Pharmacokinetics of Imlunestrant in Participants With Hepatic Impairment
Phase: PHASE1
Conditions: Hepatic Insufficiency, Healthy
Sponsor: Eli Lilly and Company

Protocol 
 
-MC-
 ( ) 
 
NCT0
Approval Date: 1 -
-20

CONFIDENTIAL 
Protocol number J2J-MC-JZLG (d) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of imlunestrant (LY3484356) unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: Pharmacokinetics of Imlunestrant in Participants with Hepatic Impairment
Protocol Number: J2J-MC-JZLG 
Amendment Number: (d) 
Compound: Imlunestrant (LY3484356) 
Brief Title: Pharmacokinetics of Imlunestrant in Participants with Hepatic Impairment 
Study Phase: 1 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana 46285, USA 
Regulatory Agency Identifier Number(s) 
IND: 145311 
Approval Date: Protocol Amendment (d) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-074209 

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Protocol number J2J-MC-JZLG (d) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 

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Protocol number J2J-MC-JZLG (d) 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY
Document 
Date
Original Protocol
07-Jan-2022
Amendment (a)
02-Mar-2022
Amendment (b)
30-Jun-2022
Amendment (c)
18-Sep-2022
Amendment (d) 
Overall Rationale for the Amendment: 
 
This will allow 
data from all participants with mild, moderate, and severe hepatic impairment enrolled to date to 
inform the label at the time of the initial imlunestrant submission. Statistical analysis methods 
were also updated to provide a more appropriate analysis. 
Section # and Name 
Description of Changes 
Brief Rationale 
Section 1.1 Synopsis 
Section 4.1 Overall Design 
Section 9.4 Interim analysis 
 
 
 
 
 
 
 
 
 
 
Section 9.3.4.1 Pharmacokinetic 
Parameter Estimation 
Added that dose normalized 
parameters may be calculated, 
as appropriate. 
Clarification of methods for 
analysis of data including 
participants with severe hepatic 
impairment. 
Section 9.3.4.2 Pharmacokinetic 
Statistical Inference 
Replaced paired t-test with 
details of analysis of covariance 
method and graphical 
assessment of the relationship 
between PK and Child-Pugh 
classification parameters. 
During a planned interim review 
of data, the planned paired t-test 
was deemed inappropriate for 
the analysis. 
 

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Protocol number J2J-MC-JZLG (d) 
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Table of Contents  
Section 
Page  
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................13 
2. 
Introduction ...................................................................................................................15 
2.1. 
Study Rationale ...............................................................................................................15 
2.2. 
Background .....................................................................................................................15 
2.2.1. 
Pharmacokinetics of Imlunestrant...................................................................................16 
2.3. 
Benefit/Risk Assessment ................................................................................................17 
3. 
Objectives and Endpoints ............................................................................................20 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.1.1. 
Screening.........................................................................................................................23 
4.1.2. 
Treatment and Assessment Period ..................................................................................23 
4.1.3. 
Follow-up ........................................................................................................................23 
4.2. 
Scientific Rationale for Study Design ............................................................................23 
4.3. 
Justification for Dose ......................................................................................................23 
4.4. 
End of Study Definition ..................................................................................................25 
5. 
Study Population ...........................................................................................................26 
5.1. 
Inclusion Criteria ............................................................................................................26 
5.2. 
Exclusion Criteria ...........................................................................................................27 
5.3. 
Lifestyle Considerations .................................................................................................29 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................29 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................29 
5.3.3. 
Activity ...........................................................................................................................30 
5.3.4. 
Other ...............................................................................................................................30 
5.4. 
Screen Failures ................................................................................................................30 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................31 
6.1. 
Study Intervention(s) Administered................................................................................31 
6.1.1. 
Administration Details ....................................................................................................31 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................31 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................32 
6.4. 
Study Intervention Compliance ......................................................................................32 
6.5. 
Dose Modification ..........................................................................................................32 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................32 
6.8. 
Concomitant Therapy .....................................................................................................33 
7. 
Participant Discontinuation/Withdrawal ...................................................................34 
7.1. 
Participant Discontinuation/Withdrawal from the Study ................................................34 
7.1.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................34 

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7.2. 
Lost to Follow Up ...........................................................................................................35 
8. 
Study Assessments and Procedures.............................................................................36 
8.1. 
Efficacy Assessments .....................................................................................................36 
8.2. 
Safety Assessments .........................................................................................................36 
8.2.1. 
Physical Examinations ....................................................................................................36 
8.2.2. 
Vital Signs .......................................................................................................................36 
8.2.3. 
Electrocardiograms .........................................................................................................36 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................37 
8.2.5. 
Safety Monitoring ...........................................................................................................38 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................39 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................40 
8.4. 
Pharmacokinetics ............................................................................................................41 
8.4.1. 
Bioanalysis ......................................................................................................................41 
8.5. 
Pharmacodynamics .........................................................................................................42 
8.6. 
Genetics ..........................................................................................................................42 
8.7. 
Biomarkers ......................................................................................................................42 
8.8. 
Immunogenicity Assessments.........................................................................................42 
8.9. 
Health Economics ...........................................................................................................42 
9. 
Statistical Considerations .............................................................................................43 
9.1. 
Statistical Hypotheses .....................................................................................................43 
9.2. 
Analyses Sets ..................................................................................................................43 
9.2.1. 
Study Participant Disposition .........................................................................................43 
9.2.2. 
Study Participant Characteristics ....................................................................................43 
9.2.3. 
Treatment Compliance ....................................................................................................43 
9.3. 
Statistical Analysis ..........................................................................................................43 
9.3.1. 
General Considerations ...................................................................................................43 
9.3.2. 
Clinical Evaluation of Safety ..........................................................................................43 
9.3.3. 
Statistical Evaluation of Safety .......................................................................................44 
9.3.4. 
Pharmacokinetic Analyses ..............................................................................................44 
9.4. 
Interim Analysis ..............................................................................................................44 
9.5. 
Sample Size Determination ............................................................................................45 
10. 
Supporting Documentation and Operational Considerations ..................................46 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................46 
10.1.1. Regulatory and Ethical Considerations ...........................................................................46 
10.1.2. Financial Disclosure........................................................................................................46 
10.1.3. Informed Consent Process ..............................................................................................47 
10.1.4. Data Protection................................................................................................................47 
10.1.5. Dissemination of Clinical Study Data.............................................................................48 
10.1.6. Data Quality Assurance ..................................................................................................48 
10.1.7. Source Documents ..........................................................................................................50 
10.1.8. Study and Site Start and Closure ....................................................................................50 
10.1.9. Publication Policy ...........................................................................................................51 
10.1.10. Investigator Information .................................................................................................51 

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10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................52 
10.2.1. Blood Sampling Summary ..............................................................................................54 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting ...........................................................................................................55 
10.3.1. Definition of AE .............................................................................................................55 
10.3.2. Definition of SAE ...........................................................................................................56 
10.3.3. Definition of Product Complaints ...................................................................................57 
10.3.4. Recording and Follow-up of AE and/or SAE and Product 
Complaints ......................................................................................................................57 
10.3.5. Reporting of SAEs ..........................................................................................................59 
10.3.6. Regulatory Reporting Requirements ...............................................................................59 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................61 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments ....................................................................................................................62 
10.6. 
Appendix 6: Abbreviations and Definitions ...................................................................64 
10.7. 
Appendix 7: Protocol Amendment History ....................................................................68 
11. 
References ......................................................................................................................74 
 
 

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Protocol number J2J-MC-JZLG (d) 
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List of Tables 
Table 
Page 
Table JZLG.1. 
Child-Pugh System of Hepatic Impairment ......................................................21 
Table JZLG.2. 
Exposure Margins in Rat and Monkey Toxicity Studies Relative to 
Observed Clinical PK Following a Single Dose of 
 
Imlunestrant .......................................................................................................24 
Table JZLG.3. 
Study Interventions Administered .....................................................................31 
 
 
 

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Protocol number J2J-MC-JZLG (d) 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: Pharmacokinetics of Imlunestrant in Participants with Hepatic Impairment 
Brief Title: Pharmacokinetics of Imlunestrant in Participants with Hepatic Impairment 
Regulatory Agency Identifier Number: IND: 145311 
Rationale: 
Imlunestrant (LY3484356) is an orally bioavailable, non-covalent binding, selective estrogen 
receptor degrader. It is a potent degrader and selective antagonist of wild-type and mutant 
estrogen receptor . This compound is intended for oncology indications (breast cancer and 
endometrial cancer), in patients where the disease has become less responsive to endocrine 
therapy, and options are often limited to chemotherapy. 
As the intended patient population for imlunestrant may include patients with hepatic 
impairment, it is important to ascertain how to safely prescribe imlunestrant in this patient 
population. It is possible that hepatic impairment could lead to a substantial change in the 
pharmacokinetic (PK) profile of imlunestrant, potentially leading to recommending a dose 
adjustment to maintain safety, tolerability, and/or efficacy. 
A pilot evaluation of the human microsomal cytochrome P450 (CYP)-mediated clearance of 
imlunestrant by in vitro methods indicated the major role of CYP3A4 in the CYP-mediated 
oxidative metabolism. Independently, uridine 5 -diphospho-glucuronosyltransferase (UGT) 
enzymes involved in the formation of the O-glucuronide metabolite were investigated using 
recombinant human enzymes. The involvement of UGT1A1 and 1A8 and to a lesser extent 
UGT1A3, 1A9 and 1A10 were identified based on the unbound intrinsic clearance per milligram 
of total protein. The magnitude of the contribution of CYP3A4 and different UGTs toward the 
overall clearance of imlunestrant is unknown since the in vivo clearance pathways of 
imlunestrant have not yet been determined. However, prior experience with drugs metabolized 
by these pathways suggests that a reduction in activity of the CYP and UGT enzymes may occur 
in hepatic insufficiency. This study will be conducted to evaluate the PK of imlunestrant in 
participants with impaired hepatic function based on Child-Pugh hepatic impairment 
classifications of mild, moderate, and severe. The tolerability of imlunestrant will also be 
assessed. The design is in alignment with the Food and Drug Administration guidance 
recommendation for studies when hepatic metabolism and/or excretion accounts for >20% of the 
elimination of a parent drug or active metabolite. 
Notable changes in PK as a result of hepatic impairment identified in this study will be 
considered with emerging exposure-safety/tolerability or response relationships from patient 
trials to determine the need for dosage adjustment in the hepatically impaired patient population. 
 
 

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Protocol number J2J-MC-JZLG (d) 
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To evaluate the PK of imlunestrant in women 
of non-childbearing potential with hepatic 
impairment compared to control women of 
non-childbearing potential with normal 
hepatic function. 
Plasma concentration data (total) should be 
analyzed to estimate measures or parameters 
describing the PK of imlunestrant (e.g., area 
under the concentration versus time curve, 
maximum observed drug concentration) after 
a single 
 (or lower) imlunestrant dose. 
   Secondary 
 
To evaluate the tolerability of imlunestrant in 
women of non-childbearing potential with 
hepatic impairment and control women of 
non-childbearing potential with normal 
hepatic function. 
Incidence of treatment-emergent adverse 
events and serious adverse events. 
 
Overall Design 
Brief Summary: 
Study JZLG is an open-label, single-dose study. The study will be conducted in up to 4 groups: 
Group 1: participants with normal hepatic function (Control); Group 2: participants with mild 
hepatic impairment (Child-Pugh A); Group 3: participants with moderate hepatic impairment 
(Child-Pugh B); and Group 4: participants with severe hepatic impairment (Child-Pugh C). 
Participants with normal hepatic function and mild hepatic impairment can be dosed 
concurrently from the onset of the study. A review to assess imlunestrant safety and PK will be 
conducted after at least 3 participants with mild hepatic impairment have completed all PK 
sampling; imlunestrant will not be administered to participants with moderate hepatic 
impairment until the review has been completed. 
 
 
 imlunestrant will 
not be administered to participants with severe hepatic impairment until this analysis and review 
have been completed. Additional reviews to assess imlunestrant safety and PK will be conducted 
after 3 participants with severe hepatic impairment have completed all PK sampling.  
 

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Protocol number J2J-MC-JZLG (d) 
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A final analysis will be conducted and a clinical study report produced after all cohorts have 
completed all PK samples, unless no further participants with severe hepatic impairment are 
enrolled after production of the interim clinical study report.  
Group 1 (normal hepatic function) will be matched by age ( 10 years), sex, and body mass index 
(BMI, 15%) to participants either in Group 2 (mild hepatic impairment) or Group 3 (moderate 
hepatic impairment) as far as reasonably possible but allowing timely completion of the study. 
Reasonable attempts will be made to match Group 4 (severe hepatic impairment) participants 
with the other groups. 
Group 3 and/or 4 participants may be omitted if safety results indicate important clinically 
significant safety concerns. Control participants (Group 1) may be enrolled in parallel with 
participants in Groups 2, 3, and 4. The demographics of these 6 control participants will be 
selected to ensure the best chance of matching demographics of hepatically impaired participants 
in Group 2 and Group 3, based on historical data from the study sites. 
Participants who do not complete dosing and PK sampling may be replaced in order to target 
6 completers for hepatic impairment Groups 2, 3, and 4, and a minimum of 6 and maximum of 
12 completers for the control group; these numbers may be reduced if the study objectives are 
met earlier. 
Attempts will be made to recruit and dose 6 severe hepatic impairment participants; however, 
recruiting participants with severe hepatic impairment (Child-Pugh C) may be difficult. The 
sponsor may elect to complete fewer than 6 participants in Group 4 if the study sites cannot 
recruit sufficient numbers for this group. In addition, Cohorts 2 and 3 may be expanded to 
include a total of 9 participants, dependent on the results from Cohort 4. 
Safety assessments, including adverse events, concomitant medications, medical assessments, 
clinical laboratory tests, vital signs, and electrocardiograms, and blood sampling for PK, will be 
performed. 
Screening 
All participants will be screened within 28 days prior to enrollment. 
Treatment and Assessment Period 
Eligible participants will participate in 1 treatment period. Participants will be admitted to the 
clinical research unit (CRU) on Day -1. All participants will receive a single dose of 
 (or 
lower for hepatically impaired participants) imlunestrant on Day 1 in the fasted state. Participants 
may either remain resident in the CRU until discharge on Day 5, and attend outpatient visits on 
each of Days 6 through 11; or may remain resident in the CRU until discharge on Day 11. 
If it becomes necessary for the participant to leave the study site during this period, continued 
participation may be allowed at the discretion of the investigator if they are felt to be able to 
comply with study procedures and restrictions without negative impact to safety or study 
integrity. 
Follow-up 
Participants will attend a follow-up visit 5 to 7 days post final CRU discharge. 

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Protocol number J2J-MC-JZLG (d) 
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Study Population: 
Participants will be at least 18 years old and will be included if they are either healthy or have 
mild, moderate, or severe hepatic impairment. Participants with hepatic impairment must have 
had a diagnosis of chronic hepatic impairment and no clinically significant changes within 
90 days before dosing with study drug. These participants may have other medical conditions 
that are mild and that would not affect the health of the participant or the study conduct. 
Number of Participants: 
The study will be conducted in up to 4 groups, based on the Child-Pugh classification of hepatic 
impairment, as follows: 
 Group 1: participants with normal hepatic function (Control); minimum of  and 
maximum of 
 completers 
 Group 2: participants with mild hepatic impairment (Child-Pugh A);  completers 
 Group 3: participants with moderate hepatic impairment (Child-Pugh B);  completers 
 Group 4: participants with severe hepatic impairment (Child-Pugh C);  completers 
Intervention Groups and Duration: 
This study will be conducted in 4 groups; each participant is expected to participate in the study 
for up to 44 to 46 days. 
Data Monitoring Committee: No 

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Protocol number J2J-MC-JZLG (d)
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1.2. 
Schema  
 
Abbreviation: PK = pharmacokinetic. 
 

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Protocol number J2J-MC-JZLG (d)
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1.3. 
Schedule of Activities (SoA)  
 
Procedure 
Screening 
(up to 
28 days 
before 
Day 1) 
Treatment Perioda 
Follow-up 
(5 to 7 days 
post final 
CRU 
discharge) 
or ED 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
including 
Child-Pugh 
Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination 
including height 
and weight 
X 
 
P 
 
 
 
 
 
 
 
 
 
X 
X 
After screening, 
medical assessment 
only performed to 
include medical 
review and targeted 
examination, as 
appropriate. 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past and current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary drugs of 
abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethanol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments 
X 
X 
P 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 

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Protocol number J2J-MC-JZLG (d)
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Procedure 
Screening 
(up to 
28 days 
before 
Day 1) 
Treatment Perioda 
Follow-up 
(5 to 7 days 
post final 
CRU 
discharge) 
or ED 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12-lead 
electrocardiogram 
X 
 
P 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Vital sign (supine) 
X 
X 
P, 2, 4, 6, 
8, 10, 12h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Genetic sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse 
event/Serious 
adverse event 
review 
X 
X 
==================================================
 
X 
 
Concomitant 
medication review 
X 
X 
==================================================
 
X 
 
Abbreviations: AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; P = predose; PK = pharmacokinetic; 
SAE = serious adverse event. 
Note: Participants may either remain resident in the CRU from admission on Day -1 until discharge on Day 5, and attend outpatient visits on each of Days 6 
through 11, or may remain resident in the CRU until discharge on Day 11. 
 

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Protocol number J2J-MC-JZLG (d) 
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2. 
Introduction  
Imlunestrant (LY3484356) is an orally bioavailable, non-covalent, SERD. It is a potent degrader 
and selective antagonist of wild-type and mutant Er  (or ESR1). This compound is intended for 
oncology indications (breast cancer and endometrial cancer), in patients where the disease has 
become less responsive to endocrine therapy, and options are often limited to chemotherapy. 
Full details of the preclinical safety, efficacy, and PK may be found in the IB. 
2.1. 
Study Rationale  
As the intended patient population for imlunestrant may include patients with hepatic 
impairment, it is important to ascertain how to safely prescribe imlunestrant in this patient 
population. It is possible that hepatic impairment could lead to a substantial change in the PK 
profile of imlunestrant, potentially leading to recommending a dose adjustment to maintain 
safety, tolerability, and/or efficacy. 
A pilot evaluation of the human microsomal CYP-mediated clearance of imlunestrant by in vitro 
methods indicated the major role of CYP3A4 in the CYP-mediated oxidative metabolism. 
Independently, UGT enzymes involved in the formation of the O-glucuronide metabolite were 
investigated using recombinant human enzymes. The involvement of UGT1A1 and 1A8 and to a 
lesser extent 1A3, 1A9, and 1A10 were identified based on the unbound intrinsic clearance per 
milligram of total protein. The magnitude of the contribution of CYP3A4 and different UGTs 
toward the overall clearance of imlunestrant is unknown because the in vivo clearance pathways 
of imlunestrant have not yet been determined. However, prior experience with drugs metabolized 
by these pathways suggests that a reduction in activity of the CYP and UGT enzymes may occur 
in hepatic insufficiency. This study will be conducted to evaluate the PK of imlunestrant in 
participants with impaired hepatic function based on Child-Pugh hepatic impairment 
classifications of mild, moderate, and severe. The tolerability of imlunestrant will also be 
assessed. The design is in alignment with the FDA guidance recommendation for studies when 
hepatic metabolism and/or excretion accounts for >20% of the elimination of a parent drug or 
active metabolite. Albumin concentrations may be lower in people with hepatic impairment than 
in people with normal hepatic function. Therefore, it will be important to measure the unbound 
concentration of imlunestrant in this study because of its high protein-binding ability. 
Notable changes in PK as a result of hepatic impairment identified in this study will be 
considered with emerging exposure-safety/tolerability or response relationships from patient 
trials to determine the need for dosage adjustment in the hepatically impaired patient population. 
2.2. 
Background  
Breast cancer is the most frequent cancer among women and is a major cause of cancer-related 
deaths worldwide. It is estimated that more than 2 million new cases of breast cancer occurred 
worldwide in women in 2018 (Bray et al. 2018). Clinical decision-making for the management of 
patients with advanced breast cancer takes into account multiple clinical factors such as 
HR/HER2 status, age, comorbidities, and patient preference. More specifically, treatment options 
for women with breast cancer are largely determined by tumor HR/HER2 status (NCCN 2018; 
Waks and Winer 2019). 

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Protocol number J2J-MC-JZLG (d) 
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Over two thirds of breast cancers express ER, which is a key driver of breast cancer initiation 
and progression. Hormone receptor-positive metastatic breast cancer is incurable and therefore 
considered a serious and life-threatening disease, with a median overall survival of only 2 to 
3 years (Cardoso et al. 2012). For patients with advanced HR+/HER2- status, treatment includes 
endocrine therapy (e.g., tamoxifen, anastrozole, letrozole, fulvestrant) alone or in combination 
CDK4 and CDK6 inhibitors as indicated (e.g., abemaciclib, palbociclib, or ribociclib), as well as 
standard chemotherapy (e.g., capecitabine, docetaxel, paclitaxel, and nab-paclitaxel [NCCN 
2018; Waks and Winer 2019]). For patients with advanced HR+/HER2+ status, treatment 
includes HER2-directed therapies (e.g., trastuzumab, pertuzumab, trastuzumab emtansine 
administered alone and in combination with other HER2-directed therapies, chemotherapy, or 
endocrine therapy). 
In most ER+ breast cancers, ER is an important therapeutic target even after development of 
resistance to endocrine therapies (Weatherman et al. 1999; Baselga et al. 2012; Turner et al. 
2015; Finn et al. 2016; André et al. 2019). 
SERDs are one of the treatment options for ER+/ HER2- breast cancer patients. Fulvestrant is 
currently the only regulatory agency-approved SERD for the treatment of ER+ metastatic breast 
cancer (Nardone et al. 2019). Its efficacy is highly dose-dependent, where increasing the 
administered dose led to improved survival (Di Leo et al. 2014). However, the intramuscular 
route of fulvestrant administration limits the amount of fulvestrant that can be given to patients. 
Even though doses higher than 
 per month may lead to better ER degradation, the 
intramuscular administration route limits the amount of fulvestrant that can be given to patients 
(Nardone et al. 2019). In addition, several studies have shown that with the current maximum 
feasible dose, fulvestrant treatment is not able to completely degrade ER in patients and can be 
associated with early progression (van Kruchten et al. 2015). Thus, there is unmet medical need 
to develop oral SERDs with higher bioavailability, greater ER targeting, and degradation 
efficiency (Nardone et al. 2019). 
EC, while less frequently diagnosed than breast cancer, is increasing worldwide. In the United 
States, the incidence of EC has increased by approximately 12,000 cases between 2013 and 2019 
(Howlader et al. 2019). Endometrioid EC represents about 80% of EC cases, and overexpression 
of estrogen may contribute to tumor proliferation (Ellenson et al. 2011). Standard of care for EC, 
regardless of subtype, consists of the surgery followed by adjuvant radiotherapy and/or 
chemotherapy. In the advanced setting, a variety of endocrine therapy, such as megestrol acetate, 
tamoxifen, aromatase inhibitors, fulvestrant, are commonly used (NCI 2019; NCCN 2020). 
2.2.1. 
Pharmacokinetics of Imlunestrant  
As of 01 November 2021, imlunestrant PK parameters were available from 85 patients in study 
J2J-MC-JZLA (JZLA) across a 
 QD dose range. After single oral administration, 
maximum plasma concentrations of imlunestrant were reached approximately 4 hours postdose. 
The mean t1/2 was approximately 25 to 30 hours and exposures of imlunestrant increased with 
dose. The fasted exposures (AUC and Cmax) of healthy participants in study J2J-MC-JZLD 
(JZLD) were within range of the fasted exposures observed in patient studies after the same 
doses. 
A pilot study of protein binding was conducted in vitro using equilibrium dialysis in human 
plasma, human liver microsomes, and solutions of human alpha-1-acid glycoprotein and HSA 

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Protocol number J2J-MC-JZLG (d) 
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protein. Imlunestrant was 
 bound in human plasma and 
 bound in human liver 
microsomes. Binding to human 
 was less than that observed 
. 
The binding to 
 was consistent with binding observed in human plasma. 
The in vitro metabolism of imlunestrant was evaluated in human liver microsomes, intestine 
microsomes, and hepatocytes. Imlunestrant displayed low intrinsic clearance in liver microsomes 
in the presence of nicotinamide adenine dinucleotide phosphate, with minimal oxidative 
metabolism being observed. However, the metabolism of imlunestrant in both liver and intestinal 
microsomes was greater in the presence of uridine diphosphate glucuronic acid, with formation 
of a direct glucuronide conjugate being observed. In the human hepatocyte incubations, 
metabolites from direct glucuronidation and sulfation were predominant while minor metabolites 
from CYP mediated oxidation were also observed. 
The preliminary analysis of study JZLD indicated that the AUC and Cmax of imlunestrant were 
increased by approximately 2-fold in a drug-drug interaction study with itraconazole. This is 
consistent with a significant but not dominant role of CYP3A4 in the bioavailability and/or 
hepatic clearance of imlunestrant. 
2.3. 
Benefit/Risk Assessment  
Imlunestrant is a potent antagonist and degrader of ER  and has demonstrated significant 
activity in preclinical models against ER wild-type and mutant tumors. There is no anticipated 
benefit for the women of non-childbearing potential in this study. 
Due to the early stage of the development of imlunestrant, the clinical safety profile has not been 
fully established. There are currently ongoing clinical studies in healthy participants (JZLD and 
J2J-MC-JZLE [JZLE]). As of 01 November 2021, study JZLD has a total of 38 healthy female 
participants. In this study, participants receive 
 of 
 imlunestrant (Cohorts 
1, 2, and 4), or 
 single doses of 
 imlunestrant (Cohort 3). Study JZLE has 5 healthy 
female participants that are receiving a single dose of 
 imlunestrant (Parts 1 or 2). These 
studies are still ongoing. 
Imlunestrant has also been administered to patients in ongoing clinical studies JZLA (
 to 
 QD for a 28 day cycle) and J2J-MC-JZLB, a window of opportunity study (
 and 
), for a period of 15 to 22 days. 
As of 01 November 2021, 134 patients have received imlunestrant monotherapy (N=22, 
; 
N=64, 
; N=20, 
; N=25, 
; and N=3, 
) in study JZLA. No 
dose-limiting toxicities have been reported at any of the dose levels tested. Imlunestrant was well 
tolerated across dose levels in dose escalation, and a maximum tolerated dose was not reached. 
In the 134 patients receiving JZLA monotherapy (all dose levels), the most frequently reported 
TEAEs were nausea (46 [34%]), fatigue (37 [28%]), and diarrhea (36 [27%]). Most TEAEs were 
There were 10 
SAEs reported in 7 patients (5.2%) who received imlunestrant monotherapy (all dose levels). Of 
note, 1 patient reported SAEs of diarrhea and nausea, which were considered by the investigator 
to be related to study treatment. The remaining SAEs were considered not related to 
imlunestrant, being mostly likely due to underlying disease, preexisting conditions, or 
concomitant medications. No maximum tolerated dose was established during dose escalation. 

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Protocol number J2J-MC-JZLG (d) 
18 
Given the totality of efficacy, clinical PK, and safety data, the sponsor is proceeding into 
additional clinical trials with the 
 QD dose level. 
Overall, the majority of TEAEs were low grade, monitorable, manageable and reversible. The 
risk to participants receiving the 
 dose is considered low, as only 1 dose of imlunestrant 
will be received in this study and the patients will be closely monitored as documented in the 
SoA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Non-reproductive imlunestrant-related toxicities have demonstrated partial to full reversibility. 
As the pharmacologic mechanism of imlunestrant is to degrade the ER, effects on female 
reproductive organs are expected. Similar female reproductive tract findings have been observed 
with other approved agents, known to antagonize or degrade the ER, including tamoxifen 
(Nolvadex) and fulvestrant (Faslodex®). Therefore, this trial will enroll only women of 
non-childbearing potential, defined as postmenopausal or infertile due to surgical sterilization or 
alternate medical cause/congenital anomaly as outlined in Appendix 4 (Section 10.4). 
Potential toxicities will be regularly monitored during this study through ongoing assessment of 
participant symptoms, hematological and chemistry levels, and ECG readings, as detailed in 
Section 8.2. Participants will also be advised to use sunscreen and to wear clothing such as long 
sleeve tops that cover the arms, pants and/or other garments that cover the legs and hats to cover 

CONFIDENTIAL 
Protocol number J2J-MC-JZLG (d) 
19 
the head if out in direct sunlight, 
 
.
Genotoxicity 
Imlunestrant was negative for mutagenicity in the Ames assay. It was positive for chromosomal 
 via a mixed, 
predominantly aneugenic mechanism. The chromosomal damage observed in vitro occurred at 
levels of imlunestrant higher than participants will receive. In vivo, imlunestrant did not induce 
chromosomal damage in rats 
  
 
(Table JZLG.2). The high threshold 
concentration for in vitro aneugenicity and the lack of chromosomal damage in vivo represent a 
weight of evidence indicating that the risk of imlunestrant in vivo genotoxicity is low, in 
accordance with ICH S2, and establishes safe exposures for clinical trial participants, including 
healthy participants. The risk to healthy participants in the present study is further reduced by 
administration of 1 dose of imlunestrant. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of imlunestrant may be found in the IB. 

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Protocol number J2J-MC-JZLG (d) 
20 
3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To evaluate the PK of imlunestrant in women 
of non-childbearing potential with hepatic 
impairment compared to control women of 
non-childbearing potential with normal 
hepatic function. 
Plasma concentration data (total) should be 
analyzed to estimate measures or parameters 
describing the PK of imlunestrant (e.g., AUC, 
Cmax), after a single 
 (or lower) 
imlunestrant dose. 
Secondary 
 
To evaluate the tolerability of imlunestrant in 
women of non-childbearing potential with 
hepatic impairment and control women of 
non-childbearing potential with normal 
hepatic function. 
Incidence of TEAEs and SAEs. 
 

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Protocol number J2J-MC-JZLG (d) 
21 
4. 
Study Design  
4.1. 
Overall Design  
Study JZLG is an open-label, single-dose study. 
The study will be conducted in up to 4 groups, based on the Child-Pugh classification of hepatic 
impairment (Child and Turcotte, 1964; Pugh et al. 1973): 
 Group 1: participants with normal hepatic function (Control); minimum of  and 
maximum of 
 completers 
 Group 2: participants with mild hepatic impairment (Child-Pugh A);  completers 
 Group 3: participants with moderate hepatic impairment (Child-Pugh B);  completers 
 Group 4: participants with severe hepatic impairment (Child-Pugh C);  completers. 
The Child-Pugh system of hepatic impairment is provided in Table JZLG.1. 
 
Table JZLG.1. 
Child-Pugh System of Hepatic Impairment  
 

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Protocol number J2J-MC-JZLG (d) 
22 
The schema in Section 1.2 illustrates the study design. Participants with normal hepatic function 
and mild hepatic impairment can be dosed concurrently from the onset of the study. A review to 
assess imlunestrant safety and PK will be conducted after at least 3 participants with mild hepatic 
impairment have completed all PK sampling; imlunestrant will not be administered to 
participants with moderate hepatic impairment until the review has been completed.
 
 imlunestrant will not be administered to participants with severe hepatic impairment 
until this analysis and review have been completed. Additional reviews to assess imlunestrant 
safety and PK will be conducted after 3 participants with severe hepatic impairment have 
completed all PK sampling.  
 
A final analysis will be conducted and a clinical study report produced after all cohorts have 
completed all PK samples, unless no further participants with severe hepatic impairment are 
enrolled after production of the interim clinical study report. Further information is provided in 
Section 9.4.  
Group 1 (normal hepatic function) will be matched by age ( 10 years), sex, and BMI 15% to 
participants either in Group 2 (mild hepatic impairment) or Group 3 (moderate hepatic 
impairment) as far as reasonably possible but allowing timely completion of the study. 
Reasonable attempts will be made to match Group 4 (severe hepatic impairment) participants 
with the other groups. 
Group 3 and/or 4 participants may be omitted if safety results indicate important clinically 
significant safety concerns. Control participants (Group 1) may be enrolled in parallel with 
participants in Groups 2, 3, and 4. The demographics of these  control participants will be 
selected to ensure the best chance of matching demographics of hepatically impaired participants 
in Group 2 and Group 3, based on historical data from the study sites. 
Participants who do not complete dosing and PK sampling may be replaced in order to target 
completers for hepatic impairment Groups 2, 3, and 4, and a minimum of  and maximum of 
 completers for the control group; these numbers may be reduced if the study objectives are 
met earlier. 
Attempts will be made to recruit and dose 6 severe hepatic impairment participants; however, 
recruiting participants with severe hepatic impairment (Child-Pugh C) may be difficult. The 
sponsor may elect to complete fewer than  participants in Group 4 if the study sites cannot 
recruit sufficient numbers for this group. In addition, Cohorts 2 and 3 may be expanded to 
include a total of  participants, dependent on the results from Cohort 4. 
Safety assessments, including AEs, concomitant medications, medical assessments, clinical 
laboratory tests, vital signs, and ECGs, and blood sampling for PK, will be performed according 
to the SoA (Section 1.3). 

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Protocol number J2J-MC-JZLG (d) 
23 
4.1.1. 
Screening  
All participants will be screened within 28 days prior to enrollment. 
4.1.2. 
Treatment and Assessment Period  
Eligible participants will participate in 1 treatment period. Participants will be admitted to the 
CRU on Day -1. All participants will receive a single dose of 
 (or lower for hepatically 
impaired participants) imlunestrant on Day 1 in the fasted state. Participants may either remain 
resident in the CRU until discharge on Day 5, and attend outpatient visits on each of Days 6 
through 11, or may remain resident in the CRU until discharge on Day 11. 
If it becomes necessary for the participant to leave the CRU during this period, continued 
participation may be allowed at the discretion of the investigator if they are felt to be able to 
comply with study procedures and restrictions without negative impact to safety or study 
integrity. 
4.1.3. 
Follow-up  
Participants will attend a follow-up visit 5 to 7 days post final CRU discharge. 
4.2. 
Scientific Rationale for Study Design  
This study has been designed in accordance with the FDA regulatory guidance for the study of 
PK in participants with impaired hepatic function. 
This study will be open label because the study endpoints are not considered subjective. 
A single-dose, parallel design is the standard design to investigate the PK of a drug in 
participants with hepatic impairment. A parallel design is required to include participants with 
hepatic impairment and control participants with normal hepatic function. Control healthy 
participants with normal hepatic function will be enrolled in this study to serve as a reference 
group for interpretation of the results. The safety and PK assessments are standard parameters for 
clinical studies in drug development. 
Healthy females of non-childbearing potential have been selected as the study population since 
the pharmacologic mechanism of imlunestrant is to degrade the ER, and effects on the female 
reproductive organs are expected. 
4.3. 
Justification for Dose  
The clinical safety experience from study JZLA is described in Section 2.3. Imlunestrant was 
well tolerated at dose levels of 
 with no dose-limiting toxicities in Cycle 1. 
No maximum tolerated dose was established during dose escalation. Given the totality of 
efficacy, clinical PK, and safety data, the sponsor has selected the 
 dose level to be 
evaluated in planned patient trials. 
The recommended Phase 3 dose of 
 will be used, though may be reduced within a hepatic 
impairment group and for subsequent groups based on review of safety and PK data. 
In vitro studies indicate that imlunestrant undergoes oxidation by CYP3A4 and glucuronidation 
by UGT1A1, UGT1A8, UGT1A3, UGT1A9, and UGT1A10. The relative contribution of these 

CONFIDENTIAL 
Protocol number J2J-MC-JZLG (d) 
24 
enzymes to imlunestrant bioavailability and/or clearance in humans is unknown. Preliminary 
analysis of data from study JZLD indicates that imlunestrant Cmax and AUC were increased 
approximately 2-fold, indicating a significant, but not dominant, role of CYP3A4 in 
bioavailability and/or hepatic clearance. 
As described in the IB and Section 2.3, the nonclinical safety profile of imlunestrant is 
characterized primarily by pharmacologically mediated female reproductive organ toxicity. 
Adverse findings unrelated to the reproductive tract have not been observed up to the highest 
dose tested in monkeys or the highest tolerated dose in rats. Based on observed mean Cmax and 
AUC over the last 24-hour dosing interval at 
 and 
 in study JZLA
 
(Table JZLG.2). Imlunestrant exposures in this study are expected to maintain an appropriate 
margin of safety relative to key toxicities. 
Across all dose levels, the majority of events were low grade, monitorable, reversible, and 
manageable, the most frequent being gastrointestinal effects (nausea and diarrhea), and fatigue. 
Specifically at doses over 
 (
 N=20; 
 N=25; and 
 N=3), the 
majority of TEAEs reported were also low grade, with a similar incidence of Grade 3 TEAEs as 
observed at the 
 dose level. One patient reported SAEs of diarrhea and nausea, which 
were considered by the investigator to be related to study treatment. 
The planned safety monitoring (Section 8.2), clinical tolerability, and favorable nonclinical 
toxicity profile of imlunestrant support administration of a 
 imlunestrant to 
healthy females of non-childbearing potential in the present study. 
Table JZLG.2. 
Exposure Margins in Rat and Monkey Toxicity Studies Relative to 
Observed Clinical PK Following a Single Dose of 
Imlunestrant  
Species 
Animal or Human Dose Level
Cmax 
(ng/mL)
Cmax Margin
AUC0-  
(ng h/mL)
AUC Margin
 
 
 
 
Human 
Rat 
Non-reproductive NOAEL 
/kg/dayb
LOAEL reproductive toxicity
/kg/dayb
LOAEL maternal, EFD toxicity
/kg/dayc
NOEL in vivo micronucleus
/kg/dayd
STD10 
/kg/daye
Monkey
Non-reproductive NOAEL, HNSTD
/kg/dayf 
LOAEL reproductive toxicity
/kg/dayf

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Protocol number J2J-MC-JZLG (d) 
25 
Abbreviations: EFD = embryofetal development; HNSTD = highest non-severely toxic dose; 
LOAEL = lowest-observed adverse effect level; NOAEL = no-observed adverse effect level; 
NOEL = no-observed effect level. 
a Geometric mean clinical PK data following a single dose administration of 
 (N=23) 
 (N=18) 
imlunestrant in Study JZLA (data cut 01 November 2021) 
b Determined in 3-month rat toxicity study (Study 8003221); end-of-study male-female average exposures. 
c Determined in enhanced rat embryofetal development pilot study (Study 9001840). 
d Exposures measured on Day 2 of a confirmatory toxicokinetics study (Study 8451175) under the same 
experimental conditions as the in vivo rat micronucleus assay.  
e Determined in 4-week rat toxicity study (Study 8002568); end-of-study male-female average exposures. 
f Determined in 3-month monkey toxicity study (Study 8003147); end-of-study male-female average exposures. 
4.4. 
End of Study Definition  
A participant is considered to have completed the study if she has completed all scheduled 
procedures shown in the SoA (Section 1.3). 
The end of the study is defined as the date of the last visit of the last participant in the study. 

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Protocol number J2J-MC-JZLG (d) 
26 
5. 
Study Population  
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG. All 
participants will be women of non-childbearing potential. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Inclusion Criteria Applicable to ALL Participants: 
Age
1. participant must be at least 18 years at the time of signing the informed consent. 
Type of Participant 
2. participants who have venous access sufficient to allow for blood sampling as per the 
protocol. 
Weight 
3. BMI within the range 18.0 to 42.0 kg/m2 (inclusive). 
Sex 
4. female participants of non-childbearing potential as defined in Appendix 4 (Section 10.4) 
Informed Consent 
5. capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol 
Additional Inclusion Criteria for Control Participants (Group 1) 
6. participants who are overtly healthy as determined by medical assessment including medical 
history, physical examination, laboratory tests, and vital signs 
7. participants who have clinical laboratory test results within the normal reference range for 
the population or investigative site, or results with acceptable deviations that are judged to 
be not clinically significant by the investigator 
Additional Inclusion Criteria for Participants with Hepatic Impairment (Groups 2 to 4) 
8. individuals with hepatic impairment classified as Child-Pugh class A, B, or C (mild, 
moderate or severe impairment; Child and Turcotte 1964; Pugh et al. 1973) who are 
considered acceptable for participation in this study by the investigator. Participants must 
have diagnosis of chronic hepatic impairment (>6 months), with no clinically significant 
changes within 90 days prior to study drug administration (Day 1). Participants may have 

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Protocol number J2J-MC-JZLG (d) 
27 
mild stable baseline medical conditions for which neither the condition nor treatments 
received would negatively affect the health of the participant or study conduct. 
9. clinical laboratory test results with deviations that are judged by the investigator to be 
compatible with the hepatic impairment of the participant, or are of no additional clinical 
significance for this study 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Exclusion Criteria for ALL Participants: 
10. are investigational site personnel directly affiliated with this study and their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted 
11. are Lilly employees 
 
12. have known allergies to imlunestrant, related compounds or any components of the 
formulation, as appropriate, or history of significant atopy  
13. significant history or clinical manifestation of any metabolic, allergic, dermatological, 
pulmonary, or psychiatric disorder, as determined by the investigator (or designee) 
14. history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, 
or other substance, unless approved by the investigator (or designee) 
15. have a clinically significant abnormality of blood pressure and/or pulse rate as determined 
by the investigator 
16. have a history or presence of cardiovascular, respiratory, renal, gastrointestinal, endocrine, 
hematological, or neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the investigational 
product; or of interfering with the interpretation of data. Appendectomy, hernia repair, and 
cholecystectomy are considered as acceptable  
17. history of alcoholism or drug/chemical abuse within 2 years prior to check-in  
18. alcohol consumption of >14 units per week. One unit of alcohol equals 1/2 pint (285 mL) of 
beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits  
19. positive ethanol breath/urine test result or positive urine drugs of abuse screen at screening 
or check-in 
20. have evidence of HIV infection and/or positive human HIV antibodies. 
21. have donated blood of more than 500 mL within the previous 2 months of study screening  
22. have had lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no evidence 
of metastatic disease for 3 years 
23. have had breast cancer within the past 10 years 
24. hepatocellular cancer unless treated by locoregional therapy that demonstrates ablation 
without evidence of recurrent hepatocellular cancer >1 year prior to check-in 
25. have severe encephalopathy (Grade 3 to 4) 

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Protocol number J2J-MC-JZLG (d) 
28 
 
26. use or intend to use medications that are strong inhibitors or inducers of CYP3A4 within 
14 days prior to dosing until completion of the follow-up visit. Exceptions to the 2-week 
restriction may be allowed on a case-by-case basis and only after review and approval by the 
Lilly clinical pharmacologist, clinical research physician, or designee. 
27. participation in a clinical study involving administration of an investigational drug (new 
chemical entity) in the past 30 days prior to dosing, or 5 half-lives, whichever is longer 
28. have previously completed or withdrawn from this study or any other study investigating 
imlunestrant, and have previously received imlunestrant 
29. have previously received a SERD in the past 30 days prior to dosing, or 5 half-lives; 
whichever is longer 
30. smoke more than 10 cigarettes or use the equivalent tobacco, smoking-cessation products, 
nicotine-containing products, or e-cigarettes (nicotine and non-nicotine) per day. 
Participants must be willing to abstain from smoking approximately 2 hours prior to and 
2 hours post dosing  
31. ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 
7 days prior to check-in 
32. receipt of blood products within 2 months prior to check-in 
33. donation of plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to 
screening 
34. participants who, in the opinion of the investigator (or designee), should not participate in 
this study 
Additional Exclusions for Control Participants (Group 1) 
35. show evidence of positive hepatitis B surface antigen, as confirmed with HBV DNA. 
Participants who test positive for hepatitis B surface antigen may be included if they do not 
have active infection, as confirmed by a polymerase chain reaction test 
36. show evidence of hepatitis C and/or positive hepatitis C antibody. Participants who test 
positive for hepatitis C antibody may be included if they do not have active infection, as 
confirmed by a polymerase chain reaction test 
37. use or intend to use any medications/products known to alter drug absorption, metabolism, 
 dosing, unless 
deemed acceptable by the investigator (or designee) 
38. use or intend to use any prescription medications/products within 14 days prior to dosing 
until completion of the follow-up visit, unless deemed acceptable by the investigator (or 
designee) 
39. use or intend to use slow-release medications/products considered to still be active within 
14 days prior to check-in, unless deemed acceptable by the investigator (or designee) 
40. use or intend to use any nonprescription medications/products including vitamins, minerals, 
and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check-in until 
completion of the follow-up visit, unless deemed acceptable by the investigator (or 
designee) 

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Protocol number J2J-MC-JZLG (d) 
29 
41. current or chronic history of liver disease or known hepatic or biliary abnormalities 
Additional Exclusion Criteria for Participants with Hepatic Impairment (Groups 2 to 4) 
42. evidence of any significant active disease other than that responsible for or associated with 
hepatic impairment that would significantly affect the ability of the participant to safely 
participate in the trial, in the opinion of the investigator 
43. 
d Gault formula 
44. evidence of spontaneous bacterial peritonitis within 3 months of dosing 
45. have had variceal bleeding within 3 months of check-in (unless banded) 
46. evidence of severe hyponatremia (sodium approximately <120 mmol/L) 
47. have severe ascites 
48. presence of an active portal shunt, or newly placed shunt (within the last 6 months). 
49. have hemoglobin <9.0 g/dL 
50. have serum bilirubin >15 mg/dL 
51. have used concomitant medication known to interfere with hepatic metabolism (such as 
barbiturates, phenothiazines,) or known to alter other major organs or systems within 
2 weeks prior to dosing 
52. regularly use drugs of abuse and/or have positive findings on urinary drug screen, except 
those prescribed for the treatment of liver disease or related complications (e.g., pain, 
insomnia, anxiety). 
5.3. 
Lifestyle Considerations  
5.3.1. 
Meals and Dietary Restrictions  
During the confinement period, participants will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (e.g., breakfast, lunch, dinner, and snack) 
will be provided to the participants while resident at the CRU. 
Imlunestrant will be dosed in the fasted state. Participants will be fasted overnight (at least 
) prior to dosing and refrain from consuming water from 
 predose until 
 
postdose, excluding the amount of water consumed at dosing. Food is allowed from 
 
postdose. At all other times during the study, participants may consume water ad libitum.
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to check-in. In addition, all other citrus fruits and tomato-based products will 
not be allowed from the time of check-in until final discharge from the CRU. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco  
 
Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., 
coffee, tea, cola drinks, and chocolate) for 48 hours before the start of dosing until after 
collection of the final PK sample. 
 
Participants will abstain from alcohol for 24 hours before the check-in until after 
collection of the final PK sample. 
 
Participants are required to refrain from smoking more than 10 cigarettes or using the 
equivalent in tobacco, smoking-cessation products, nicotine-containing products, per 
day, and e-cigarettes (nicotine and non-nicotine) from check-in and through final 

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Protocol number J2J-MC-JZLG (d) 
30 
discharge from the CRU. Participants must be willing to abstain from smoking 
approximately 2 hours prior to and 2 hours post dosing. 
5.3.3. 
Activity  
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during studies 
(e.g., watching television, reading). 
5.3.4. 
Other  
Imlunestrant demonstrated the potential for phototoxicity in an in vitro study. Participants will be 
advised to use sunscreen and to wear clothing such as long sleeve tops that cover the arms, pants 
and/or other garments that cover the legs, and hats to cover the head if out in direct sunlight, to 
reduce the possibility of phototoxicity. 
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Individuals may be rescreened up to 1 time. The interval between re-screenings 
should be at least 1 week. Each time rescreening is performed, the individual must sign a new 
ICF and will be assigned a new identification number. 
If participants have minor deviations in screening assessments (e.g., laboratory safety tests, vital 
 

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Protocol number J2J-MC-JZLG (d) 
31 
6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
This table lists the interventions used in this study. 
Table JZLG.3. 
Study Interventions Administered  
Intervention Name 
imlunestrant 
(Groups 1, 2, 3, and 4)
Authorized as defined by EU CTRa 
Not authorized as defined by EU CTR 
Unit Dose Strength(s)/ 
Dosage Level(s)
 tablets 
(
 imlunestrant)
Route of Administration 
Oral 
Abbreviation: CTR = Clinical Trials Regulations 
a Authorized means a medicinal product authorized in accordance with Regulation (EC) No 726/2004 or in any 
Member State concerned in accordance with Directive 2001/83/EC, irrespective of the labeling, packaging, and 
whether CT or commercial material is being supplied. 
Packaging and Labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Administration Details  
All doses of imlunestrant will administered with approximately 
 of room temperature 
water while in a sitting position. 
Imlunestrant tablets should be swallowed whole. Participants should not break, crush, or chew 
the study intervention. 
Participants will not be allowed to lie supine for 
 after dosing, unless clinically indicated 
or for study procedures. 
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1. 
6.2. 
Preparation, Handling, Storage, and Accountability  
 
The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 
Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 

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Protocol number J2J-MC-JZLG (d) 
32 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized study personnel. 
 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records). 
 
Further guidance and information for the final disposition of unused study interventions 
are provided in the study materials. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is an open-label, non-randomized study. 
6.4. 
Study Intervention Compliance  
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and in the CRF. 
6.5. 
Dose Modification  
 
 
 
 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Imlunestrant will not be made available to participants after completion of the study. 
6.7. 
Treatment of Overdose  
For this study, any dose of imlunestrant greater than 
 within a 24-hour time period will be 
considered an overdose. 
In the event of an overdose, the investigator or treating physician should 
 
Contact the Lilly CP immediately 
 
Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
In case of overdose, supportive therapy should be used. There is no known antidote to 
imlunestrant overdose. 

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Protocol number J2J-MC-JZLG (d) 
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6.8. 
Concomitant Therapy  
Participants in Groups 2 to 4 who are on stable concomitant medication at the time of study entry 
should continue their regular, unchanged dose throughout the study. Participants will be asked to 
delay dosing of any concomitant medications from 2 hours prior, until 4 hours after dosing of 
imlunestrant on study Day 1, unless this delay is not deemed to be appropriate by the investigator 
for the 
 medical condition. 
For all participants, any medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency for concomitant therapy of special 
interest 
The CP/CRP should be contacted if there are any questions regarding concomitant or prior 
therapy. 
If acetaminophen (or paracetamol) treatment is needed for pain management, the maximal 
allowed dose will be 3 g/day from all acetaminophen-containing medicinal products. Additional 
drugs are to be avoided during the study unless required to treat an AE or for the treatment of an 
ongoing medical problem. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Lilly CP/CRP, or designee. 

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34 
7. 
Participant Discontinuation/Withdrawal  
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up/early discontinuation procedures as per the SoA (Section 1.3). 
Discontinuation of the study as a whole is described in Appendix 1 (Section 10.1). 
7.1. 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study: 
 
at any time at her own request 
 
at the request of her designee (for example, parents or legal guardian) 
 
at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 
if the participant becomes pregnant during the study  
 
if enrollment in any other clinical study involving an IP or enrollment in any other type 
of medical research judged not to be scientifically or medically compatible with this 
study 
 
if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
Discontinuation is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. The 
participant will be permanently discontinued both from the study intervention and from the study 
at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
7.1.1. 
Discontinuation of Inadvertently Enrolled Participants  
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from the study treatment. 
If the investigator and the Lilly CP agree it is medically appropriate to continue, the investigator 
must obtain documented approval from the sponsor CRP to allow the inadvertently enrolled 
participant to continue in the study. Safety follow-up should be performed as outlined in 
Section 1.3 (Schedule of Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse 
Events, Serious Adverse Events, and Product Complaints) of the protocol. 

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7.2. 
Lost to Follow Up  
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 

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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA (Section 1.3). 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments  
Not applicable. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations  
Physical examinations and routine medical assessments will be conducted as specified in the 
SoA (Section 1.3) and as clinically indicated. 
8.2.2. 
Vital Signs  
For each participant, supine blood pressure, supine pulse rate, and oral body temperature should 
be assessed at the times indicated in the SoA (Section 1.3). 
Blood pressure and pulse rate should be measured singly after at least 5 minutes supine. For each 
individual participant, the same cuff size should be used throughout the study for the 
measurements of blood pressure. The cuff should be attached to the 
 dominant arm. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Where orthostatic measurements are required, participants should be 
supine for at least 5 minutes and then participants will stand, and standing blood pressure will be 
measured after 2 minutes, but no longer than 3 minutes. If the participant feels unable to stand, 
supine vital signs only will be collected. Additional vital signs may be measured if warranted. 
8.2.3. 
Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
Electrocardiograms must be recorded before collecting any blood samples. Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site. 

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Electrocardiograms will be interpreted by the investigator or qualified designee at the site as 
soon after the time of ECG collection as possible, and, ideally, while the participant is still 
present. This interpretation is to determine whether the participant meets entry criteria at the 
relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the participant can 
continue in the study. The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE. 
8.2.4. 
Clinical Safety Laboratory Tests  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3) for the timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator, CP, or CRP. 
 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the SoA, standard collection requirements. 
If laboratory values from non-protocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose modification), then 
report the information as an AE. 

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8.2.5.
Safety Monitoring
8.2.5.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 5, Section 10.5), including ALT, AST, ALP, TBL, direct bilirubin, 
GGT, and CK, should be repeated within 48 to 72 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if one or more of these conditions occur:
If a participant with baseline results of... 
develops the following elevations:
ALT or AST <1.5x ULN
ALP <1.5x ULN
TBL <1.5x ULN
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
l tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:
If a participant with baseline results of... 
develops the following elevations:
ALT or AST <1.5x ULN
a, or 
ALP <1.5x ULN
TBL <1.5x ULN
baseline with hepatic signs/symptomsa, or
a
Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.

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At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
consultation with the Lilly-designated medical monitor, including tests for HDV, CMV, EBV, 
blood alcohol levels, urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the 
investigator should consider referring the participant for a hepatologist or gastroenterologist 
consultation, magnetic resonance cholangiopancreatography, endoscopic retrograde 
cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 4 conditions: 
1. 
baseline ALT <1.5x ULN) 
 
3x 
baseline on 2 or more consecutive tests 
2. 
 ULN (if baseline TBL <1.5x ULN) (except for cases of 
 
 
 
3. 
more consecutive blood tests (if 
baseline ALP <1.5x ULN) 
 
baseline on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE. 
Note: The interval between the two consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
 
AEs 
 
SAEs 
 
Product complaints 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 

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Protocol number J2J-MC-JZLG (d) 
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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
signing of 
the ICF 
participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates  prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
with study 
procedures 
signing of 
the ICF 
start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates  after 
start of study 
intervention 
start of 
intervention 
participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE*  after 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
Product Complaint 
form 
N/A 

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Protocol number J2J-MC-JZLG (d) 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
 
 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product Complaint 
form 
 
Abbreviations: AE = adverse event; ICF = informed consent form; N/A = not applicable; PC = product complaint; 
SAE = serious adverse event. 
* Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.4. 
Pharmacokinetics  
At the visits and times specified in the SoA (Section 1.3), venous blood samples of up to 2 mL 
each will be collected to determine the plasma concentrations of imlunestrant and venous blood 
samples of up 10 mL will be collected to determine 
 
. 
Up to 3 samples may be collected at additional time points during the study if warranted and 
agreed upon between both the investigator and sponsor. 
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded, as well 
as the date and time of each imlunestrant dose. 
8.4.1. 
Bioanalysis  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of imlunestrant will be assayed using a validated liquid chromatography mass 
spectrometry method. The unbound concentration in plasma will also be measured. Samples 
collected for the analysis of plasma concentrations of imlunestrant may be stored and analyzed 
for future exploratory analysis. 
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last participant visit for the study. 

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Protocol number J2J-MC-JZLG (d) 
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8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3), where local regulations allow. 
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments  
Not applicable for this study. 
8.9. 
Health Economics  
This section is not applicable for this study. 

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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
This study will evaluate the PK of imlunestrant in women of non-childbearing potential with 
hepatic impairment compared to control women of non-childbearing potential with normal 
hepatic function. 
9.2. 
Analyses Sets  
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the ICF. 
Enrolled/Intent-to-Treat 
All participants assigned to treatment, regardless of whether they 
take any doses of IP, or if they take the correct treatment. 
Safety 
All participants who take 1 dose of IP.  
Pharmacokinetic Analysis 
All participants who received 1 dose of IP and have evaluable 
PK. 
9.2.1. 
Study Participant Disposition  
A detailed description of participant disposition will be provided at the end of the study. 
9.2.2. 
Study Participant Characteristics  
summarized. 
9.2.3. 
Treatment Compliance  
The date and time of dosing will be recorded and listed. 
9.3. 
Statistical Analysis  
9.3.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Additional exploratory analysis of the data will be conducted as deemed appropriate. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in SAP, where appropriate. Adjustments to the planned analyses are 
described in the final clinical study report. 
9.3.2. 
Clinical Evaluation of Safety  
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 

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The incidence of AEs for each treatment will be presented by severity and by association with 
investigational product as perceived by the investigator. Adverse events reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each AE will be classified by the most suitable term from the medical regulatory 
dictionary. 
The number of investigational product-related SAEs will be reported. 
9.3.3. 
Statistical Evaluation of Safety  
Safety parameters that will be assessed include safety laboratory parameters, and vital signs. The 
parameters will be listed and summarized using standard descriptive statistics. Additional 
analysis will be performed if warranted upon review of the data. 
9.3.4. 
Pharmacokinetic Analyses  
9.3.4.1. 
Pharmacokinetic Parameter Estimation  
Pharmacokinetic parameter estimates will be calculated by standard noncompartmental methods. 
The primary PK parameters for analysis of imlunestrant (total) will be AUC0- , AUCtlast, and 
Cmax, or their equivalent dose normalized parameters, as appropriate. Other noncompartmental 
parameters, such as t1/2, CL/F, and Vdz/F, may be reported as appropriate. The impact of hepatic 
impairment on plasma protein binding of imlunestrant will be summarized using descriptive 
statistics of plasma protein binding data. 
9.3.4.2. 
Pharmacokinetic Statistical Inference  
A statistical analysis will be conducted to evaluate the PK of imlunestrant following a single 
dose in participants with mild, moderate, or severe hepatic impairment (test) compared to 
matched healthy participants with normal hepatic function (reference function) for primary PK 
parameters (AUC0- , AUCtlast, and Cmax). 
Statistical analysis to compare each test hepatic function participant to their corresponding 
reference hepatic function participant will be performed separately. The PK parameters AUC0- , 
AUCtlast, and Cmax will be analyzed in logarithmic scale using an analysis of covariance model 
with hepatic function group as a fixed effect and body weight as a covariate. The difference 
between each test (hepatic impairment) group and the reference (normal hepatic function) group 
will be presented. The 90% confidence interval for the geometric mean ratio between each test 
group versus the reference group will be presented. 
The relationship between the PK and Child-Pugh classification parameters Child-Pugh score, 
serum albumin concentration, total bilirubin concentration, and prothrombin time will also be 
assessed graphically.  
Further details of these analyses are provided in the SAP. 
9.4. 
Interim Analysis  
Participants with normal hepatic function and mild hepatic impairment can be dosed 
concurrently from the onset of the study. 

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A review (not an interim analysis) to assess imlunestrant safety and PK will be conducted after at 
least 3 participants with mild hepatic impairment have completed all PK sampling. Study 
enrollment can continue in Groups 1 and 2 during the review but imlunestrant will not be 
administered to participants with moderate hepatic impairment until the review has been 
completed. 
Another review along with an interim analysis will be conducted after data from 6 participants 
with mild hepatic impairment (Group 2) and 6 participants with moderate hepatic impairment 
(Group 3) have been obtained. The SAP will describe the planned interim analyses in greater 
detail. The timing of dissemination of data summaries based on interim analyses is addressed in 
Appendix 1, Section 10.1.5. Study enrollment can continue in Groups 1 through 3 during the 
interim analysis and review but imlunestrant will not be administered to participants with severe 
hepatic impairment until this analysis and review have been completed. Additional reviews to 
assess imlunestrant safety and PK will be conducted after 3 participants with severe hepatic 
impairment have completed all PK sampling.  
 
A final analysis will be conducted and a clinical study report produced after all cohorts have 
completed all PK samples, unless no further participants with severe hepatic impairment are 
enrolled after production of the interim clinical study report. 
The dose of 400 mg imlunestrant may be reduced within a hepatic impairment group and for 
subsequent groups based on review of safety and PK data. Doses may be reduced based on the 
magnitude of any differences in exposure observed between the control group and hepatically 
impaired participants. 
Additional data reviews may occur at any time if deemed appropriate based on safety, 
tolerability, or PK information. 
9.5. 
Sample Size Determination  
Overall, up to approximately 35 participants may be enrolled to ensure 24 completers, as 
follows: 
 
Group 1: participants with normal hepatic function (Control); minimum of 6 and 
maximum of 12 completers 
 
Group 2: participants with mild hepatic impairment (Child-Pugh A); 6 completers 
 
Group 3: participants with moderate hepatic impairment (Child-Pugh B); 6 completers 
 
Group 4: participants with severe hepatic impairment (Child-Pugh C); 6 completers. 

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Protocol number J2J-MC-JZLG (d) 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
o Providing oversight of study conduct for participants under their 
responsibility and adherence to requirements of 21 CFR, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
o Reporting significant issues related to participant safety, participant 
rights, or data integrity 
 
Investigational sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 

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Protocol number J2J-MC-JZLG (d) 
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certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
 The investigator or 
 representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
 Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
 A copy of the ICF(s) must be provided to the participant and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
 Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
 The participant must be informed that 
 personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent. 
 The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
 The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 

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Protocol number J2J-MC-JZLG (d) 
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10.1.5. 
Dissemination of Clinical Study Data  
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.6. 
Data Quality Assurance  
 All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
 The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
 Monitoring details describing strategy (for example, 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 are 
provided in the Monitoring Plan. 

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 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
 The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
clinical trial agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
 In addition, the sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the study site. The study 
may be audited by the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An EDC will be used in this study for the collection of CRF data. The investigator maintains a 
separate source for the data entered by the investigator or designee into the sponsor-provided 
EDC system. The investigator is responsible for the identification of any data to be considered 
source and for the confirmation that data reported are accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture systems will be stored at third-parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 

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10.1.7. 
Source Documents  
 Source documents provide evidence for the existence of the participant and substantiate 
 
 Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
 Definition of what constitutes source data can be found in Section 10.1.6. 
10.1.8. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or Site Termination 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
 Discontinuation of further study intervention development 
For site termination: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
 Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 

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10.1.9. 
Publication Policy  
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.10. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests  
 The tests detailed in the table below will be performed by the local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 Investigators must document their review of the laboratory safety results. 
 
 

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Clinical Laboratory Tests 
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin 
Potassium
Erythrocyte count 
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration 
Phosphorus  
Leukocytes
Glucose
Platelets
Creatine kinase
 
Gamma-glutamyl transferase
Coagulation
Blood urea nitrogen
Prothrombin time
Direct bilirubin
 
Uric acid 
Activated partial thromboplastin time
Total protein
International normalized ratio
Albumin
 
Total bilirubin
Differential White Blood Cells (absolute counts) of
Alkaline phosphatase 
Neutrophils
Aspartate aminotransferase
Lymphocytes
Alanine aminotransferase
Monocytes 
Creatinine
Eosinophils
Lipase
Basophils 
Amylase
 
Urinalysis
Specific gravity
pH 
Protein 
 
Glucose 
Ethanol testinga
Ketones 
Urine drug screena
Bilirubin 
Hepatitis B surface antigenb,c,d
Urobilinogen
Hepatitis B DNAb,d 
Blood
Hepatitis C antibodyb,c,d
Nitrite 
Human immunodeficiency virus antibodiesb
Follicle-stimulating hormone (if applicable)b
a Performed at screening and check-in only. 
b Performed at screening only. 
c Positive result will be confirmed by polymerase chain reaction test to determine active infection. 
d Control Participants (Group 1) only. 
 
 

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10.2.1. 
Blood Sampling Summary  
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling during the study. 
Protocol J2J-MC-JZLG Sampling Summary 
 
Purpose 
Blood Volume per 
Sample (mL) 
Maximum Number 
of Blood Samples 
Maximum Total 
Volume (mL) 
Screening tests a 
18.8 
1 
18.8 
Clinical laboratory tests a 
11 
7 
77 
Pharmacokinetics - imlunestrant (total) b 
2 
21 
42 
Pharmacokinetics 
 b 
10 
3 
30 
Genetic sample 
10 
1 
10 
Total 
 
 
177.8 
Total for clinical purposes 
 
 
180 
a Additional samples may be drawn if needed for safety purposes. 
b A maximum of 3 samples may be collected at additional timepoints if warranted, as outlined in Section 8.4. 
 
 

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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, 
and Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 
An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
 
Events NOT Meeting the AE Definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
condition. 
 
Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 

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Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physicia
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 
The term disability means a substanti
normal life functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 

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f. 
Other situations: 
 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 
Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 
Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 
An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 
When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event. 
 
The investigator will then record all relevant AE/SAE/product complaint information 
in the 
 medical records, in accordance with 
clinical practice. AE/SAE information is reported on the appropriate CRF page and 
product complaint information is reported on the Product Complaint Form. 

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Protocol number J2J-MC-JZLG (d) 
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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 
It is not 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 
There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories: 
 
Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 
Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 
Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with a SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 
A reasonable possibility  of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 

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Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
The investigator will also consult the IB in their assessment. 
 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 
The investigator may change their opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
 
Follow-up of AEs and SAEs 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via Paper Form 
 
Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in the SAE report. 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 

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investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
 

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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
Definitions: 
Woman not of Childbearing Potential 
Females are considered women not of childbearing potential if: 
 
they have a congenital anomaly such as Mullerian agenesis,  
 
they are infertile due to surgical sterilization or alternate medical cause, or  
 
they are post-menopausal. 
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, bilateral tubal occlusion, bilateral tubal ligation. 
records, medical examination, or medical history interview. 
The post-menopausal state is defined as: 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note; or 
2. A woman at least 40 years of age and up to 55 years of age with an intact uterus, not on 
hormone therapy*, who has had cessation of menses for at least 12 consecutive months 
without an alternative medical cause, AND with a follicle-stimulating hormone 
>40 mIU/mL; or 
3. A woman 55 years of age or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea; or  
4. A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone-replacement therapy. 
*Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
 
 

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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
See protocol Section 8.2.5.1 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (red blood cells) 
Alkaline phosphatase 
Leukocytes (white blood cells) 
Alanine aminotransferase 
Differential: 
Aspartate aminotransferase 
    Neutrophils, segmented 
Gamma-glutamyl transferase 
    Lymphocytes 
Creatine kinase 
    Monocytes 
Other Chemistry
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (red blood cells and white blood 
cells) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol 
Prothrombin time, INR 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus testing: 
Immunoglobulin IgG (quantitative) 
    Hepatitis A virus total antibody 
Immunoglobulin IgM (quantitative) 
    Hepatitis A virus IgM antibody 
Phosphatidylethanol 
Hepatis B virus testing: 
Urine Chemistry 
    Hepatitis B surface antigen 
Drug screen 
    Hepatitis B surface antibody 
Ethyl glucuronide 
    Hepatitis B core total antibody 
Other Serology
    Hepatitis B core IgM antibody 
Anti-nuclear antibody 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody a 

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Hematology
Clinical Chemistry 
    Hepatis B virus DNA b 
Anti-actin antibody c 
Hepatis C virus testing: 
Epstein-Barr virus testing: 
    Hepatis C virus antibody 
    Epstein-Barr virus antibody 
    Hepatis C virus RNA b 
    Epstein-Barr virus DNA b 
Hepatitis D virus testing: 
Cytomegalovirus testing: 
    Hepatitis D virus antibody 
    Cytomegalovirus antibody 
Hepatitis E virus testing: 
    Cytomegalovirus DNA b 
    Hepatitis E virus IgG antibody 
Herpes simplex virus testing: 
    Hepatitis E virus IgM antibody 
    Herpes simplex virus (Type 1 and 2) antibody 
    Hepatitis E virus RNA b 
    Herpes simplex virus (Type 1 and 2) DNA b 
Microbiology d 
Liver kidney microsomal type 1 antibody 
Culture: 
    Blood 
    Urine 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 

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10.6. 
Appendix 6: Abbreviations and Definitions  
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC0-  
area under the concentration versus time curve from time zero extrapolated to infinity 
AUCtlast 
area under the concentration versus time curve from time zero to the last quantifiable 
concentration 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
CMV 
cytomegalovirus 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, GCP, and applicable regulatory requirements. 
CP 
clinical pharmacologist 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant. 
CRP 
clinical research physician:  Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 

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Term 
Definition 
CRU 
clinical research unit 
CT 
computed tomography 
CYP 
cytochrome P450 
DMC 
data monitoring committee. A data monitoring committee, or data monitoring board is 
a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study. 
EBV 
Epstein-Barr virus 
EC 
endometrial cancer 
EDC 
electronic data capture 
ECG 
electrocardiogram 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the ICF directly or through their 
legally acceptable representatives. 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
HDV 
hepatitis D virus 
HIV 
human immunodeficiency virus 
HR 
hormone receptor 
HER2 
human epidermal growth factor receptor 2 
HSA 
human serum albumin 
IB 
 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 

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Protocol number J2J-MC-JZLG (d) 
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Term 
Definition 
Ig 
immunoglobulin 
IMP 
 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
means of a written, signed and dated ICF. 
INR 
international normalized ratio 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked. 
investigational 
product (IP) 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
institutional review board 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or 
right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
 
dose omission associated with an AE or a product complaint 
 
dispensing or use of expired medication 
 
use of medication past the recommended in-use date 
 
dispensing or use of an improperly stored medication 
 
use of an adulterated dosage form or administration technique inconsistent with 
the medication's labeling (for example, Summary of Product Characteristics, IB, 
local label, protocol), or 
 
shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
NIMP 
Non-investigational Medicinal Product. See AxMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. 

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Term 
Definition 
participant 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK/PD 
pharmacokinetic(s)/pharmacodynamics 
PT 
prothrombin time 
QD 
once daily 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study. 
SERD 
selective estrogen receptor degrader 
t1/2 
half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment. 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
Vdz/F 
apparent volume of distribution 
 
 
 

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10.7. 
Appendix 7: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment (c): 18 September 2022 
This amendment is considered to be substantial because it is likely to have a significant impact 
on the reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
The protocol was amended to increase the number of completers from 3 to 6 in both the mild and 
moderate hepatic impairment groups. 
 
These additions will aid in having the mild and moderate hepatic impairment data to 
inform the label at the time of the initial imlunestrant submission. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis Updated timing of data reviews and 
added information regarding an 
interim analysis. 
 
 
Updated the target number of 
the context of replacing participants 
who do not complete dosing and PK 
sampling. 
Increased the number of participants 
that Cohorts 2 and 3 may be expanded 
 
Updated the number of completers in 
Group 2 with mild hepatic impairment 
 
Updated the number of completers in 
Group 3 with moderate hepatic 
 
The interim analysis will 
provide finalized data for 
participants with mild and 
moderate hepatic damage for 
the submission. 
 
To increase the reliability and 
robustness of the data 
generated in the study. 
 
 
 
 
 
 
 
Section 4.1 Overall 
Design 
Updated the number of completers in 
Group 2 with mild hepatic impairment 
 
To increase the reliability and 
robustness of the data 
generated in the study. 

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Section # and Name 
Description of Change 
Brief Rationale 
Updated the number of completers in 
Group 3 with moderate hepatic 
 
Updated the target number of 
the context of replacing participants 
who do not complete dosing and PK 
sampling. 
 
Increased the number of participants 
that Cohorts 2 and 3 may be expanded 
 
 
Updated the timing of data reviews 
and added information regarding an 
interim analysis. 
 
 
 
 
 
 
 
 
 
The interim analysis will 
provide finalized data for 
participants with mild and 
moderate hepatic damage for 
the submission. 
 
 
 
 
 
 
 
 
Section 9.5 Sample 
Size Determination 
Updated the overall number of 
 
Updated the number of completers in 
Group 2 with mild hepatic impairment 
 
Updated the number of completers in 
Group 3 with moderate hepatic 
 
To increase the reliability and 
robustness of the data 
generated in the study. 
Section 11 
References 
Added one reference. 
The reference was 
inadvertently left off of the 
reference list. 
Throughout 
Editorial changes made. 
 
 

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Amendment (b): 30 June 2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis, 
Section 1.2, Schema, 
Section 1.3, Schedule 
of Activities, and 
Section 4.1.2 
Treatment and 
Assessment Period  
Flexibility surrounding 
length of stay in the clinical 
research unit was added to 
the study design. 
To aid recruitment.  
Section 1.1, Synopsis, 
Section 4.1, Overall 
Design, and Section 
9.5, Sample Size 
Determination  
Number of completers in 
Group 1 updated. 
To allow flexibility in matching with 
Groups 2 through 4. 
Section 1.1, Synopsis, 
Section 1.2, Schema, 
Section 1.3, Schedule 
of Activities, and 
Section 4.1.3 
Follow-up 
Follow-up now specified as 
5 to 7 days post final CRU 
discharge. 
For clarity. 
Section 5.2, Exclusion 
Criteria 
Exclusions #16, #31, and 
#42 amended. 
Exclusion #43 was 
removed. 
New exclusions added as 
#22, #23, #24, and #25. 
Per site request. 
 
Per site and team requests. 
Section 5.3.1, Meals 
and Dietary 
Restrictions, and 
Section 5.3.2, 
Substance Use: 
Caffeine, Alcohol, and 
Tobacco 
used in these sections is 
referring to final discharge 
from the CRU. 
For clarity. 
Section 6.8, 
Concomitant Therapy 
Timing for which 
concomitant medications 
should be restricted prior to 
dosing added. 
Per site request. 

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Protocol number J2J-MC-JZLG (d) 
71 
Section # and Name 
Description of Change 
Brief Rationale 
Section 10.2, 
Appendix 2: Clinical 
Laboratory Tests 
Hepatitis B core antibody 
test removed. Hepatitis B 
Virus DNA test added. 
Footnoted that hepatitis tests 
are applicable to control 
participants only. 
Per site request. 
 
 
For clarity. 
Section 10.2.1, Blood 
Sampling Summary 
Addition of blood volume 
table. 
Unintentionally omitted from original 
protocol. 
 
Amendment (a): 02 March 2022 
Overall Rationale for the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis 
Regulatory agency identifier 
and lay summaries of study 
population were added. 
As advised by European Union 
Clinical Trials Regulations questions 
and answers, published October 2021. 
Section 1.1, Synopsis 
Removal of 
pharmacokinetic parameter 
estimation of unbound 
imlunestrant. 
Descriptive statistics of plasma protein 
binding data will be presented instead. 
Section 1.3, Schedule 
of Activities 
Pharmacokinetic sampling 
timepoints for unbound 
imlunestrant were updated. 
Unbound concentrations are only 
needed at certain timepoints. 
Section 2.1, Study 
Rationale 
Removal of repeated 
information from Section 2. 
Unintentionally duplicated in original 
protocol. 
 
Rationale for measurement 
of unbound imlunestrant 
added. 
Unintentionally omitted from original 
protocol. 
Section 2.2.1, 
Pharmacokinetics of 
Imlunestrant 
Addition of summary of 
pharmacokinetic findings 
from Study JZLD, a 
drug-drug interaction study 
with itraconazole. 
New data available at the time of 
protocol amendment. 

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Protocol number J2J-MC-JZLG (d) 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3, Objectives 
and Endpoints 
Removal of 
pharmacokinetic parameter 
estimation of unbound 
imlunestrant. 
Descriptive statistics of plasma protein 
binding data will be presented instead. 
Section 4.3, 
Justification for Dose 
Addition of summary of 
pharmacokinetic findings 
from Study JZLD, a 
drug-drug interaction study 
with itraconazole. 
New data available at the time of 
protocol amendment. 
Section 5.2, Exclusion 
Criteria 
Clarified that participants 
who test positive for 
hepatitis B surface antigen 
or hepatitis C antibody may 
be included if they are 
negative by polymerase 
chain reaction testing. 
Intent of exclusion criteria was to 
exclude participants with active 
infection. Participants may still be 
positive for hepatitis B surface antigen 
or hepatitis C antibody without active 
infection. This can be confirmed by 
polymerase chain reaction testing. 
Section 6.1, Study 
Intervention(s) 
Administered 
Reorganization and 
clarification of information 
related to the study 
intervention. 
Requirements of European Union 
Clinical Trials Regulations 536/2014 
Article 59(2) and Annex 1 (17 [b]) 
8.2.5, Safety 
Monitoring 
8.2.5.1, Hepatic 
Safety 
Added language for safety 
monitoring in case of 
hepatic abnormalities. 
Unintentionally omitted from original 
protocol. 
Section 8.4, 
Pharmacokinetics 
Pharmacokinetic sampling 
methods for unbound 
imlunestrant were updated. 
Unbound concentrations are only 
needed at certain timepoints. 
Section 9.3.1, General 
Considerations 
Added statement regarding 
handling is missing, unused 
or spurious data. 
Requirements of European Union 
Clinical Trials Regulations 536/2014 
Annex 1 (17 [u]) 
Section 9.3.4.1, 
Pharmacokinetic 
Parameter Estimation 
Removal of 
pharmacokinetic parameter 
estimation of unbound 
imlunestrant. 
Descriptive statistics of plasma protein 
binding data will be presented instead. 

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Protocol number J2J-MC-JZLG (d) 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.1, 
Regulatory and 
Ethical Considerations 
Added additional 
investigator responsibilities. 
Requirements of European Union 
Clinical Trials Regulations 536/2014 
Section 10.1.5, 
Dissemination of 
Clinical Study Data 
Added information related 
to dissemination of 
summary of results. 
Requirements of European Union 
Clinical Trials Regulations 535/2014 
Article 37 (8) and Annex I (17 [aj]). 
Section 10.2, 
Appendix 2: Clinical 
Laboratory Tests 
Clarified that participants 
who test positive for 
hepatitis B surface antigen 
or hepatitis C antibody may 
have a polymerase chain 
reaction test to confirm 
active infection. 
Participants may still be positive for 
hepatitis B surface antigen or hepatitis 
C antibody without active infection. 
This can be confirmed by polymerase 
chain reaction testing. 
Section 10.3.1, 
Definition of an 
Adverse Event 
Updates to definition of 
events meeting the adverse 
event definition. 
Requirements of European Union 
Clinical Trials Regulations 536/2014 
Annex III (2.1 [2]). 
10.5, Appendix 5: 
Liver Safety: 
Suggested Actions 
and Follow-up 
Assessments 
Added actions and 
follow-up items in case of 
hepatic abnormalities. 
Unintentionally omitted from original 
protocol. 

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11. 
References  
André F, Ciruelos E, Rubovszky G, et al.; SOLAR-1 Study GROUP. Alpelisib for 
PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 
2019;380(20):1929-1940. https://doi.org/10.1056/NEJMoa1813904 
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone 
receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. 
https://doi.org/10.1056/NEJMoa1109653 
Bray F, Ferlay J, Soerjomatram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 
2018;68(6):394-424. https://doi.org/10.3322/caac.21492 
Cardoso F, Costa A, Norton L, et al. 1st international consensus guidelines for advanced breast 
cancer (ABC 1). Breast. 2012;21(3):242-252. 
Child, C. and Turcotte, J. Surgery and Portal Hypertension. Major Problems in Clinical Surgery, 
1964;1, 1-85. 
Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg 
in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337. 
https://doi.org/10.1093/jnci/djt337 
Ellenson LH, Ronnett BM, Kurman RJ. Precursor lesions of endometrial carcinoma. In: Kurman 
RJ, Ellenson LH, Ronnett BM, editors. 
. 
Boston, MA: Springer; 2011:p 359-391. 
Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl 
J Med. 2016;375(20):1925-1936. https://doi.org/10.1056/NEJMoa1607303 
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2016, 
National Cancer Institute. Bethesda, MD. Based on November 2018 SEER data submission, 
posted to the SEER web site, April 2019. Accessed November 22, 2021. 
https://seer.cancer.gov/csr/1975_2016/ 
Nardone A, Weir H, Delpuech O, et al. The oral selective oestrogen receptor degrader (SERD) 
AZD9496 is comparable to fulvestrant in antagonizing ER and circumventing endocrine 
resistance. Br J Cancer. 2019;120(3):331-339. https://doi.org/10.1038/s41416-018-0354-9 
[NCCN] Abu-Rustum NR, Yashar CM, Bean S, et al. NCCN Clinical Practice Guidelines in 
Oncology Uterine Neoplasms, Version 1.2020 - March 2020. 
[NCCN] Gradishar WJ, Anderson BO, Aft R, et al. NCCN Clinical Practice Guidelines in 
Oncology Breast Cancer, Version 1.2018 - March 2018. 
[NCI] National Cancer Institute. PDQ® Adult Treatment Editorial Board. PDQ Endometrial 
Cancer Treatment. Bethesda, MD. Updated December 2019. Accessed November 22, 2021. 
https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietrini MC, Williams R. Transection of the esophagus 
for bleeding oesophageal varices. Br J Surg. 1973;60:646 649. 

CONFIDENTIAL 
Protocol number J2J-MC-JZLG (d) 
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Turner NC, Ro J, André F, et al.; PALOMA3 Study Group. Palbociclib in 
hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219. 
https://doi.org/10.1056/NEJMoa1505270 
van Kruchten M, de Vries EG, Glaudemans AW, et al. Measuring residual estrogen receptor 
availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 
2015;5(1):72-81. https://doi.org/10.1158/2159-8290.CD-14-0697 
Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288-300. 
https://doi.org/10.1001/jama.2018.1932 
Weatherman RV, Fletterick RJ, Scanlan TS. Nuclear-receptor ligands and ligand-binding 
domains. Annu Rev Biochem. 1999;68:559-581. 
https://doi.org/10.1146/annurev.biochem.68.1.559