prior to initiation of study treatment and at monthly intervals during 
treatment. In Arm #3 (Parts F and G) only, patients and their male partners must agree 
to use non-oral contraception if sexually active during the treatment and 1 week after 
the last dose. In Arm #4 (Parts H and I) only, patients and their male partners must 
agree to use non-oral contraception if sexually active during the treatment and 8 weeks 
after the last dose. In Arm #5 (Parts J and K) only, patients and their male partners 
must agree to use non-oral contraception if sexually active during the treatment and 
3 weeks after the last dose. 
I 02. Patients with histological or cytological proven diagnosis of the breast adenocarcinoma 
with evidence of either locally advanced not amenable to radiation therapy or surgery in 
a curative intent, inoperable and/or metastatic disease. 
I 03. Either the primary tumor or any metastatic site must be positive for ER (>1% tumor cell 
staining by IHC). 
I 04. Either the primary tumor or any metastatic site must be HER2 non over expressing by IHC 
(0, 1+), or in situ hybridization-negative based on single-probe average HER2 copy 
number <4.0 signals/cell or dual-probe HER2/centromeric probe for chromosome 
17 (CEP17) ratio <2 with an average HER2 copy number <4.0 signals/cell as per 
American Society of Clinical Oncology guidelines (39). 
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I 05. Prior chemotherapy for advanced disease is allowed. Prior chemotherapy for advanced 
disease is not allowed in dose expansion of Arms #3, #4, and #5 (Part G, I and K 
respectively).  (NOTE: Antibody drug conjugates (ADCs) are considered as chemotherapy 
in this study): 
- 
Patients must have received no more than 3 prior chemotherapeutic regimens in Arm 
#1 Part A (dose escalation, monotherapy). 
- 
Patients must have received no more than 1 prior chemotherapeutic regimen in Arms 
#1, #2, #3, #4, and #5 (Parts B, C, D, F, H and J respectively).   
I 06. Patients must have received at least 6 months of prior endocrine therapy for advanced 
breast cancer.  
Dose Escalation study parts: 
Arm #3: - Part F: up to 2 prior lines of either single endocrine therapy and/or endocrine-
based therapy 
Arm #4: - Part H: up to 2 prior lines of either single endocrine therapy and/or endocrine-
based therapy (exemestane not allowed) 
Arm #5: - Part J: up to 2 prior lines of either single endocrine therapy and/or endocrine-
based therapy 
Dose Expansion study parts: 
Arm #2: - Part D: no more than 2 prior lines of advanced endocrine therapy for advanced 
disease are allowed 
Arm #3: - Part G: patients must have received and progressed on the combination of 
Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first line (1L) treatment for advanced 
disease 
Arm#4: - Part I: patients must have received and progressed on the combination of 
Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first line (1L) treatment for advanced 
disease (exemestane not allowed) 
Arm#5: - Part K: up to 1 prior line of a single endocrine therapy for advanced disease 
Note: Additional patients who relapsed while on previous adjuvant endocrine therapy that 
was initiated ≥24 months ago, OR relapsed <12 months after completion of adjuvant 
endocrine therapy are also allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J 
and K) 
I 07. Age ≥18 years old. 
I 08. Measurable lesion by RECIST v1.1 (Appendix C). 
I 09. The patient is capable of understanding the informed consent and complying with the 
protocol and has signed the informed consent form (ICF) before any study (specific 
screening procedures or evaluations). 
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Arm #1 Part A only 
I 10. Patient entering Part A must agree to undergo: 
a) Two 18F-FES-PET/CT imaging scans, one at baseline and one between Day 11 and 
Day 15 of study treatment intake and 
b) Two FDG PET/CT for Part A BID, one at baseline and one between Day 11 and 
Day 15 of study treatment intake before 18F-FES-PET (patients whose baseline FDG 
PET/CT results are negative for tumors will not be eligible), and 
c) Paired biopsies (before treatment and during treatment): For baseline samples, 
formalin-fixed and paraffin-embedded (FFPE) archived biopsy samples (within past 
3 months prior initiation of study treatment) can be used, but preferably fresh biopsies 
from primary tumor or recurrence or metastasis, will be collected. It is recommended 
that the end of Cycle 2 biopsy (on-treatment biopsy) be collected at the same location 
as the baseline biopsy, whenever the tumor is accessible and during treatment. 
Arm #1 Part B  
I 11. For patients who consent to paired biopsies (before treatment and during treatment): for 
baseline samples, formalin-fixed and paraffin-embedded (FFPE) archived biopsy sample 
can be used (within past 3 months prior initiation of study treatment) but preferably fresh 
biopsies from primary tumor or recurrence or metastasis will be collected. It is 
recommended that the end of Cycle 2 biopsy (on-treatment biopsy) be collected at the 
same location as the baseline biopsy, whenever the tumor is accessible during treatment. 
Arm #3 Part F and G only 
I 12. In Parts F and G, patient must have confirmed/detected PIK3CA mutation determined in 
tumor tissue and/or plasma cfDNA. The PIK3CA testing should be performed locally. 
7.3 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the 
following exclusion criteria:  
7.3.1 Exclusion criteria related to study methodology  
E 01. Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (see Appendix A). 
E 02. Significant concomitant illness, including psychiatric condition that, in the opinion of the 
Investigator or Sponsor, would adversely affect the patient’s participation in the study. 
E 03. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of 
oral IMPs. Patients unable to swallow normally and to take capsules. Predictable poor 
compliance to oral treatment. 
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E 04. Any malignancy related to human immunodeficiency virus (HIV); or unresolved viral 
hepatitis. 
E 05. Patients with a life expectancy less than 3 months. 
E 06. Patients not suitable for participation, whatever the reason, as judged by the Investigator, 
including medical or clinical conditions, or patients potentially at risk of noncompliance to 
the study procedures (ie, unwillingness and inability to comply with scheduled visits, drug 
administration plan, laboratory tests, other study procedures, and study restrictions). 
E 07. Major surgery within 4 weeks prior to first study treatment administration. 
E 08. Patient with any other cancer. Adequately treated basal cell or squamous cell skin cancer 
or in situ cervical cancer or any other cancer from which the patient has been disease free 
for >3 years are allowed. 
E 09. Patient is the Investigator or any sub investigator, research assistant, pharmacist, study 
coordinator, or other staff or relative thereof directly involved in the conduct of the 
protocol. 
Arm #1 Part A only 
E 10. Patient with liver metastases only. 
7.3.2 Exclusion criteria related to the disease  
E 11. Patients with known brain metastases, leptomeningeal carcinomatosis or/and spinal cord 
compression. Patients with brain metastases that have been previously totally resected or 
irradiated are eligible provided no progression or relapse is observed within 4 weeks of the 
treatment. 
E 12. Treatment with anticancer agents (including investigational drugs) less than 2 weeks 
before first study treatment administration (less than 4 weeks if the anticancer agents were 
antibodies). 
E 13. Prior treatment with another selective ER down-regulator (SERD): 
- 
Dose Escalation study parts (Parts F, H and J): SERDs are not allowed except for 
fulvestrant which will need a washout of at least 6 weeks prior to the first study drug 
administration. 
- 
Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD 
including fulvestrant will not be allowed. 
E 14. Inadequate hematological function including neutrophils <1.5 x 109/L; platelet count 
<100 x 109/L. 
E 15. Prothrombin time: International normalized ratio >1.5 times the upper limit of normal 
(ULN) or out of therapeutic range if receiving anticoagulation that would affect the 
PT/INR. 
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E 16. Inadequate renal function with serum creatinine ≥1.5 x ULN or, if between 1.0 and 
1.5 x ULN with eGFR <60 mL/min/1.73m2 as estimated using the abbreviated 
Modification of Diet in Renal Disease formula (Appendix I).  
E 17. Liver function: aspartate aminotransferase (AST) >3 x ULN, or alanine aminotransferase 
(ALT) >3 x ULN. Alkaline phosphatase (ALP) up to Grade 2 (2.5 to 5 x ULN), gamma 
glutamyl transferase (GGT) up to Grade 2 (2.5 to 5 x ULN) would be acceptable only if 
related to the presence of bone and/or liver metastases as judged by the Investigator. Total 
bilirubin >1.5 x ULN. 
E 18. Patients with Gilbert disease. 
E 19. Non-resolution of any prior treatment related toxicity to < Grade 2, except for alopecia 
according to the NCI-CTCAE v4.03 (Appendix B). 
E 20. E20 criterion removed per amendment 10 
E 21. a. All study parts, treatment with strong CYP3A inducers within 2 weeks before first study 
treatment administration or 5 elimination half-lives whichever is longest (see Appendix E).  
b. In Arm#1 (Part A and B) and Arm#5 (Part J and K, full PK sampling only), in patients 
with 4β-OH cholesterol assessment: Treatment with strong and moderate CYP3A 
inhibitors within 2 weeks before first study treatment administration or 5 elimination half-
lives whichever is longest (see Appendix E). 
E 22. More than 1 prior advanced CDK4/6 inhibitor-based therapy in Arm #1, Arm #2 (Part C), 
Arm #3 (Parts F and G), and Arm#4 (Part H). 
E 23. Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment 
administration or 5 elimination half-lives whichever is longest in Arm#2 (Parts C and D) 
only according to palbociclib labeling (Appendix E). 
E 24. Medical conditions requiring concomitant administration of medications with a narrow 
therapeutic window metabolized by CYP3A and for which a dose reduction cannot be 
considered in Arm #2 (Part C and D) according to palbociclib labeling (see Appendix F).  
E 25. Arm #2 (Part D) and Arm #5 (Parts J, and K) only: Prior therapy with targeted therapy for 
advanced disease (ie, CDK 4/6 inhibitors, PI3K inhibitors, mTOR inhibitors and AKT 
inhibitor) 
Part E only (Canceled as per Amendment 08) 
E 26. E26 criterion removed per Amendment 08. 
E 27. E27 criterion removed per Amendment 08. 
E 28. E28 criterion removed per Amendment 08. 
E 29. E29 criterion removed per Amendment 08. 
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E 30. Arm #2, #3, #4 and #5 (Part C, D, F, G, H, I, J, and K) only: Patients with concurrent or 
history of pneumonitis  
E 31. Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment therapies that target 
the PI3K axis (mTOR inhibitors, AKT inhibitors, PI3K inhibitors)  
E 32. Arm #3 and #4 (Parts F, G, H, and I) only: Patients with Diabetes Mellitus type-I or 
uncontrolled Diabetes Mellitus type-II: ie, fasting plasma glucose ≥140 mg/dL 
(7.7 mmol/L) or HbA1C >6.2% 
E 33. Arm #3 and #4 (Parts F, G, H, and I) only: History of severe cutaneous reactions 
(eg, SJS, EM, TEN, DRESS) 
E 34. Arm #3 (Parts F and G) only: Ongoing osteonecrosis of jaw 
New Exclusion Criteria added in Amendment 09  
E 35. Arm #4 (Parts H and I) only: Any active, untreated, or uncontrolled infection (eg, viral, 
bacterial, fungal etc.) 
E 36. Arm #4 (Parts H and I) only: Patients with active and uncontrolled Stomatitis, 
Angioedema due to the concomitant treatment with ACE Inhibitors, impaired wounds 
E 37. Arm #4 (Parts H and I) only: Uncontrolled Hypercholesterolemia, Hypertriglyceridemia 
and Hyperglycemia in non-diabetic patients 
E 38. Arm #4 (Parts H and I) only: Treatment with strong or moderate CYP3A4 inhibitors, 
strong CYP3A4 inducers and/or P-gp inhibitors within 2 weeks before the first study 
treatment administration or 5 elimination half-lives, whichever is the longest 
E 39. Arm #5 (Parts J and K) only: History or current (controlled/not controlled) Venous 
Thromboembolism (ie, Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), 
Cerebral Venous Sinus Thrombosis (CVST) 
Patients who have been withdrawn from the study treatment cannot be reincluded in the study. 
Their inclusion and treatment numbers must not be reused. 
New Exclusion Criterion added in Amendment 10 
E 40. Treatment with drugs that are sensitive substrate of OATP1B1/1B3 (eg, asunaprevir, 
atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, 
pravastatin, repaglinide, rosuvastatin and simvastatin acid) within 5 days before first study 
treatment administration or 5 half-lives whichever is longer, and for which this drug cannot 
be replaced. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
If needed, the study drug may be supplied from the PI/site/Sponsor to the participants via a 
Sponsor-approved courier/delivery company as a Direct to Patient (DTP) delivery option if it is 
allowed by local regulations and agreed upon by the participant. Refer to Appendix J.  
8.1.1 Pharmaceutical form   
8.1.1.1 Amcenestrant   
Amcenestrant will be supplied as 100 mg capsules.  
8.1.1.2 Palbociclib  
Palbociclib (Ibrance®) will be supplied as 75 mg, 100 mg and 125 mg capsules. 
8.1.1.3 Alpelisib  
Alpelisib will be supplied as 50 mg and 200 mg tablets.  
8.1.1.4 Everolimus  
Everolimus will be supplied as 5 mg tablets 
8.1.1.5 Abemaciclib  
Abemaciclib will be supplied as 50 mg, 100 mg, and 150 mg 
8.1.2 Dose of drug per administration  
During the first cycle visits (all parts) and first visit of the second cycle, study treatment should be 
administered at the clinics with dosing appropriately timed relative to blood sampling for the PK 
determination (Section 1.4). For all other days of treatment, patients can take their medication at 
home. For subsequent cycles, only Day 1 therapy may be given at the clinic. Therefore, in each 
case, patients will receive an adequate supply of capsules to take their medication at home for the 
remaining treatment duration.  
8.1.2.1 Amcenestrant   
The starting QD dose of amcenestrant is described in Section 6.2. Amcenestrant will be dispensed 
every 2 weeks.  
In Arm #1 Part A, amcenestrant will be administered at assigned dose levels once daily, within a 
28-day cycle. During Cycle 1, one dose will be taken on Day 1 in the fasted state, no dose on 
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Day 2 and the repeated once daily administration will start from Day 3. On Day 3 only, the dose 
will be taken in the fed state for a food effect evaluation, and then all subsequent administration 
will be taken in the fasted state, and at approximately the same time each day (±3 hours). If the 
patient vomits or misses a dose, an additional dose should not be taken and date and time of 
vomiting has to be recorded in the diary. The next prescribed dose should be taken at the usual 
time. 
In the fasting condition, patients will receive the drug after an overnight fast of at least 10 hours 
with no food intake up to at least 3 hours following dosing on Days 1 and 22. On the other days, 
patients will receive the drug after an overnight fast of at least 10 hours with no food intake up to 
at least 2 hours following dosing (Table 18). The assigned daily dose is to be taken once in the 
morning, at approximately the same time each day (±3 hours), throughout treatment cycles. The 
appropriate daily dose of amcenestrant capsules 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). Patients should be instructed not to bite or chew on the capsules. In case 
of breakage of the capsules in the oral cavity, an additional glass of water should be taken 
immediately. 
Table 18 - Fasting condition  
  
Fasted condition 
 
Before drug adm 
After drug adm 
Example 
Day 1 and Day 22 
Cycle 1 (PK sampling) 
Overnight fasting for 
approximately 10 hours 
 
At least 3 hours 
 
amcenestrant intake at 6:00 AM and breakfast at 
9:00 AM 
Or amcenestrant intake at 8:30 AM with no 
breakfast before intake, lunch from 11:30 AM  
Other days 
Overnight fasting for 
approximately 10 hours 
At least 2 hours 
amcenestrant intake at 6:00 AM or 7:00 AM and 
breakfast at 8:00 AM or 9:00 AM, respectively 
Fed conditions on Day 3 (Table 19) require a standard meal (total calorie of 400 to 500 kcal with 
approximately 27% fat content) ingested within 30 minutes after an overnight fast of at least 
10 hours and amcenestrant administered within 5 minutes after meal completion. An example of 
the composition of this meal is described in Appendix D. 
Table 19 - Fed condition  
 
Fed condition 
 
Before drug adm 
After drug adm 
Example 
Day 3, Cycle 1 
5 minutes 
N/A 
Breakfast within 30 min from 8:00 AM to 8:30 AM 
with amcenestrant intake between 8:30 AM and 
8:35 AM 
In the fasting or fed condition, water will only be allowed ad libitum after 2 hours postdosing. 
Pilot food effect: A pilot food effect will be assessed by PK sampling after drug administration 
with a standard meal on Day 3 of Cycle 1 in all patients treated in Part A. All other dosing in Part 
A will be taken in fasted condition. If results from the QD dosing regimen allow conclusions to be 
drawn, this will not be implemented for other dosing regimens (eg, BID) that are explored. 
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For the BID dosing regimen, amcenestrant will be administered once on Day 1, then BID from 
Day 3 onwards (no dose on Day 2) independent of food conditions at approximately the same 
time each day 12 hours apart (±1 hour).  
Based on preliminary PK results observed in patients treated in Part A with the QD dosing 
regimen, less restrictive definitions were fixed for fasting and fed conditions for patients enrolled 
subsequently: 
• Fasting condition: amcenestrant intake at least after 2 hours of fasting and at least 2 hours 
before next meal. 
• Fed condition: amcenestrant intake less than 2 hours before or after meal. 
In Arm #1 Part B, amcenestrant will be administered from Day 1 (without omission on Day 2) at 
the RD fixed in Part A, within a 28-day cycle, either in fasting or fed condition (as defined after 
preliminary PK results) even the days of PK sampling, and at approximately the same time each 
day (±3 hours). A BID regimen may also be explored if found to be needed.  
In Arm #2, Parts C and D, amcenestrant will be administered from Day 1 at assigned dose levels, 
within a 28-day cycle in fed condition, and at approximately the same time each day (±3 hours). 
Amcenestrant and palbociclib must be taken together, 5 minutes apart. Both IMPs must be taken 
with food, regardless of the order of intake.  
In Arm #3, Parts F and G, amcenestrant will be taken in fed condition QD from Cycle 1 Day 4 at 
200 mg (or other amcenestrant doses) together with alpelisib 300 mg QD (or lower alpelisib 
doses) at approximately the same time each day (±3 hours) within a 28-day cycle. The days of PK 
assessment (ie, on C1D3 and C1D22) the drugs will have to be taken with a standard breakfast 
(see appendix D). 
In Arm #4, Parts H and I, amcenestrant will be taken in fed condition QD from Cycle 1 Day 1 at 
200 mg (or other amcenestrant doses) together with everolimus 10 mg QD (or lower doses) at 
approximately the same time each day (±3 hours) within a 28-day cycle. The days of PK 
assessment (ie, on C1D1 and C1D22) the drugs will have to be taken together with a standard 
breakfast. 
In Arm #5, Parts J and K, amcenestrant will be taken in fed condition QD from Cycle 1 Day 1 at 
200 mg (or other amcenestrant doses) together with abemaciclib 150 mg BID (or lower doses) at 
approximately the same time each day (±3 hours) within a 28-day cycle. In the morning, 
amcenestrant and abemaciclib will be administered together. The days of PK assessment (ie, on 
C1D1 and C1D22) the drugs will have to be taken together with a standard breakfast. 
If a dose is vomited or omitted, the patient should not take the dose later or 2 doses at the next 
planned dose, and this information has to be recorded in the diary. Amcenestrant dose omission or 
reduction could occur in case of toxicity, as well as cycle delay in Arms #2, #3, #4, and #5 
(see Section 6.5). 
Advise to avoid sun exposure and wear protective clothing, sunscreen, and lip balm with high sun 
protection (eg, SPF ≥30) when outdoors during study treatment and 5 days after the last 
amcenestrant administration. 
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8.1.2.2 Palbociclib  
The RD of palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days 
followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be 
taken with food at approximately the same time each day. Palbociclib will be dispensed every 
4 weeks. 
If the patient vomits or misses a dose, an additional dose should not be taken and this information 
has to be recorded in the diary. The next prescribed dose should be taken at the usual time. 
Palbociclib capsules should be swallowed whole (not chewed, crushed or opened prior to 
swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact. 
The capsules should be swallowed with a full glass of water (not fruit juices). 
8.1.2.3 Alpelisib  
The RD of alpelisib is 300 mg. In both study parts, Part F (refer to the dose per pharmacy manual) 
and in Part G (refer to the dose per pharmacy manual) tablets should be taken orally once daily 
with food at approximately the same time each day. 
Alpelisib will be dispensed every 4 weeks. 
If the patient vomits or misses a dose, an additional dose should not be taken, and this information 
has to be recorded in the diary. The next prescribed dose should be taken at the usual time. 
Alpelisib tablets should be swallowed whole (not chewed or crushed).  
The tablets should be swallowed with a full glass of water (not fruit juices). 
8.1.2.4 Everolimus  
Everolimus will be taken orally as 2x5 mg (10 mg) once a day at approximately the same time 
each day with food. Dose omission or reduction could occur in case of toxicity (see Section 6.5).  
Everolimus will be dispensed every 4 weeks. 
If the patient vomits or misses a dose, an additional dose should not be taken, and this information 
has to be recorded in the diary. The next prescribed dose should be taken at the usual time. 
Everolimus tablets should be swallowed whole (not chewed or crushed).  
The tablets should be swallowed with a full glass of water (not fruit juices). 
8.1.2.5 Abemaciclib  
Abemaciclib will be taken orally, twice a day, with food as 2x100 mg and 2x150 mg, at 
approximately same times each day. Dose omission or reduction could occur in case of toxicity 
(see Section 6.5).  
Abemaciclib will be dispensed every 4 weeks. 
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If the patient vomits or misses a dose, an additional dose should not be taken, and this information 
has to be recorded in the diary. The next prescribed dose should be taken at the usual time. 
Abemaciclib tablets should be swallowed whole (not chewed or crushed).  
The tablets should be swallowed with a full glass of water (not fruit juices). 
8.2 
NON INVESTIGATIONAL MEDICINAL PRODUCT  
Not applicable. 
8.3 
PACKAGING AND LABELING  
Packaging is described in the pharmacy manual. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.4 
STORAGE CONDITIONS AND SHELF LIFE  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the study 
treatment in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures.  
Control of study treatment storage conditions, especially control of temperature (eg, refrigerated 
storage) and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor in the Pharmacy Manual. 
8.5 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
study treatment will be responsible for ensuring that the study treatment used in the clinical trial is 
securely maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. 
The study treatment will be dispensed in accordance with the Investigator's prescription and it is 
the Investigator's responsibility to ensure that an accurate record of study treatment issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of a study treatment provided by the sponsor 
(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. 
A potential defect in the quality of study treatment 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 study treatment and eliminate 
potential hazards. 
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Under no circumstances will the Investigator supply study treatment to a third party, allows the 
study treatment to be used other than as directed by this clinical trial protocol, or dispose of study 
treatment in any other manner. 
8.5.1 Treatment accountability and compliance  
Administration of the study treatment will be supervised by the Investigator or sub-investigator. 
The person responsible for drug dispensing is required to maintain adequate records of the study 
treatment. These records (eg, drug movement form) include the date the study treatment is 
received from the Sponsor, dispensed for patient, and destroyed or returned to the Sponsor. The 
packaging batch number (PR Nr) on the pack must be recorded on the drug accountability form. 
Compliance to amcenestrant and palbociclib/alpelisib/everolimus/abemaciclib intake will be 
assessed using a patient diary and study medical record (study source documentation), which will 
document the return of any unused drug for compliance assessment. On Day 1, while the patient is 
in the clinic, the study staff will demonstrate to the patient how to record information on 
amcenestrant (for Arms #1 to #5), palbociclib (for Arm #2) and alpelisib (for Arm #3), everolimus 
(Arm #4) and abemaciclib (Arm #5) intake in the log. Patients will note every day the hours of 
study drug(s) intake or omission, if any. If vomiting occurs, they need to report the time and 
frequency in the same diary. In case of an early vomiting event, the administered dose of 
amcenestrant and/or palbociclib/alpelisib/everolimus/abemaciclib should not be repeated, and 
this information should be recorded in the diary. Patients will have to complete this log every day, 
for each dose and will return it to the study personnel at each visit, so that CRF can be completed 
on an ongoing basis. 
Patients will be requested to return all unused amcenestrant and 
palbociclib/alpelisib/everolimus/abemaciclib to the study site at the end of the treatment period for 
each cycle for a full compliance assessment. Clinic staff will record the study medication dosing 
information including the actual clock time of each dose as per data recorded on the diary by the 
patient, or on the patient chart when the study medication is taken at site. 
8.5.2 Return and/or destruction of treatments  
Partially used and unused study treatment 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 study treatment unless Sanofi provides written 
authorization. 
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8.6 
CONCOMITANT TREATMENT  
A concomitant medication is any treatment received by the patient concomitantly to any study 
treatment(s). 
All treatments being taken by the patient from the date of the consent form to the first study 
treatment administration, at any time during the treatment period and up to 30 days after the last 
dose are regarded as prior and concomitant treatments respectively and will be reported on the 
appropriate screen of the eCRF. 
Premenopausal patients treated with a GnRH analog for at least 6 months to be eligible before 
study treatment initiation must continue this GnRH analog during study treatment period and 
should be reported as concomitant medications. 
Special caution should be taken with regards to the following therapies for the amcenestrant 
treatment arm: 
• Drugs that are sensitive substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 
(See Appendix F) or UGTs since it may result in loss of efficacy of these agents. 
In addition, for Part F and G (related to alpelisib administration): 
• Avoid the use of BCRP inhibitors (See Appendix G). If unable to use alternative drugs, 
closely monitor for increased adverse reactions. 
• Closely monitor when alpelisib is co-administered with CYP2C9 substrates (eg, warfarin 
or any other coumarin-derivative anticoagulant) (See Appendix G) which may decrease 
these drugs’ plasma concentration and may reduce their activity. Alternatively, therapeutic 
anticoagulation may be accomplished by using low- molecular weight heparin or Direct 
Thrombin Inhibitors (DTIs) and Factor Xa inhibitors. 
• Avoid the use of P-gp, BCRP and OAT3 substrates. In vitro evaluations indicated that 
alpelisib (and/or its metabolite BZG791) has a potential to inhibit the activities of OAT3 
drug transporters and intestinal BCRP and P-gp. Alpelisib should be used with caution in 
combination with sensitive substrates of these transporters which exhibit a narrow 
therapeutic index because alpelisib may increase the systemic exposure of these substrates.  
• Avoid the use of Herbal medications such as Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone, yohimbe, saw palmetto, black cohosh and ginseng due to their 
potential for complex interactions. Since cannabinoids have been shown to inhibit BCRP 
in vitro, medical cannabis should be used with caution. Patients should be closely 
monitored for increased adverse reactions (as the relevance of this interaction in vivo is 
currently unknown). In case of unexpected toxicities, patients should stop using all herbal 
medications. Use of all such medications (including frequency of administration) should 
be documented. 
• Closely monitor when alpelisib is co-administered with bisphosphonates due to an 
increased risk of development of osteonecrosis of jaw (ONJ). For prevention and clinical 
management of ONJ, prescribing information of bisphosphonates should be followed. 
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• Avoid concomitant use of alpelisib with the following medicinal products: antipsychotics 
(haloperidol, ziprasidone, quetiapine, thioridazine, olanzapine, and risperidone), 
antiarrhythmics (amiodarone, sotalol, dofetilide, procainamide, quinidine, and flecainide), 
antibiotics (macrolides and fluoroquinolones), antidepressants (amitriptyline, imipramine, 
and citalopram), and other medicines such as, methadone, sumatriptan, ondansetron, 
cisapride. If the listed medicinal products still need to be used, caution and additional EKG 
monitoring should be used as clinically indicated. 
• A maculopapular rash, pruritus, and dry skin, as the most frequent reported skin adverse 
events (only a minority present acneiform rash), can occur. The onset is typically within 
the first 2 months of treatment initiation and is reversible with adequate co-medication and 
alpelisib omission if needed. Consultation with a dermatologist is highly recommended for 
better assessment and management of alpelisib-induced skin toxicity at any grade and 
mandated if severe cutaneous reaction occurs. Workup for skin toxicity events may 
include a complete blood count with differential, and a full chemistry panel. 
Antihistamines administered prior to rash onset may decrease incidence and severity of 
rash; therefore, at the Investigator’s discretion, non-sedating antihistamines (eg, cetirizine 
(Zyrtec©), loratadine (Claritin)) may be used as prophylactic treatment starting at Cycle 1 
Day 1 to reduce severity of rash in all patients and especially for patients with a history of 
atopy such as allergic rhinitis, asthma, atopic dermatitis, or drug allergies. Recommended 
therapies for skin toxicity events of all grades and as clinically indicated include:  
- 
Consultation with a dermatologist should always be considered. 
- 
Mid to high potency topical steroids: triamcinolone 0.01% or fluocinonide 
0.05% twice daily for at least 28 days. Recommend spray, lotion, or cream preparation 
for ease of application on trunk. For scalp involvement, recommend a foam or solution 
preparation. 
- 
Gamma-aminobutyric acid (GABA) Agonists: Gabapentin 300 mg every 8 hours, 
Pregabalin 50-75 mg every 8 hours (to adjust of renal impairment). Depending on 
patient’s clinical condition, be aware of potential and common side effects observed 
with GABA agonists such as: somnolence, dizziness (both drugs) and peripheral 
edema (Gabapentin) among others adverse events. 
For Grade 4 skin events or any grade of severe cutaneous reactions (including SJS, TEN, 
EM, DRESS), alpelisib treatment must be permanently discontinued without any re-
challenge. 
If dry skin is reported, it is recommended that patients with dry skin use mild and 
fragrance-free soaps and detergents. 
In addition, in Arm #4 (Part H and I) (related to everolimus administration): 
• The use of strong and moderate CYP3A4 inhibitors, including grapefruit and grapefruit 
juice (see Appendix E) and/or P-gp inhibitors is prohibited (see Appendix H) 
• The use of strong CYP3A4 inducers is prohibited  
• Avoid live vaccines and close contact with those who received live vaccines. Complete 
recommended childhood vaccinations prior to starting study treatment in order to prevent 
potential increased risk of infection or reduced immune response.  
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In addition, in Arm #5 (Part J and K) (related to abemaciclib administration): 
• Avoid the use of strong CYP3A4 inhibitors 
• Avoid the use of strong CYP3A4 inducers  
• Avoid ingesting grapefruit and grapefruit juice 
While participating in this study, patients may not receive any standard or investigational agents 
for treatment of their tumor other than the following treatments: 
• Amcenestrant alone in Arm #1 (Parts A and B), 
• Amcenestrant with palbociclib in Arm #2 (Parts C and D), 
• Amcenestrant and alpelisib in Arm #3 (Parts F and G) of the study 
• Amcenestrant with everolimus in Arm #4 (Parts H and I), and 
• Amcenestrant with abemaciclib in Arm #5 (Parts J and K) 
Any medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator, with the exception of those listed below. 
Prohibited in all treatment arms: 
• Systemic nonauthorized anticancer agents or concomitant radiotherapy (localized radiation 
therapy for pain control is permitted without any change in the study treatment). 
• Among herbal medications and food products, it is recommended to avoid consumption of 
St John’s Wort and genistein during treatment period. 
• Patients should avoid direct exposure to natural or artificial sunlight during the study 
treatment period.  
• The concomitant use of strong CYP3A4 inducers (see full list in Appendix E) since they 
may decrease amcenestrant exposure. 
• Drugs that are sensitive substrates of OATP1B1/1B3 including asunaprevir, atorvastatin, 
bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin and simvastatin acid, since amcenestrant is a potential inhibitor 
and may decrease their elimination. 
In addition, in Arm #1 Part A and B (for the 12 patients with full PK sampling) and Arm#5 Part J 
and K (for patients with full PK sampling): 
• Initiation of any treatment with known strong and moderate CYP3A inhibitors  
(Appendix E) is not allowed 2 weeks before initiation and during Cycle 1. These 
treatments would interfere with 4β-hydroxy/ total cholesterol test interpretation. 
In addition, for Arm #2 Parts C and D (from Cycle 2 if on combination with palbociclib) the 
following are also prohibited: 
• Strong CYP3A4 inhibitors (see full list in Appendix E). 
• Medications with narrow therapeutic window metabolized by CYP3A and for which 
a dose reduction cannot be considered (see full list in Appendix F). 
• Grapefruit or grapefruit juice as it may increase plasma concentrations of palbociclib and 
should be avoided. 
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Patients taking any of the above medications at the time of the screening visit will be ineligible to 
enter study until administration of the prohibited agent can be safely discontinued, and an 
appropriate period of time has elapsed (2 weeks before first study treatment administration or 
5 elimination half-lives whichever is longest). 
If a patient’s clinical status requires administration of any of the above medications during the 
study, administration of the study drug should be stopped, and the patient will be withdrawn from 
the study. The change in clinical status mandating the use of the medication in question must be 
reported as the reason for study drug discontinuation. 
8.7 
POST INVESTIGATIONAL PRODUCT  
As per discretion of the Investigator. 
In case a new anticancer therapy is administered within 30 days of last study treatment 
administration or before recovery or consolidation of any related AEs or SAEs or before 
documented disease progression at the time of study treatment discontinuation, the date of start 
and the name of the new therapy will be collected in the eCRF. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
SAFETY  
The major purpose of this Phase 1 study is to establish, based on DLTs, the MTD of amcenestrant, 
administered as monotherapy, then in combination with palbociclib, alpelisib, everolimus, and 
abemaciclib to postmenopausal women with advanced ER-positive breast cancer. Safety is thus 
the primary study endpoint and will be assessed continuously. 
The safety profile will be assessed from the findings of physical examination (preferably by the 
same physician in each center), laboratory tests and reports of AEs, etc, and will be based on 
incidence, severity (as graded by the NCI-CTCAE v.4.03), and cumulative nature of 
treatment-emergent adverse events (TEAEs) (defined as AEs that develop or worsen in grade or 
become serious during the on-treatment period). 
9.1.1 Dose-limiting toxicities  
Arms #1, #2, #3, and #4 (Part A, C, F, H and J) only: 
Potential Dose Limiting Toxicities (DLTs) are defined as the occurrence of any of the following 
treatment-emergent adverse events (TEAEs) related to the study therapy using NCI-CTCAE scale 
(version 4.03) during Cycle 1:  
• Any Grade ≥3 nonhematological toxicity, except: 
- 
Grade 3 nausea and vomiting resolving to Grade ≤1 within 48 hours, with or without 
adequate antiemetic treatment (all study arms), 
- 
Grade 3 diarrhea, if controlled with adequate antidiarrheal therapy and lasting less than 
48 hours (all study arms), 
- 
Grade 3 hyperglycemia resolving to Grade ≤1 within 48 hours, with or without 
adequate treatment (Arm #4 Part H only). 
• Any Grade ≥3 hematological toxicity in all study arms, except: 
- 
Grade 3 anemia 
- 
Grade 4 neutropenia <7 days 
- 
Grade 3 neutropenia without fever or infection* 
- 
Grade 3 thrombocytopenia without bleeding  
• Any elevated total serum bilirubin >2 x ULN in all study arms, except Part F 
• Arm#3 (Parts F) only: 
- 
Grade 3 hyperglycemia (confirmed with a repeat FPG within 24 hours) not resolving 
to Grade ≤2 within 7 days after initiation of oral antidiabetic treatment, provided 
hyperglycemia did not lead to diabetic keto-acidosis, hospitalization for intravenous 
insulin infusion, or non-ketonic coma, 
- 
Grade 2 hyperglycemia (confirmed with a repeat FPG within 24 hours) not resolving 
to Grade ≤1 within 21 consecutive days (after initiation of oral antidiabetic treatment), 
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- 
Grade 2 ALT increase in conjunction with total blood bilirubin Grade ≥2 of any 
duration in the absence of liver metastases, 
- 
Grade ≥3 ALT and/or AST increase for more than 4 consecutive days, 
- 
Grade 3 Rash and Maculopapular Rash not resolving to Grade ≤1 within 7 days, with 
or without adequate treatment (including systemic steroid use as per protocol). 
• Any toxicity related to study treatment, resulting in omission of the study treatment for 
7 days or more during Cycle 1, or in Cycle 2 delay of more than 2 weeks in Arm #2 
Parts C. 
• A TEAE that in the opinion of the Study Committee is possibly or probably study 
treatment-related and of potential clinical significance such that further dose escalation 
would expose patients to unacceptable risk. 
* G-CSF may be used to treat patients who have developed dose-limiting neutropenia, as per 
institutional guidelines (for Arm#3, alpelisib should be discontinued as per dose modification 
recommendations). 
DLTs will be considered as adverse event of special interest (AESI). As such, the Investigators 
will be required to report them to the Sponsor within 24 hours of the Investigator becoming aware 
of each event. The Investigator will attach the DLT-specific eCRF page to the transmitted 
DLT/AESI form or will complete the specific DLT form in the eCRF. 
These TEAE(s) will be considered as study treatment-related in the absence of evidence to the 
contrary and if not related to disease progression. If multiple toxicities are seen, the presence of 
DLT will be based on the most severe experienced toxicity. At the end of Cycle 1, each patient 
must be assessed by the Investigator as to whether or not the patient experienced DLT, and this 
information must be recorded on the appropriate screen of the eCRFs, and an electronic DLT 
notification (either DLT or not) will be sent to the Sponsor. 
The reported potential DLTs will be reviewed by the Study Committee in order to determine their 
relationship to the study treatment. 
9.1.2 Adverse events  
Adverse events will be collected from the signing of the study main informed consent up to 
30 days after the last study treatment administration. During the follow-up period, ongoing SAEs 
regardless of relationship to study treatment and ongoing or new study treatment related AEs will 
be followed until resolution or stabilization. Adverse events encountered before the start of study 
treatment will be summarized separately. 
Adverse events will be graded according to the NCI-CTCAE v.4.03 (Appendix B), and will be 
coded to a “Preferred Term” and associated primary “System Organ Class” using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be summarized with respect to the 
type, frequency, severity, seriousness, and relatedness. 
The study-specific and general safety criteria are developed in Section 10. 
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9.1.3 Laboratory safety variables  
Please refer to Study Procedures Section 12. 
9.1.4 Clinical examinations  
Please refer to Study Procedures Section 12. 
9.1.5 Other safety endpoints  
Please refer to Study Procedures Section 12. 
9.2 
PHARMACOKINETIC EVALUATION  
9.2.1 Sampling time and sample blood volume  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications.  
Samples missed or lost, for any reason should be recorded. Actual times of blood collection 
should be recorded in the eCRF. The days of sampling and times of drug administration should 
also be precisely recorded for the day of PK (Days 1, 3, 8, 11 to 15, 22) as well as the day before 
(Day 2 in Part A and Days 7, 21, 28) and after (Day 4 in Part A and Day 23). 
In Part A, for the 6 patients treated in the BID dosing regimen, the PK/PD Flow chart of Part A 
(Section 1.4.1.1) will be used. Some PK samples will not be collected: Day 3 PK profile (from 
P12 to P22) and Day 22-T24h sample (P35).  
The sampling times for blood collection can be found in the PK Flow Chart (Section 1.4). 
The tables below summarize the sampled blood volume per patient during all treatment arms (Part 
A, B, C, D, F, G, H, I, J and K): 
Table 20 - Blood sample volume collected per patient during study Arm #1 Part A  
 
Volume  
(mL)/sample 
Number of samples 
Volume  
(mL)/patient 
PK amcenestrant 
2 mL 
37 
74 
 
TOTAL volume 
 
74 mL 
Table 21 - Blood sample volume collected per patient during study Arm #1 Part A, BID regimen  
 
Volume  
(mL)/sample 
Number of samples 
Volume  
(mL)/patient 
PK amcenestrant 
2 mL 
25 
50 
 
TOTAL volume 
 
50 mL 
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Table 22 - Blood sample volume collected per patient during study Arm #1 Part B  
 
 
Volume 
(mL)/sample 
Number of samplesa 
Total volume 
(mL)/patient 
PK amcenestrant  
Full sampling  
2 mL 
23 
46 mL 
 
Sparse sampling 
2 mL 
13 
26 mL 
4β-hydroxycholesterol will be assayed in the same tubes as the amcenestrant for the 12 patients with full PK sampling schedule only. 
a At least 12 patients will undergo a full PK sampling schedule, remaining patients will follow a sparse sampling schedule  
Table 23 - Blood sample volume collected per patient during study Arm #2 Part C  
 
Volume  
(mL)/sample 
Number of samples 
Volume  
(mL)/patient 
PK amcenestrant and palbociclib 
2 mL 
23a 
46 
TOTAL volume 
 
46 mL 
a in case of BID dosing regimen, the number of PK samples would be 21, thus a total of 42 mL per patient 
Table 24 - Blood sample volume collected per patient during study Arm #2 Part D  
 
 
Volume 
(mL)/sample 
Number of samplesa 
Total volume 
(mL)/patient 
PK amcenestrant 
and palbociclib 
Full sampling  
2 mL 
23b 
46 
Sparse sampling 
2 mL 
13 
26 mL 
a At least 12 patients will undergo a full PK sampling schedule, remaining patients will follow a sparse sampling schedule. 
b In case of BID dosing regimen, the number of PK samples would be 21, thus a total of 42 mL per patient. 
Table 25 - Blood sample volume collected per patient during study Arm #3 (Part F and G)  
 
 
Volume 
(mL)/sample 
Number of samples 
Volume 
(mL)/patient 
PK amcenestrant 
and alpelisib 
Full samplinga 
2 mL 
21 
42 mL 
Sparse sampling 
2 mL 
10 
20 mL 
a 18 patients will undergo a full PK sampling schedule, remaining patients will follow a sparse sampling schedule. 
Table 26 - Blood sample volume collected per patient during study Arm #4 (Part H and I)  
 
Volume  
(mL)/sample 
Number of samples 
Volume  
(mL)/patient 
PK amcenestrant and everolimus 
2 mL 
19 
38 mL 
Table 27 - Blood sample volume collected per patient during study Arm #5 (Part J and K)  
 
 
Volume 
(mL)/sample 
Number of samples 
Volume 
(mL)/patient 
PK,amcenestrant, 
abemaciclib and 
its metabolites  
(M2, M18, M20) 
Full sampling 
3 mL 
20 
60 mL 
Sparse sampling 
3 mL 
10 
30 mL 
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9.2.2 Pharmacokinetic sample handling procedure  
Detailed instructions for PK sample preparation, storage, and shipping are summarized in 
Table 28, Table 29, Table 30, Table 31, Table 33, and Table 34. Further details will be provided 
to the study sites in a separate Laboratory Manual. 
Table 28 - Summary of blood sample handling procedures for amcenestrant (Arm #1 Part A)  
Blood sample volume: 
2 mL 
Anticoagulant tube type: 
Blood will be collected into tubes with K2EDTA 
Handling procedures: 
Keep blood on ice until plasma harvest (must be within 30 minutes of blood sampling time) by 
centrifugation at approx. 1500 g for approx. 10 minutes at 4°C. 
Plasma aliquot split: 
2 aliquots, 500 μL in aliquot 1 and the remaining in aliquot 2. 
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation between -60°C and -80°C). 
Plasma shipment conditions: 
Frozen in dry ice 
See lab manual for details concerning handling procedures. 
K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
Table 29 - Summary of blood sample handling procedures for amcenestrant and metabolic profiling 
(Arm #1 Part B)  
Blood sample volume: 
2 mL 
Anticoagulant tube type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood on ice until plasma harvest (must be within 30 minutes of blood sampling time) by 
centrifugation at approx. 1500 g for approx. 10 minutes at 4°C. 
Plasma aliquot split: 
3 aliquots (only 2 aliquots for Part B sparse sampling schedule), 300 µL each in aliquots 1 and 
2 (for amcenestrant) and the remaining in aliquot 3 (for metabolic profiling; only for full PK 
sampling schedule), Only 2 aliquots for Part B sparse sampling schedule with 500 μL in aliquot 
1 and the remaining in aliquot 2. 
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation between -60°C and -80°C. 
Plasma shipment conditions: 
 Frozen in dry ice. 
See lab manual for details concerning handling procedures. 
K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
Plasma will be kept for metabolic profiling (Arm #1 Part B only, ie, expansion phase of 
monotherapy). Data obtained from exploratory analysis will not be included in the clinical study 
report (CSR). 
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Table 30 - Summary of blood sample handling procedures for amcenestrant and palbociclib 
(Arm #2 [Parts C and D])  
Blood sample volume: 
2 mL 
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood on ice until plasma harvest (must be within 30 minutes of sampling time) by 
centrifugation at approx. 1500 g for approx. 10 minutes at 4°C. 
Plasma aliquot split: 
3 aliquots (only 2 aliquots for sparse sampling schedule), 300 µL each in aliquots 1 and 2 (for 
amcenestrant) and the remaining in aliquot 3 (for palbociclib; only in the full sampling schedule). 
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation between -60°C and -80°C, aliquot for palbociclib stored at -20°C. 
Plasma shipment conditions: 
Frozen in dry ice. 
See lab manual for details concerning handling procedures. K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
Table 31 - Summary of blood sample handling procedures for amcenestrant (Arm #3, #4, and #5 
[Parts F to Part K])  
Blood sample volume: 
1 mL 
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood at room temperature until plasma harvest (must be within 30 minutes of sampling 
time) by centrifugation at approx. 1500 g for approx. 10 minutes at room temperature. 
Plasma aliquot split: 
1 aliquot   
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation at -20°C or lower. 
Plasma shipment conditions: 
Frozen in dry ice. 
See lab manual for details concerning handling procedures. K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
Table 32 - Summary of blood sample handling procedures for alpelisib (Arm #3 [Parts F and G])  
Blood sample volume: 
1 mL 
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood at room temperature until plasma harvest (must be within 30 minutes of sampling 
time) by centrifugation at approx. 1500 g for approx. 10 minutes at room temperature. 
Plasma aliquot split: 
2 aliquots   
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation) at -20°C or lower. 
Plasma shipment conditions: 
Frozen in dry ice. 
See lab manual for details concerning handling procedures.  
K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
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Table 33 - Summary of blood sample handling procedures for everolimus (Arm #4 [Parts H and I])  
Blood sample volume: 
1 mL  
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Everolimus: after blood homogenization, five drops of 10 µL of liquid blood will be deposited 
into filter paper Whatman 903”’ and let dried at room temperature for at least 2 hours. 
The remaining liquid blood samples are guard samples. They must remain stored in the BA 
lab until the end of the analysis of the DBS samples. 
DBS sample: 
1 card 
DBS storage condition: 
After drying the DBS card and a desiccant will be introduced into a Ziploc bag and stored at 
room temperature. 
Liquid blood storage conditions: 
Liquid blood samples will be frozen at -60°C or lower.  
DBS shipment conditions: 
Room temperature. 
Liquid blood shipment conditions:  
Frozen in dry ice. 
See lab manual for details concerning handling procedures.  
Table 34 - Summary of blood sample handling procedures for abemaciclib and its metabolites M2, 
M18, M20 (Arm #5 [Parts J and K])  
Blood sample volume: 
2 mL 
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood on ice until plasma harvest (must be within 30 minutes of sampling time) by 
centrifugation at approx. 1500 g for approx. 10 minutes at 4°C. 
Plasma aliquot split: 
 2 aliquots, 500 µL each in aliquots. 
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation between -20°C or lower). 
Plasma shipment conditions: 
Frozen in dry ice. 
See lab manual for details concerning handling procedures. 
Table 35 - Summary of blood sample handling procedures for 4β-OH cholesterol and total 
cholesterol (Arm #5 [Parts J to Part K])  
Blood sample volume: 
1 mL 
Anticoagulant Tube Type: 
Blood will be collected into tubes with K2EDTA. 
Handling procedures: 
Keep blood at room temperature until plasma harvest (must be within 30 minutes of 
sampling time) by centrifugation at approx. 1500 g for approx. 10 minutes at room 
temperature. 
Plasma aliquot split: 
1 aliquot   
Plasma storage conditions: 
Polypropylene tubes with screw caps and frozen promptly (within 30 minutes of plasma 
preparation at -20°C or lower. 
Plasma shipment conditions: 
Frozen in dry ice. 
See lab manual for details concerning handling procedures.  
K2EDTA = di-potassium ethylene diamine tetra-acetic acid 
Incurred sample reproducibility analysis for amcenestrant, palbociclib, alpelisib, everolimus and 
abemaciclib will be performed on selected samples in order to assess the reliability of all sample 
concentration data. These analyses will be reported in addition to the final concentration data. 
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9.2.3 Bioanalytical method  
Table 36 summarizes the bioanalytical methods to be used for quantifying amcenestrant, 
palbociclib, alpelisib and 4β-hydroxy/ total cholesterol in plasma. Table 37 summarizes the 
bioanalytical methods to be used for quantifying everolimus in whole blood and abemaciclib and 
its M2, M18 and M20 metabolites in plasma. 
Table 36 - Bioanalytical method for amcenestrant, palbociclib, alpelisib, 4β-hydroxycholesterol and 
total cholesterol in plasma  
Analyte 
Amcenestrant 
Palbociclib 
4β-hydroxycholesterol 
and total cholesterol 
Alpelisib 
Matrix: 
Plasma 
Plasma 
Plasma 
Plasma 
Analytical technique: 
LC-MS/MS 
LC-MS/MS 
LC-MS/MS 
LC-MS/MS 
Lower limit of quantificationa: 
5 ng/mL 
1 ng/mL 
4 ng/mL 
5 ng/mL 
Site of bioanalysis: 
Pyxant, (SLC, US) 
Pyxant, (SLC, US) 
Pyxant, (SLC, US) 
Pyxant (SLC, US) 
a For amcenestrant, palbociclib and alpelisib, the LLOQs are given as target. 
Table 37 - Bioanalytical method for everolimus, abemaciclib and its metabolites  
Analyte 
everolimus 
Abemaciclib and its M2, M18 and 
M20 metabolites  
Matrix: 
Whole blood 
Plasma 
Analytical technique: 
LC-MS/MS 
LC-MS/MS 
Lower limit of quantificationa: 
 0.5 ng/mL 
1 ng/mL 
Site of bioanalysis: 
LabCorp, (Indi, US) 
Pyxant (SLC, US) 
a For everolimus and abemaciclib, the LLOQs are given as target. 
9.2.4 Urine sampling times and handling procedures  
Urine samples will be collected from at least 12 patients selected for the full PK design after QD 
administration at the times specified in Table 38, for analysis of the parent compound during 
Part B, ie, the expansion phase of amcenestrant monotherapy. 
Amcenestrant assay in urine will be performed using a fit-to-purpose method. 
Table 38 - Urine sampling times  
Day 
Interval 
Drug administration 
Sample ID 
Day 22 (first cycle only) 
0-24 h 
amcenestrant 
U00 
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The handling procedures for urine samples are described in Table 39. 
Table 39 - Urine handling procedure  
Urine handling procedures 
Keep at +4°C during collection interval. For each patient, at the end of the collection period, 
combine the urine fractions from that period and mix thoroughly. Record the total weight (or 
volume) of urine collected during each collection period in the CRF. 
Urine sample volume 
2 aliquots of 5 mL 
Urine storage conditions 
Keep in upright position between -60°C and -80°C 
Detailed instructions for urine sample collection, sample storage and shipping will be provided to 
the study sites in a separate laboratory manual. 
9.2.5 Pharmacokinetic parameters  
Pharmacokinetic analyses will be carried out at the Sponsor by Pharmacokinetics, Dynamics and 
Metabolism (PKDM) department. Pharmacokinetic parameters will be determined by non-
compartmental analysis using PKDMS (running Phoenix® software) for patients undergoing a 
full PK sampling scheme. Other patients may be analyzed using a population PK approach. 
The parameters will include, but may not be limited to the following: 
Table 40 - List of pharmacokinetic parameters and definitions  
Parameters 
Drug  
Matrix 
Definition/calculation 
Cmax 
amcenestrant, palbociclib, 
alpelisib, everolimus, 
abemaciclib, M2, M18 and M20 
Plasma, 
blooda 
Maximum concentration observed 
Ctrough 
 
amcenestrant 
Plasma 
Plasma concentration observed just before treatment 
administration during repeated dosing 
AUC0-12 
amcenestrant, abemaciclib, 
M2, M18 and M20 
Plasma 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method over the dosing 
interval (12 hours) 
AUC0-24 
amcenestrant, palbociclib, 
alpelisib, everolimus 
Plasma, 
blooda 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method over the dosing 
interval (24 hours) 
AUC  
amcenestrant, (Part A, Day 1 
only) 
 
Plasma 
Area under the plasma concentration versus time curve 
extrapolated to infinity according to the following equation: 
z
C
AUC
AUC
last
last

+
=
 
Values with percentage of extrapolation >30% will not be 
reported 
AUClast 
amcenestrant 
 
Area Under the Concentration versus time curve calculated 
using the trapezoidal method from time 0 to the real time 
tlast 
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Parameters 
Drug  
Matrix 
Definition/calculation 
CL/F (Part A, 
Day 1 only) 
Amcenestrant 
Plasma 
Apparent total body clearance of a drug from the plasma 
calculated using the following equation: 
CL/F =   𝐷𝑜𝑠𝑒𝐸𝑉
AUC  
CLss/F 
Amcenestrant, palbociclib, 
alpelisib, everolimus 
Plasma, 
blooda 
Apparent total body clearance after repeated extra-vascular 
(EV) doses of a drug at steady state from the matrix 
(plasma) calculated using the following equation: 
 
 
tlag 
Amcenestrant 
Plasma 
Lag time, interval between administration time and the 
sampling time preceding the first concentration above the 
lower limit of quantification 
tmax 
Amcenestrant, palbociclib, 
alpelisib, everolimus, 
abemaciclib, M2, M18 and M20 
Plasma, 
blooda 
First time to reach Cmax 
t1/2z  
Amcenestrant  
(Part A, Day 1 only) 
Plasma 
Terminal half-life associated with the terminal slope (λz) 
determined according to the following equation:  
z
1/2Z
0.693
 
t

=
 
where λz is the slope of the regression line of the terminal 
phase of the plasma concentration versus time curve, in 
semi logarithmic scale. Half-life is calculated by taking the 
regression of at least 3 points. 
Ae0-24 
(Arm #1 
Part B, Day 22 
only) 
Amcenestrant 
Urine 
Cumulated amount excreted in urine from time 0 to 24 hours 
after the drug administration on Day 1 
fe0-24 
(Arm #1 
Part B, Day 22 
only) 
Amcenestrant 
Urine 
Fraction of dose excreted in urine from time 0 to 24 hours 
after the drug administration on Day 1 
CLR 0-24 
(Arm #1 
Part B, Day 22 
only) 
Amcenestrant 
Urine 
Renal clearance of the drug determined in the 0-24 hour 
interval, according to the following equation: 
t-
0
t-
0
t-
R0
AUC
Ae
 
CL
=
 
a blood matrix is for everolimus assay only 
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9.3 
PHARMACOGENETIC ASSESSMENT  
9.3.1 Optional drug metabolizing enzymes and transporters DNA sample  
For those patients who select to do the optional pharmacogenetic assessment in the Main ICF, at 
the study visit as specified in the study flow chart, a blood sample will be collected to investigate 
pharmacogenetic variants related to ADME (Absorption, Distribution, Metabolism, Excretion) 
using validated methods as intrinsic factors potentially associated with pharmacokinetic and 
pharmacodynamic variability of amcenestrant.  
Special procedures for collection, storage and shipping of DNA pharmacogenetic samples will be 
described in a separate laboratory manual which will be available at the investigational site. 
9.4 
PHARMACODYNAMIC ASSESSMENTS  
See Section 1.4 for the scheduling of PD assessments. 
9.4.1 18 fluorestradiol-positron emission tomography and 18 fluorodesoxyglucose scans 
(Part A only)  
Inhibition of ER occupancy investigation using 18F-FES-PET imaging is a limited invasive 
procedure that allows assessment of ER presence by assessing the binding of radiolabelled 
estradiol, the ligand of ER (signal extinction). ER-positive tumor sites will be detected with 
18F-FES-PET/CT scan imaging at baseline and will be compared to a scan evaluated at steady 
state. For patients on a QD regimen, the second scan will be performed after at least 8 continuous 
days of treatment (ie, between Day 11 and Day 15) and between 16 to 24 hours after the previous 
administration of the study drug, with a time window of 2 hours around 24 hour theoretical time. 
For patients on a BID regimen, the second scan will be performed after at least 8 continuous days 
of treatment (ie, between Day 11 and Day 15) and between 7 to 12 hours after the previous 
administration of the study drug. In case of limited response observed by PK and 18F-FES-PET, 
a twice daily schedule of administration will be considered for the RD decision after using 
18F-FES-PET at an earlier time window. Patients should be instructed to take the previous study 
treatment dose at the appropriate time in line with availability of the PET/CT scan at sites. The 
signal extinction between baseline and on study treatment 18F-FES-PET scans (ΔSUV) will 
constitute the PD readout of the ER engagement. A decrease ≥90% inhibition of SUV should 
represent an inhibition of the estrogen ligand binding or the near-to complete degradation of ER. 
The 18F-FES-PET will follow the extent of ER inhibition and this will help with the RD decision. 
No 18F-FES-PET imaging will be performed in Arm #1 and #2 (Parts B, C, or D). 
All the procedures concerning the 18F-FES-PET and FDG scans will be described in a specific 
manual. 
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9.4.2 Estrogen receptor 1 gene mutation status in circulating free DNA  
ESR1 mutations have emerged as a resistance mechanism to endocrine therapies. While rare or 
absent in naïve patients, an average of 25% to 35% of patients with ER+ breast cancer tumors will 
acquire a dominant activating mutation of ESR1, the gene encoding ER, after prolonged/repeated 
treatment with endocrine therapies (in particular AI). The presence of ESR1 mutation is linked to 
a poor prognosis. 
ESR1 activating mutations emerge essentially in the ligand domain and render the ER ligand 
independent, therefore less sensitive to ligand competing endocrine therapies. 
Twelve independent mutations of ESR1 gene, including the hotspot mutations described in the 
ligand domain, will be determined in all patients at baseline and at end of Cycle 2 by multiplex 
droplet digital polymerase chain reaction (ddPCR) from plasma extracted cfDNA. For Parts F, G, 
H, I, J and K, ESR1 mutation will be provided by cfDNA NGS mutation profile also used for 
PI3KCA assessment.  
The impact of ESR1 mutation status on clinical outcomes in patients treated by the monotherapy 
amcenestrant or by amcenestrant in combination with palbociclib at RD will also be assessed in 
the ESR1 wild type and the ESR1 mutated population separately. 
Special procedures for collection, handling, storage and shipment will be described in a separate 
laboratory manual which will be available at the investigational site. 
9.4.3 Mutational profiling in circulating free DNA  
Cancer gene mutation present in the tumor at baseline might influence the response to 
amcenestrant. It is also possible that emergent mutation might constitute the root cause of the 
escape mechanism to amcenestrant treatment. To evaluate and generate hypothesis on both 
intrinsic and emerging resistance mutations, the plasma of all patients treated in this study will be 
collected at baseline and at the EOT and cfDNA will be extracted. For Parts F, G, H, I, J and K 
plasma will be collected in all patients to monitor the molecular profile of the tumor in cfDNA at 
Screening, end of Cycle 2 and 4 (at the time of tumor assessment) and at the EOT/progression. 
Saliva will be collected at baseline in order to extract germline DNA which will be used as a 
reference to subtract single nucleotide polymorphisms in the mutational analysis. The mutation 
status of a limited number of cancer genes will be determined by next generation sequencing 
(NGS) and will be used to explore the potential link between specific mutation and intrinsic or 
acquired resistance to the amcenestrant treatment. The list of genes will include but is not limited 
to ESR1, PI3K and the p53 pathways. 
Special procedures for collection, handling, storage and shipment will be described in a separate 
laboratory manual which will be available at the investigational site. 
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9.4.4 Tumor biopsy to assess estrogen receptor degradation (Arm #1, #3, #4, and #5 
[Part A BID, Parts B, F G, H, I, J, and K])  
While the 18F-FES-PET imaging can assess ER accessibility to its ligand estrogen, it does not 
constitute the formal proof that our agent is readily degrading ER in tumors. In all patients in Arm 
#1 (Part A and in at least 10 patients in Part B [optional]), and Arm #3, #4, and #5 (F, G, H, I, J, 
and K [optional]) with accessible tumor will be asked to contribute the most recent archived 
biopsied tumor (within past 3 months prior to initiation of study treatment) or preferably to a fresh 
tumor biopsy at baseline. In addition, during treatment, these patients will be asked to provide a 
biopsy of either a primary or secondary tumor site at the end of Cycle 2. The collected tissue 
should be fixed and preserved. Approximately 9 FFPE slides (5 micron each for IHC analysis) 
and 3 FFPE slides (10-micron each for RNA analysis, if possible) will be collected for each 
biopsy. The presence of ER will be determined by central IHC and the ER results at baseline and 
on treatment will be compared to assess ER degradation. In addition, expression levels of Ki67, 
Bcl-2, PgR and potentially other proteins (eg, Cyclin D1) that may be related to cancer will also 
be evaluated by IHC, and tumor gene expression profiles will be obtained.  
9.4.5 Estradiol  
Estradiol is the natural ligand to ER and amcenestrant antagonizes the binding of estradiol to ER. 
Estradiol will be assayed to explore possible influence of circulating levels of estradiol on 
preliminary efficacy. Circulating estradiol will be measured before and after treatment. 
Special procedures for collection, handling, storage and shipment will be described in a separate 
laboratory manual which will be available at the investigational site.  
9.5 
SAMPLED BLOOD VOLUME  
Table 41 summarizes the volume of blood to be collected during Cycle 1 and further cycles, as 
appropriate in all treatment arms.  
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Table 41 - Sampled blood volume during the study  
 
 
Part A 
Part B 
Part C 
Part D 
Part F and G 
Part H and I 
Part J and K 
Type 
Volume 
per 
sample 
Number 
of 
samples  
Volume 
per 
patient 
Number 
of 
samples  
Volume 
per 
patient 
Number 
of 
samples  
Volume 
per 
patient 
Number 
of 
samples  
Volume 
per 
patient 
Number 
of 
samples  
Volume 
per 
patient 
Number 
of 
samples 
Volume 
per 
patient 
Number 
of 
samples 
Volume 
per 
patient 
Optional for 
DMET/ADME 
genotyping 
6 mL 
1 
6 mL 
1 
6 mL 
1 
6 mL 
1 
6 mL 
1 
6 mL 
1 
6 mL 
1 
6 mL 
PK sample 
amcenestrant and/or 
palbociclib 
2 mL 
37a 
74 mL 
23b 
46 mL 
23 
46 mL 
23b 
46 mL 
 
 
 
 
 
PK sample 
amcenestrant and/or 
alpelisib  
2 mL 
 
 
 
 
 
 
 
 
21 
42 mL 
 
 
 
 
PK sample 
amcenestrant and 
everolimus 
2 mL 
 
 
 
 
 
 
 
 
 
 
19 
38 mL 
 
 
PK sample 
amcenestrant and 
abemaciclib 
3 mL 
 
 
 
 
 
 
 
 
 
 
 
 
20 
60 mL 
PK sample  4βOH-
cholesterol and total 
cholesterol 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
3 
3ml 
PD sample (cfDNA 
for ESR1 status) 
10 mL 
2 
20 mL 
2 
20 mL 
2 
20 mL 
2 
20 mL 
 
 
 
 
 
PD sample (cfDNA 
for mutational 
profiling) 
10 mL 
2 
20 mL 
2 
20 mL 
2 
20 mL 
2 
20 mL 
4 
40 mL 
4 
40 mL 
4 
40 mL 
PD sample (Estradiol) 
2 or 4 mL 
- 
- 
2 
4 mL 
- 
- 
2  
4 mL 
2 
8 mL 
2c  
8 mL 
2c 
8 mL 
Total  
 
42 
120 mL 
30 
96 mL 
28 
92 mL 
30 
96 mL 
28 
96 mLd 
26 
92 mLe 
30 
117 mLf 
CfDNA = circulating free DNA; DMET = drug metabolizing enzymes and transporters; PD = pharmacodynamics; PK = pharmacokinetic 
a If amcenestrant is taken in a BID regimen, the number of PK samples would be 25 in Part A, thus a total of 50 mL per patient for a total of 96 mL. 
b For Arm #1 and #2 (Part B and D), at least 12 patients will undergo a full PK sampling schedule with 23 samples collected. Remaining patients will follow a sparse sampling schedule with 13 samples collected, thus for a total 
volume of 26 mL per patient for PK samples. 
c For dose expansion only (Part I and K) 
d For Arm #3 Part G, up to 12 patients will undergo a full PK sampling schedule. Remaining patients will follow a sparse sampling schedule with 10 sample collected for amcenestrant assay, thus total blood volume per patient 
will be 54mL. 
e For arm#4, Part H the total blood volume per patient will be 64 mL as PD sample for estradiol is collected in Part I only  
f 
For arm#5, Part J the total blood volume per patient will be 89 mL as PD sample for estradiol is collected in Part K only. In Part K, patients under sparse sampling schedule 10 sample will be collected for amcenestrant assay 
and no PK sample for 4βOH-cholesterol and total cholesterol; the total blood volume per patient will be 64 mL 
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9.6 
FUTURE USE OF SAMPLES  
Not all the samples collected during this study may be required for the tests planned in this 
clinical trial. For subjects who have consented to it, the samples that are unused or are leftovers 
from the used samples, may be used for oncology-related research (excluding genetic analysis 
providing information on the likelihood of developing diseases), and other research purposes than 
those defined in the present protocol. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers used during the study (ie, Subject 
ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be located outside 
of the country where the study is conducted. The Sponsor has included safeguards for protecting 
subject confidentiality and personal data (see Section 16.3 and Section 16.5). 
9.7 
EFFICACY (ALL STUDY PARTS)  
9.7.1 Criteria for response (antitumoral activity)  
RECIST v1.1 (Response Evaluation Criteria In Solid Tumors) will be followed for assessment of 
tumor response (40). 
All patients treated in the study must have at least one measurable lesion for inclusion according 
to RECIST v1.1 (see Section 7.2 Inclusion Criteria I 08). 
Tumor assessment (either CT scan or magnetic resonance imaging [MRI]) will be performed to 
assess disease status at baseline and then every 8 weeks from Cycle 1 Day 1 with flexibility of 
+/- 7 days, approximately corresponding to the even-numbered cycles. 
Antitumoral response information, ie, category of response such as CR, PR, SD as best response, 
or progressive disease, will be determined by the Investigator in patients with evaluable disease 
(RECIST v1.1, [Appendix C]). Furthermore, a PR or a CR must be confirmed on 
a second examination done at least 4 weeks apart, in order to confirm the antitumoral response. In 
addition to investigator’s/local radiologist’s assessments, copies of all imaging sets will be 
systematically collected for the purpose of ICR in Part B only (refer to specific imaging charter 
and manual). 
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10 
PATIENT SAFETY (ALL STUDY PARTS)  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
Refer to Section 9.1 for definition of safety criteria, parameters to be analyzed and method of 
sample collection. 
10.2 
SAFETY INSTRUCTIONS  
Please refer to Section 6.7. 
10.3 
ADVERSE EVENTS MONITORING  
All AEs will be managed and reported in compliance with all applicable regulations and included 
in the final CSR. 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT  
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered with a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death or; 
• Is life-threatening or; 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization or; 
• Results in persistent or significant disability/incapacity or; 
• Is a congenital anomaly/birth defect; 
• Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. 
Note: Examples of such events (list is not exhaustive) are intensive treatment in an emergency 
room or at home (for allergic bronchospasm, blood dyscrasias, or convulsions) or asymptomatic 
ALT increase ≥10 x ULN that does not result in hospitalization, or development of drug 
dependency or drug abuse. 
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10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.5.1 Adverse events  
All AEs regardless of seriousness or relationship to the study treatment, spanning from the 
signature of the ICF (ie, occurring during the baseline period even in the absence of any 
administration of study treatment), up to 30 days following the last administration of study 
treatment, are to be recorded on the corresponding page(s) included in the eCRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to study 
treatment, corrective treatment/therapy given, additional investigations performed, outcome, and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by the study 
treatment. 
Vital signs or electrocardiogram (ECG) abnormalities are to be recorded as AEs only if they are 
symptomatic and/or requiring corrective treatment and/or leading to treatment discontinuation 
and/or modification of dosing and/or fulfilling a seriousness criterion and/or is defined as an AESI 
(see Section 10.5.5). 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a seriousness criterion and/or are defined as an AESI 
(see Section 10.5.5). 
10.5.2 Serious adverse events  
In the case of a SAE, an AESI, a pregnancy report, or an overdose, the Investigator must 
immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screen of 
the eCRF; the system will automatically send e-notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In such cases, care should be taken to ensure that the patient’s identity is 
protected and the patient’s identifiers in the clinical trial are properly mentioned on any 
copy of source document provided to the Sponsor. For laboratory results, include the 
laboratory normal ranges. 
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medication, patient status) should be sent (by fax or e-mail) to the monitoring team within 
24 hours of knowledge. In addition, any effort should be made to further document each 
SAE that is fatal or life threatening within the week (7 days) following initial notification. 
• A back-up plan is used (using paper flow) when the eCRF system does not work. 
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10.5.3 Follow-up  
• The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow up the outcome of any AEs (clinical signs, laboratory values 
or other, etc) until the return to normal or consolidation of the patient's condition. Ongoing 
related AEs at the end of study treatment will be followed until resolution or stabilization. 
• In case of any SAE/AESI, the patient must be followed up until clinical recovery is 
complete and laboratory results have returned to normal, or until outcome has been 
stabilized. This may imply that follow-up may continue after the patient has discontinued 
study treatment or has left the clinical trial and that additional investigations may be 
requested by the monitoring team. 
• In case of any AE or AESI brought to the attention of the Investigator at any time after the 
end of the study for the patient and considered by him/her to be caused by the study 
treatment with a reasonable possibility, should be reported to the monitoring team. 
10.5.4 Treatment discontinuation due to nonserious adverse event  
In the case of a treatment discontinuation due to a nonserious AE: 
• ENTER (within 24 hours) the information related to treatment discontinuation due to 
a non-SAE in the appropriate screen of the eCRF (AE with the box “action taken with 
study treatment” ticked “permanently discontinued”, together with the EOT form with 
reason that should be ticked “AE”); the system will automatically send the notification to 
the monitoring team after approval of the Investigator within the eCRF or after a standard 
delay. 
10.5.5 Adverse event of special interest  
An 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. 
Study treatment-related DLTs (as defined in Section 9.1.1) are considered as AESIs, and as such, 
the Investigators will be required to report them to the Sponsor within 24 hours of the Investigator 
becoming aware of the event. The Investigator will attach the DLT-specific CRF page to the 
DLT/AESI form. 
AESIs in this study are: 
• Pregnancy of a female subject entered in a study. 
- 
Pregnancy occurring in a female patient entered in the clinical trial. It will be qualified 
as an SAE only if it fulfills one of the seriousness criteria (see Section 10.4). 
- 
In the event of pregnancy in a female participant, study treatment should be 
discontinued.  
- 
Follow-up of the pregnancy in a female participant is mandatory until the outcome has 
been determined. 
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• Symptomatic overdose with study treatment (serious or nonserious)  
- 
An overdose (accidental or intentional) with the study treatment is an event suspected 
by the Investigator or spontaneously notified by the patient (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.  
Symptomatic overdose has to be reported to the Sponsor immediately (within 
24 hours). 
• Grade ≥3 Increase of ALT (Alanine Amino -Transferase)  
- 
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). 
- 
Omit study-treatment and repeat LFTs within 2-3 days. If not recovered, monitor LFTs 
weekly until recovery to Grade ≤1 (or baseline grade) (refer to Dose modification 
Section 6.5. section of the appropriate study arm) 
- 
Confounding factors such as, liver metastasis, hepato-biliary disorders, concomitant 
medications, etc. should be excluded prior to dose modifications.  
- 
Close monitoring of study patients is recommended in cases of increase of Grade ≥3 
ALT. The LFTs should be performed in patients with onset of otherwise unexplained 
nausea, jaundice, right upper abdominal pain, fever, or rash.  
- 
An ultrasound, or other imaging of liver, should be considered based on the clinical 
presentation. 
- 
A consultation with hepatologist should be undertaken if there is: 
- 
Unexplained or persistent Grade ≥3 ALT regardless of the dose omissions 
- 
ALT Grade >3 ULN and concomitant jaundice (total bilirubin Grade >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. 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. 
10.5.6 Laboratory abnormalities  
Laboratory abnormalities should be monitored, documented, and managed according to the 
related flowchart (see Section 1.3). Laboratory values will be reported in the appropriate screen of 
eCRF. 
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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 if they are DLTs/AESIs  
(see Section 10.5.1). 
10.6 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are unexpected and are at least reasonably related to the study treatment 
(ie, suspected unexpected serious adverse reactions), to the regulatory authorities, 
Institutional Ethics Committees (IECs)/Institutional Review Boards (IRBs) as appropriate 
and to the Investigators. 
• All SAEs that are expected and at least reasonably related to the study treatment to the 
regulatory authorities, according to local regulations. 
• The AESIs (ie, DLT, pregnancy, overdose, ALT ≥ Grade 3, photosensitivity) to those 
regulatory authorities who require such reporting. 
Adverse events that are considered expected will be specified by the reference safety information 
(Investigator’s Brochure).   
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
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11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
Pregnancy will lead to definitive treatment discontinuation in all cases. 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
MEDICINAL PRODUCT(S)  
11.1.1 List of criteria for permanent treatment discontinuation  
Patients may withdraw from study treatment if they decide to do so, at any time and irrespective 
of the reason, or this may be done at the discretion of the Investigator. All efforts should be made 
to document the reason(s) for discontinuation, and this should be documented in the eCRF. 
In Arms #2, #3, #4, and #5 (Parts C/D, F/G, H/I and J/K), Palbociclib / alpelisib / everolimus / 
abemaciclib can be prematurely discontinued; in that case, amcenestrant can be continued as a 
monotherapy until the EOT criterion is met. The EOT visit in this case will be 30 days after the 
date of last amcenestrant administration. The reason for premature discontinuation will be 
captured in the appropriate eCRF screen. 
Treatment with the study treatment should be discontinued in any of the following cases: 
• At the patient’s request, at any time and irrespective of the reason (consent’s withdrawal), 
or at the request of their legally authorized representative. “Legally authorized 
representative” is considered to be an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research. Withdrawal of consent for treatment should be 
distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for nonpatient contact follow-up, eg, medical records check. The value of all their 
study data collected during their continued involvement will be emphasized as important 
to the public health value of the study. Patients who withdraw should be explicitly asked 
about the contribution of possible AEs to their decision to withdraw consent, and any AE 
information elicited should be documented. Preferably the patient should withdraw 
consent in writing and, if the patient or the patient’s representative refuses or is physically 
unavailable, the site should document any case of withdrawal of consent.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing, such as: 
- 
Disease progression 
- 
Unacceptable AE 
- 
Poor compliance to the study protocol 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
• Patient is lost to follow-up. 
If patients are clinically stable, and possibly deriving clinical benefit from therapy with minimal 
toxicity, the patient will be maintained on treatment for the maximum period of time defined in 
Section 6.8. 
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11.1.2 Handling of patients after permanent treatment discontinuation  
All permanent study treatment discontinuation must be recorded by the Investigator in the 
appropriate screen of eCRF when considered as confirmed. After study treatment is discontinued, 
patients should complete a visit 30 days after the last administration of the study treatment or 
before other anti-cancer therapy initiation, whichever occurs first as described in Section 12.7. 
Patients who have been withdrawn from the study treatment cannot be re-entered in any other part 
of the study. 
11.2 
REPLACEMENT OF PATIENTS  
During the dose escalation part of the study, a patient may be considered not evaluable for DLT 
and may be replaced at the same dose level as described in Section 6.3. 
Patients treated in the expansion part of the study who are withdrawn from study treatment will 
not be replaced. 
11.3 
CRITERIA FOR TEMPORARILY DELAYING  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix J should be considered.  
 
 
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12 
STUDY PROCEDURES  
12.1 
VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedule outlined in the flow charts in Section 1 and described below. The results of the 
evaluation will be recorded in the eCRF pages until the patient is not followed anymore.  
After the baseline visit, all eligible patients included in the study will return to the site for a study 
visit every week during Cycle 1 and 2, every 2 weeks from Cycle 3 to Cycle 6 (inclusive), and 
once a month from Cycle 7 onwards. A final visit will be performed 30 days after the last 
administration of the study treatment corresponding to the EOT visit (see flow chart for 
investigations to be performed).  
The patients will be followed until recovery or consolidation of any SAE or study treatment-
related AE.  
Patients who discontinue the study treatment prior to documentation of disease progression will 
be followed-up every 2 months until disease progression or initiation of further anti-cancer 
therapy, or COD, whichever comes first. 
12.2 
BASELINE EVALUATION  
The pretreatment examinations are to be performed within 28 days prior to the first administration 
of the study treatment, unless otherwise specified below. 
The study (main) ICF (mandatory) and optional pharmacogenetics ICF (if applicable) will have to 
be signed by the patient before any procedure specific to the study can be performed. The 
following assessments are to be performed at this visit. 
For Arm #3 (Parts F and G) only, for eligibility purposes, a PIK3CA Testing ICF will have to be 
signed prior to the PIK3CA test for patients who have never had this test done to confirm/detect 
the PIK3CA mutation that is necessary for treatment with amcenestrant and alpelisib combination. 
Upon signing the PIK3CA Testing ICF (ie, pre-screening), the test should be performed prior to 
the study main ICF is signed and initiation of any screening procedure (ie, any time before the  
28-day screening period). No fresh biopsy will be required from Sponsor for eligibility purposes. 
All PIK3CA reports regardless of the time of testing (recent/archival) are acceptable. 
• Breast cancer diagnosis and history. 
• Prior breast anticancer therapies. 
• Prior medications use from the date of informed consent. 
• Tumoral evaluation: chest, abdomen and pelvis CT or MRI scan. Throughout the course of 
the study the same techniques for imaging evaluation than the ones used during the 
baseline phase should be used. 
• Preferably fresh tumor biopsy or archived tumor samples (within past 3 months prior to 
study treatment initiation) for patients who consent for paired biopsies (prior and during 
treatment) and with accessible tumor. Biopsy is optional for patients in Arm #1 Part B (in 
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at least 10 patients) and Arm #3 Parts F/G and mandatory for all patients in Arm #1 Part 
A. Access to tissue FFPE blocks for IHC and RNA analysis is the preferred option. 
Alternatively, approximately 9 FFPE slides will be collected for central IHC and 3 FFPE 
slides for RNA analysis.   
The following will be performed within 7 days prior to Day 1: 
• Inclusion/exclusion criteria. 
• Clinical examination including: major body system examination, ECOG performance 
status (Appendix A), height, weight, vital signs (body temperature, blood pressure, heart 
rate, respiration rate) and signs and symptoms. 
• Laboratory assessments: 
- 
Hematology: hemoglobin, white blood cell count with differential, platelet count 
- 
Coagulation: international normalized ratio, prothrombin time 
- 
Arm #3 Part F and G only: activated Partial Thromboplastin Time (aPTT) done in 
addition to INR and PT 
- 
Blood chemistry: 
- 
Liver function tests: AST, ALT, total bilirubin, conjugated bilirubin, ALP, GGT. 
- 
Electrolytes: sodium, potassium, chloride, magnesium, calcium, phosphate, 
bicarbonate or BUN 
- 
Serum Albumin 
- 
Renal function tests: creatinine 
- 
Arm #3 and #4 (Part F, G, H and I) only: FPG, HbA1c 
- 
Arm #4 (Parts H and I): lipid panel, low-density lipoprotein (LDL), high-density 
lipoprotein (HDL), triglycerides and total cholesterol 
- 
Additional tests to be performed when clinically appropriate. 
• Urine analysis on morning spot: dipstick or qualitative analysis for pH, glucose, ketones, 
blood, protein and leucocytes. A 24-hour urine collection may be done for determination 
of proteinuria if 3+ protein on dipstick. 
• 12-lead ECG. 
• Arm #1 Part A only: 18F-FES-PET scan (Part A QD and BID) and FDG PET/CT (Part A 
BID) 3 days or more before the first dose of study treatment). 
The procedures described above are not to be repeated before study treatment administration 
for Cycle 1, provided they were performed during the baseline process, within 7 days of the 
start of administration and that they did not show significant abnormalities. 
All patients who signed the study ICF will be assigned a patient number. Each patient will 
receive an incremental identification number per site corresponding to their order of enrollment 
in the study. Those patients, who meet all the inclusion criteria and none of the exclusion 
criteria, will be eligible for registration in the study.  
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12.3 
BEFORE THE FIRST INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
(WITHIN 2 DAYS BEFORE) IF NOT PERFORMED WITHIN THE 7 PREVIOUS DAYS  
Before Cycle 1, evaluations such as vital signs, body weight, ECOG performance status, signs and 
symptoms, physical examination, ECG, hematology, coagulation, chemistry and urinalysis should 
be repeated within 2 days before the study treatment administration if abnormal or performed 
more than 7 days before study treatment administration. 
12.4 
DURING THE TREATMENT PERIOD AT CYCLE 1  
See flow charts in Section 1.3 and Section 1.4. 
Assessments should be performed when possible prior to administration of study treatment unless 
otherwise indicated. Results should be reviewed by the Investigator. Every effort should be made 
to keep the schedule of assessments on time for each patient. All visits should be performed on the 
day specified, unless otherwise noted. Additional safety tests (eg, ECG) can be performed 
whenever clinically indicated. All the tests or procedures on Day 1 should be done at predose time 
unless otherwise stated. 
12.4.1 Cycle 1, Day 1  
In Arms #1, #2, #4, #5 (Parts A, B, C, D, H, I, J and K), Cycle 1 Day 1 corresponds to the first 
administration of amcenestrant or amcenestrant combined with palbociclib (Arm #2 Parts C and 
D) / everolimus (Arm #4 Parts H and I)/abemaciclib (Arm #5 Parts J and K). The drug(s) will be 
administered at the study site at each protocol-defined visit. Other doses will be self-administered 
daily. 
In Arm #3 Parts F and G, Cycle 1 Day 1 corresponds to the first administration of alpelisib alone. 
Alpelisib PK sampling will be done on Cycle 1 Day 3 (ie, on the third day after the start of 
alpelisib administration). 
The day on which the patient receives the initial dose of study medication is referred as Cycle 1 
Day 1 (Day 1 of the study). The examinations described in Section 12.2 are not to be repeated for 
Cycle 1, provided they were performed within 7 days of the start of study treatment and provided 
that they did not show significant abnormalities. 
• PK/PD blood sample collection are collected at different time points and are detailed in the 
PK/PD flow chart (Section 1.4) 
12.4.2 Cycle 1, Day 3  
• PK/PD blood sample collection collected at different time points, detailed in the PK/PD 
flow chart (Section 1.4).  
• Patient diary review 
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12.4.3 Cycle 1, Day 8 (±1 day)  
• Physical examination, vital signs (temperature, blood pressure, heart rate, respiration rate) 
• Laboratory assessments: hematology and blood chemistry. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• PK/PD blood sample collection collected predose, as detailed in the PK/PD flow chart 
(Section 1.4). 
• Patient diary review 
12.4.4 Cycle 1, between Day 11 and Day 15 (Arm #1 Part A only)  
• Part A only: 18F-FES-PET scan (all Part A QD and BID patients) and FDG PET/CT 
(Part A BID only) 
• PK/PD blood sample collection as detailed in the PK/PD flow chart (Section 1.4). 
• Patient diary review 
12.4.5 Cycle 1, Day 15 (±2 days)  
• Physical examination, ECOG performance status (Appendix A), weight, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology, coagulation, and blood chemistry. 
• Urine analysis: dipstick on morning spot. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• PK/PD blood sample collection collected at different time points, detailed in the PK/PD 
flow chart (Section 1.4).  
• Patient diary review. 
12.4.6 Cycle 1, Day 22 (±2 days)  
Note, for Arm #2 Parts C and D, the following assessments should be performed on Day 21. 
• Physical examination, vital signs (temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology and blood chemistry. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• PK/PD blood sample collection collected at different time points, detailed in the PK/PD 
flow chart (Section 1.4). 
• Patient diary review 
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12.5 
DURING SUBSEQUENT CYCLES  
See flow charts in Section 1.3 and Section 1.4. 
12.5.1 Subsequent cycles, Day 1 (±2 days)  
• Physical examination, ECOG performance status (Appendix A), weight, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology, coagulation, and blood chemistry. 
• Urine analysis: dipstick on morning spot. 
• 12-lead ECG. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• PK/PD blood sample collection collected in Cycle 2 only, detailed in the PK/PD flow 
chart (Section 1.4).  
• Patient diary review. 
12.5.2 Cycle 2, Day 8 (±2 days)  
• Physical examination, vital signs (temperature, blood pressure, heart rate, respiration rate).  
• Laboratory assessments: hematology and blood chemistry. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• Patient diary review. 
12.5.3 Cycle 2, Day 15 (±2 days)  
• Physical examination, ECOG performance status (Appendix A), weight, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology, coagulation, and blood chemistry. 
• Urine analysis: dipstick on morning spot. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• Patient diary review. 
12.5.4 Cycle 2, Day 22 (±2 days)  
• Physical examination, vital signs (temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology and blood chemistry. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• At the end of Cycle 2, between D15 to D28, tumor biopsy for patients who consent for 
paired biopsies and with accessible tumor, (optional in at least 10 patients in Part B and 
mandatory for Part A). 
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• At the end of Cycle 2, between D15 to D28, blood sample for ESR1 mutation status.  
• Patient diary review. 
12.5.5 Subsequent cycles (up to and including C6), Day 15 (±2 days)  
• Physical examination, ECOG performance status (Appendix A), weight, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology, coagulation, and blood chemistry. 
• Urine analysis: dipstick on morning spot. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• Patient diary review. 
12.5.6 Subsequent cycles (starting from C7 and onwards), Day 1 (±2 days)  
• Physical examination, ECOG performance status (Appendix A), weight, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments: hematology, coagulation, and blood chemistry. 
• Urine analysis: dipstick on morning spot. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications. 
• Patient diary review. 
12.5.6.1 Every 8 weeks  
• Tumoral evaluation: chest, abdomen and pelvis CT only or MRI scan only (whichever was 
used at baseline). Either one of the exams is to be performed every 8 weeks from Cycle 1 
Day 1 with flexibility of +/- 7 days, approximately corresponding to the even-numbered 
cycles starting at Cycle 2, or when clinically indicated during study treatment, whenever 
disease progression is suspected, or to confirm a PR or CR (at least 4 weeks after 
documentation of response). To ensure comparability, the imaging should be performed 
using identical radiology techniques throughout the study treatment period (ie, scans 
performed immediately following bolus contrast administration using a standard volume 
of contrast, the identical contrast agent, and the same scanner). 
• PK/PD blood sample collection collected in Cycle 2, 4 and 6 only, detailed in the PK/PD 
flow chart (Section 1.4). 
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12.5.6.2 Additional Tests for Arms #3 and #4 (Parts F, G, H, and I)  
FPG and HbA1C monitoring will be in Arm #3 and #4 only:  
• Fasting Serum Glucose sample for safety assessment will be collected after 8-12 hours of 
an overnight fasting prior to the light breakfast, at the following time points: 
− 
Baseline (in the screening period): approximately 2 weeks, and no later than Day-1 
prior to study treatment (C1D1) 
− 
Cycle 1: Day 8 and Day 15 
− 
Cycle 2: Day 1, Day 15, and Day 28 
− 
Subsequent cycles: Day 1  
− 
EOT 
− 
 As clinically indicated 
• Hemoglobin A1C (HbA1C) will be assessed for safety, after 8-12 hours of an overnight 
fasting, pre-dose prior to the light breakfast, at the following time points: 
− 
Baseline (in the screening period): approximately 2 weeks, and no later than Day-1 
prior to study treatment (C1D1) 
− 
Cycle 1 and Cycle 2 Day 1, and thereafter, on every 3rd cycle Day 1 (ie, C5D1, C8D1 
etc.) 
− 
EOT 
− 
As clinically indicated 
12.6 
END OF TREATMENT VISIT (TO BE PERFORMED BETWEEN 22 AND 30 DAYS 
AFTER THE LAST ADMINISTRATION OF THE STUDY TREATMENT)  
All patients must continue to be observed for at least 22 to 30 days after the final dose of study 
treatment or prior to start of further anticancer therapy, whichever comes first. The following 
procedures should be performed approximately 30 days following the final dose of study 
treatment: 
• ECOG performance status (Appendix A), weight, physical examination, vital signs 
(temperature, blood pressure, heart rate, respiration rate). 
• Laboratory assessments:  
- 
Hematology 
- 
Coagulation  
- 
Arm #3 Part F and G only: activated partial thromboplastin time (aPTT) done in 
addition to INR and PT 
- 
Blood chemistry  
- 
Arm #3 and #4 (Part F, G, H and I) only: FPG, HbA1c 
- 
Arm #4 (Parts H and I) only: lipid panel 
• Urine analysis: dipstick on morning spot. 
• 12-lead ECG. 
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• AE collection to 30 days after the last administration of study treatment (will be collected 
in last treatment cycle). Ongoing SAEs and ongoing related AEs should be followed 
beyond EOT until resolution or stabilization. 
• Concomitant medications to be collected up to 30 days from last study treatment 
administration and after the EOT if associated with an ongoing SAE or ongoing related 
AE. 
• Tumoral evaluation: chest, abdomen and pelvis CT or MRI scan (whichever was used at 
baseline) unless already performed at previous cycle. 
• Blood samples for molecular profiling in cfDNA (NGS, plasma). 
In case the EOT visit is performed before Day 22 due to the initiation of the further anti-cancer 
therapy, the final collection of safety information (stabilization or recovery of TEAEs) should be 
done either as phone call or visit on/around Day 30 as per protocol allowed window. 
12.7 
PERIOD POST END OF TREATMENT  
Follow up will be performed for patients with ongoing SAEs regardless of relationship to study 
treatment and ongoing study treatment-related AEs 30 days after the last study treatment 
administration, and for patients with new study treatment-related AEs/SAEs. Those events will be 
followed until resolution or stabilization as described in Section 10.5.3 and Section 11.1.2.   
Follow up will be performed for patients who discontinued study treatment without disease 
progression (for reasons: the post-treatment follow-up period includes either telephone calls or 
visits every 2 months to collect date of disease progression or date of further anticancer therapy 
(whichever occurs first). 
12.8 
POST STUDY CUT-OFF PERIOD  
If a patient continues to benefit from the treatment after the final study COD, the patient can 
continue study treatment. Such patients will be followed until 30 days after the last administration 
of the study treatment and will continue to undergo selected study assessments. After the final 
study COD, ongoing patients will receive study therapy until disease progression, occurrence of 
unacceptable toxicities, whichever is earlier, and they will only be followed for study treatment 
administration, SAEs, study treatment-related AEs and AEs leading to study treatment 
discontinuation. 
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13 
STATISTICAL CONSIDERATIONS  
The content of this section is the Statistical Analysis Plan for the study. 
13.1 
DETERMINATION OF SAMPLE SIZE  
A total of up to approximately 251 patients may be enrolled in this study, in all treatment arms 
overall. The study will be conducted in the European Union, United States and Canada. 
13.2 
ARM #1  
13.2.1 Sample size of the escalation phase for amcenestrant as monotherapy (Part A)  
This study aims to establish the MTD as well as the RD of amcenestrant according to DLTs 
observed. 
The actual sample size is expected to vary depending on DLTs observed, cohort sizes and number 
of dose levels. It is anticipated that around 31 to 42 evaluable patients will be enrolled in the 
escalation part (Part A). 
13.2.2 Sample size of the expansion phase for amcenestrant as monotherapy (Part B)  
In case of a QD administration, a Simon’s 2-stage design (minimax) will be used. If 4 or fewer 
responses (CR + PR) are observed on the first 45 patients evaluable for response, the alternative 
hypothesis of at least a 20% response rate will be rejected. Otherwise, accrual will continue to the 
full sample size of 78 patients. Overall, this procedure has 80% statistical power (1-sided alpha of 
0.05) to reject a null response rate of 10% in a 1-sample test for a binomial proportion (East 
version 6.3, Cytel Software, Cambridge, MA). Thirteen responses on 78 evaluable patients for 
response will be necessary to reject the null hypothesis. 
13.3 
ARM #2  
13.3.1 Sample size of the escalation phase for amcenestrant in combination with 
palbociclib (Part C)  
This study aims to establish the MTD of amcenestrant in combination with palbociclib according 
to DLTs observed. 
The actual sample size is expected to vary depending on DLTs observed and number of dose 
levels. The study will follow a standard 3 + 3 design evaluating escalating dose levels of 
amcenestrant in combination with palbociclib.  
For the dose escalation phase (Part C) it is anticipated that approximately 12 patients will be 
enrolled depending on the DLTs observed. 
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13.3.2 Sample size of the expansion phase for amcenestrant in combination with 
palbociclib (Part D)  
It is anticipated that approximately 28 patients will be treated in an expansion phase at each 
selected RD of amcenestrant in combination with palbociclib in order to further assess the safety, 
tolerability and PK profiles and to explore preliminary antitumoral activity. 
With a sample size of 28 patients, there is a 76% probability of detecting a safety event with a true 
incidence of 5%. 
 
Safety event 
incidence rate 
Number of patients 
12 
24 
28 
40 
56 
1% 
0.11 
0.21 
0.25 
0.33 
0.43 
2.5% 
0.26 
0.46 
0.51 
0.64 
0.76 
5% 
0.46 
0.71 
0.76 
0.87 
0.94 
10% 
0.72 
0.92 
0.95 
0.99 
1.00 
15% 
0.86 
0.98 
0.99 
1.00 
1.00 
13.4 
ARM #3  
13.4.1 Sample size of the safety run-in part for amcenestrant in combination with alpelisib 
(Part F)  
This part of the study aims to confirm the RD of amcenestrant in combination with alpelisib 
according to DLTs observed. 
The actual sample size is expected to vary depending on DLTs observed and number of dose 
levels. This part of the study will follow the decision tree in Section 6.2.1 to assess the 
combination of amcenestrant with alpelisib. Additional patients may be enrolled to better evaluate 
the PK profile of each drug.  
It is anticipated that approximately 6 patients will be enrolled depending on the DLTs observed 
and tested doses. 
13.4.2  Sample size of the expansion phase for amcenestrant in combination with alpelisib 
(Part G)   
It is anticipated that approximately 34 patients will be treated in an expansion phase at the 
selected RD of amcenestrant in combination with alpelisib in order to further assess the safety, 
tolerability, PK profiles for preliminary exploration of antitumoral activity.  
With a sample size of 34 patients, there is an 83% probability of detecting a safety event with a 
true incidence of 5%. 
 
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Safety event 
incidence rate 
Number of patients 
12 
24 
28 
34 
40 
1% 
0.11 
0.21 
0.25 
0.29 
0.33 
2.5% 
0.26 
0.46 
0.51 
0.58 
0.64 
5% 
0.46 
0.71 
0.76 
0.83 
0.87 
10% 
0.72 
0.92 
0.95 
0.97 
0.99 
15% 
0.86 
0.98 
0.99 
1.00 
1.00 
13.5 
ARM #4  
13.5.1 Sample size of the dose escalation part for amcenestrant in combination with 
everolimus (Part H)  
This part of the study aims to confirm the RD of amcenestrant in combination with everolimus 
according to DLTs observed. 
The actual sample size is expected to vary depending on DLTs observed and number of dose 
levels. This part of the study will follow the decision tree in Section 6.2.1 to assess the 
combination of amcenestrant with everolimus. Additional patients may be enrolled to better 
evaluate the PK profile of each drug.  
It is anticipated that approximately 12 patients will be enrolled depending on the DLTs observed 
and tested doses. 
13.5.2 Sample size of the expansion phase for amcenestrant in combination with 
everolimus (Part I)  
It is anticipated that approximately 12 patients will be treated in an expansion phase at each 
selected RD of amcenestrant in combination with everolimus in order to further assess the safety, 
tolerability and PK profiles and to explore preliminary antitumoral activity. 
With a sample size of 12 patients, there is a 72% probability of detecting a safety event with a true 
incidence of 10%. 
 
Safety event 
incidence rate 
Number of patients 
6 
12 
15 
18 
1% 
0.06 
0.11 
0.140. 
0.17  
2.5% 
0.14 
0.26 
0.32  
0.37 
5% 
0.27 
0.46 
0.54 
0.60 
10% 
0.47 
0.72 
 0.79 
0.85 
15% 
0.62 
0.86 
0.91 
0.95 
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13.6 
ARM #5  
13.6.1 Sample size of the dose escalation part for amcenestrant in combination with 
abemaciclib (Part J)  
This part of the study aims to confirm the RD of amcenestrant in combination with abemaciclib 
according to DLTs observed. 
The actual sample size is expected to vary depending on DLTs observed and number of dose 
levels. This part of the study will follow the decision tree in Section 6.2.1 to assess the 
combination of amcenestrant with abemaciclib. Additional patients may be enrolled to better 
evaluate the PK profile of each drug. It is anticipated that approximately 12 patients will be 
enrolled depending on the DLTs observed and tested doses. 
13.6.2 Sample size of the expansion phase for amcenestrant in combination with 
abemaciclib (Part K)  
It is anticipated that approximately 20 patients will be treated in an expansion phase at each 
selected RD of amcenestrant in combination with abemaciclib in order to further assess the safety, 
tolerability and PK profiles and to explore preliminary antitumoral activity. 
With a sample size of 20 patients, there is a 71% probability of detecting a safety event with a true 
incidence of 5%. 
 
Safety event 
incidence rate 
Number of patients 
6 
20 
23 
26 
1% 
0.06 
0.21 
0.21 
0.23 
2.5% 
0.14 
0.46 
0.44 
0.48 
5% 
0.27 
0.71 
0.69 
0.74 
10% 
0.47 
0.92 
0.91 
0.94 
15% 
0.62 
0.98 
0.98 
0.99 
13.7 
PATIENT DESCRIPTION  
Dose escalation of monotherapy Arms #1 (Part A), dose escalation monotherapy Arm #1 (Part B) 
dose escalation combination Arm #2 (Part C), dose expansion combination Arm #2, #3, #4, and 
#5 (Parts D, G, I, K), safety run-in combination Arm #3 (Part F), dose escalation combination 
Arm #4 and #5 (Parts H and J) results will be displayed separately. Pooled analysis for a given 
treatment could be considered (eg, Arm #1 Part A and B). 
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13.7.1 Disposition of patients  
Disposition of patients will be depicted by intended dose level (including expanded cohort) for 
both the patient study status and also for the patient analysis populations. For patient study status, 
the total number of patients for each one of the following categories will be presented in the CSR 
using a flow-chart diagram or summary table: 
• Registered patients are patients who sign the study informed consent, and who plan to 
receive the study treatment. 
• All-treated/safety population. 
• Patients who complete the study treatment period. 
• Patients who discontinue study treatment and reasons for discontinuation. 
• Patients evaluable for DLT assessment. 
• PK population. 
• PD population. 
• Activity/efficacy population. 
For all categories of patients, percentages will be calculated using the number of exposed patients 
(all-treated population). Reasons for treatment discontinuation will be provided in tables giving 
numbers and percentages by dose level. 
Additionally, the analysis populations for safety, efficacy, PK, and PD will be summarized in 
a table by patient counts for the all-treated population. 
13.7.2 Protocol deviations  
Major protocol deviations which compromise the evaluation of the MTD will be derived 
adequately (mainly algorithmically and/or following medical review) and determination of 
deviations will be finalized based on data review conducted prior to database lock. Decisions 
made on a patient’s status will be documented. 
13.8 
ANALYSIS POPULATIONS  
13.8.1 All-treated/safety population  
The all-treated/safety population is defined as all registered patients exposed to the study 
treatment, regardless of the amount of treatment administered.  
13.8.2 Patients evaluable for DLT assessment  
To be evaluable, patients should have received 1 cycle (28 days, oral administration), with intake 
of at least 75% of the intended doses, unless they discontinued study treatment before Cycle 1 
completion due to a DLT (a patient who discontinues the study treatment before the end of 
Cycle 1 for another reason than DLT will be replaced), and in Part A have an evaluable 
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18F-FES-PET scan at baseline and between Days 11 and 15 of the first cycle. Any patient who 
develops a DLT in Part A despite the absence of evaluable 18F-FES-PET scan will be included in 
the DLT population. 
A complete safety evaluation should be performed during Cycle 1, and a DLT form should be 
completed at the end of the cycle. This concerns both patients followed up to the end of the 
evaluation period and patients who experience a DLT validated by the Study Committee. Patients 
with incomplete safety evaluation during Cycle 1 and who experience a DLT at this cycle will be 
considered as evaluable for DLT. 
Patients who are not evaluable for DLT assessment in the dose escalation part will be replaced. 
13.8.3 Pharmacokinetic population  
The PK analysis will be performed on patients having received at least 1 cycle of study treatment, 
without any major deviations related to study treatment administration (eg, early vomiting just 
after administration), and for whom any PK parameter can be derived. In order to derive PK 
parameters, the corresponding dosing information (time and amount) and sampling information 
(time) must be recorded. 
13.8.4 Activity/efficacy population  
The activity/efficacy population (called response-evaluable population) is defined as all treated 
patients with measurable disease at study entry who provided a baseline and at least 
one postbaseline evaluable tumor assessment. Patients with an early progression as per RECIST 
v1.1, or who died from disease progression will also be included in this set. 
13.8.5 Pharmacodynamic population  
PD analyses will be performed on all treated patients who had an evaluable 18F-FES-PET scan at 
baseline and between Days 11 and 15 of Cycle 1 for Arm #1 Part A only. 
13.9 
STATISTICAL METHODS  
Unless otherwise specified, analyses will be descriptive and performed based on the all-treated 
population. 
Continuous data will be summarized using number of available data, mean, standard deviation, 
median, minimum and maximum for each dose level. Categorical and ordinal data will be 
summarized using number and percentage of patients in each dose level.  
13.9.1 Demographics and baseline characteristics  
Standard demographic and baseline characteristics (including age, race, gender, ECOG 
performance status), medical history, cancer diagnosis, and tumor characteristics will be collected 
at baseline and described by dose level. 
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The following parameters regarding prior anticancer therapy will be summarized: 
• For surgery and radiotherapy: time from last procedure to first intake of study treatment. 
• For chemotherapy, gene therapy, immunotherapy, hormonal therapy, targeted therapy: 
time from last administration to first intake of study treatment. 
Parameters will be summarized by dose level and overall using descriptive statistics. 
13.9.2 Extent of investigational medicinal product exposure  
The extent of study treatment exposure will be assessed and summarized by dose level within the 
all-treated population.  
In addition, dose information will be assessed for the following variables: 
• Cumulative dose for amcenestrant, palbociclib, alpelisib, everolimus and abemaciclib: 
eg, the cumulative dose at Cycle K is the sum of all doses from Cycle 1 to and including 
Cycle K. 
• Actual dose intensity for amcenestrant, palbociclib, alpelisib, everolimus and abemaciclib 
is defined as the cumulative dose divided by the number of weeks on study treatment. 
• Relative dose intensity for amcenestrant, palbociclib, alpelisib, everolimus and 
abemaciclib is defined as the ratio of the actual dose intensity to the planned dose 
intensity. The relative dose intensity is an indicator of the feasibility of the chosen 
schedule of administration. 
• Dose reduction: reduction of the administered amcenestrant, palbociclib, alpelisib, 
everolimus and abemaciclib dose at an intake on day n + 1 compared to the previous 
intake on day n or the day before dose(s) omitted. 
• Dose omission: one omission of an amcenestrant, palbociclib, alpelisib, everolimus or 
abemaciclib dose corresponds to a dose with a dose equal to 0 mg/day. Omission can 
occur within cycle n or Cycle n +1. 
• Cycle delays (Arms #2, #3, #4 and #5): A cycle is deemed to have been delayed if start 
date of the current cycle - start date of previous cycle >31 days (28 +3 days). 
• Partially administered cycle: cycle with at least one dose omitted. 
Dose information variables will be summarized descriptively (n, mean, standard deviation, 
median, minimum, and maximum). Analyses will be performed based on the number of patients 
and on the number of cycles. 
13.9.3 Prior/concomitant medication/therapy  
Medications will be summarized by treatment group according to the World Health Organization 
Drug Dictionary, considering the first digit of the anatomical, therapeutic, and chemical (ATC) 
class (anatomic category) and the first three digits of the ATC class (therapeutic category). All 
ATC codes corresponding to a medication will be summarized patients will be counted once in 
each ATC categories (anatomic or therapeutic) linked to the medication.  
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Medications of specific interest such as antibiotics and hematopoietic growth factors 
(granulocyte-colony stimulating factor, granulocyte macrophage colony stimulating factor and 
erythropoietin or red blood cells transfusion) will be summarized and listed by dose level. 
Further treatment of interest for the analysis and given to the patient after withdrawal from study 
treatment will be listed. 
13.9.4 Analyses of safety data  
13.9.4.1 Dose-limiting toxicities  
The DLTs observed during DLT observation period will be summarized on the DLT-evaluable 
population, by dose level. In addition, AEs that meet the DLT criteria in subsequent cycles will be 
summarized on the safety population. Details will be provided (characteristics of DLTs) by 
patient. 
13.9.4.2 Analyses of adverse events  
Adverse events will be collected from the time informed consent is signed until at least 30 days 
after the last administration of the study treatment and will be categorized according to 
NCI-CTCAE v4.03. All AEs will be classified by system organ class and preferred term 
according to the latest available version of the MedDRA dictionary. 
Definitions 
Period of observation: The observation period will be divided into 3 segments: pretreatment, 
on-treatment, and posttreatment. The pretreatment period is defined as the time from when the 
patients give informed consent and the first administration of the study treatment. The 
on-treatment period is defined as the time from the first dose of study treatment up to 30 days 
after the last dose of study treatment. The posttreatment period is defined as the time starting 
31 days after the last dose of study treatment to the study closure. 
Pretreatment AEs are defined as any AE occurring during the pretreatment period. 
Treatment-emergent AEs are defined as AEs that developed or worsened (according to the 
Investigator’s opinion) or became serious during the on-treatment phase.  
Post-treatment AEs are defined as AEs that are reported during the posttreatment period. 
The NCI-CTCAE v.4.03 grade will be provided in the summary. For patients with multiple 
occurrences of the same preferred term, the maximum grade will be used. 
The primary focus of AE reporting will be the TEAEs. Pre and posttreatment AEs will be 
described separately.  
Adverse event incidence tables will be presented for each dose level, the number (n) and 
percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the all treated population within each dose level. 
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Sorting within tables should ensure the same presentation for the set of all AE within the 
observation period (pre, on-, and posttreatment). For that purpose, the table of all TEAEs 
presented by system organ class and preferred term will be sorted by internationally agreed order, 
unless otherwise specified. Full 4-level hierarchy will be provided, if needed. 
The following TEAE summaries will be generated: 
• Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Grade ≥3 TEAE 
- 
Grade 3 or 4 TEAE 
- 
Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period) 
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent or premature treatment discontinuation. 
13.9.4.3 Deaths  
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (pretreatment, on-treatment, 
posttreatment) 
A listing of deaths will be provided. 
13.9.4.4 Clinical laboratory evaluations  
For patients with multiple occurrences of the same laboratory variable during the on-treatment 
period, the maximum grade (worst) per patient will be used. Hematological and clinical 
biochemistry toxicities will be assessed from laboratory test parameters. Each test result will be 
graded by NCI common terminology criteria (version 4.0.3). The number of patients with 
abnormal lab tests at baseline will be presented by grade. The frequency of patients in each grade 
of lab tests during treatment will be summarized (similar analysis will be performed based on data 
recorded at Cycle 1). When appropriate, the summary table will present the frequency of patients 
with any grade of abnormal laboratory tests and with Grade 3 or 4 of abnormal laboratory tests. 
13.9.4.5 Vital signs  
The summary statistics (including mean, median, standard error, minimum and maximum) of all 
vital signs variables (raw data and changes from baseline) will be calculated for each visit or study 
endpoint (baseline, each post baseline time point, last on treatment value and/or worst value) by 
dose level. Mean changes from baseline with the corresponding standard error (or boxplots) will 
be plotted over time (at same time points) in each dose level. 
13.9.4.6 Analyses of other safety variables  
Target engagement will be summarized by descriptive statistics and will be displayed with 
waterfall plots. 
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13.9.5 Analyses of pharmacokinetic and pharmacodynamic variables  
13.9.5.1 Analyses of pharmacokinetic variables  
Individual plasma concentrations and PK parameters of amcenestrant when given as 
monotherapy, and then of amcenestrant and palbociclib or amcenestrant and alpelisib or 
amcenestrant and everolimus or amcenestrant and abemaciclib when given in combination will be 
tabulated with standard descriptive statistics by dose level and study part under the responsibility 
of the PKDM department. Individual and mean profiles will be presented graphically. 
The following statistical analyses will be performed for amcenestrant. 
Dose proportionality will be assessed on data from Arm #1 Parts A of the QD regimen using a 
power model on Cmax, and AUC0-24 on Day 1 and Day 22. 
Accumulation ratio (Day 22 or Day 21/Day 1) for Cmax and AUC0-24 (amcenestrant QD regimen) 
or AUC0-12 (amcenestrant BID regimen) for each dose level and dosing regimen will be estimated 
with 90% CIs using a linear fixed effects model on log transformed parameters (Arm #1, #2, #4, 
and #5 [Parts A, B, C, D, H, I, J, and K]). 
Within-subject and total standard deviations for log(Cmax) and log(AUC0-24) will be estimated 
(Arm #1 and #2 [Parts A, B, C and D]). 
The food effect will be assessed by comparing AUC0-24 and Cmax between Day 1/Cycle 1 and 
Day 3/Cycle 1 Arm #1 Part A. 
4β-hydroxycholesterol concentration ratio (Day 22/Day 1) will be estimated with 90% CI. 
Time dependence will be investigated with plasma concentration observed before treatment 
administration (Ctrough) after repeated administration, if relevant, using descriptive statistics and 
concentration versus day graphs over Cycle 1 and 2 (Arm #1 and #2 [Part A/B and C/D]). 
Effect of palbociclib, alpelisib, everolimus or abemaciclib on amcenestrant 
PK parameters of amcenestrant when given with palbociclib (Arm #2 Part C/D), alpelisib 
(Arm #3 Part F/G), everolimus (Arm #4 Part H/I) or abemaciclib (Arm #5 Part J/K) will be 
compared to PK parameters of SERD when given as single agent (Arm #1 Part A/B). 
For amcenestrant BID regimen, similar analyses as for QD regimen will be performed on PK 
parameters, when applicable, except that AUC0-24 will have to be replaced by AUC0-12 when 
needed. 
4β-hydroxy/total cholesterol concentration ratio (Cycle2/Cycle1) will be estimated with 90% CI. 
For alpelisib parameters 
Effect of amcenestrant treatment on alpelisib exposure (Cmax and AUC0-24h) will be assessed with 
a linear mixed effect model for each amcenestrant dose level. Treatment (amcenestrant with 
alpelisib/alpelisib alone) differences and 90% CIs will be computed by first taking the mean 
logarithmic differences within the mixed model framework, and then converting them to ratios of 
geometric means using the anti-logarithmic transformation. 
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13.9.5.2 Analyses of pharmacodynamic variables  
Pharmacodynamic variables (such as 18F-FES PET scan results) will be summarized by dose level 
using descriptive statistics and waterfall plots. 
13.9.6 Analyses of antitumor activity/efficacy variables  
The following variables may be calculated for the efficacy population: 
• ORR according to RECIST v1.1 
• Response duration defined as the time from initial response to the first documented tumor 
progression 
• CBR (CR + PR + SD ≥24 weeks) per RECIST v.1.1 
• Time to first tumor response (CR or PR) in Parts B, D and G defined as time from 
first amcenestrant intake to the first observation of PR or CR 
• Progression-free survival (PFS)  
The ORR and response duration will be described along with relevant parameters (characteristics 
of patients/disease). If appropriate, summaries will be provided. 
13.10 INTERIM ANALYSIS  
In Arm #1 Part B, an interim analysis is planned when 45 patients are treated in order to decide, 
based on preset criteria, if the recruitment of planned additional patients is justified. If 4 or less 
responses (CR + PR) are observed on the first 45 patients evaluable for response, the study will be 
stopped for futility. 
In order to support project strategic planning and design of future studies, interim analyses may be 
conducted during the study in addition to the futility interim analyses described in Section 13.1. 
They will have no impact on the trial itself. Within the framework of these analyses, calculations 
of posterior probabilities for response rate will be performed. 
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14 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff, 
and subinvestigator(s), in accordance with consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for Good Clinical 
Practice (GCP), all applicable laws, rules, and regulations. 
Information regarding the clinical trial will be recorded in a free, publicly accessible, 
internet-based registry, no later than 21 days after the first patient enrollment, in compliance with 
applicable regulatory requirements and with Sanofi public disclosure commitments. 
14.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator and under the Investigator’s responsibility, should fully inform the patient of all 
pertinent aspects of the study, including the written information giving approval/favorable opinion 
by the IRB/IEC. All participants should be informed to the fullest extent possible about the study, 
in language and terms they are able to understand. 
Prior to the patient’s participation in the clinical trial, the written Main ICF should be signed, and 
for Arm#3, the Pre-Screening ICF must be signed prior to the PIK3CA testing and signing of the 
Main ICF (ie, start of the screening procedures). Both ICFs must be signed with the patient's 
name, and must be dated by the patient or the patient’s legally acceptable representative, as well 
as the person who conducted the informed consent discussion. In addition, in the Main ICF, 
patients will have an option to select the blood collection for optional pharmacogenetics testing 
(DMET). A copy of both signed and dated written ICFs will be provided to the patient. 
Both, the Main and Pre-Screening ICFs which will be used by the Investigator for obtaining the 
patient’s informed consent, must be reviewed and approved by the Sponsor prior to the 
submission to the appropriate IRB/IEC) for approval/favorable opinion. 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the Chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure with any addenda, Investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written IRB/IEC 
approval/favorable opinion. 
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The study treatment will not be released at the study site and the Investigator will not start the 
study before the written and dated approval/favorable opinion is received by the Investigator and 
the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure will be 
sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report will be sent to the IRB/IEC at least annually and a summary of the clinical 
trial’s outcome at the end of the clinical trial. 
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15 
STUDY MONITORING  
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, discrepancy resolution form [DRF], or other appropriate 
instrument) in an accurate manner according to the instructions provided and to ensure direct 
access to source documents by the Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All subinvestigators shall be appointed and listed in a timely manner. The 
subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
15.2 
RESPONSIBILITIES OF SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, study treatment allocation, 
patient compliance with the study treatment regimen, study treatment accountability, concomitant 
therapy use, and quality of data. 
15.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allowing the Sponsor’s duly authorized personnel, the 
IRB/IEC, and the regulatory authorities to have direct access to original medical records which 
support the data on the eCRF (eg, patient’s medical file, appointment books, original laboratory 
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records). These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS  
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to the Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety to ensure accurate interpretation of data.  
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF.  
The computerized handling of the data by the Sponsor when available in the eCRF may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
eCRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS  
Procedures shall be employed and controls designed to ensure the confidentiality of electronic 
records. Such procedures and controls shall include validation of systems to ensure accuracy and 
reliability, ability to generate accurate and complete copies of records, protection of records to 
enable retrieval, use of secure, computer-generated, time-stamped entries, use of operational 
system checks, use of device checks to determine validity of source data input, determination that 
person who develop, maintain, or use such systems have adequate education and training, the 
establishment and adherence of written policies to deter record falsification, the use of appropriate 
controls over systems documentation including the distribution of or use of documentation for 
system operation and maintenance, and revision and change control procedures which document 
time-sequenced development and modifications of systems documentation. 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
15.6 
DATA QUALITY ASSURANCE  
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. 
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16 
ADDITIONAL REQUIREMENTS  
16.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and subinvestigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
16.2 
RECORD RETENTION IN STUDY SITES(S)  
The Investigator must maintain confidential all study documentation and take measures to prevent 
accidental or premature destruction of these documents. 
It is recommended that the Investigator retain the study documents at least 15 years after the 
completion or discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that 
a longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator’s personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to 
a mutually agreed upon designee. 
16.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the eCRFs, the Investigator’s Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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16.4 
PROPERTY RIGHTS  
All information, documents, and study treatment provided by the Sponsor or its designee are and 
remain the sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/subinvestigator not to 
mention any information regarding the product in any application for a patent or for any other 
intellectual property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
16.5 
DATA PROTECTION  
• The patient’s personal data, which may be included in the Sponsor database, shall be 
treated in compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding the Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race/ethnicity will be collected in this study because these data are required by several 
regulatory authorities. 
16.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy as required by applicable law. 
An insurance certificate will be provided to the IECs/IRBs or regulatory authorities in countries 
requiring this document. 
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16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will 
inform the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified, and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
16.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
• The information on the study treatment leads to doubt as to the benefit/risk ratio 
• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all study treatment, means and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon 
• Noncompliance by the Investigator or subinvestigator, or delegated staff with any 
provision of the clinical trial protocol, or breach of any applicable laws, regulations, or 
ICH GCP guidelines 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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16.8.2 By the Investigator  
The Investigator may terminate his/her participation upon 30 days prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
16.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
Investigator. 
16.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold his approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study. The Investigator shall 
provide the Sponsor with a copy of any such presentation or publication for review and comment 
at least 30 days in advance of any presentation or submission for publication. In addition, if 
requested by the Sponsor, any presentation or submission for publication shall be delayed for 
a limited time, not to exceed 90 days, to allow for filing of a patent application or such other 
justified measures as the Sponsor deems appropriate to establish and preserve its proprietary 
rights.  
The Investigator shall not use the name(s) of the Sponsor and/or of its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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17 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be recollected if necessary. 
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18 
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Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, et al. Fulvestrant 
plus anastrozole or placebo versus exemestane alone after progression on non-steroidal 
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Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Primary results from a 
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33. 
Rugo H. Alpelisib (ALP)+ fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) 
hormone receptorpositive (HR+), human epidermal growth factor receptor 2-negative 
(HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 
4/6 inhibitor (CDKi)+ aromatase inhibitor (AI): BYLieve study results. 2020 ASCO Annual 
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Everolimus [package insert]. East hanover (NJ): Norvartis; 2020. 
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Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. MONARCH 1, A 
Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients 
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Hamilton E, Cortes J, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, et al. 
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Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib 
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Johnston S, Martin M, Di Leo A, Im S-A, Awada A, Forrester T, et al. MONARCH 3 final 
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Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
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Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
[Internet]. 2020 [cited 2020 Sep 18]. Available from: https://www.fda.gov/drugs/drug-
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Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: 
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19 
APPENDICES  
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Appendix A 
Eastern cooperative oncology group performance status scale  
 
Performance Status 
Description 
0 
Normal, fully functional 
1 
Fatigue without significant decrease in daily activity 
2 
Fatigue with significant impairment of daily activities or bed rest <50% of waking hours 
3 
Bed rest/sitting >50% of waking hours 
4 
Bedridden or unable to care for self 
 
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Appendix B 
National cancer institute common terminology criteria for adverse 
events  
Refer to NCI-CTCAE v.4.03 (2) in the Study Reference Manual, or online at the following NCI 
website: http://ctep.cancer.gov/reporting/ctc.html 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not 
an average. 
When 2 criteria are available for similar toxicities, the one resulting in the more severe grade 
should be used. 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
An accurate baseline prior to therapy is essential. 
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Appendix C 
Modified response evaluation criteria in solid tumors (RECIST 1.1)  
Details provided in bibliographic reference (40). 
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:  
- 
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 nonmeasurable). 
- 
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 [40]). 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 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 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 nonmeasurable. 
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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 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. 
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. 
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• 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 
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. 
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 patients 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 one measurable 
lesion. In studies where the primary endpoint is tumor progression (either TTP or proportion with 
progression at a fixed date), the protocol must specify if entry is restricted to those with 
measurable disease or whether patients having nonmeasurable disease only are also eligible. 
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.s. 
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. 
 
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Evaluation of nontarget lesions 
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph 
nodes must be nonpathological in size (<10 mm short axis). 
Incomplete Response/Stable 
Disease (SD):  
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression (see comments below)a of existing nontarget lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
a Although a clear progression of “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 patients 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 
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 
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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 (for 
example, 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 unevaluable. 
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. 
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Appendix D 
Standard meal example  
 
Food 
Amount 
Slices of bread  
40 g  
Jam  
30 g  
Butter  
10 g  
Semi skimmed milk  
or powdered milk  
or natural yogurt  
150 mL  
15 g  
1  
 
This type of diet generally contains approximately 9% protein, 27% lipids, and 64% carbohydrate, 
which provides about 400 to 500 kcal. 
No fruit juice. 
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Appendix E 
List of CYP3A4 prohibited modulators  
Concomitant administration of medications that are: 
• Strong CYP3A4 inhibitors are not permitted in Arm #1 Part B (Cycle 1), Arm #2 Part C 
and D, Arm #4 (Parts H and I), and Arm #5 (Parts J and K) 
• Moderate CYP3A4 inhibitors are not permitted in Arm #1 Part B (Cycle 1) and Arm #4 
(Parts H and I) 
• Strong CYP3A inducers are not permitted in any part of the study 
The following tables were extracted in January 2017 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 
vardenafil 
16,25 
Ketoconazole 
Antifungals 
midazolam 
15,90 
Troleandomycin 
Antibiotics 
midazolam 
14,80 
Saquinavir / RIT 
Protease inhibitors 
midazolam 
12,48 
Itraconazole 
Antifungals 
midazolam 
10,80 
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 
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MODERATE CYP3A INHIBITORS 
CYP3A inhibitors 
Precipitant Therapeutic 
Class 
Victim (oral, unless otherwise 
specified) 
AUC Ratio 
Moderate CYP3A Inhibitors (AUCratio ≥2 and <5) 
Erythromycin 
Antibiotics 
midazolam 
4,99 
Fluconazole 
Antifungals 
midazolam 
4,93 
Atazanavir / RIT 
Protease inhibitors 
maraviroc 
4,90 
Darunavir 
Protease inhibitors 
saquinavir 
4,90 
Diltiazem 
Calcium Channel Blockers 
midazolam 
4,06 
Darunavir / RIT 
Protease inhibitors 
sildenafil 
4,00 
Dronedarone 
Antiarrhythmics 
simvastatin 
3,66 
Crizotinib 
Kinase Inhibitors 
midazolam 
3,65 
atazanavir 
Protease Inhibitors 
maraviroc 
3,57 
GSK2647544 
Alzheimer's Disease & Dementia simvastatin 
3,30 
aprepitant 
Antiemetics 
midazolam 
3,29 
casopitant 
Antiemetics 
midazolam 
3,13 
amprenavir 
Protease Inhibitors 
rifabutin 
2,93 
faldaprevir 
Antivirals 
midazolam 
2,92 
imatinib 
Antineoplastic Agents 
simvastatin 
2,92 
verapamil 
Calcium Channel Blockers 
midazolam 
2,92 
netupitant 
Antiemetics 
midazolam 
2,44 
nilotinib 
Kinase Inhibitors 
midazolam 
2,40 
grapefruit juice 
Food Products 
midazolam 
2,39 
tofisopam 
Benzodiazepines 
midazolam 
2,36 
cyclosporine 
Immunosuppressants 
midazolam 
2,21 
ACT-178882 
Renin Inhibitors 
midazolam 
2,19 
ciprofloxacin 
Antibiotics 
sildenafil 
2,12 
schisandra sphenanthera 
Herbal Medications 
midazolam 
2,05 
isavuconazole 
Antifungals 
midazolam 
2,03 
cimetidine 
H-2 Receptor Antagonists 
midazolam 
2,02 
FK1706 
Central Nervous System Agents 
midazolam 
2,01 
The following tables were extracted in April 2019 from the Drug-Drug Interaction Database from 
the University of Washington (www.druginteractioninfo.org). 
 
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STRONG CYP3A INDUCERS 
Inducers 
Therapeutic 
Class 
Victim (oral 
unless otherwise 
specified) 
% of AUC 
decrease 
% oral CL 
increase 
Precipitant dose (oral) 
Potent Inducers of CYP3A (AUC decreased by ≥80% or CL increased by more than 5-fold [400%]) 
Rifampin 
Antibiotics 
Budesoinide 
99.7 
36904.5 
600 mg QD (7 days) 
Mitotane 
Other 
Antineoplastics 
Midazolam 
94.5 
Not provided 
Maximum of 3.5g TID (chronic 
therapy) 
Avasimibe 
Other 
Antilipemics 
Midazolam 
93.5 
Not provided 
750 mg/day (7 days) 
Phenytoin 
Anticonvulsants Nisoldipine 
89.5 
Not provided 
200-450 mg/day (chronic 
treatment) 
Carbamazepine Anticonvulsants Quetiapine 
86.6 
643.1 
200 mg TID (26 days) 
Enzalutamide 
Antiandrogens 
Midazolam 
85.9 
Not provided 
160 mg QD (85±3 days) 
St John’s Wort 
extract 
Herbal 
Medicines 
Midazolam 
80.0 
Not provided 
300 mg TID 14 days 
Rifabutin 
Antibiotics 
Delavirdine 
Not provided 458.0 
300 mg QD 14 days 
Phenobarbital 
Anticonvulsants Verapamil 
76.6 
400.9 
100 mg QD 21 days 
 
MODERATE CYP3A INDUCERS 
Inducers 
Therapeutic 
Class 
Victim (oral 
unless otherwise 
specified) 
% of AUC 
decrease 
% oral CL 
increase 
Precipitant dose (oral) 
 
Moderate inducers of CYP3A (AUC decreased by 50-80% or CL increased by 2 to 5-fold 
[100%-400%]) 
Ritonavir and St 
John’s Wort 
None 
Midazolam 
77.2 
Not provided Ritanovir 300 mg BID; St John’s 
Wort 300 mg TID (14 days) 
Semagacestat 
Alzheimer’s 
Treatments 
Midazolam 
76.4 
324.6 
140 mg QD (10 days) 
Tipranavir and 
ritonovir 
Protease 
inhibitors 
Saquinavir 
75.6 
Not provided Tipranavir 500 mg; ritonavir 200 mg 
BID (14 days) 
Bosentan 
Endothelin 
receptor 
antagonist 
Sildenafil 
69 
239.8 
62.5-125 mg BID 8 weeks 
Genistein 
Food Products 
Midazolam 
13.7 
136.9 
1000 mg QD (14 days) 
hioridazine 
Antipsychotics 
Quetiapine 
68.7 
104.5 
100-300 mg QD (15 days) 
Naficillin 
Antibiotics 
Nifedipine 
62.6 
145.1 
500 mg 4 times daily 5 days 
Talviraline 
NNRTIs 
Indinavir 
61.7 
181.2 
500 mg TID 14 days 
Efavirenz 
NNRTIs 
Simvastatin acid 
60.4 
Not provided 600 mg QD 28 days 
Lopinavir 
Protease 
inhibitors 
Amprenavir 
59.7 
Not provided 400 mg BID (4 weeks) 
Modafinil 
Psycho-
stimulants 
Triazolam 
57.6 
35.7 
200-400 mg QD 28 days 
Etravirine 
NNRTIs 
Sildenafil 
56.7 
Not provided 800 mg BID 13.5 days 
Lersivirine 
NNRTIs 
Midazolam 
51.4 
105.5 
1000 mg BID (14 days) 
 
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Appendix F 
List of CYP substrate with a narrow therapeutic range and list of 
substrates mainly metabolized by CYP3A/2B/2C/UGT  
Patients treated or intended to be treated with the following drugs presented as CYP substrates 
with narrow therapeutic range should be carefully monitored:  
In vivo CYP3A Narrow Therapeutic Range (NTR) Substrates 
 
CYP enzyme 
NTR Substrates 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, tacrolimus, 
cisapride, astemizole, terfenadine, pimozide 
CYP Substrates with a Narrow Therapeutic Range - drugs with an exposure-response relationship that indicates that relatively small 
increases in their exposure levels by coadministered CYP inhibitors may lead to safety concerns 
Patients treated or intended to be treated with the following drugs metabolized by 
CYP3A/CYP2B6/CYP2C and/or UGT should be carefully monitored for their efficacy, since their 
exposure may be decreased by amcenestrant:  
Drugs mainly metabolized by CYP3A, CYP2Cs and/or UGTs: 
 
Drug 
Therapeutic Class 
(R)-(-)-hexobarbital 
Hypnotics - Sedatives 
(R)-mephobarbital 
Anticonvulsants 
(S)-mephenytoin 
Anticonvulsants 
(S)-warfarin 
Anticoagulants and Antiplatelets 
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 
benzbromarone 
Anticoagulants and Antiplatelets 
blonanserin 
Antipsychotics 
brecanavir 
Protease Inhibitors 
brotizolam 
Benzodiazepines 
budesonide 
Corticosteroids 
bupropion 
Anticoagulants and Antiplatelets 
buspirone 
Anxiolytics 
capravirine 
Antivirals 
casopitant 
Neurokinin-1 Receptor Antagonists 
celecoxib 
NSAIDS 
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Drug 
Therapeutic Class 
clobazam (parent drug) 
Benzodiazepines 
conivaptan 
Vasopressin Antagonists 
danoprevir 
Antivirals 
daprodustat 
Other 
darifenacin 
Muscarinic Antagonists 
darunavir 
Protease Inhibitors 
dasabuvir 
Antivirals 
diazepam 
Benzodiazepines 
dronedarone 
Antiarrhythmics 
ebastine 
H1 Receptor Antagonists 
efavirenz 
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 
eletriptan 
Triptans 
eliglustat (in subjects CYP2D6 PMs) 
Glucosylceramide Synthase Inhibitors 
elvitegravir 
HIV-Integrase Strand Transfer Inhibitors 
eplerenone 
Diuretics 
everolimus 
Immunosuppressants 
felodipine 
Calcium Channel Blockers 
gliclazide 
Sulfonylureas 
glimepiride 
Sulfonylureas 
glipizide 
Sulfonylureas 
ibuprofen 
NSAIDS 
indinavir 
Protease Inhibitors 
isavuconazole 
Antifungals 
itacitinib 
Kinase Inhibitors 
ivabradine 
Cardiovascular Drugs 
ivacaftor 
Miscellaneous Agents 
lansoprazole (dexlansoprazol) 
Proton Pump Inhibitors 
levomethadyl (LAAM) 
Drug Addiction Treatments 
lomitapide 
Other Antilipemics 
lopinavir 
Protease Inhibitors 
lornoxicam 
NSAIDS 
lovastatin 
HMG CoA Reductase Inhibitors (Statins) 
lumefantrine 
Antimalarials 
lurasidone 
Antipsychotics 
maraviroc 
CCR5 Receptor Antagonists 
meloxicam 
NSAIDS 
midazolam 
Benzodiazepines 
morphothiadin 
Antivirals 
naloxegol 
Gastrointestinal Agents 
nisoldipine 
Calcium Channel Blockers 
omeprazole 
Proton Pump Inhibitors 
pantoprazole 
Proton Pump Inhibitors 
paritaprevir 
Antivirals 
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Drug 
Therapeutic Class 
perospirone 
Antipsychotics 
piroxicam 
NSAIDS 
proguanil (prodrug) 
Antimalarials 
quetiapine 
Antipsychotics 
rabeprazole 
Proton Pump Inhibitors 
repaglinide 
Meglitinides 
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 
tilidine 
Treatments of Pain and Inflammation 
tipranavir 
Protease Inhibitors 
tolbutamide 
Sulfonylureas 
tolvaptan 
Vasopressin Antagonists 
triazolam 
Benzodiazepines 
ubrogepant 
Migraine Treatments 
ulipristal 
Hormones 
(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 
 
  
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Appendix G 
List of BCRP inhibitors, CYP2C9 substrates and P-gp, BCRP and 
OAT3 substrates  
The following tables were extracted from the FDA website (41). 
BCRP inhibitors 
 
Transporter 
Gene 
Inhibitor 
BCRP 
ABCG2 
curcumin, cyclosporine A, eltrombopag 
Note: Criteria for selecting BCRP in vivo inhibitor are as follows: 
• AUC fold-increase of sulfasalazine ≥1.5 with co-administration and (2) in vitro inhibitor. 
Cyclosporine A and eltrombopag were also included, although the available DDI 
information was with rosuvastatin, where inhibition of both BCRP and OATPs may have 
contributed to the observed interaction. 
This table is prepared to provide examples of clinical inhibitors for various transporters and not 
intended to be an exhaustive list. DDI data were collected based on a search of the University of 
Washington Metabolism and Transport Drug Interaction Database (42).  
CYP2C9 substrates 
 
 
Sensitive substrates 
Moderate senstive substrates 
CYP2C9 
celecoxiba 
glimepiride, phenytoin, tolbutamide, warfarin 
a Listed based on pharmacogenetic studies 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong 
index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive 
substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies. Other elimination pathways may 
also contribute to the elimination of the substrates listed in the table above and should be 
considered when assessing the drug interaction potential. 
This table is prepared to provide examples of clinical substrates and not intended to be an 
exhaustive list. DDI data were collected based on a search of the University of Washington 
Metabolism and Transport Drug Interaction Database (42).  
P-gp, BCRP and OAT3 substrates 
 
Transporter 
Gene 
Substrate 
P-gp 
ABCB1 
dabigatran etexilate, digoxin, fexofenadinea 
BCRP 
ABCG2 
rosuvastatin, sulfasalazine 
OAT1 
OAT3 
SLC22A6, 
SLC22A8 
adefovirb, cefaclor, ceftizoxime, famotidinec, furosemide, ganciclovirb, methotrexate, 
oseltamivir carboxylatec, penicillin Gc 
a Fexofenadine is a substrate for both P-gp and OATP1B. 
b In vitro data suggested higher contribution of OAT1 than OAT3. 
c In vitro data suggested higher contribution of OAT3 than OAT1. 
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Note: Criteria for selecting clinical substrates are as follows: 
• P-gp: (1) AUC fold-increase ≥2 with verapamil or quinidine co-administration and (2) in 
vitro transport by P-gp expression systems, but not extensively metabolized. 
• BCRP: (1) AUC fold-increase ≥2 with pharmacogenetic alteration of ABCG2 (421C>A) 
and (2) in vitro transport by BCRP expression systems. 
• OAT1/OAT3: (1) AUC fold-increase ≥1.5 with probenecid co-administration, (2) fraction 
excreted unchanged into urine as an unchanged drug ≥0.5, and (3) in vitro transport by 
OAT1 or OAT3 expression systems. 
 
This table is prepared to provide examples of clinical substrates for various transporters and not 
intended to be an exhaustive list. DDI data were collected based on a search of the University of 
Washington Metabolism and Transport Drug Interaction Database (42).  
 
 
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Appendix H 
In vivo Inhibitors of P-gp Probes  
 
Inhibitora 
Therapeutic Class 
Inhibitor Dose 
(oral) 
Substrateb 
Max AUCR or  
CL Ratio           
alogliptin 
Dipeptidyl Peptidase-4 
Inhibitors 
100 mg QD (7 days) 
fexofenadine 
1.26 
amiodarone 
Antiarrhythmics 
600 mg SD 
dabigatranc 
1.58 
400 mg/day (5 days) 
digoxin (IV) 
0.74 (CL ratio) 
800 mg/day (7 days) 
digoxin 
1.68 
asian ginseng (Panax 
ginseng) 
Herbal Medications 
70 mL fermented red ginseng 
liquid (14 days) 
fexofenadine 
1.31 
asunaprevir 
Antivirals 
200 mg BID (13 days) 
digoxin 
1.30 
asunaprevir/ 
beclabuvir/daclatasvir 
Antivirals 
200 mg/75 mg/30 mg BID (15 
days) 
digoxin 
1.22 
atorvastatin (acid) 
HMG CoA Reductase 
Inhibitors (Statins) 
80 mg QD (10 days) 
digoxin 
1.20 (Cmax ratio) 
AZD5672 
CCR5 Receptor 
Antagonists  
150 mg QD (13 days) 
digoxin 
1.33 
azithromycin 
Antibiotics 
250 mg QD (5 days)  
fexofenadine  
1.72 
canagliflozin 
Sodium-dependent Glucose 
Cotransporter 2 (SLGT2) 
Inhibitors 
300 mg QD (7 days) 
digoxin 
1.20 
capmatinib 
Kinase Inhibitors 
400 mg BD (median: 7.14 
weeks) 
digoxin 
1.47 
captopril 
Angiotensin Converting 
Enzyme (ACE) Inhibitors 
12.5 mg TID (7 days) 
digoxin 
1.39 
carvedilol 
Alpha/Beta Adrenergic 
Antagonists 
6.25 mg BID (7 days) 
digoxin 
1.57 
cimetidine 
H-2 Receptor Antagonists 
400 mg SD 
digoxin 
1.26 
clarithromycin 
Antibiotics 
500 mg BID (5 days) 
dabigatrand 
4.02 
500 mg BID (7 days) 
digoxin 
1.68 
  
  
500 mg BID (7 days) 
fexofenadine 
2.54 
clopidogrel 
Anticoagulants and 
Antiplatelets 
300 mg SD 
dabigatran 
1.35 
cobicstat 
Pharmacokinetic Enhancer 
150 mg QD (22 days) 
dabigatran 
2.37 
  
  
150 mg QD (10 days) 
digoxin 
1.41 (Cmax ratio) 
conivaptan 
Vasopressin Antagonist 
40 mg BID (10 days) 
digoxin 
1.43 
cremophor EL 
Excipients 
1440 mg SD 
fexofenadine 
1.28 
cremophor RH 
Excipients 
600 mg TID (9 days) 
digoxin 
1.21 
curcumin 
Food Products 
1000 mg QD (14 days) 
talinolol 
1.54 
daclatasvir 
Antivirals 
60 mg QD (10 days) 
digoxin 
1.27 
diltiazem 
Calcium Channel Blockers 
60 mg TID (10 days) 
digoxin 
1.44 
diosmin 
Herbal Medications 
150 mg QD (10 days) 
fexofenadine 
1.66 
diprafenone 
Antiarrhythmics 
100 mg TID (7 days) 
digoxin 
1.41 (Cmax ratio) 
dronedarone 
Antiarrhythmics 
400 mg BID (10 days) 
digoxin 
2.33 
elagolix 
Other 
200 mg SD 
digoxin 
1.32 
eliglustat 
Glucosylceramide Synthase 
Inhibitors 
100 mg (PMs) and 150 mg 
(others) (7 days) 
digoxin 
1.49 
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Inhibitora 
Therapeutic Class 
Inhibitor Dose 
(oral) 
Substrateb 
Max AUCR or  
CL Ratio           
erythromycin 
Antibiotics 
500 mg TID (7days) 
fexofenadine 
2.09 
  
  
2 g SD 
talinolol 
1.52 
felodipine 
Calcium Channel Blockers 
2.5 mg SD 
digoxin 
1.49 
flibanserin 
Central Nervous System 
Agents 
100 mg QD (8 days) 
digoxin 
1.93 
fluvoxamine 
Selective Serotonin 
Reuptake Inhibitors (SSRIs) 
50 mg QD (7 days) 
fexofenadine 
1.78 
fostamatinib 
Other 
0.25 mg QD (15 days) 
digoxin 
1.37 
ginkgo (Ginkgo 
biloba) 
Herbal Medications 
120 mg TID (14 days) 
talinolol 
1.25 
glecaprevir/ 
pibrentasvir 
Antivirals 
300 mg/120 mg QD (10 days) 
dabigatran 
2.38 
  
  
400 mg/120 mg QD (12 days) 
digoxin 
1.48 
indinavir  
Protease Inhibitors 
80 mg TID (21 days) 
fexofenadine 
3.31 
indinavir/ritonavir 
Protease Inhibitors 
800 mg/100 mg BID (1 day) 
fexofenadine 
4.84 
isavuconazole 
Antifungals 
Not Provided 
digoxin (not 
provided) 
1.25 
istradefylline 
Other Antiparkinsonians 
40 mg QD (21 days) 
digoxin 
1.21 
itraconazole 
Antifungals 
200 mg QD (5 days) 
dabigatrand 
6.92 
200 mg QD (5 days) 
digoxin 
1.68 
  
  
100 mg BID (5 days) 
fexofenadine 
3.01 
ivacaftor 
Other 
150 mg Q12H (9 days) 
digoxin 
1.32 
ketoconazole 
Antifungals 
400 mg QD (8 days) 
dabigatran 
2.53 
  
  
400 mg QD (7 days) 
fexofenadine 
2.74 
lapatinib 
Kinase Inhibitors  
Not Provided 
digoxin 
2.80 
lopinavir/ritonavir 
Protease Inhibitors 
400 mg/100 mg BID (14 days) 
digoxin 
1.81 
  
  
400 mg/100 mg SD 
fexofenadine 
4.14 
maribavir 
Antivirals 
400 mg BID (8 days) 
digoxin 
1.22 
mibefradil 
Calcium Channel Blockers 
150 mg QD (7 days) 
digoxin 
1.31 
mifepristone 
Antiprogestins 
1200 mg QD (10 days) 
digoxin 
1.36 
milk thistle (Silybum 
marianum) 
Herbal Medications 
140 mg TID (14 days) 
talinolol 
1.30 
mirabegron 
Beta3-Adrenoreceptor 
Agonist 
100 mg QD (14 days) 
digoxin 
1.26 
nefazodone 
Serotonin Modulators 
200 mg BID (8 days) 
digoxin 
1.29 (Cmax ratio) 
nelfinavir 
Protease Inhibitors 
1250 mg BID (14 days) 
digoxin 
1.35 
neratinib 
Kinase Inhibitors 
240 mg QD (multiple doses) 
digoxin 
1.32 
nifedipine 
Calcium Channel Blockers 
10 mg TID (7 days) 
digoxin 
1.23 
nitrendipine 
Calcium Channel Blockers 
20 mg QD (7 days) 
digoxin 
1.16 
ombitasvir/ 
paritaprevir/ ritonavir 
Antivirals 
150/100/25 mg QD (19 days) 
digoxin 
1.35 
osimertinib 
Kinase Inhibitors 
80 mg SD 
fexofenadine 
1.54 
paroxetine 
Selective Serotonin 
Reuptake Inhibitors (SSRIs) 
20 mg QD (7 days) 
fexofenadine 
1.38 
pexidartinib 
Kinase Inhibitors 
1800 mg SD 
digoxin 
1.32 (Cmax ratio) 
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Inhibitora 
Therapeutic Class 
Inhibitor Dose 
(oral) 
Substrateb 
Max AUCR or  
CL Ratio           
piperine 
Food Products 
20 mg QD (10 days) 
fexofenadine 
1.70 
propafenone 
Antiarrhythmics 
300 mg TID (3 days) 
digoxin (IV) 
1.29 
600 mg QD (7 days) 
digoxin 
0.69 (CL ratio) 
  
  
250-500 mg/kg QD (7 days) 
digoxin 
0.33 (CL ratio)e 
quercetin 
Herbal Medications 
500 mg TID (7 days) 
fexofenadine 
1.56 
quinidine 
Antiarrhythmics 
1000 mg (200 mg Q2H) 
dabigatran 
1.53 
200 mg QID (6 days) 
digoxin (IV) 
0.36 (CL ratio) 
600 mg BID (8 days) 
digoxin 
2.66 
  
  
25 mg SD 
fexofenadine 
2.14 
quinine 
Antimalarial 
200 mg TID (9 days) 
digoxin (IV) 
0.75 (CL ratio) 
ranolazine 
Cardiovascular Drugs 
750 mg BID (6 days) 
digoxin 
1.88 
rifampin 
Antibiotics  
600 mg QD SD 
dabigatrand 
2.32 
600 mg QD (28 days) 
digoxin 
1.46 
600 mg QD SD 
fexofenadine 
(S) 3.57 (R) 3.21f 
ritonavir 
Protease Inhibitors 
100 mg QD (10 days; PBPK 
Modeling) 
dabigatran 
1.27 
300 mg BID (11 days) 
digoxin (IV) 
1.86 
400 mg BID (14 days) 
digoxin 
1.47 
  
  
200 mg TID (1 day), 300 mg BID 
(7 days), 400 mg BID (13 days) 
fexofenadine 
2.75 
rolapitant 
Antiemetics 
180 mg SD 
digoxin 
1.27 
rucaparib 
Cancer Treatments 
600 mg TID (12 days) 
digoxin 
1.21 
saquinavir/ ritonavir 
Protease Inhibitors 
1000 mg/100 mg BID (16 days) 
digoxin 
1.68 
sarecycline 
Antibiotics 
150 mg SD  
digoxin 
1.26 (Cmax ratio) 
schisandra chinensis 
Herbal Medications 
300 mg BID (14 days) 
talinolol 
1.52 
simeprevir 
Antivirals 
150 mg QD (7 days) 
digoxin 
1.39 
sofosbuvir/ 
velpatasvir/ 
voxilaprevir 
Antivirals 
400/100/200 mg QD (11 days) 
dabigatran 
2.59 
St. John's wort 
(Hypericum 
perforatum) 
Herbal Medications 
900 mg SD 
fexofenadine 
1.31 
suvorexant 
Hypnotics - Sedatives 
40 mg (11 days) 
digoxin 
1.27 
talinolol 
Alpha/Beta Adrenergic 
Antagonists 
100 mg SD 
digoxin 
1.23 
telaprevir 
Antivirals 
750 mg TID (16 days) 
digoxin 
1.82 
telithromycin 
Antibiotics 
800 mg QD (5 days) 
digoxin 
1.36 
telmisartan 
Angiotensin II Inhibitors 
(Angiotensin Receptor 
Blockers or ARBs) 
120 mg QD (7 days) 
digoxin 
1.22 
tezacaftor/ivacaftor 
Other 
100/150 mg QD (14 days) 
digoxin 
1.30 
ticagrelor 
Anticoagulants and 
Antiplatelets 
400 mg QD (16 days) 
digoxin 
1.28 
tipranavir/ritonavir 
Protease Inhibitors 
500/200 mg BID (2 days) 
digoxin (IV) 
1.46 
  
  
500/200 mg BID (2 days) 
digoxin 
1.65 
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Inhibitora 
Therapeutic Class 
Inhibitor Dose 
(oral) 
Substrateb 
Max AUCR or  
CL Ratio           
tocophersolan (TPGS, 
Vitamin E-TPGS) 
Excipients 
0.04% intraduodenal SD 
talinolol 
1.20 
tolvaptan 
Vasopressin Antagonists 
60 mg QD (5 days) 
digoxin 
1.18 
tucatinib 
Kinase Inhibitors  
300 mg BID (14 days) 
digoxin 
1.50 
valbenazine 
Central Nervous System 
Agents 
80 mg SD 
digoxin 
1.33 
valspodar (PSC 833) 
Transporter Modulators 
200 mg BID (5 days) 
digoxin 
3.05 
vandetanib 
Kinase Inhibitors 
300 mg SD 
digoxin 
1.22 
velpatasvir 
Antivirals 
100 mg QD (4 days) 
digoxin 
1.34 
vemurafenib 
Kinase Inhibitors 
960 mg BID (28 days) 
digoxin 
1.91 
venetoclax 
Cancer Treatments 
100 SD 
digoxin 
1.38 (Cmax ratio) 
verapamil 
Calcium Channel Blockers 
120 mg SD 
dabigatran 
2.42 
80 mg BID (4 days) then TID (10 
days) 
digoxin (IV) 
1.24 
80 mg BID (4 days) then TID (10 
days) 
digoxin 
1.50 
  
  
80 mg TID (6 days)  
fexofenadine 
2.51 
vilazodone 
Serotonin Modulators 
Not Provided 
digoxin 
1.20 
voclosporin 
Immunosuppressants 
0.4 mg/kg Q12H (11 days) 
digoxin 
1.25 
vorapaxar 
Anticoagulants and 
Antiplatelets 
2.5 and 40 mg (7 days) 
digoxin 
1.57 (Cmax ratio) 
zanubrutinib 
Kinase Inhibitors 
160 mg BID (7 days) 
digoxin 
1.34 (Cmax ratio) 
a Inhibitors are presented alphabetically due to differences in the sensitivity of substrates 
b Oral administration, unless otherwise indicated 
c Administered as the prodrug, dabigatran etexilate, which is a P-gp substrate, though the active dabigatran, for which the PK is measured, is 
not 
d Micro dose study 
e Study was performed in a pediatric population 
f 
AUC ratios for repeated dosing of rifampin (6 days): (S) - 2.40, (R) - 1.90 (Accession #23115085) 
* Probes were selected based on regulatory agency recommendations: dabigatran etexilate, digoxin, fexofenadine (FDA, EMA, MHLW), and 
talinolol (FDA) 
Note - fexofenadine and talinolol are also transported by other transporters, such as OATPs 
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Appendix I 
Abbreviated modification of diet in renal disease formula  
GFR (mL/min/1.73 m2) = 175 x (Scr) -1.154 x (Age)-0.203 x (0.742 if Female) x (1.212 if 
African-American). 
 
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Appendix J 
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 11.3). 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, 
etc.) may be planned for the collection of possible safety and/or efficacy data (eg safety 
assessments, efficacy assessments especially the tumor assessment, PRO). 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed. 
• The Direct-to-Patient (DTP) supply of the IMP from the site/sponsor where allowed by 
local regulations and agreed upon by participant. (Section 8.1). 
Contingencies implemented due to emergency will be documented. 
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The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (Section 14.1). 
 
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Appendix K 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Clinical Trial Summary. 
AMENDED PROTOCOL 09 (Date 23 March 21) 
This Amended Protocol 09 (Amendment 09) 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: 
1. Discontinue Arm #1 study Part A-BID dose levels which enrolled 6 patients. Considering 
that PK, PD, safety and activity data so far in AMEERA-1 and AMEERA-2 studies as 
well as healthy volunteers’ study provided sufficient information regarding the BID 
dosing, additional exploration of this dosing in monotherapy (Arm #1 Part A-BID and Part 
B-BID) is not to be considered as needed anymore. Therefore, Arm #1 Part A-BID and 
Part B-BID will be removed from the study.  
2. Addition of 2 new Arms to investigate safety, efficacy, pharmacokinetic and 
pharmacodynamic of 2 new combination therapies: a) combination of amcenestrant with 
everolimus (Arm #4), and b) combination of amcenestrant with abemaciclib (Arm #5). In 
both cohort, amcenestrant will be administered at the RP2D established in combination so 
far, ie, 200 mg/day and both everolimus and abemaciclib will be administered at 2 
different approved doses in a dose escalation part (Arm #4 Part H and Arm#5 Part J, 
respectively), followed by an expansion part at the selected dose (Arm #4 Part I and Arm 
#5 Part K respectively). 
In this study, each, everolimus and abemaciclib will be used at their approved, standard 
dose levels of 5 mg and 10 mg QD (everolimus) / 100 mg and 150 mg BID (abemaciclib) 
by oral route (with, as per label for both drugs, permitted dose reductions, if needed) in 
combination with amcenestrant 200 mg QD dose which was selected dose for the 
combination therapy. Additionally, in each of the combinations, a possibility of exploring 
additional doses of amcenestrant (eg, 300 mg QD or 400 mg QD etc.) with everolimus / 
abemaciclib could be considered depending on safety and pharmacokinetics profile of both 
combinations.  
3. Change of the compound name, SAR439859 to the INN name: amcenestrant. 
4. Additional tablet strength of alpelisib (ie, 150 mg) is added to the existing tablet strengths 
of 50 mg and 200 mg to secure the IMP for both study parts in Arm #3 
5. Additional safety language for Arm#3 with more detailed instructions for DLTs and 
alpelisib dose modification 
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6. Additional exclusion criteria (E38) to prevent potential DDI with everolimus in Arm #4. 
The treatments listed in E38, were also prohibited as concomitant treatment in Arm #4. 
7. Correct typo and inconsistencies 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Updated SAR439859 to amcenestrant 
throughout document. 
This content was updated to provide 
the INN name of the product. 
Global 
Corresponding treatment arms to study 
parts were added throughout the 
document. Arm #1 is Part A/B, Arm #2 
is Part C/D, Arm #3 is F/G, Arm #4 is 
H/I, and Arm #5 is J/K.. 
These study arms were included in 
order to provide more organization 
and clarity throughout the document. 
Global 
New combination study arms added 
throughout the document. 
This content was added in order to 
provide new study parts for the 
AMEERA-1 study design. 
Clinical Trial Summary 
Overall number of sites updated to 
40 sites 
This content was updated in order to 
reflect the new expected number of 
sites  
Clinical Trial Summary and Section 4.4.4.1 
Part H (Dose escalation with everolimus), 
Section 4.4.4.2 Part I (Dose expansion, 
combination with everolimus), Section 4.4.5.1 
Part J (Dose escalation phase with 
abemaciclib), Section 4.4.5.2 Part K (Dose 
expansion, combination with abemaciclib) 
New combination study arms, ie Arm #4 
(Part H and I) and Arm#5 (Part J and K) 
were added as new sections. 
This content was added in order to 
reflect the new study design. 
Clinical Trial Summary, Section 5.1 Primary 
objections, Section 5.2 Secondary objectives, 
Section 5.3 exploratory objectives, Section 
9.1.1 Dose limiting toxicities 
Primary, secondary, and exploratory 
objections and endpoints were modified 
to include the new study arms and Arm 
#3 (Part F). 
This content was modified to reflect 
the new study design and to 
eliminate redundancies. 
Clinical Trial Summary and Section 6.2.1 
Starting Dose and Dose Levels, and Section 
8.1.2.1 Amcenestrant  
Deleted “An additional BID dose could 
be tested in Part C assuming that BID 
monotherapy in Part A indicates a 
benefit compared to the RD given QD”. 
This content was removed due to 
study design changes. 
Clinical Trial Summary and Section 6.2.1 
Starting dose and dose levels 
Footnote b in Table 3 amcenestrant 
and alpelisib in Part F was updated. 
Footnote b was updated to provide 
clarity regarding the dose levels 
tested. 
Clinical Trial Summary, Section 6.5.3 Arm #4 
Dose Modification in Parts H and I, Section 
6.5.4 Arm #5 Dose modification in Parts J and 
K  
Dose modification for Arm #4 (Part H 
and I) and Arm#5 (Part J and K) were 
added. 
This content was added in order to 
reflect the new study design. 
Clinical Trial Summary and Section 6.8.1 
Duration of study participations for each 
patient 
 Content on COD and enrollment period 
was updated. 
This content was updated in order to 
clarify when COD will occur and 
what is the expected enrollment 
period. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary and Section 7.2 
Inclusion Criteria 
I01, I05, and I06 were updated to 
include inclusion criteria for the new 
study arms.  
I10 clarified to specify two FDG PET/CT 
were done in Arm #1 Part A BID only. 
This content was updated in order 
reflect the new study design and to 
provide clarity to the study design. 
Clinicial Trial Summary and Section 7.3.2 
Exclusion criteria related to the disease 
E13, E25, E30, E31, E32, and E33 
were updated to include exclusion 
criteria related to the new study parts 
New exclusion criteria E35, E36, E37, 
E38, and E39 were added. 
This content was updated to reflect 
new study design and to provide 
clarity. 
Clinical Trial Summary, Section 7.3.2 
Exclusion criteria related to the disease, and 
Appendix E List of CYP3A4 prohibited 
modulators 
Moderate CYP3A and CYP2C8 
inducers were removed in E21 and 
Appendix E. 
This content was updated to reflect 
new clinical results showing that a 
strong inducer (Rifampin) can lead 
to a modest decrease of 
amcenestrant exposure. 
Clinical Trial Summary, Section 8.1.1.3 
Alpelisib and Section 8.1.2.3 Alpelisib 
Additional tablet strength of alpelisib 
(ie, 150 mg) is added as a possibility to 
the existing tablet strengths of 50 mg 
and 200 mg. Statement “2 x 50 mg 
tablets + 1 x 200 mg tablet” was 
removed. 
This change reflects an update in 
the clinical supply due to 
uncertainities in supply caused by 
COVID-19. 
Clinical Trial Summary, Section 8.1.1.4 
Everolimus, Section 8.1.1.5 Abemaciclib, 
Section 8.1.2.4 Everolimus, Section 8.1.2.5 
Abemaciclib, and Section 13.9.2 Extent of 
investigational medicinal product exposure  
Content added regarding everolimus 
and abemaciclib as IMPs and how they 
can be taken. 
This content was added to reflect 
the change in study design. 
Clinical Trial Summary and Section 8.1.2.1 
Amcenestrant 
New content added on how 
amcenestrant will be taken for  Arm #4 
(Parts H and I) and Arm #5 (J and K). 
This content was added to reflect 
new study design. 
Clinical Trial Summary and Section 13.1 
Determination of sample size 
Sample size was changed to 
251 patients. 
This content was updated in order to 
reflect the addition of 2 new study 
Arms and removal of parts that are 
no longer occuring. 
Clinical Trial Summary, Section 13.2.2 Sample 
size of the expansion phase for amcenestrant 
as monotherapy (Part B) and Section 13.10 
Interim analysis 
BID regimen and related information 
was removed for Part B. 
This content was removed to reflect 
an update in the study design. 
Clinical Trial Summary, Section 13.1 
Determination of sample size, Section 13.5.1 
Sample size of the dose escalation part for 
amcenestrant in combination with everolimus 
(Part H), Section 13.5.2 Sample size of the 
expansion phase for amcenestrant in 
combination with everolimus (Part I), Section 
13.6.1 Sample size of the dose escalation part 
for amcenestrant in combination with 
abemaciclib (Part J), and Section 13.6.2 
Sample size of the expansion phase for 
amcenestrant in combination with  abemaciclib 
(Part K) 
Sample size was adjusted and Arm #4 
(Part H and I) and Arm#5 (Part J and K) 
sample size content were added. 
This content was adjusted and 
added in order to reflect the sample 
size for new study parts. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary and Section 13.9.6 
Analyses of antitumor activity/efficacy 
variables  
Modified efficacy endpoint ‘non-PFS 
rate at 6 months’ to Progression Free 
Survival. 
The PFS rate at 6 months was 
removed and replaced by PFS to 
better characterize the whole PFS 
curve. 
Section 1.3 Study flowchart 
Hematological and blood chemistry test 
frequency have been decreased after 
cycle 6 from every 2 weeks to every 4 
weeks. Footnote b, d, e, f, g, h i, l, o, z, 
and aa were modified. Footnote gg, hh, 
and ii were added. Subsequent 
footnotes were realphabetized. 
Footnotes were modified to provide 
clarity and inclusion of new footnote 
content for Arm #4 (Part H and I) 
and Arm#5 (Part J and K). 
Section 1.4.1 Arm #1, Section 1.4.2 Arm #2, 
Section 1.4.3 Arm #3, Section 1.4.4 Arm #4, 
Section 1.4.4.1 Parts H and I, Section 1.4.5 
Arm #5, 1.4.5.1 Parts J and K, 
Section 1.4.5.1.1 Parts J and K full PK 
sampling, Section 1.4.5.1.2 Part K, sparse PK 
sampling, Section 4.4.1 Arm #1, Section 4.4.2 
Arm #2, Section 4.4.3 Arm #3, Section 4.4.4 
Arm #4, Section 4.4.5 Arm #5, Section 13.2 
Arm #1, Section 13.3 Arm #2, Section 13.4 
Arm #3, Section 13.5 Arm #4, and 
Section 13.6 Arm #5 
A new section for each study arm 
corresponding to a study part was 
created. Subsequent sections were 
reordered.  
These sections were created in 
order to provide more organization 
and clarity throughout the document. 
Section 1.4.1.1 Part A 
Footnote d modified to only include 
FDG for Part A BID patients only. 
The footnote was modified for 
clarification. 
Section 4.1 Introduction 
New content added on BOLERO-2 
study. Reference was updated 
accordingly. 
This content and reference was 
added in order to provide more 
context to the study. 
Section 4.4 Rationale for the study and Section 
9.1 Safety 
Everolimus and abemaciclib were 
added as part of the section. 
Everolimus and abemaciclib was 
added in order to reflect the new 
study design. 
Section 4.4.3.1 Part F (Safety run-in phase 
with alpelisib) 
Statement of fulvestrant sharing the 
same mechnism of action as 
amecenestrant was added. Cross over 
design content was removed.  
This content was added to provide 
further clarify of the mechanism of 
action of fulvestrant. 
Section 6.2.1 Starting dose and dose levels 
Footnote a was added and subsequent 
footnotes realphabetized. Footnote d 
was updated. 
Footnote a was added and footnote 
d was modified in order to provide 
consistency with the clinical trial 
summary. 
Section 6.3 Maximum Adminstrated 
Dose/Maximum Tolerated Dose 
Arm #4 and #5 (Parts H and J) were 
included. 
This content was added to reflect 
the new study design. 
Section 6.2.2 Dose escalation Arms #1, #2, #4, 
and #5 (Parts A, C, H, and J) and Safety Run-
in Arm #3 (Part F) strategy 
Corresponding Arm #4 (Part H) and #5 
(Part J) added to the title. Statement 
referencing BID regimen for Part A and 
Part C was removed. Sample size for 
Arm #3 (Part F),Arm #4 (Part H)  and 
Arm #5 (Part J) was updated to 
12 patients. 
This content was added to reflect 
the new study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5 Dose delays modification  
New content and Table 8 for everolimus 
and abemaciclib were added.  
This content was added to reflect 
the new study design and dose level 
reduction for everolimus and 
abemaciclib. 
Section 6.5.2 Arm #3 Dose modification in 
Parts F and G 
Details on hypersensitivity was added. 
Table 12 content and footnotes were 
modified. 
New content was added in order to 
further describe hypersenstivity 
symptoms and dose modifications 
for CTCAE grades.  
Section 6.5.3 Arm#4 Dose modification in 
Parts H and I 
New section added for Arm #4 Parts H 
and I. Tables 13 and 14 were added 
and subsequent tables were 
renumbered. 
This content was added to describe 
dose modifications and 
management in Arm #4 Part H 
and I. 
Section 6.5.4 Arm #5 Dose modification in 
Parts J and K, 
New section added for Arm #5 Parts J 
and K. Table 15 and 16 were added 
and subsequent tables were 
renumbered. 
This content was added to describe 
dose modifications and 
management in Arm #5 Part K and J 
Section 6.7 Guidelines for management of 
adverse events 
Examples of clinical data available for 
amcenestrant was added. 
This content was added to provide 
examples of clinical data available. 
Section 6.9 Interim analysis and Section 13.10 
Interim analysis 
Interim analysis for Arm #2 and #4 
Parts D and G and BID regimen for Arm 
#1 Part B was removed. 
This content was removed because 
an interim analysis is no longer 
planned for these study parts. 
Section 8.4 Storage conditions and shelf life 
Content regarding temperature storage 
was removed. 
Specific temperature storage was 
removed because compound will be 
managed according to the 
Pharmacy Manual provided by the 
Sponsor. 
Section 8.5.1 Treatment accountability and 
compliance 
Text regarding everolimus and 
abemaciclib added. 
The new text was included to 
specifiy all unused medication from 
the study must be returned at the 
end of treatment. 
Section 8.6 Concomittant treatment 
Content regarding concomittant 
medications in treatment arms updated. 
Concomittant medications related to 
new study parts added.  
This content was updated to include 
new information regarding 
concomittant medications in the 
treatment arms. 
Section 9.2.1 Sampling time and sample blood 
volume, Section 9.2.2 Pharmacokinetic sample 
handling procedure and Section 9.5 Sampled 
blood volume 
New content was added in tables for 
blood samples and volume for Arm #4 
and #5 Parts H, I, J, and K. Subsequent 
table numbers renumbered. 
This content was added in order to 
show sampled blood volume per 
patient and sample handling in Arm 
#4 and #5 Parts H, I, J, and K.  
Section 9.2.3 Bioanalytical method, Section 
9.2.5 Pharmacokinetic parameters, Section 
13.9.5 Analyses of pharmacokinetic and 
pharmacodynamic variables 
New content added for bioanalytical 
methods for everolimus and 
abemaciclib and its metabolites. 
This content was added to include 
additional bioanalytical methods due 
to the new study design. 
Section 9.5 Sampled blood volume 
PD sample (cfDNA for mutational 
profiling) was updated for Arm #3 
Parts F and G. 
The table was updated to reflect the 
4 samples needed for cfDNA 
mutational profiling. 
Section 10.5.5 Adverse event of special 
interest and Section 10.6 Obligations of the 
sponsor 
Details on investigation in case of 
ALT ≥Grade 3 and new AESI 
photosensitivity were added. 
The list of AESIs was updated in 
order to provide additional details on 
AEs relevant to the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.2 Baseline evaluation 
Text regarding PIK3CA mutation 
determination for Arm #3 (Part F and G) 
was removed. 
Content removed due to 
redundancy. It was mentioned in a 
separate portion of the protocol. 
Section 12.2 Baseline evaluation, Section 
12.4.4 Cycle 1, between Day 11 and Day 15 
(Arm #1 Part A only) 
Content modified to show 18F-FES-PET 
scan will be done for Part A QD and 
BID and FDG PET/CT will only be done 
for Part A BID. 
This content was added in order to 
clarify which scans would be done 
for Part A QD and BID. 
Section 12.2 Baseline evaluation and Section 
12.6 End of treatment visit (to be performed 
between 22 and 30 days after the last 
administration of the study treatment)   
Laboratory assessment to include Parts 
H and I. 
This content was added to include 
assessments done in Parts H and I. 
Section 12.5.5 Subsequent cycles (up to and 
including C6), Day 15 (±2 days) and Section 
12.5.6 Subsequent cycles (starting from C7 
and onwards), Day 1 (±2 days) 
New section added for subsequent 
cycles. Following sections were 
renumbered. 
This content was added in order to 
provide additional  subsequent 
cycles during the study. 
Section 12.5.6.2 Additional tests for Arms #3 
and #4 (Parts F, G, H, and I) 
New section added for additional tests 
done for Arms #3 (Parts F and G) and 
#4 (Parts H and I). Subsequent 
sections renumbered. 
This section was added in order to 
reflect the new study design. 
Section 13.9.5.1 Analyses of pharmacokinetic 
variables 
Content regarding everolimus and 
abemaciclib added. 
This content was added to reflect 
the new study design. 
Section 13.9.5.2 Analyses of 
pharmacodynamic variables  
New section added for analyses of 
pharmacodynamic variables. 
Subsequent sections renumbered. 
This section was added for 
organization purposes and to 
provide a separate section regarding 
pharmacodynamic variables. 
Section 18 Bibliographic references 
New reference added and updated. 
This section was updated to include 
new sources referenced in the body. 
Section 19 Appendix E List of CYP3A4 
Prohibited Modulators 
Content updated to reflect 
strong/moderate CYP3A4 inhibitors are 
not permitted in Arm #4. 
This section was modified to prevent 
a drug drug interaction in Arm #4. 
Section 19 Appendix F List of CYP substrate 
with a narrow therapeutic range and list of 
substrates mainly metabolized by 
CYP3A/2B/2C/UGT 
Table for drugs mainly metabolized by 
CYP3A, CYP2Cs and/or UGTs 
updated. 
This content was updated to show 
reflect a current list of drugs that are 
sensitive substrates of CYP3A, 
CYP2Cs and/or UGTs. 
Section 19 Appendix H In vivo inhibitors of P-
gp probes  
New appendix added. Subsequent 
appendix re-alphabatized. 
This new appendix was added to 
include a list of in vivo inhibitors of 
P-gp probes. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
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Amendment [08] [30 October 2020] 
This Amended Protocol 08 (Amendment 08) 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. 
The objective of the amendment is to: 
1. Modify description of alpelisib formulation throughout the protocol in accordance with the 
change in supply from the commercial material to the clinical trial material. 
2. Remove study Part E with midazolam. The part E of the study was planned to assess the 
interaction of SAR439859 at 200 mg and 400 mg with midazolam. Considering that 
results obtained in a separate study in healthy volunteers are satisfactory for the 
midazolam and SAR439859 interaction, Part E of the TED14856 study is closed and, 
therefore, removed from the objective of this study.  
3. Modify study design of Part F (combination with alpelisib) from dose escalation to the 
safety run-in phase which will explore combination of the approved (standard) dose of 
alpelisib (300 mg QD) with SAR439859 200 mg QD dose as selected dose for 
combination therapy of SAR439859 and other agents, with an option, if needed, to test 
additional doses of SAR439859 (eg, 300 mg QD or 400 mg QD etc.) depending on safety 
and pharmacokinetics profile of the combination. SAR439859 400 mg QD was established 
as the recommended dose for monotherapy in heavily pretreated patients; however, the 
dose of 200 mg QD of SAR439859 in combination with targeted therapy may be optimal 
dose based on the pharmacodynamic results observed so far on 18F-FES-PET scans with 
almost 90% of ER inhibition and, therefore, the goal is to confirm this dose in combination 
with alpelisib (Part F).  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Study name AMEERA-1 was added on 
title page. 
Title page was updated to provide the 
study’s name.  
Global 
Part E Midazolam has been removed 
throughout the study protocol and 
subsequent sections, tables, and 
footnotes were renumbered 
accordingly. Dose escalation of Part F 
was changed to safety run-in 
throughout the document. 
This content was updated to reflect 
new study design and provide clarity.  
Clinical Trial Summary and Section 4.4.4 
Part D (dose expansion, combination with 
palbociclib), Section 4.4.6 Part G (dose 
expansion, combination with alpelisib), 
and Section 6.2.1 Starting dose and dose 
levels 
Sentence “Intra-patient dose escalation 
or re-escalation of any study drug is not 
allowed” was added.  
This content was added in order to 
provide clarity in the study design.  
Clinical Trial Summary and Section 6.2.1 
Starting dose and dose levels 
In Part A , dose re-escalation will not 
be permitted.  
This content was updated in order to 
provide clarity in the study design.  
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary and Section 5.1 
Primary Objectives 
Safety run-in Part F primary objective 
was modified. In Part B, ICR was 
added. 
This content was modified in order to 
provide clarity.  
Clinical Trial Summary and Section 6.1 
Description of the Study 
Clarification of study design was made.  
This content was added to provide 
clarity and consistency with the new 
study design. 
Clinical Trial Summary and Section 6.2.1 
Starting Dose and Dose Levels 
Part A additional dose exploration  and 
Part F study description was modified. 
New decision tree was added. Dose 
level in Table 4 and Table 3 were 
removed. Subsequent table numbers 
renumbered.   
This content was modified to provide 
consistency in study design. Decision 
tree was added in order to provide 
further details about the study design.  
Clinical Trial Summary and Section 6.8.1 
Duration of Study Participation for Each 
Patient 
Expected enrollment period, cycles of 
treatment, and COD were updated. 
This content was updated to reflect 
new study design.  
Clinical Trial Summary and Section 7.2 
Inclusion Criteria 
I06 and I12 was modified. 
This content was modified to provide 
new information/clarification and 
consistency in the study design.  
Clinical Trial Summary and Section 7.3 
Exclusion Criteria 
Part E exclusions are removed per 
amendment 08. E13, E20, E31, and 
E33 were modified. New exclusion 
criteria E34 was added. 
This content was modified to provide 
clarification and consistency in the 
study design. A new exclusion criteria 
was added as per requirement for 
Parts F and G. 
Clinical Trial Summary and Section 
8.1.2.1 SAR439859 
In Part F and G, dose modified from 
400 mg to 300 mg QD. Statement 
added to address taking study drugs in 
a fed or unfed condition.  
The dose was modified to reflect 
changes in the design plan. New 
information added in order to explain 
which study drugs are to be taken with 
or without food.  
Clinical Trial Summary, Section 8.1.1.3 
Alpelisib and Section 8.1.2.3 Alpelisib  
Alpelisib clinical supply was modified.  
This content was modified to reflect 
alpelisib clinical supply type in the 
study.  
Clinical Trial Summary endpoints 
Specification for primary endpoints in 
part A, C and F was added if additional 
patients were enrolled.  
This content was added to provide 
consistency in study design. 
 
 
Clinical Trial Summary and Section 
13.1.5 Sample Size of the Safety Run-in 
Part for SAR439859 in Combination with 
Alpelisib (Part F) 
Header and study design updated. 
This content was modified and updated 
to be consistent with the new study 
design. 
Section 1.1: Graphical Study Design - 
Dosing Scheme 
Part F dosing scheme was updated. 
This content was updated to reflect 
new study design. 
Section 1.2 Graphical Study Design – 
Study Scheduling 
PIK3CA testing Period (F&G) was 
added to the diagram and new footnote 
added.  
This content was added as new 
information for pre-screening for parts 
F and G only.   
Section 1.3: Study Flowchart 
Study flowchart updated.  
Footnote bb and dd were removed and 
subsequent footnotes were reordered.  
This content was added and updated 
to provide clarity and consistency 
within the study design.  
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Section # and Name 
Description of Change 
Brief Rationale 
Footnotes g, h, i, l, r, y, z aa, and dd 
were updated. New footnotes, ee and 
ff, were added.  
Section 1.4.1 Part A  
Analysis for pharmacodynamics in 
plasma was updated. 
New row for saliva collection added 
and footnote e updated.  
This content was added to provide 
clarity and consistency in study design. 
 
Section 1.4.2.1 Part B Full PK Sampling 
Analysis for pharmacodynamics in 
plasma was added. New footnote and 
row for saliva collection added. 
Footnote f was updated.  
This content was added to provide 
clarity and consistency in study design. 
Section 1.4.2.2 Part B Sparse PK 
Sampling 
Analysis for pharmacodynamics in 
plasma was added. 
New footnote for saliva collection 
added. Footnote d was updated.  
This content was added to provide 
clarity and consistency in study design. 
 
 
Section 1.4.3.1 Part C and D Full PK 
Sampling and Section 1.4.4.1 Full PK 
Sampling (Part F and G) 
Analysis for pharmacodynamics in 
plasma was added. New footnote and 
row for saliva collection added. 
This content was added to provide 
clarity and consistency in study design.  
 
Section 1.4.3.2 Part D Sparse PK 
Sampling 
Analysis for pharmacodynamics in 
plasma was added. Footnote c was 
updated.  
This content was added and updated 
to provide clarity and consistency in 
study design. 
Section 1.4.4 Part F and G 
Clarification made on analysis used for 
Part F and G. 
This content was added to provide 
clarity and consistency in study design. 
Section 1.4.4.2 Sparse PK sampling 
(Remaining patients in Part G) 
Analysis for pharmacodynamics in 
plasma and footnote related to it was 
updated. 
This content was added to provide 
clarity and consistency in study design. 
Section 4.1 Introduction  
BYLieve study was added. References 
were updated accordingly.  
This content was added to provide 
clarity.  
Section 4.3.1 Preclinical Data 
Text was added related to BCRP 
sensitive substrates. 
This content was added to provide 
consistency. 
Section 4.4.5 Part F (Safety run-in phase 
with alpelisib)  
Additional content on the BYLieve 
study, additional text regarding 
exploring of SAR439859, and alpelisib 
doses were added. 
This content was added to provide 
more information on adverse events 
and exploration of SAR439859 and 
alpelisib doses.  
Section 6.3 Maximum Adminstration 
dose/Maximum Tolerated Dose 
MAD definition updated. 
This content was updated to provide 
consistency. 
Section 6.2.2 Dose Escalation (Parts A 
and C) and Safety run-in (Part F) 
Strategy 
Header title was modified and 
enrollment plan of patients in Part F 
was updated. 
This content was modified to improve 
clarity and provide new information on 
enrollment plan. 
Section 6.5 Dose delays/Modification 
Sentence “Therefore, no cycle delay is 
defined in any study parts” was 
removed. 
This content was removed to provide 
consistency.  
Section 6.5.2 Dose Modification in parts 
F and G  
Clarification regarding dose 
modifications was made in table 10. 
Footnote b was updated.  
This content was added to provide 
clarity and consistency in study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6 Expansion Cohorts to 
Confirm the Maximum Tolerated Dose 
Deleted text “+ additional 34 if 
randomization is used in Part G; total 
339”.  
This content was deleted in order to 
provide consistency in the study 
design.  
Section 6.8.1 Duration of Study 
Participation for Each Patient 
Statement added for testing PIK3CA 
status in patients who have  never 
undergone PIK3CA testing for parts F 
and G only.  
This content was added to provide 
additional information regarding 
eligibility in the study for parts F and G 
only.   
Section 8.1 Investigational Medicinal 
Product 
New statement added to address direct 
to patient delivery option. Appendix I 
added as a reference.  
This content was added to provide 
information regarding the study drug’s 
Direct to Patient delivery option.  
Section 8.4 Storage conditions and shelf 
life 
Storage condition for alpelisib was 
updated. 
This content was modified based on 
alpelisib’s storage conditions.  
Section 8.6 Concomitant Treatment 
Drug-drug interactions with alpelisib 
were described. Appendix G added as 
a reference.  
Appendix G and drug drug interactions 
with aleplisib was added to provide 
caution for drug interactions.  
Section 9.2.2 Pharmacokinetic sample 
handling procedure 
Part G was added to Table 21 header. 
Table 23 was removed in order to 
reflect new study design. The header 
for Table 21 was updated to include 
Part G to provide consistency within 
the study design.  
Section 9.2.3 Bioanalytical Method 
Table 22 header was modified.  
This content was updated in order to 
provide consistency with new study 
design.  
Section 9.3.1 Optional drug Metabolizing 
Enzymes and Transporters DNA sample 
Clarification of sampling used to 
investigate phArmacogenitic variability 
related to ADME of SAR439859 on 
PK/PD. 
This content was updated to provide 
clarity.  
Sectin 9.4.3 Mutational Profiling in 
Circulating Free DNA 
ESR1 pathway added to list of genes.  
The pathway was added to provide an 
example of an additional gene that will 
be analyzed.  
Section 9.4.4 Tumor biopsy to assess 
Estrogen Receptor Degradation (Part A 
BID, Part B, F and G) 
Added part G to header. 
This content was updated to be 
consistent with study design. 
Section 9.5 Sampled Blood Volume 
Removed PK sample SAR439859 
(sparse PK). Updated PD sample 
(estradiol) volume per sample, volume 
per patient, total number of samples 
and footnote c.  
Table was updated to provide 
consistency with the study design.  
Section 9.7.1 Criteria for response 
(antitumoral activity) 
Tumor assessment updated. 
This content was updated to provide 
additional information and clarification 
on when tumor assessment will occur.  
Section 10.5.5 Adverse Event of Special 
Interest 
A new AESI was added. 
This content was modified to provide 
an additional AESI in the study.  
Section 10.5.6 Laboratory Abnormalities  
DLTs were added as laboratory 
abnormalities.  
 This content was modified to provide 
further clarification on what should be 
considered a laboratory abnormality.  
Section 11.1.2 Handling of Patients After 
Permanent Treatment Discontinuation 
Clarification of handling patients after 
permanent discontinuation made.  
This content was updated to be 
consistent with study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 11.3 Criteria for Temporarily 
Delaying  
This is a new section to Amended 
Protocol 08 for contingency measures 
for temporarily delaying study. 
This content was added to provide 
contingency measures. 
Section 12.2 Baseline Evaluation 
Clarification for Part F and G added to 
coagulation assessment and in blood 
chemistry. Additional content provided 
for PIK3CA Testing ICF for Part F and 
G.   
This content was added to provide 
clarity and consistency with study 
design.  
Section 12.4.1 Cycle 1, Day 1 
Updated PK/PD blood sample 
collection details. 
This content was updated in order to 
provide clarity. 
Section 12.5.4.1 Every 8 weeks 
Tumor evaluation and details of 
Hemoglobin A1C assessment was 
updated.  
This content was updated to provide 
additional information.  
Section 12.6 End of treatment visit (to be 
performed between 22 and 30 days after 
the last administration of the study 
treatment 
Laboratory assessments for 
coagulation and blood chemistry 
updated.   
This content was updated to provide 
additional details regarding coagulation 
and blood chemistry.  
Section 12.8 Post Study Cut-Off Period 
Clarification of post study treatments 
were made. 
This content was modified in order to 
clarify  the post study treatment and 
follow up.  
Section 13.1 Determintation of Sample 
Size 
Clarification of sample size was made. 
This content was modified to clarify 
and provide the number of patients that 
will be enrolled.   
Section 13.1.5 Sample size of the safety 
run-in part for SAR439859 in combination 
with alpelisib (Part F) 
Header and number of patients were 
updated. Reference to Section 6.2.1 
decision tree added.  
This content was updated in order to 
provide further information and 
consistency for Part F.  
Section 15.6 Data Quality Assurance 
This is a new section to Amended 
Protocol 08 for monitoring source data.  
This content was added to provide 
monitoring details. 
Section 18 Bibliographic references 
Updated references. 
This content was updated to be 
consistent with the new added 
reference. 
Appendix E List of CYP3A4 and CYP2C8 
prohibited modulators 
Weak CYP3A inhibitors and weak  
CYP3A inducers were removed from 
the appendix. 
This content was removed because 
Part E was cancelled.  
Appendix I Contingency Measures for a 
Regional or National Emergency that is 
Declared by a Governmental Agency 
New appendix for Amended Protocol 
08 added for contingency measures for 
a regional or national emergency that is 
declared by a governmental agency. 
This content was added to provide 
contingency measures. 
Appendix G List of BCRP Inhibitors, 
CYP2C9 Substrates and P-gp, BCRP 
and OAT3 Substrates 
New appendix for Amended Protocol 
08 added for BCRP inhibitors, CYP2C9 
substrates and P-gp, BCRP and OAT3 
substrates. Susequent appendix 
numbers were renumbered 
accordingly.   
This content was added to provide a 
list of concomitant medications that 
should be avoided.  
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Amendment 07 [03 April 2020] 
This amended protocol 07 (Amendment 07) 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. 
The objective of the amendment is to: 
1. Modify treatment options in Part E (midazolam drug-drug interaction part) after Cycle 1 in 
order to facilitate recruitment, ie, from Cycle 2, investigators will have the option to either 
select the RD of monotherapy (ie, SAR439859 400 mg QD single agent) or the RD of the 
combination therapy with palbociclib (ie, SAR439859 200 mg QD + palbociclib 125 mg 
QD) or in combination with alpelisib (at RD for Part G). 
2. Explore the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of the 
combination of SAR439859 with alpelisib (PIQRAY®). 
Alpelisib (PIQRAY®) has recently been approved by the FDA for the treatment of 
postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal 
growth factor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer 
following progression on or after an endocrine therapy. 
In the newly added study cohorts (Parts F and G) of this study, alpelisib will be used at the 
approved dose level, 300 mg QD by oral route (as per label, permitted dose reductions, if needed) 
in combination with SAR439859.  Two dose levels of SAR439859: 200 mg QD and 400 mg QD 
by oral route will be tested. The effect of SAR439859 on alpelisib’s PK will be explored with a 
first step with 3-day dosing of alpelisib alone followed by continuous co-administration with 
SAR439859 in 28-day cycles. This combination will be investigated in dose escalation (Part F) 
and dose expansion (Part G) study parts. Dose escalation will explore safety, PK and PD profile of 
the SAR439859 and alpelisib combination, and dose expansion (Part G) will assess safety, 
tolerability and the preliminary antitumor activity of the combination. Upon completion of the 
dose escalation, a decision from the Study Committee about recommended dose for dose 
expansion will be made based on safety, PK and PD profile of the combination. A 
single-sequence cross-over design is proposed to determine the effect of SAR439859 on alpelisib 
between two timepoints in Cycle 1 Day 3 (alpelisib alone) and Cycle 1 Day 22 (alpelisib in 
combination with SAR439859). This will be done for each dose level of SAR439859. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page and tabulated clinical trial summary 
Changed palbociclib to other anti-
cancer therapies in the title. 
To be consistent with the updated 
study design. 
Tabulated clinical trial summary, Section 1.1 
Graphical study design -Dosing scheme, 
Section 1.2 Graphical study design - Study 
scheduling, Section 1.3 Study flow chart, and 
Section 1.4.5 Part F and G PK sampling, and 
Section 4.4.6 Part F (dose escalation, 
combination with alpelisib), Section 4.4.7 Part 
G (dose expansion, combination with alpelisib), 
Section 6.10 Study committees 
Updates made to include Part F 
and G. 
Details added for the new study 
design. 
Tabulated clinical trial summary, Section 1.1 
Graphical study design -Dosing scheme, 
Section 1.2 Graphical study design - Study 
scheduling, Section 1.3 Study flow chart, 
Section 1.4.4, Part E PK sampling, Section 
6.2.1 Starting dose and dose levels, and 
Section 8.1.2.1 SAR439859 
Added new dosing options after 
Cycle 2 in Part E. 
To be consistent with the updated 
study design. 
Tabulated clinical trial summary, and Section 
5.1 Primary Objective 
Added new objectives for Part F 
and G. 
Details added for the new study 
design. 
Tabulated clinical trial summary, Section 5.2 
Secondary objectives 
Updated this section to include 
Part F and G. 
Details added for the new study 
design. 
Tabulated clinical trial summary, Section 5.3 
Exploratory objectives 
Updated this section to include 
Part F and G. 
Details added for the new study 
design. 
Tabulated clinical trial summary, Section 6.1 
Description of the study, Section 6.2.1 Starting 
dose and dose levels, Section 6.2.2 Dose 
escalation strategy, Section 6.3 MAD/MTD and 
Section 8.1.1.3 alpelisib, Section 8.1.2.1 
SAR439859 and Section 8.1.2.4 Alpelisib 
Added details of SAR439859 and 
alpelisib administration in Part F 
and G. 
To assess the new study part as 
described above. 
Tabulated clinical trial summary, Section 9.4.2 
Estrogen receptor 1 gene mutation status, 
Section 9.4.3 mutational profiling in cfDNA and 
Section 9.4.4. tumor biopsy to assess ESRD  
Updates made to include Part F 
and G. 
Details added for the new study 
design. 
Section 4.1 Introduction 
Updated the Introduction with 
alpelisib information. 
To be consistent with the new study 
design. 
Section 6.5.2 Dose delays and modifications in 
Parts F and G 
Added alpelisib dose delays. 
For simplification and for alignment 
with alpelisib label. 
Tabulated clinical trial summary and Section 
6.8.1 Duration of study participation for each 
patient  
Updated the enrolment period time 
and included cycle durations for 
Part F and G. 
Based on the new study design for 
Part F and G. 
Tabulated clinical trial summary and Section 
7.2 Inclusion criteria 
Modified I01. 
Modified as per alpelisib label. 
Tabulated clinical trial summary and Section 
7.2 Inclusion criteria 
Modified I05. 
For clarification of inclusion criteria 
specific for Part G. 
Tabulated clinical trial summary and Section 
7.2 Inclusion criteria 
Modified I06 to include Part F. 
For clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary and Section 
7.2 Inclusion criteria 
Added new inclusion criteria I12. 
As per requirement in Parts F and G. 
Tabulated clinical trial summary and Section 
7.3.2 Exclusion criteria related to the disease 
Added new details to Exclusion 
Criteria E13 for Part G. 
For clarification on the exclusion 
criteria specific for Part G. 
Tabulated clinical trial summary, Section 7.3.2 
Exclusion criteria related to the disease 
Modified Exclusion criteria E20. 
For consistency with other 
SAR439859 studies. 
Tabulated clinical trial summary and Section 
7.3.2 Exclusion criteria related to disease 
Modified E22, E23 and E24. 
For clarification. 
Tabulated clinical trial summary and Section 
7.3.2 Exclusion criteria related to disease 
Added new exclusion criteria E30, 
E31, E32 and E33 for Part F and G 
only. 
As per the dosing label for alpelisib. 
Tabulated clinical trial summary  
Updated expected number of sites. 
Change in sample size. 
Section 8.6 Concomitant treatment 
Updated section to include 
prohibited medication as per 
alpelisib label and update the 
prohibited medications for 
SAR439859. 
As per new study design for Part F 
and G. 
Tabulated clinical trial summary, Section 
1.4.5.1 and 1.4.5.2 PK and PD flow chart, 
Section 9.2.1 Sampling time and sample blood 
volume, Section 9.2.2. PK sample handling 
procedure, Section 9.2.3 Bioanalytical method, 
Section 9.2.5 PK parameters, Section 9.5 
Sampled blood volume, Section 13.4.5 
Analyses of PK and PD variables 
Updated the PK sampling schedule 
to include Part F and G and added 
PK parameters for Part F and 
added alpelisib bioanalytic 
methods. 
To include the Part F and G study 
design. 
Tabulated clinical trial summary and 
Section 9.1.1 DLT  
Added new DLT criteria for Part F 
only. 
As per alpelisib label. 
Tabulated clinical trial summary, 
Section 8.1.1.3 alpelisib and Section 8.1.2.4 
Alpelisib,  
Added alpelisib administration, 
formulation. 
New details added as per study 
design for Part F and G. 
Tabulated clinical trial summary, Section 6.6 
Expansion cohorts to confirm the MTD, 
Section 13.1 Determination of sample size, 
Section 13.1.6 Sample size of the dose 
escalation phase for SAR439859 in 
combination with alpelislib (Part F) and Section 
13.1.7 Sample size expansion phase 
combination with alpelisib (Part G) 
Updated the sample size number to 
include Part F and G. 
To include Part F and G new study 
design. 
Section 1.3 Flowchart and Section 12.1 Visit 
Schedule 
Changed visit structure from Cycle 
7 onwards to only have monthly 
visit. 
To simplify study visits requirement 
for patients after first 6 cycles of 
treatment as per patients’ feedback. 
Section 12.2 Baseline evaluation, Section 12.4. 
During the treatment period in Cycle 1 and 
Section 12.5 During subsequent cycles 
Updates made to include Part F 
and G. 
Details added for the new study 
design. 
Section 6.9 Interim analyses and Section 13.5 
interim analyses 
Updated with Part G information. 
To align with the new study design. 
Section 13.2 Patient description, and 
Section 13.4.2 Extent of IMP exposure  
Added Part F and G. 
To align with the new study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary and Section 13.4.5 
Analyses of PK and PD variables 
Added details for alpelisib. 
To align with new study design for 
Part F and G. 
Section 18 Bibliographic references 
Updated references. 
Consistent with the new added text. 
Global 
Added clarifications for testing in 
different parts of the study. 
To improve clarity. 
Amendment 06 [02 October 2019] 
This amended protocol (amendment 06) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it either significantly impacts the safety or physical/mental integrity of 
participants or the scientific value of the study. 
This amendment has been issued to implement safety monitoring measures following 
identification of a new risk related to palbociclib. Palbociclib may increase the risk of interstitial 
lung disease (ILD)/ pneumonitis as per recent FDA communication and the United States 
Prescribing Information (USPI) update in September 2019 and the Canada Product Monograph of 
Palbociclib (IBRANCE®) update in August 2019. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5 Dose delays and 
modifications 
Addition of measures for 
management of suspected or 
confirmed ILD/Pneumonitis for 
patients treated in Part C and D. 
Implementation of safety monitoring measures 
following identification of new risk identified for 
palbociclib. 
Amendment [5] [02 August 2019] 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it either significantly impacts the safety or physical/mental integrity of 
participants or the scientific value of the study. 
This amendment has two objectives:  
1. To add a new study part (Part E) which will assess the effect of SAR439859 on CYP3A 
enzyme activity by using midazolam as a probe in a new cohort of patients. The selection 
and assessment criteria for Part E will remain the same as in Part A and B but with the 
omission of the pilot food effect as well as FES-PET and FDG-PET scan. 
2. To add a new option and to modify the selection criteria in Part D (details below).  
Part D of this study has been modified and simplified by adding a randomized two-Arm option 
(potentially in replacement of the single Arm currently present in the protocol), depending on 
a decision at the end of Cycle 1 of Part C. The aim of Part C is to select the recommended dose of 
the SAR439859 and palbociclib combination based on the safety and pharmacokinetic (PK) data. 
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Two doses of SAR439859, 200 mg and 400 mg combined with one dose of palbociclib 125 mg 
have been studied in Part C in the first 6 patients. There was no DLT observed for these two doses 
and the combination was well tolerated. The preliminary PK results from Part C in these patients 
(3 patients per dose level) indicated a possible decrease of palbociclib exposure when given with 
SAR439859. A decision was made by the Study Committee to treat 6 additional patients at the 
same two dose levels (3 patients per dose) in order to have a supplementary PK data to analyze 
this potential drug-drug interaction. When the last patient (ie, 12th patient) in Part C completes 
Cycle 1, the Study Committee will determine at least 1 RD for Part D primarily based on DLTs, 
overall safety at all cycles (early and late toxicities), PK and antitumor activity data. The Study 
Committee may decide to select more than one RD for evaluation in Part D. Data from Part A and 
Part B may also be considered as applicable in decision making of the RD dose for Part D. If more 
than 1 dose is selected for Part D, patients will be manually randomized to each dose.  
The selection criteria for Part D have also been revised. The current Part D selection criteria 
allows patients with multiple prior therapies and it is anticipated that allowing number of prior 
therapies will jeopardize the chance to evaluate an appropriate efficacy of the combination. 
Therefore the following selection criteria will be added for Part D only: 
• No more than 3 prior lines of therapy in the metastatic setting: no more than two hormonal 
therapies and no more than 1 line of chemotherapy. 
• The following prior therapies for advanced disease are not allowed: CDK4/6 inhibitors, 
PI3K inhibitors and mTOR inhibitors  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary, Section 
1.1 Graphical study design -Dosing 
scheme, Section 1.2 Graphical study 
design - Study scheduling, Section 1.3 
Study flow chart, Section 1.4.3 Parts C and 
D, and Section 1.4.3.2 Part D sparse PK 
sampling, and Section 4.4.4 Part D (dose 
expansion, combination with palbociclib) 
Updates made to Part D. 
Updated study design based on the 
results of Part C as described above. 
Tabulated clinical trial summary, Section 
1.1 Graphical study design -Dosing 
scheme, Section 1.2 Graphical study 
design - Study scheduling, Section 1.3 
Study flow chart, and Section 1.4.4 Part E 
PK sampling, and Section 4.4.5 Part E 
(midazolam drug drug interaction) 
Updates made to include Part E. 
To assess the effect of SAR439859 on 
CYP3A enzyme activity by using 
midazolam as a probe. 
Tabulated clinical trial summary, and 
Section 5.1 Primary Objective 
Updated primary objective for Part D 
and added new objective for Part E. 
Details added for the new study design. 
Tabulated clinical trial summary, Section 
5.2 Secondary objectives 
Updated this section to include Part E 
and new Part D study design. 
For consistency. 
Tabulated clinical trial summary, Section 
6.1 Description of the study, Section 6.2.1 
Starting dose and dose levels, and Section 
8.1.2.1 SAR439859 
Added details of the SAR439859 
administration in Part E. 
To assess the new study part as 
described above. 
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Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary and 
Section 6.8.1 Duration of study participation 
for each patient  
Updated the enrolment period time 
and the cut-off-date for Part D. 
Based on the new study design for 
Part D. 
Tabulated clinical trial summary and 
Section 7.2 Inclusion criteria 
Modified I05. 
To be consistent with the new selection 
criteria for Part D. 
Tabulated clinical trial summary and 
Section 7.2 Inclusion criteria 
Removed I12 and added it as a part 
of I06. 
For clarity. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
Removed E12. 
Preclinical toxicity data with 
SAR439859 has not shown signal of 
endometrial disorders. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
Modified Exclusion criteria E20 to 
include probenecid. 
For consistency with other SAR439859 
studies. 
Tabulated clinical trial summary, Section 
1.4.1 Part A and Section 7.3.2 Exclusion 
criteria related to the disease 
Modified E21. 
To include Part A (BID) in 4B-OH 
cholesterol test. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
disease 
Modified E22. 
To improve clarity. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
disease 
Added new exclusion criteria E25 for 
Part D only. 
Based on the new selection criteria for 
Part D as discussed above. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
Added new exclusion criteria E26, 
E27, E28 and E29 for Part E only. 
As per the dosing label for midazolam. 
Tabulated clinical trial summary  
Updated expected number of sites. 
Change in sample size. 
Section 1.3 Study flow chart, Section 6.8.1 
Duration of participation for each patient 
and Section 12.6 end of treatment visit 
Added details on follow-up after 
further therapy is initiated before D22 
or after study treatment 
discontinuation. 
For clarity. 
Section 8.6 Concomitant medication 
Updated section to include prohibited 
medication as per midazolam label 
and update the prohibited 
medications for SAR439859. 
As per new study design for Part E. 
Tabulated clinical trial summary, Section 
1.4 PK and PD flow chart, Section 9.2.1 
Sampling time and sample blood volume, 
Section 9.2.2. PK sample handling 
procedure, Section 9.2.3 Bioanalytical 
method, Section 9.2.5 PK parameters, 
Section 9.5 Sampled blood volume, Section 
13.4.5 Analyses of PK and PD variables 
Updated the PK sampling schedule to 
include Part E and added PK 
parameters for Part E and added 
midazolam bioanalytic methods. 
To include the Part E study design. 
Tabulated clinical trial summary, Section 
7.3.2 exclusion criteria related to disease 
and Section 12.2 Baseline evaluation 
Added GGT to E17 and 
correspondingly added GGT testing 
at baseline. 
Based on new safety findings. 
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Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary, Section 
8.1.1.3 midazolam, Section 8.1.2.3 
Midazolam, Section 12.3 Before first IMP 
administration 
Added Midazolam administration, 
formulation and storage conditions. 
New details added as per study design 
for Part E. 
Tabulated clinical trial summary, Section 
6.6 Expansion cohorts to confirm the MTD, 
Section 13.1 Determination of sample size, 
Section 13.1.4 Sample size of the 
expansion phase for SAR439859 in 
combination with palbociclib (Part D) and 
Section 13.1.5 Sample size of midazolam 
drug-drug interaction (Part E) 
Updated the sample size number to 
include Part E and new sample size 
of Part D. 
To include Part E and Part D new study 
design. 
Section 1.4.2.2 Part B sparse PK sampling, 
Section 1.4.3.1 Part C and D full PK 
sampling, Section 1.4.3.2 Part D sparse PK 
sampling, Section 1.4.4 Part E PK sampling 
and Section 9.4.5 Estradiol 
Serum estradiol sampling added. 
To explore possible influence of 
circulating levels of estradiol on 
preliminary efficacy of SAR439859. 
Section 13.2 Patient description  
Added Part E (midazolam drug-dug 
interaction). 
To align with the new study design. 
Section 13.4.4.1 Dose limiting toxicities 
Updated the analyses section. 
To improve clarity. 
Section 6.9 Interim analysis, and 13.5 
Interim analyses 
Updated requirements for interim 
analyses in Part D. 
Based on the new study design and 
sample size, the interim analysis has 
been modified. 
Appendix E List of CYP3A4 inhibitors and 
CYP2CA inducers 
Modified and added weak CYP3A 
inhibitors, inducers and moderate 
CYP2C8 inducers. 
To align with the addition of Part E of 
the study and new requirements for 
midazolam administration. 
Global 
Added clarifications for testing in 
different parts of the study. 
To improve clarity. 
Amendment [4]: [29-Jan-2019] 
This amended protocol (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. 
Part A of the current study consisted of dose escalation of SAR439859 starting from 20 mg to 
600 mg once daily (QD). A total of 16 patients have been treated in Part A of the study. No DLTs 
were observed and the study drug has been well tolerated; the recommended dose for further 
exploration was determined at 400 mg QD based on pharmacokinetic (PK) (mainly, Ctrough at 24h) 
and pharmacodynamic results (≥90% inhibition of estrogen receptor as per 18FES-PET scan). 
The objective of this amendment is to assess the new schedule of SAR439859 administration at 
the same dose intensity as the highest tested dose of 600 mg QD but given as 300 mg twice daily 
(BID). This new schedule is an extension of the dose escalation Part A of the study. 
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Pharmacokinetic data obtained from all patients treated in Part A (n=16) were analyzed using 
a preliminary population 2-compartment PK model with lag time and showed that a BID dosing 
regimen will modify the PK plasma concentration-time profile of SAR439859 for the same total 
daily dose. The Ctrough concentrations are expected to be increased by around 1.8-fold and Cmax is 
expected to be decreased by 1.7-fold, whilst maintaining the same AUC over 24-hour period at 
steady-state. 
Finally, from PK simulation, it is anticipated that in order to optimize the likelihood of a maximal 
target inhibition, an administration of 300 mg BID would have a higher probability of ER 
saturation than 400 mg and 600 mg QD dose regimens as well as 200 mg BID by increasing 
median Ctrough up to about 900 ng/mL and reducing the peak and trough fluctuations. The schedule 
of 300 mg BID could potentially be the recommended dose for patients who have progressed after 
receiving several lines of hormonal therapies, either as monotherapy or in combination with 
targeted agents. 
It is expected that SAR439859 300 mg BID will be well tolerated since the daily dose of 600 mg 
has already been assessed with a favorable safety profile. In addition, Cmax levels with 300 mg 
BID will be decreased compared to 600 mg QD, potentially reducing the risk of adverse events 
(AEs) that are correlated with Cmax. However, in case of an occurrence of DLTs during the 
exploration of the DL5bis (300 mg BID) dose level, an assessment of the DL4bis (200 mg BID) 
will be done as per the evaluation criteria used for other previously tested Part A dose levels 
(ie, evaluation of DLT occurrence during the first cycle, PK results and 18FES-PET scan results). 
The compliance will be analyzed in order to assess the impact of a BID dosing regimen compared 
to a QD one. Moreover, the omission of one dose of SAR439859 when given once a day would be 
expected to have a negative impact on the 24-hour coverage of the estrogen receptors whereas if 
one capsule of the BID regimen is omitted, there would be less impact on the plasma 
concentration level, resulting in a decreased impact on the estrogen receptor coverage.  
This new schedule is now detailed in Part A of the protocol; the selection and assessment criteria 
will remain the same as in Part A but with the omission of the pilot food effect testing for which 
sufficient information were collected from the once-daily dosing regimen. The BID dose at 
600 mg will be split in two intakes (without omission on Day 2): 300 mg taken two times a day, 
12 hours apart (ie, 2 x 300 mg) ±1 hour and will be taken independent of food conditions.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Graphical study design -Dosing 
scheme, Section 1.2 Graphical study 
design - Study scheduling, Section 1.3 
Study flow chart, and Section 1.4 PK and 
PD flow chart, and Section 4.4.1 Part A 
(dose escalation, monotherapy 
SAR439859) 
Updates made to include the BID 
dosing regimen. 
To further assess the dosing regimen in 
a BID schedule. 
Tabulated clinical trial summary, Section 
4.4.2 Part B (dose expansion monotherapy 
SAR439859), Section 6.6 Expansion 
cohorts to confirm the MTD, Section 6.9 
Interim analysis, Section 13.1.2 Sample 
size of the expansion phase for 
SAR439859 as monotherapy (Part B) and 
Section 13.5 Interim analysis 
Added details of a potential BID 
regimen administration in Part B 
including sample size updates and 
an interim analysis in Part B. 
For clarification and consistency of the 
BID across sections. 
Tabulated clinical trial summary, Section 
4.4.3 Part C (dose escalation combination 
with palbociclib), Section 6.2.1 Starting 
dose and dose levels and Section 6.2.2. 
Dose escalation strategy (Parts A and C) 
Added clarification that a BID 
dosing regimen could be explored 
in Part C. 
For clarification and consistency of the 
BID across sections. 
Tabulated clinical trial summary, Section 
5.3 Exploratory objectives, Section 9.4.4 
Tumor biopsy to assess estrogen receptor 
degradation 
Added the biomarker Bcl-2 to the 
exploratory objective. 
To evaluate other breast cancer 
biomarkers over time. 
Tabulated clinical trial summary and 
Section 6.2.1 Starting dose and dose 
levels, Section 6.2.2. Dose escalation 
strategy (Parts A and C), Section 8.1.2.1 
SAR439859 
Added details of the BID dose 
regimen in Part A. 
To assess a new dosing schedule as 
described above. 
Tabulated clinical trial summary and 
Section 7.2 Inclusion criteria 
Modified Inclusion criteria I01. 
For clarification. 
Tabulated clinical trial summary and 
Section 7.2 Inclusion criteria 
Modified Inclusion criteria I05. 
For clarification. 
Tabulated clinical trial summary and 
Section 7.2 Inclusion criteria 
Added Inclusion criteria 12 for Part 
C and D only. 
To expand exploration in early 
progressed patients within or after 
adjuvant therapy. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
Modified Exclusion criteria E14. 
For clarification. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
Modified Exclusion criteria E17. 
For clarification. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
To specify prior therapy with 
CDK4/6 inhibitors in exclusion 
criteria E23. 
For clarification. 
Tabulated clinical trial summary and 
Section 7.3.2 Exclusion criteria related to 
the disease 
To remove strong and moderate 
CYP3A inducers in exclusion 
criteria E24. 
To correct and update. 
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Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary, Section 
1.4 PK and PD flow chart, Section 9.2.1 
Sampling time and sample blood volume, 
Section 9.5 Sampled blood volume, Section 
13.4.5 Analyses of PK and PD variables 
Updated the PK sampling schedule 
to include the BID sampling 
schedule in Parts A, B, C and D 
and follow-up in Part B and D, and 
to specify that food effect 
assessment is not needed for BID 
Schedule dose in Part A. 
To include BID patient and plan the 
PK/PD follow-up. 
Tabulated clinical trial summary, Section 
13.1 Determination of sample size, and 
Section 13.1.1 Sample size of the 
escalation phase for SAR439859 as 
monotherapy (Part A) 
Updated the sample size number to 
include the BID extension in Part A. 
To include the BID patients in Part A. 
Appendix H Pharmacokinetic and 
pharmacodynamics flow chart for Part C 
and D 
Removed this appendix. 
For consistency with new schedule. 
Appendix H Protocol Amendment History 
Added an Appendix with details of 
past protocol amendment changes 
as per the new template 
requirements. 
Added this Appendix as per the new 
template requirements. 
Global 
Minor edits and typo fixes. 
To improve clarity. 
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Amended Clinical Trial Protocol 10  
08-Dec-2021 
SAR439859-TED14856  amcenestrant 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 227 
Amendment [3]: [27-Jul-2018] 
This amendment is considered to be non-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. 
Rationale for the amendment  
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary and 
Section 8.1.1.1 SAR439859 
Removed the 10 mg formulation for 
SAR439859. 
Administrative changes/correction to 
SAR439859 10 mg dose strength. 
Amendment [2]: [23-Jul-2018] 
This amendment is not 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. 
Rationale for the amendment  
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary, 
Section 1.3 Flow Chart, 
Section 9.7.1 Criteria for 
response and Section 13.4.6 
Analyses of antitumor 
activity/efficacy analyses 
Added independent imaging 
central reading of tumor 
assessment to patients 
treated in Part B monotherapy 
expansion phase. 
Objective response rate (ORR) is the primary efficacy 
objective in Part B of the study. The purpose of this 
amendment is to introduce the evaluation of tumor 
assessment using an independent central review (ICR) 
to reduce bias, inconsistency, variability, and to enhance 
credibility of assessments, whilst ensuring interpretability 
and in view of any potential submission to a health 
authority. The primary and secondary efficacy endpoints 
will be modified to take into account the evaluation made 
by the ICR. 
Tabulated clinical trial summary, 
Section 5.2 Secondary Objectives 
and Section 13.4.6 Analyses of 
antitumor activity/efficacy 
analyses 
Added evaluation of “Time to 
first tumor response (CR, 
PR)” as a secondary objective 
in Parts B and D. 
Time to first tumor response (CR, PR), is added to allow 
efficacy comparison and alignment of SAR439859 with 
competitors, to see if the tumor response with study 
treatment is induced rapidly at first tumor evaluation or 
later. 
Tabulated clinical trial summary, 
Section 5.3 Exploratory objectives 
and Section 9.4.4 Tumor biopsy 
to assess estrogen receptor 
degradation 
Added other breast cancer 
biomarkers exploration as an 
exploratory objective. 
In addition to the analysis of ER by 
immunohistochemistry (IHC) as described in the protocol 
for patients who will consent to paired biopsies, 
additional exploratory biomarker analyses include: 
• 
Ki67 is a widely used marker of cellular 
proliferation, and Progesterone receptor (PgR) 
expression is regulated by ER activity. IHC of 
Ki67 and PgR in biopsies will be performed to 
determine the effect of SAR439859 on the 
tumor. 
• 
ER-regulated gene signature. Effects of 
SAR439859 on expression of genes regulated 
by the ER can reflect biological activity of 
SAR439859. RNA will be extracted from the 
biopsies and levels of all of the RNA expressed 
in the tumor will be assessed (with a focus on 
ER regulated genes). 
VV-CLIN-0093825 11.0

Amended Clinical Trial Protocol 10  
08-Dec-2021 
SAR439859-TED14856  amcenestrant 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 228 
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary, 
Section 1.3 Flow chart, Section 
1.4.1 Part A, Section 1.4.2 Part B, 
Section 5.3 Exploratory 
objectives, Section 7.2 Inclusion 
criteria, Section 9.4.4 Tumor 
biopsy to assess estrogen 
receptor degradation, 
Section 12.2 Baseline evaluation, 
Section 12.4.5 Cycle 1 Day 15 
and Section 12.5.4 Cycle 2 
Day 22 
Modified the study plans with 
regards to tumor biopsy. 
In order to gain a greater understanding across a larger 
number of patients than previously planned, and after 
approval of amendment 02, biopsies will be mandatory 
for all patients enrolling in Part A. The inclusion criterion 
I10 will be modified accordingly. Also, the number of 
patients with optional paired biopsies will be increased 
from 3 to at least 10 in Part B, in order to obtain more 
data on target engagement and biological activity of 
SAR439859, to explore the effect of SAR439859 on 
various biomarkers and potential correlation with clinical 
and radiological effect. The criteria I.11 will be modified 
accordingly. In addition, the timing of these biopsies will 
be modified and changes are implemented in the 
appropriate sections throughout the protocol. In order to 
ensure consistency in the assays, a central laboratory 
will be used for each of the biomarker analysis and either 
the biopsy block (preferred option) or approximately  
8 x 5-µm freshly-sectioned FFPE slices on slides (for 
IHC analysis) and 3 x 10-µm freshly-sectioned FFPE 
slices (for RNA analysis, if available) will be obtained 
from each biopsy. 
Baseline biopsy will be either a fresh biopsy (preferred) 
or a recent/archival biopsy (within past 3 months prior to 
initiation of study treatment) from a tumor site, (primary 
tumor, local recurrence or metastatic site) in order to 
most accurately capture the tumor characteristics at the 
start of the study. The on-treatment biopsy will be 
performed at the end of Cycle 2 and should be from the 
same tumor site as the baseline biopsy.  
Tabulated clinical trial summary 
and Section 7.2 Inclusion criteria 
Modified Inclusion Criteria I05 
for patients enrolled in Part B. 
Regarding chemotherapy in Part B, only one prior 
chemotherapy line for advanced disease is allowed. 
Tabulated clinical trial summary, 
Section 1.3 Flow chart, Section 
1.4.1 Part A, Section 5.3 
Exploratory objectives, Section 
7.2 Inclusion criteria, Section 12.2 
Baseline evaluation and Section 
12.4.4 Cycle 1, between Day 1 
and Day 15 (Part A only) 
Added FDG PET/CT as a 
procedure in addition to FES 
PET in Part A. 
FDG PET/CT is sensitive and specific for evaluating 
tumor response; the tumor density measurement is a 
good indicator and provides a reliable quantitative means 
of monitoring the tumor. It should be noted that a 
negative FES-PET does not rule out the presence of 
tumor, as ER-negative metastases are not visible on 
FES-PET. The combination of FES-PET and CT may, 
however, largely overcome this issue by giving insights 
in tumor lesions on CT that are FES negative. Similarly, 
the effect of upfront PET/CT with the tracers FES and 
FDG is anticipated to improve tumor detection. The FDG 
PET/CT is to be done at baseline and on-treatment. FDG 
PET/CT is sensitive and specific for evaluating tumor 
response but cannot be used in patients whose baseline 
FDG PET/CT results are negative for tumors. 
Tabulated clinical trial summary 
and Section 7.3.2 Exclusion 
criteria related to the disease 
Modified Exclusion Criteria 
E14 by adding fulvestrant 
washout period. 
Since the ERs may remain occupied even after 
fulvestrant treatment is completed due to the 
fulvestrant’s half-life of ~6 weeks, a withdrawal of 
fulvestrant prior to FES PET scan is necessary to 
prevent effects on FES uptake in Part A of the study and 
to allow ER receptor binding by SAR439859. 
VV-CLIN-0093825 11.0

Amended Clinical Trial Protocol 10  
08-Dec-2021 
SAR439859-TED14856  amcenestrant 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 229 
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary 
and Section 7.3.2 Exclusion 
criteria related to the disease 
Modified Exclusion Criteria 
E16. 
Clarification of prothrombin value within therapeutic 
range in case of treatment with anticoagulation. 
Tabulated clinical trial summary 
and Section 8.1.1.1 SAR439859 
Updated SAR439859 dose 
strengths. 
SAR dose strengths of 1mg, 10 mg, 50 mg, and 100 mg 
were planned for use during the study. Even though 
1 mg was produced and used during preclinical studies, 
it was never released and will not be used for this study. 
Tabulated clinical trial summary, 
Section 1.3 Flow chart, Section 
1.4.1 Part A, Section 1.4.2 Part B, 
Section 1.4.3 Parts C and D and 
Section 9.4.2 Estrogen receptor 1 
gene mutation status in 
circulating free DNA 
Added estrogen receptor 
sampling (ESR001) 
exploratory analysis at end of 
Cycle 2. 
To capture the change in ESR1 tumor cfDNA level 
during treatment with SAR439859. Levels of tumor-
derived cfDNA may reflect tumor volume and effects of 
SAR on the tumor. Levels of ESR1 in cfDNA will be 
assessed pre-treatment (at baseline) and during 
treatment (at the end of Cycle 2) in all parts of the study. 
Tabulated clinical trial summary, 
Section 4.3.1 Preclinical data, 
Section 7.3.2 Exclusion criteria 
related to the disease, Section 
8.6 Concomitant treatment 
Updated recommendation 
with regards to concomitant 
treatment to be avoided 
during treatment period. 
As described in Investigator brochure (section 7.2.3), 
available in vitro data showed that the biotransformation 
of SAR439859 occurs mainly through non-CYP enzymes 
(around 80% of hepatic clearance) involving UGT1A1 
and 1A4. CYP2C8 and CYP3A are involved in 
SAR439859 oxidative metabolism. Therefore, drugs that 
are potent inhibitors of CYP3A or CYP2C8 and UGTs 
(atazanavir, lopinavir, ketoconazole, and quercetin) 
should not be administered with SAR439859, as well as 
drugs that are strong or moderate inducers of CYP3A. In 
vitro studies results showed that SAR439859 has a 
potential to induce CYP3A, CYP2B6, CYP2Cs and 
UGTs, therefore drugs which are mainly metabolized by 
these enzymes should be closely monitored since the 
efficacy of these drugs may be decreased by 
concomitant use of SAR439859. In addition, SAR439859 
has potential in vitro to inhibit P-gp transporters. 
As a consequence, criteria E21, E22 and concomitant 
medication Section 8.6 will be modified accordingly. 
Section 1.4.2 Part B and Section 
1.4.3 Parts C and D, Section 8.6 
Concomitant treatment, Section 
9.2.1 Sampling time and sample 
blood volume and Section 9.5 
Sampled blood volume and 
Appendix H 
Revised PK sampling in parts 
B and D. 
It was planned to collect samples according to a full PK 
sampling schedule in at least 12 subjects when 
SAR439859 is given alone (Part B) or in combination 
with Palbociclib (Part D). This sample size is deemed 
adequate to address PK objectives of TED14856 study 
and to build population PK structural model. The other 
patients of the expansion part are to be sampled 
according to a sparse sampling design in order to limit 
patient burden and to be able to derive individual PK 
parameters using the population PK model. PK 
parameters will be used to establish the exposure-
response/safety relationship analysis. At this stage of the 
knowledge on PK profiles of the compound time windows 
for PK sample collection are defined in this 
amendment#2. 
Section 9.2.5 PK parameters 
Updated PK parameters. 
CLss/F is added for SAR439859. 
Section 9.5 Sampled blood 
volume 
Updated footnote for blood 
sample volume in Table 19. 
Footnote added to specify full and sparse samplings. 
Appendix I Time window range 
for PK sampling  
Appendix I deleted. 
 
VV-CLIN-0093825 11.0

Amended Clinical Trial Protocol 10  
08-Dec-2021 
SAR439859-TED14856  amcenestrant 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 230 
Amendment [1]: [15-Jun-2017] 
This amendment is considered to be non-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. 
Rationale for the amendment  
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial 
summary and Section 7.2 
Inclusion criteria 
Clarified Inclusion criteria I06. 
Advanced treatment setting of prior endocrine therapy 
is specified for patients entering all parts of the study 
(A, B, C, and D) in the formulation of inclusion 
criteria 06. 
Tabulated clinical trial 
summary and Section 7.3 
Exclusion criteria 
Modified exclusion criteria E04. 
Clarification of exclusion criteria 04 to reflect the actual 
concern related to potential inclusion of HIV positive 
patients and allowing such patients to be treated. 
Tabulated clinical trial 
summary and Section 7.3 
Exclusion criteria 
Clarified exclusion criteria E11. 
The length of time without recurrence/relapse for 
patients with brain metastases that have been 
previously totally resected or irradiated is specified. 
Tabulated clinical trial 
summary and Section 7.3 
Exclusion criteria 
Clarified exclusion criteria E23. 
Reformulation of exclusion criteria 23 for better clarity. 
Section 6.2.2 Classical dose 
phase dose escalation 
strategy (Part A and C) 
Improve clarity of Table 2 - Classical 
dose escalation phase. 
Reformulation of the statement “or implementation or 
prophylactic/curative therapies” for better clarity. 
Section 8.6 Concomitant 
treatment 
Correct inconsistent duration of 
washout period for prior medications. 
Patients taking atazanavir, lopinavir ritonavir, 
saquinavir (antiviral), ketoconazole, itraconazole 
(antifungal), and quercetin (antioxidant), strong and 
moderate CYP3A inducers, strong and moderate 
CYP3A inducers, or strong CYP3A inhibitors at the time 
of the screening visit should remain ineligible to enter 
the study until administration of the prohibited agent 
can be safely discontinued, and an appropriate period 
of time has elapsed (2 weeks before first study 
treatment administration or 5 elimination half-lives 
whichever is longest). 
 
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