The Effect of Repeat Dosing of Imlunestrant on CYP3A Activity in Healthy Women of Non-childbearing Potential
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
Protocol: J2J-MC-JZLK (a) 
 
 
The Eﬀect of Repeat Dosing of Imlunestrant on CYP3A AcƟvity in Healthy Women of Non-
childbearing PotenƟal 
 
 
NCT05509816 
 
 
Approval Date: 08-Sep-2022 

CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
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 Exemption 4 and may not be reproduced or otherwise 
disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
The Effect of Repeat Dosing of Imlunestrant on CYP3A Activity in Healthy Women of 
Non-childbearing Potential  
Protocol Number: J2J-MC-JZLK 
Amendment Number: (a) 
Compound: imlunestrant  
Brief Title: imlunestrant and CYP3A activity 
Study Phase: 1 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana 46285, USA 
Regulatory Agency Identifier Number 
IND: 145311 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-074156 
Medical Monitor Name and Contact Information will be provided separately. 
Approved on 08 Sep 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
2 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
07-Jun-2022 
Overall Rationale for the Amendment: 
Protocol J2J-MC-JZLK has been amended for the purposes of clarification and to align with 
current clinical practices. The new protocol is indicated by amendment (a) and will be used to 
conduct study in place of any preceding version of the protocol. The overall changes and 
rationale for the changes made to the protocol are described in the following table. Note that 
minor edits have been made throughout the protocol, which are not captured in the amendment 
summary table. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
(SoA) 
It was clarified which 
assessments were conducted at 
both the screening visit and 
Day -1 or the screening visit 
only.  
Updated to be consistent with other 
sections of the protocol.  
1.3 Schedule of 
Activities 
(SoA) 
The laboratory assessments 
notes column was updated to 
state that labs were to be 
‘collected’ rather than 
‘checked’ before participants 
were sent home. 
The laboratory results would not be 
available to check prior to discharge 
of participants.  
5. Study 
Population 
It was clarified that enrollment 
would be based upon screening 
results, unless otherwise stated 
in the inclusion and exclusion 
criteria. 
Updated to align with inclusion and 
exclusion criteria that were required to 
be confirmed at check-in or prior to 
dosing.  
5.2 Exclusion 
Criteria 
Exclusion criterion 19 was 
removed.  
Exclusion criterion 19 duplicated the 
requirements for donation of blood 
already outlined in in exclusion 
criterion 32.  
5.2 Exclusion 
Criteria 
Exclusion criterion 16 was 
updated to remove reflex 
polymerase chain reaction 
testing for hepatitis B. Reflex 
polymerase chain reaction 
testing for hepatitis C was 
The polymerase chain reaction test is 
not available for hepatitis B.  
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CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
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Section # and 
Name 
Description of Change 
Brief Rationale 
moved to exclusion criterion 
17. 
8.2.3 
Electrocardiograms 
The requirement for the 
investigator to document their 
review of the electrocardiogram 
printed at the time of collection 
was removed.  
This documentation is not required 
and was erroneously included.  
Appendix 2: 
Clinical 
Laboratory Tests 
The requirement for ‘counts’ of 
white blood cells was removed 
and ‘%’ was added. 
Absolute and % white blood cells only 
were sufficient. 
Appendix 2: 
Clinical 
Laboratory Tests 
Footnote ‘a’ was amended to 
remove that urine drug screen 
would be performed on Day 8. 
Updated to be consistent with 
Schedule of Activities.  
Appendix 2: 
Clinical 
Laboratory Tests 
Footnote ‘c’ was removed from 
hepatitis B surface antigen. 
The polymerase chain reaction test is 
not available for hepatitis B.  
Appendix 2: 
Clinical 
Laboratory Tests 
White blood cell esterase was 
added to the list of urinalysis 
parameters.  
This will be analyzed as part of the 
standard urine dipstick.  
Appendix 4: 
Contraceptive and 
Barrier Guidance 
Bilateral tubal occlusion was 
removed as an example of 
surgical sterilization.  
Bilateral tubal occlusion is not an 
acceptable form of sterilization.  
Appendix 4: 
Contraceptive and 
Barrier Guidance 
The section ‘Male patients with 
partners who become pregnant’ 
has been removed. 
Males were not enrolled in this study.  
 
 
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CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
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 ............................................................................................19 
4. 
Study Design ..................................................................................................................20 
4.1. 
Overall Design ................................................................................................................20 
4.1.1. 
Screening.........................................................................................................................20 
4.1.2. 
Treatment and Assessment Period ..................................................................................20 
4.1.3. 
Follow-up ........................................................................................................................20 
4.2. 
Scientific Rationale for Study Design ............................................................................20 
4.3. 
Justification for Dose ......................................................................................................20 
4.3.1. 
Imlunestrant ....................................................................................................................20 
4.3.2. 
Midazolam ......................................................................................................................21 
4.4. 
End of Study Definition ..................................................................................................21 
5. 
Study Population ...........................................................................................................22 
5.1. 
Inclusion Criteria ............................................................................................................22 
5.2. 
Exclusion Criteria ...........................................................................................................22 
5.3. 
Lifestyle Considerations .................................................................................................24 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................24 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................25 
5.3.3. 
Activity ...........................................................................................................................25 
5.3.4. 
Other ...............................................................................................................................25 
5.4. 
Screen Failures ................................................................................................................25 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................25 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................26 
6.1. 
Study Intervention(s) Administered................................................................................26 
6.1.1. 
Administration Details ....................................................................................................26 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................27 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................27 
6.4. 
Study Intervention Compliance ......................................................................................27 
6.5. 
Dose Modification ..........................................................................................................27 
6.6. 
Continued Access to Study Intervention After the End of the 
Study ...............................................................................................................................27 
6.7. 
Treatment of Overdose ...................................................................................................27 
6.8. 
Concomitant Therapy .....................................................................................................28 
6.8.1. 
Supportive Management for Diarrhea ............................................................................28 
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Protocol number J2J-MC-JZLK (a) 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................30 
7.1. 
Discontinuation of Study Intervention ............................................................................30 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................30 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................31 
7.3. 
Lost to Follow-up............................................................................................................31 
8. 
Study Assessments and Procedures.............................................................................32 
8.1. 
Efficacy Assessments .....................................................................................................32 
8.2. 
Safety Assessments .........................................................................................................32 
8.2.1. 
Physical Examinations ....................................................................................................32 
8.2.2. 
Vital Signs .......................................................................................................................32 
8.2.3. 
Electrocardiograms .........................................................................................................32 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................33 
8.2.5. 
Safety Monitoring ...........................................................................................................34 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................36 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................36 
8.4. 
Pharmacokinetics ............................................................................................................38 
8.4.1. 
Bioanalysis ......................................................................................................................38 
8.5. 
Pharmacodynamics .........................................................................................................38 
8.6. 
Genetics ..........................................................................................................................38 
8.7. 
Biomarkers ......................................................................................................................39 
8.8. 
Immunogenicity Assessments.........................................................................................39 
8.9. 
Health Economics ...........................................................................................................39 
9. 
Statistical Considerations .............................................................................................40 
9.1. 
Statistical Hypotheses .....................................................................................................40 
9.2. 
Analyses Sets ..................................................................................................................40 
9.2.1. 
Study Participant Disposition .........................................................................................40 
9.2.2. 
Study Participant Characteristics ....................................................................................40 
9.2.3. 
Treatment Compliance ....................................................................................................40 
9.3. 
Statistical Analyses .........................................................................................................40 
9.3.1. 
Safety Analyses ...............................................................................................................41 
9.3.2. 
Pharmacokinetic Analyses ..............................................................................................41 
9.3.3. 
Pharmacodynamic Analyses ...........................................................................................41 
9.3.4. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................42 
9.4. 
Interim Analysis ..............................................................................................................42 
9.5. 
Sample Size Determination ............................................................................................42 
10. 
Supporting Documentation and Operational Considerations ..................................43 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................43 
10.1.1. Regulatory and Ethical Considerations ...........................................................................43 
10.1.2. Informed Consent Process ..............................................................................................43 
10.1.3. Data Protection................................................................................................................44 
10.1.4. Dissemination of Clinical Study Data.............................................................................44 
10.1.5. Data Quality Assurance ..................................................................................................45 
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Protocol number J2J-MC-JZLK (a) 
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10.1.6. Source Documents ..........................................................................................................46 
10.1.7. Study and Site Start and Closure ....................................................................................46 
10.1.8. Publication Policy ...........................................................................................................47 
10.1.9. Investigator Information .................................................................................................47 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................48 
10.2.1. Blood Sampling Summary ..............................................................................................50 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...............................................................................................51 
10.3.1. Definition of AE .............................................................................................................51 
10.3.2. Definition of SAE ...........................................................................................................52 
10.3.3. Definition of Product Complaints ...................................................................................53 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................53 
10.3.5. Reporting of SAEs ..........................................................................................................55 
10.3.6. Regulatory Reporting Requirements ...............................................................................55 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................57 
10.4.1. Definitions.......................................................................................................................57 
10.5. 
Appendix 5: Genetics......................................................................................................57 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................59 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................61 
10.8. 
Appendix 8: Protocol Amendment History ....................................................................64 
11. 
References ......................................................................................................................65 
 
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1.  
Pr ot oc ol S u m m ar y  
1. 1.  
S y n o psis  
Pr ot oc ol Title:  T h e Effect of Re peat D osi n g of I ml u nestra nt o n C Y P 3 A Acti vit y Healt h y 
W o me n  of N o n -c hil d beari n g P ote ntial  
Brief  Title:  i ml u nestra nt a n d C Y P 3 A acti vit y 
R ati o n ale : 
St u d y J 2J -M C -J Z L K (J Z L K) is a P hase 1 o pe n-la bel st u d y of i ml u nestra nt a d mi nistere d t o 
healt h y w o me n  of n o n -c hil d beari n g p ot e ntial . T he p ur p ose of t his st u d y is t o assess t he effect of 
i ml u nestra nt o n t he P K of mi daz ola m, a k n o w n se nsiti ve C Y P 3 A s u bstrate. 
O bjecti ves  a n d  E n d p oi nt s: 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o e val uate t he effect of  m ulti ple d oses of  
i ml u nestra nt o n t he P K of mi daz ola m 
( C Y P 3 A 4 s u bstrate) i n h ealt h y w o me n  of 
n o n -c hil d beari n g p ote nti al . 
A U C( 0 -∞) a n d Cma x  of mi daz ola m w he n 
a d mi nistere d al o ne a n d i n t he prese n ce of 
i ml u nestra nt. 
 
Sec o n dar y  
 
 T o e val uate t he effect of m ulti ple 
d oses of i ml u nestra nt o n t he P K of 
1’ -h y dr o x y mi daz ola m (a meta b olite of 
mi daz ola m) i n healt h y w o me n of 
n o n -c hil d beari n g p ote nti al . 
 T o e val uate t he s afet y a n d t olera bilit y 
of 
 
i n healt h y w o m e n  of n o n -c hil d beari n g 
p ote ntial . 
 E val uate t he P K of iml u n estra nt i n 
healt h y w o me n  of n o n -c hil d beari n g 
p ote ntial . 
 A U C( 0 -∞) a n d C ma x  of 
1’ -h y dr o x y mi daz ola m w he n 
mi daz ola m is a d mi nistere d al o ne a n d 
i n t he prese nce of i ml u nestra nt. 
 
 I n ci de nce a n d se v erit y of A Es a n d 
S A Es . 
 
 A U C( 0 -2 4) , ss a n d C ma x , ss of 
i ml u nestra nt. 
 
O ver all Desi g n  
Brief S u m m a r y : 
St u d y J Z L K is a n o pe n -la bel, fi x e d se q ue nce, cr oss o ver st u d y t o i n vesti gat e t he effect of 
i ml u nestra nt o n t he P K of mi daz ola m a n d its meta b olite 1’ -h y dr o x y mi d az ola m i n healt h y w o m e n  
of n o n -c hil d beari n g p ot e ntial . A d diti o nall y, t he P K, safet y, a n d t olera bilit y of i ml u nestra nt will 
als o be e val uat e d.  
A p pr o ve d o n 0 8 Se p 2 0 2 2 G M T
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S afet y assess me nts, i ncl u di n g A Es, c o n c o mita nt me dicati o ns, p h ysi cal e xa mi nati o n , cli nical 
la b orat or y tests, vital si g ns, a n d electr o car di o gra ms , a n d bl o o d sa m pli n g f or P K, will be 
perf or me d . 
N u m ber of P artici p a nts : 
A p pr o xi matel y 2 0  p artici pa nts  will be e nr olle d t o ac hie ve at least 1 8  c o m pl eters  t o st u d y 
i nter ve nti o n. 
I nter ve nti o n Gr o u ps  a n d D ur ati o n : 
Scree ni n g  
All partici pa nts  will be scree n e d wit hi n 2 8 da ys pri or t o e nr oll me nt . 
Tre at m e nt a n d Assess m e nt  Peri o d  
Partici pa nts  will be a d mitte d t o t he C R U o n Da y -1  (c hec k-i n) a n d will re mai n resi de nt u ntil 
Da y  1 1 . Wit h re gar ds t o d osi n g, partici p a nts will be d ose d as f oll o ws:  
T here will be a was h o ut peri o d  
 b et wee n d oses of mi daz ola m.  
F oll o w -u p  
Partici pa nts  will atte n d a f oll o w -u p visit 5  t o 7 da ys p ost fi nal d ose . 
D at a M o nit ori n g C o m mittee: N o  
 
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CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
15 
2. 
Introduction 
Imlunestrant (LY3484356) is an orally bioavailable, non-covalent, SERD. It is a potent degrader 
and selective antagonist of wild-type and mutant ERα or ESR1. This compound is intended for 
oncology indications (breast cancer and EC), 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 
Study J2J-MC-JZLK (JZLK) is a Phase 1 open-label study of imlunestrant administered to 
healthy women of non-childbearing potential. The purpose of this study is to assess the effect of 
imlunestrant on the PK of midazolam, a known sensitive CYP3A substrate. 
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).  
Over two thirds of breast cancers express ER, which is a key driver of breast cancer initiation 
and progression. HR+ 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 (for 
example, tamoxifen, anastrozole, letrozole, fulvestrant) alone or in combination 
cyclin-dependent kinase (CDK)4 and CDK6 inhibitors as indicated (for example, abemaciclib, 
palbociclib, or ribociclib), as well as standard chemotherapy (for example, capecitabine, 
docetaxel, paclitaxel, and nab-paclitaxel [NCCN 2018; Waks and Winer 2019]). For patients 
with advanced HR+/HER2+ status, treatment includes HER2-directed therapies (for example, 
trastuzumab, pertuzumab, TDM-1 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 500 mg per month may lead to better ER degradation, the 
intramuscular administration route limits the amount of fulvestrant that can be given to patients 
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( Nar d o ne et al. 2 0 1 9). I n a d diti o n, se veral st u dies ha ve s h o wn t hat wit h t he c urre nt ma xi m u m 
feasi ble d ose, f ul vestra nt treat me nt is n ot a ble t o c o m pletel y de gra de E R i n patie nts a n d ca n b e 
ass ociate d wit h earl y pr o gressi o n ( va n Kr uc hte n et al. 2 0 1 5). T h us, t here is u n met me dical nee d 
t o de vel o p oral S E R Ds wit h hi g her bi oa v aila bilit y, greater E R tar geti n g, a n d de gra dati o n 
efficie n c y ( Nar d o ne et al. 2 0 1 9).  
E C, w hile less fre q ue ntl y dia g n ose d t ha n breast ca ncer, is i ncreasi n g  w orl d wi de. I n t he U nite d 
States, t he i nci de nce of E C has i ncreas e d b y a p pr o xi matel y 1 2, 0 0 0  cases bet wee n 2 0 1 3 a n d 2 0 1 9 
( H o wla der et al. 2 0 1 9). E E C re prese nts a b o ut  8 0 % of E C cases, a n d o ver e x pressi o n of estr o ge n 
ma y c o ntri b ute t o t u m or pr oliferati o n  ( Elle ns o n et al. 2 0 1 1). Sta n dar d of care f or E C, r e gar dl ess 
of s u bt y pe, c o nsists of t he  s ur ger y f oll o we d b y a dj u va nt ra di ot hera p y a n d/ or c he m ot hera p y. I n 
t he a d va nce d setti n g, a v ariet y of e n d o cri ne t hera p y, s uc h as me gestr ol acetate, ta m o xife n, 
ar o matase i n hi bit ors, f ul vestra nt, are  c o m m o nl y use d ( N C C N 2 0 2 0; N CI 2 0 1 9).  
2. 2. 1.  
P h ar m a c o ki netics of I ml u nestr a nt  
As of 0 1 N o ve m ber 2 0 2 1, i ml u nestra nt P K para meters were a vaila bl e fr o m 8 5 patie nts i n st u d y 
J 2J-M C -J Z L A (J Z L A) acr oss a 2 0 0 t o 1 2 0 0 m g Q D d ose ra n ge. 
 
 
 
 
 
 
 
 
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2. 3.  
Be nefit/ R is k Assess me nt 
I ml u nestr a nt is a p ote nt a nta g o nist a n d de gra d er of E R α a n d has de m o nstrat e d si g nifica nt acti vit y 
i n precli nical m o dels a gai nst E R wil d-t y p e a n d m uta nt t u m ors. T here is n o a ntici pate d be nefit f or 
t he w o me n of n o n-c hil d beari n g p ote ntial i n t h is st u d y.  
I ml u nestr a nt has als o be e n a d mi nistere d t o patie nts i n o n g oi n g cli nical st u dies J Z L A ( 2 0 0 t o 
1 2 0 0 m g Q D f or a 2 8 -da y c ycle) a n d J 2J -M C -J Z L B a wi n d o w of o p p ort u nit y st u d y ( 4 0 0 a n d 
8 0 0  m g) f or a p eri o d of 1 5 t o 2 2 da ys  
A p pr o ve d o n 0 8 Se p 2 0 2 2 G M T
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As t he p har mac ol o gi c mec ha nis m of i ml u nestra nt is t o de gra de t he E R, effects o n fe mal e 
re pr o d ucti ve or ga ns a n d e m br y ofetal  d e vel o p me nt are e x pecte d. S i milar re pr o d ucti ve fi n di n gs 
ha ve bee n o bser ve d wit h ot her a p pr o ve d a ge nts, k n o w n t o a nta g o nize or de gra de t he E R, 
i ncl u di n g ta m o xife n ( N ol va de x) a n d f ul vestra nt ( Fasl o de x® ). T heref ore, t his trial will e nr oll 
o nl y w o me n of n o n -chil d beari n g p ote ntial, defi ne d as p ost me n o pa usal or i nfertile d ue t o s ur gical 
steriliz ati o n or alter nate me dical ca us e/c o n ge nital a n o mal y  as o utli ne d i n A p pe n di x 4 
( Secti o n 1 0. 4 ).  
Ge n ot o xicit y  
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
1 9  
3.  
O bjecti ves  a n d  E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o e val uate t he effect of m ulti ple d oses of 
i ml u nestra nt o n t he P K of mi daz ola m 
( C Y P 3 A 4 s u bstrate) i n h ealt h y w o me n  of 
n o n -c hil d beari n g p ote nti al.  
A U C ( 0-∞) a n d C ma x  of mi daz ola m w he n 
a d mi nistere d al o ne a n d i n t he prese n ce of 
i ml u nestra nt. 
 
Sec o n dar y  
 
 T o e val uate t he effect of m ulti ple 
d oses of i ml u nestra nt o n t he P K of 
1’ -h y dr o x y mi daz ola m (a meta b olite of 
mi daz ola m) i n healt h y w o me n of 
n o n -c hil d beari n g p ote nti al.  
 T o e val uate t he s afet y a n d t olera bilit y 
of 
 
i n healt h y w o m e n  of n o n -c hil d beari n g 
p o te ntial. 
 E val uate t he P K of  iml u n estra nt i n 
healt h y w o me n  of n o n -c hil d beari n g 
p ote ntial . 
 A U C( 0 -∞) a n d C ma x  of 
1’ -h y dr o x y mi daz ola m w he n 
mi daz ola m is a d mi nistere d al o ne a n d 
i n t he prese nce of i ml u nestra nt. 
 
 I n ci de nce a n d se v erit y of A Es a n d 
S A Es . 
 
 A U C( 0 -2 4) , ss a n d C ma x , ss of 
i ml u nestra nt. 
 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
2 0  
4.  
St u d y Desi g n  
4. 1.  
O ver all  Desi g n  
St u d y J Z L K is a n o pe n-la bel, fi x e d se q ue nce, cr oss o ver st u d y t o i n vesti gat e t he effect of 
i ml u nestra nt o n t he P K of mi daz ola m a n d its meta b olite 1’ -h y dr o x y mi d az ola m i n healt h y w o m e n  
of n o n -c hil d beari n g p ot e ntial . A d diti o nall y, t he P K , safet y, a n d t olera bilit y of i ml u nestra nt will 
als o be e val uat e d.  
S afet y assess me nts, i ncl u di n g A Es, c o n c o mita nt me dicati o ns, p h ysi cal e xa mi nati o n , cli nical 
la b orat or y tests, vital si g ns, a n d electr o car di o gra ms, a n d bl o o d sa m pli n g f or P K, will be 
perf or me d . 
4. 1. 1.  
Scree ni n g  
All p artici pa nts  will be scree n e d wit hi n 2 8 da ys pri or t o e nr oll me nt . 
4. 1. 2.  
Tre at me nt a n d Assess me nt Peri o d  
Partici pa nts  will be a d mitte d t o t he C R U o n Da y -1  (c hec k-i n) a n d will re mai n resi de nt until 
Da y  1 1 . Wit h re gar ds t o d osi n g, partici p a nts will be d ose d as f oll o ws:  
T here will be a was h o ut peri o d of 
 b et wee n d oses of mi daz ola m.  
4. 1. 3.  
F oll o w -u p  
Partici pa nts  will atte n d a f oll o w -u p visit 5  t o 7 da ys p ost fi nal d ose . 
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n  
T he fi x e d -se q ue nce, cr oss o ver desi g n use d i n t his st u d y is t y pical f or i nteracti o n st u dies w here a 
relati vel y s mall n u m ber of partici pa nts are re q uir e d, beca use it all o ws i ntra partici pa nt 
c o m paris o ns a n d eli mi nates i nter partici pa nt c o m p aris o ns. I n a d diti o n, a fi x e d-se q ue n ce d esi g n is 
c o nsiste nt wit h F D A g ui da nce.  
T his st u d y will be o pe n -l a bel beca use t he st u d y e n d p oi nts are n ot c o nsi dere d s u bjecti ve. 
4. 3.  
J ustific ati o n f or D ose  
4. 3. 1.  
I ml u nestr a nt 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
2 1  
4. 3. 2.  
Mi d az ol a m  
Mi daz ola m is a se nsiti ve C Y P 3 A 4 s u bstrate rec o m me n de d b y t he F D A f or q ua ntif yi n g cli nical 
per petr at or D DI. A 
 ma y be mil dl y se dati n g a n d hi g h e n o u g h t o 
e ns ure t hat mi daz ola m c o nce ntrati o ns re m ai n a b o ve t he detecti o n li mit of t he assa y 
 
t o c haracteriz e t he C Y P 3 A 4 d o w n -re g ul ati o n p ote ntial of i ml u nestra nt. A 
 
mi daz ola m is a d ose c o nsi dere d safe t o a d mi nister a n d has bee n use d i n pr e vi o us cli nical st u dies.  
4. 4.  
E n d of St u d y  Defi niti o n  
A partici pa nt  is c o nsi dere d t o ha ve c o m plet e d t he dr u g -dr u g i nteracti o n  p orti o n of t he st u d y if 
s he has c o m plete d all sc he d ule d pr oce d ures s h o w n i n t he S o A ( Secti o n 1. 3 ). 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt i n t he st u d y. 
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Protocol number J2J-MC-JZLK (a) 
22 
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, unless 
otherwise stated in the following criteria.  
The nature of any conditions present at the time of the physical examination and any pre-existing 
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: 
Age 
1. Participants must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant  
2. Participants who are overtly healthy as determined by medical assessment including 
medical history, physical examination, clinical laboratory tests, and vital signs. 
3. 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. 
4. Participants who have venous access sufficient to allow for blood sampling as per the 
protocol. 
Weight 
5. Body mass index within the range 18.0 to 35.0 kg/m2 (inclusive). 
Sex 
6. Female participants: 
a. Women of childbearing potential (WOCBP) are excluded from the trial. 
b. Women not of childbearing potential (WNOCBP) may participate in this trial.  
See Appendix 4 (Section 10.4) for definitions. 
Informed Consent 
7. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2), 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
2 3  
8.  Ha ve k n o w n aller gies t o i ml u nestra nt, relate d c o m p o u n ds or a n y c o m p o ne nts of t he 
f or m ulati o n or mi daz ola m , as a p pr o priate, or hist or y of si g nifi ca nt at o p y. 
9.  Si g nifica nt hist or y or cli nical ma nifestati o n of a n y meta b olic, aller gic, der mat ol o gical, 
he patic, re n al, he mat ol o gical, p ul m o nar y, car di o vasc ular, gastr oi ntesti nal, n e ur ol o gi cal, 
res pirat or y, e n d ocri ne, or ps yc hiatric dis or der, as deter mi ne d b y t he i n vesti gat or ( or 
desi g nee) . 
1 0.  Hist or y of  si g nifica nt h y perse nsiti vit y, i nt olera n ce, or aller g y t o a n y dr u g c o m p o u n d  
i ncl u di n g st u d y dr u gs a n d a n y c o m p o ne nt of t heir f or m ulati o ns, f o o d, or ot her s u bsta nce, 
u nless a p pr o ve d b y t he i n vesti gat or ( or desi g nee) .  
1 1.  Ha ve a cli nicall y si g nifica nt a b n or mali t y of bl o o d press ure, p ulse rate , or b ot h, as 
deter mi ne d b y t he i n vesti gat or .  
1 2.  Ha ve a hist or y or pres e nce of car di o vasc ular ( f or e x a m ple, s y m pt o matic bra d ycar dia wit h 
resti n g h eart rate of < 6 0 beats per mi n ute), res pirat or y, re nal, gastr oi ntesti n al, e n d ocri ne, 
he mat ol o gic al, or ne ur ol o gic al dis or ders ca pa ble of si g nifica ntl y alteri n g t he a bs or pti o n, 
meta b olis m, or eli mi nati o n of dr u gs; of c o nstit uti n g a ris k w he n ta ki n g t he i n vesti gati o nal 
pr o d uct; or of i nterferi n g wit h t he i nter pretati o n of data. A p pe n d ec t o m y, her nia re pair, 
a n d c h olec yste ct o m y are c o nsi dere d as acce pta ble . 
1 3.  Hist or y of alc o h olis m or dr u g/c he mical a b us e wit hi n 2 years pri or t o c h ec k -i n. 
1 4.  Alc o h ol c o ns u m pti o n of > 1 4 u nits per wee k. N u m ber of u nits  =  [t otal v ol u me of dri n k 
( m L) x alc o h ol b y v olu me ( %)]/ 1 0 0 0 . 
1 5.  P ositi ve et ha n ol breat h/ uri ne test res ult or p ositi ve uri ne dr u g scree n at scree ni n g or 
c hec k-i n. 
1 6.  S h o w e vi de nce of he patitis B, p ositi ve he patitis B c ore a nti b o d y, a n d/ or p ositi ve he patitis 
B s urface a nti ge n  at scree ni n g.  
1 7.  S h o w e vi de nce of h e patitis C a n d/ or p ositi ve he patitis C a nti b o d y  at scree ni n g. A p ositi ve 
res ult f or he p atitis C a nti b o d y  will be c o nfir me d b y p ol y merase c h ai n reacti o n test t o 
deter mi ne acti ve i nfecti o n . 
1 8.  Ha ve e vi d e nce of HI V i nfecti o n a n d/ or p ositi ve h u ma n HI V a nti b o dies  at s cree ni n g.  
1 9.  Ha ve a n y m e dical c o n diti o ns, me dical hist or y, or are ta ki n g a n y m e dicati o ns w hic h are 
c o ntrai n dicate d i n t he mi daz ola m la bel, as a p pr o priate . 
Pri or/ C o nc o mit a nt T her a p y  
2 0.  Use or i nte n d t o use a n y me dicati o ns/ pr o d ucts k n o w n t o alter dr u g a bs or pti o n, 
meta b olis m, or eli mi nati o n pr ocesses, i ncl u di n g St. J o h n’s w ort, wit hi n 3 0 da ys pri or t o 
d osi n g, u nless dee me d acce pta ble b y t he i n v esti gat or ( or desi g nee) . 
2 2.  Use or i nte n d t o use sl o w -rele ase me dicati o ns/ pr o d ucts c o nsi dere d to still be acti ve 
wit hi n 1 4 da ys pri or t o c hec k -i n, u nless dee me d acce pta bl e b y t he i n vesti gat or ( or 
desi g nee) . 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
2 4  
2 3.  Use or i nte n d t o use a n y n o n prescri pti o n me dicati o ns/ pr o d ucts i ncl u di n g vita mi ns, 
mi nerals, a n d p h yt ot hera pe utic/ her bal/ pla nt -deri v e d pre parati o ns wit hi n 7 da ys pri or t o 
c hec k-i n u ntil c o m pleti o n of t he f oll o w-u p visit, u nless dee me d acce pta ble b y t he 
Pri or/ C o nc urre nt Cli n ic al St u d y E x perie nce 
2 5.  Partici pati o n i n a cli nical st u d y i n v ol vi n g a d mi nistrati o n of a n i n vesti gati o n al dr u g ( ne w 
c he mical e ntit y) i n t he past 3 0 da ys pri or t o d osi n g, or 5 half -li ves; w hic h e v er is l o n ger. 
2 6.  Ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m t his st u d y or a n y ot h er st u d y i n vesti gati n g 
i ml u nestra nt, a n d ha ve pre vi o usl y recei v e d i ml u nestra nt. 
2 7.  Ha ve pre vi o usl y recei ve d a S E R D i n t he past 3 0 da ys pri or t o d osi n g, or 5 half -li ves; 
w hic he ver is l o n ger . 
Ot her E xcl usi o ns  
2 8.  S m o ke m ore t ha n 1 0 ci garettes or use t he e q ui vale nt t o bacc o, s m o ki n g-cess ati o n 
pr o d ucts, nic oti ne -c o ntai ni n g pr o d u cts, or e -ci garettes ( nic oti ne a n d n o n -ni c oti ne) per 
da y. Partici pa nts  m ust be willi n g t o a bstai n fr o m s m o ki n g fr o m c hec k-i n u ntil after 
c ollecti o n of t he fi nal P K sa m ple . 
2 9.  I n gestio n of p o p p y see d -, Se ville ora n ge-, or gra p efr uit-c o ntai ni n g f o o ds or be vera ges 
wit hi n 7 da ys pri or t o c h ec k -i n. 
3 0.  Recei pt of bl o o d pr o d ucts wit hi n 2 m o nt hs pri or t o c hec k -i n. 
3 1.  D o nati o n of bl o o d fr o m 3 m o nt hs pri or t o scree ni n g, plas ma fr o m 2 wee ks pri or t o 
scree ni n g, or platelets fr o m 6 wee ks pri or t o scree ni n g . 
3 2.  Partici pa nts  w h o, i n t he o pi ni o n of t he i n vesti gat or ( or desi g nee), s h o ul d n ot partici pate i n 
t his st u d y 
5. 3.  
Lifest yle C o nsi der ati o ns  
5. 3. 1.  
Me als a n d Diet ar y Restricti o ns  
 D uri n g t h e c o nfi ne m e nt peri o d, partici pa nts  will c o ns u me o nl y f o o d a n d be vera ges 
t hat are pr o vi d e d t o t he m b y t he C R U staff. Sta n dar d meals (f or e x a m ple, brea kfast, 
l u nc h, di n ner, a n d s nac k) will be pr o vi de d t o t he partici pa nts  w hile resi d e nt at t he 
C R U.  
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Protocol number J2J-MC-JZLK (a) 
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 Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not 
be allowed from 7 days prior to check-in until follow-up. In addition, all other citrus 
fruits and tomato-based products will not be allowed from the time of check-in until 
follow-up. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco 
1. Participants will abstain from ingesting caffeine- or xanthine-containing products (for 
example, coffee, tea, cola drinks, and chocolate) for 48 hours before the initial check-in 
until after collection of the final PK sample. 
2. Participants will abstain from alcohol for 24 hours before the initial check-in until after 
collection of the final PK sample. 
3. Participants are required to refrain from use of tobacco, smoking-cessation products, 
nicotine-containing products, and e-cigarettes (nicotine and non-nicotine) from initial 
check-in until after collection of the final PK sample. 
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 
(for example, 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. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant 
Not applicable for this study. 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
2 6  
6.  
St u d y I nter ve nti o n (s) a n d C o nc o mit a nt T her a p y 
St u d y i nter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), 
place b o , or me di cal de vi ce (s) i nte n d e d t o be a d mi nistere d t o/ use d b y  a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol.  
6. 1.  
St u d y I nter ve nti o n(s) A d mi nistere d  
T a ble  J Z L K .1 . 
St u d y I nter ve nti o ns A d mi nistere d  
I nter ve nti o n N a me 
i ml u nestra nt (L Y 3 4 8 4 3 5 6)  
mi daz ola m  
T y pe  
d r u g 
dr u g  
D ose F or m ul ati o n  
ta blet 
s ol uti o n (s yr u p) 
U nit D ose Stre n gt h(s)  
 
- 
D os a ge Le vel(s)  
R o ute of 
A d mi nistr ati o n  
O ral 
oral  
S o urci n g  
Pr o vi de d ce ntrall y b y t he 
sp o ns or . 
Pr o vi de d l ocall y b y t he trial site . 
6. 1. 1.  
A d mi nistr ati o n Det ails  
I ml u nestr a nt 
I ml u nestr a nt 
 All d oses of i ml u nestra nt will be 
a d mi nistere d wit h 2 4 0 m L of r o o m te m perat ure water w hile partici pa nts are i n a sitti n g p ositi o n. 
I ml u nestr a nt ta blets s h o ul d be s wall o we d w h ole. Partici pa nts  s h o ul d n ot brea k, cr us h, or c h e w 
t he st u d y i nter ve nti o n. O n d osi n g da ys, partici pa nts  will a d here t o meal r estricti o ns as o utli ne d i n 
Secti o n 5. 3. 1 . 
Partici pa nts  will n ot be all o we d t o lie s u pi ne f or 2  h o urs after eac h d osi n g  o ccasi o n , u nless 
cli nicall y i n dicat e d or f or st u d y pr oce d ures.  
Mi d az ol a m  
A si n gle d ose of  
 will be gi ve n o n Da y 1. O n Da y 9, mi d az ola m will be d ose d 
a p pr o xi matel y 
 d osi n g wit h 
 i ml u nestra nt. O n d osi n g da ys, p artici pa nts  
will a d here t o meal restri cti o ns as o utli ne d i n Secti o n 5. 3. 1 . 
N o a d diti o nal water is r e q uire d w he n mi daz ola m is 
 wit h i ml u nestra nt o n 
 
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Protocol number J2J-MC-JZLK (a) 
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6.2. 
Preparation, Handling, Storage, and Accountability 
1. 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. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. 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 study. Participants will not be randomized. 
6.4. 
Study Intervention Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff.  
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 will be provided to the sponsor as requested.  
A record of the number of imlunestrant tablets dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF. 
6.5. 
Dose Modification 
Dose modification will not be permitted in this study. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
Any dose of study intervention greater than the dose described for that study day will be 
considered an overdose. 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the Lilly CP immediately 
Approved on 08 Sep 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
28 
2. 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. In the event of midazolam overdose, flumazenil or a similar antagonist 
for midazolam should be used as an antidote. Activated charcoal may also be used in the event of 
midazolam overdose. 
6.8. 
Concomitant Therapy 
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. 
6.8.1. 
Supportive Management for Diarrhea 
Participants should receive instructions on the management of diarrhea. In the event of diarrhea, 
supportive measures should be initiated as early as possible. These include the following:  
 At the first sign of loose stools, the participant should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator for further instructions and appropriate 
follow-up. However, loperamide should not be taken the day prior to dosing with 
midazolam, or on the day of dosing with midazolam. 
 Participants should also be encouraged to drink fluids (that is, 8 to 10 glasses of clear 
liquids per day).  
 Site personnel should assess response within 24 hours.  
 If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least Grade 1 
(per CTCAE version 5.0 [that is, an increase of <4 stools per day over baseline]), and 
causes the participant to miss any dose of imlunestrant, the participant should be 
discontinued from the study.  
 For severe cases of diarrhea, or any diarrhea associated with severe nausea or vomiting, 
participants should be carefully monitored and given intravenous fluid and electrolyte 
replacement as clinically indicated.  
o Measurement of neutrophil counts and body temperature and proactive 
management of diarrhea with antidiarrheal agents should be considered.  
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o If associated with fever or severe neutropenia, further investigations along with 
broad-spectrum antibiotics such as fluoroquinolones should be considered. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Participants discontinuing from study intervention prematurely for any reason should complete 
AE and other follow-up/early discontinuation procedures as per the SoA (Section 1.3). 
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. 
Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study to complete procedures for an early discontinuation visit 
and post-treatment follow-up, if applicable and/or will remain in the study and follow procedures 
for remaining study visits, as shown in the SoA. 
A participant should be permanently discontinued from study intervention if in the opinion of the 
investigator, the participant should permanently discontinue the study intervention for safety 
reasons 
 The participant is significantly noncompliant with study procedures and/or treatment.  
 Unacceptable toxicity. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of the study intervention for abnormal liver tests should occur when a 
participant meets 1 of the following conditions after consultation with the Lilly-designated 
CP/CRP: 
 ALT or AST >5× ULN 
 ALT or AST >3× ULN and TBL >2× ULN or international normalized ratio >1.5 
 ALT or AST >3× ULN and the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 ALP >3× ULN 
 ALP >2.5× ULN and TBL >2× ULN 
 ALP >2.5× ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Participants who discontinue from study intervention due to the abnormal liver tests will undergo 
monitoring as described in Appendix 6 (Section 10.6). 
Discontinuation of the IP due to abnormal laboratory results should be considered by the 
investigator when a participant meets 1 of the following conditions after consultation with the 
CP/CRP: 
 creatine kinase elevation of >8× ULN (or >1600 IU/L)  
 lipase and/or amylase ≥3× ULN (Appendix 6 [Section 10.6]; should be considered by the 
investigator). 
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7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
● at any time at the participant’s own request 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an IP, or enrolled 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 a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and post-treatment follow-up, if applicable, as shown in the 
SoA (Section 1.3). If the participant has not already discontinued the study intervention, the 
participant will be permanently discontinued from the study intervention at the time of the 
decision to discontinue the study. 
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, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participant 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 for this study. 
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 will be conducted as specified in the schedule of assessments 
(Section 1.3) and as clinically indicated. 
8.2.2. 
Vital Signs 
 For each participant, vital signs measurements should be conducted according to 
the Schedule of Activities (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 participant’s 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. 
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 ECGs 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. ECGs may be obtained at additional times, 
when deemed clinically necessary. All ECGs recorded should be stored at the 
investigational site.  
 ECGs will be interpreted by a qualified investigator (the physician or qualified 
designee) as soon after the time of ECG collection as possible, and ideally while 
the participant is still present, 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. 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 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 or medical monitor. 
○ If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the SoA and 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 
(for example, 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 and Evaluation 
Laboratory tests (Appendix 6, Section 10.6), including ALT, AST, ALP, TBL, direct 
bilirubin, gamma-glutamyl transferase, and creatine kinase, 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 <1.5 × ULN 
ALT or AST ≥3 × ULN 
ALP <1.5 × ULN 
ALP ≥2 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline (except for participants with Gilbert’s 
syndrome) 
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 1 to 3 times weekly, based on the participant’s clinical condition and hepatic 
biochemical tests. Subsequently, the frequency of monitoring may be lowered to once 
every 1 to 2 weeks, if the participant’s clinical condition and lab results stabilize. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return 
to approximate baseline levels. 
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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 <1.5 × ULN 
ALT or AST ≥3 × ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5 × ULN 
ALP <1.5 × ULN 
ALP ≥3 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥2 × baseline (except for participants with Gilbert’s syndrome)  
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough 
medical history, as outlined above, as well as tests for prothrombin time-INR; tests for 
viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or computerized tomography scan).  
Based on the participant’s history and initial results, further testing should be considered 
in consultation with the Lilly-designated medical monitor, including tests for hepatitis D 
virus, cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein 
adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl 
glucuronide, and blood phosphatidylethanol. Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, 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 5 conditions: 
1. Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if 
baseline ALT <1.5 × ULN) 
 In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests 
2. Elevated TBL to ≥ 2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of 
known Gilbert’s syndrome) 
 In participants with baseline TBL ≥1.5 × ULN, the threshold should be 
TBL ≥2 × baseline 
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3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if 
baseline ALP <1.5 × ULN) 
 In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP 
≥2 × baseline on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event. 
Note: the interval between the 2 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 
 PCs 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet 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. 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.  
The investigator is responsible for the appropriate medical care of participants during the study.  
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 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
signing of 
the ICF 
start of 
intervention 
Within 24 hours of 
awareness 
SAE report 
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 report 
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
after 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE report 
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 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
—  
—  
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
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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 (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
* SAEs 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.  
 At the visits and times specified in the SoA (Section 1.3), venous blood samples of up to 
5 mL each will be collected to determine the plasma concentrations of midazolam and its 
metabolite 1’-hydroxymidazolam. 
● A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data (for example, to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.  
● Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
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, midazolam and 1’-hydroxymidazolam will be assayed using 
validated liquid chromatography mass spectrometry methods.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last participant visit for the study. During this 1 year period, exploratory 
analyses of drug metabolites in plasma may be conducted. 
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. 
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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 
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
The primary endpoints will be evaluated to assess any potential drug-drug interaction between 
imlunestrant and midazolam.  
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 at least 1 dose of IP.  
PK Analysis 
All participants who received at least 1 dose of IP and have 
evaluable PK data. 
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 
The participant’s age, sex, and other demographic characteristics will be recorded and 
summarized.  
9.2.3. 
Treatment Compliance 
The date and time of dosing will be recorded and listed. 
9.3. 
Statistical Analyses 
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
PK analyses will be conducted on data from all participants who received at least 1 dose of IP 
and have evaluable PK data. 
Safety analyses will be conducted for all enrolled participants who received at least 1 dose of IP, 
whether or not they completed all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
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9.3.1. 
Safety Analyses 
9.3.1.1. 
Clinical Evaluation of Safety 
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology. 
The incidence of AEs for each treatment will be presented by severity and by association with IP 
as perceived by the investigator. AEs 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 SAEs will be reported. 
9.3.1.2. 
Statistical Evaluation of Safety 
Safety parameters that will be assessed include safety laboratory parameters, and vital signs. 
Additional analysis will be performed if warranted upon review of the data. 
9.3.2. 
Pharmacokinetic Analyses 
9.3.2.1. 
PK Parameter Estimation 
Pharmacokinetic parameter estimates will be calculated by standard noncompartmental methods. 
The primary PK parameters for analysis of imlunestrant will be: Cmax, ss, AUC(0-24), ss, and 
tmax. The primary PK parameters for analysis of midazolam and 1’-hydroxymidazolam will be: 
Cmax, AUC(0-∞), and tmax. Other noncompartmental parameters, such as t1/2, apparent total 
body clearance of drug calculated after extravascular administration, and apparent volume of 
distribution during the terminal phase after extravascular administration, may be reported as 
appropriate. 
9.3.2.2. 
PK Statistical Inference 
PK parameters will be evaluated to estimate the drug-drug interaction between midazolam alone 
(reference) and midazolam + imlunestrant (test). The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90% CI.  
To estimate the effect of the drug-drug interaction of imlunestrant with midazolam, 
log-transformed Cmax and AUC(0-∞) of midazolam will be analyzed using a linear mixed-effects 
model with a fixed effect for treatment and a random effect for participant.  
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the difference between 
observed medians of test and reference, 90% CIs for the median of differences, and p-values 
from the Wilcoxon test will be calculated. 
Where appropriate, midazolam, 1’-hydroxymidazolam, and imlunestrant PK parameters will be 
summarized using descriptive statistics. 
9.3.3. 
Pharmacodynamic Analyses 
Not applicable for this study. 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber J 2J-M C -J Z L K (a) 
4 2  
9. 3. 4.  
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses  
N ot a p plica ble f or t his st u d y.  
9. 4.  
I nteri m A n al ysis  
N o i nteri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y f or reas o ns ot h er t ha n a s afet y c o n cer n, t he pr ot oc ol m ust be a me n de d.   
9. 5.  
S a m ple Size Deter mi n ati o n  
If a partici pa nt is disc o nti n ue d fr o m t he st u d y d ue t o a n A E of diarr hea ca usi n g t he m t o miss a n y 
d ose of i ml u nestra nt, t he n t hat pa rtici pa nt s h o ul d be re place d.  
A p pr o ve d o n 0 8 Se p 2 0 2 2 G M T
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ Applicable ICH Good Clinical Practice Guidelines 
● 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: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ 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 
● Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement. 
10.1.2. 
Informed Consent Process 
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
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● 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. 
10.1.3. 
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 the participant’s 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. 
10.1.4. 
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  
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The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.   
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. 
10.1.5. 
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. 
● 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 (for 
example, contract research organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
transcribed 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. 
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● In addition, 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 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 system(s) will be stored at third-party (at 
third parties). The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s). 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 
the central vendor’s database system and 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. 
10.1.6. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on 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 10.1.5. 
10.1.7. 
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 or sponsor’s 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 
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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, follow-up, or both. 
10.1.8. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.9. 
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 
Activated partial thromboplastin time 
Total protein 
International normalized ratio 
Albumin 
 
Total bilirubin 
Differential White Blood Cells (absolute and %) 
of 
Alkaline phosphatase 
Neutrophils 
Aspartate aminotransferase 
Lymphocytes 
Alanine aminotransferase 
Monocytes 
Creatinine 
Eosinophils 
Lipase 
Basophils 
Amylase 
 
Uric acid 
Urinalysis 
 
Specific gravity 
 
pH 
 
Protein 
 
Glucose 
Ethanol testinga 
Ketones 
Urine drug screena 
Bilirubin 
Hepatitis B surface antigenb 
Urobilinogen 
Hepatitis B core antibodyb 
Blood 
Hepatitis C antibodyb,c 
Nitrite 
Human immunodeficiency virus antibodiesb 
White blood cell esterase 
Follicle-stimulating hormone (if applicable)b 
 
 
 
 
a Ethanol testing and urine drug screen 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. 
 
 
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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-JZLK Sampling Summary 
 
Purpose 
Blood Volume per 
Sample (mL) 
Maximum Number 
of Blood Samples 
Maximum Total 
Volume (mL) 
Screening testsa 
18.8 
1 
18.8 
Clinical laboratory testsa 
11 
7 
77 
Pharmacokinetics - imlunestrantb 
2 
11 
22 
Pharmacokinetics – midazolam and 
1’-hydroxymidazolamb 
5 
24 
120 
Genetic sample 
10 
1 
10 
Total 
 
 
247.8 
Total for clinical purposes  
250 
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 preexisting 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. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of 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 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (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 preexisting 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 physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (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 (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
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 
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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 PC 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 PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected in order to ensure 
the safety of patients, 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 PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC 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/PC 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/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the PC Form. 
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. 
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 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the PC Form for PCs. 
 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 AE 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 AE 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 AE 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. 
An event is defined as ‘serious’ when it meets at least 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. 
 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 and/or Product Information, for marketed 
products, in their assessment. 
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 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to sponsor 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. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs 
SAE Reporting via SAE Report 
 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 
● The 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. 
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● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
● An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (for example, 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 
10.4.1. 
Definitions 
Woman not of Childbearing Potential 
Females are considered women not of childbearing potential if: 
 they have a congenital anomaly such as Müllerian agenesis,  
 they are infertile due to surgical sterilization or alternate medical cause, or  
 they are postmenopausal. 
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, and bilateral tubal ligation. 
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
The postmenopausal 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 under 60 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 FSH >40 mIU/mL; or 
3. A woman 60 years of age or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea  
* Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, GnRH, anti-estrogens, selective estrogen receptor modulators, or chemotherapy that 
could induce transient amenorrhea. 
10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to imlunestrant or breast/EC and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to imlunestrant and breast/EC. Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate). 
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● Analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to imlunestrant or study interventions of this class 
to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on imlunestrant continues but no 
longer than 15 years or other period as per local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See 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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  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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10.7. 
Appendix 7: Abbreviations and Definitions 
Term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC(0-∞) 
area under the concentration versus time curve from time zero to infinity 
AUC(0-24), ss 
area under the concentration versus time curve from time zero to 24 hours postdose at 
steady state 
CAP  
common alerting protocol  
CDK 
cyclin-dependent kinase  
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, good clinical practice, and applicable regulatory 
requirements. 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed drug concentration 
Cmax, ss 
maximum observed drug concentration at steady state 
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. 
CRU 
clinical research unit 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
EC 
endometrial cancer 
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ECG 
Electrocardiogram 
EDC 
electronic data capture  
EEC 
endometrioid endometrial cancer 
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 informed consent form directly 
or through their legally acceptable representatives. 
ER 
estrogen receptor 
ERα 
estrogen receptor α 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GnRH 
gonadotropin releasing hormone 
HIV 
human immunodeficiency virus 
HR 
hormone receptor 
HSA 
human serum albumin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
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 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form. 
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. 
IP 
investigational product. 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. 
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IRB 
institutional review board 
NIMP 
non-investigational medicinal product 
OFS 
ovarian function suppression 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK 
pharmacokinetics 
QD 
once daily 
QTc 
corrected QT interval 
SAE 
serious adverse event 
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 
SoA 
schedule of activities 
t1/2 
half-life associated with the terminal rate constant in non-compartmental analysis 
TBL 
total bilirubin level 
tmax 
time to maximum plasma concentration  
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. 
ULN 
upper limit of normal 
 
 
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10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
 
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11. 
References 
Allison KH, Hammond ME, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, Hayes DF, 
Lakhani SR, Chavez-MacGregor M, Perlmutter J, Perou CM, Regan MM, Rimm DL, Symmans 
WF, Torlakovic EE, Varella L, Viale G, Weisberg TF, McShane LM, Wolff AC. Estrogen and 
progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol. 
2020;38(12):1346-1366. 
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer 
IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, 
Wilke C, Hirawat S, Juric D, SOLAR-1 Study GROUP. Alpelisib for PIK3CA-mutated, 
hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. 
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, 
Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu 
Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone 
receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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. 
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, 
Kyriakides S, Lin N, Pagani O, Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El Saghir 
N, Ganza PA, Gelmon K, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, 
Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van’t Veer L, Viale G, 
Krop I, Winer E. 1st international consensus guidelines for advanced breast cancer (ABC 1). 
Breast. 2012;21(3):242-252. 
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, 
Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, 
Martin M. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM 
trial. J Natl Cancer Inst. 2014 Jan;106(1):djt337. doi: 10.1093/jnci/djt337. Epub 2013 Dec 7. 
PMID: 24317176; PMCID: PMC3906991. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
Ellenson LH, Ronnett BM, Kurman RJ. Precursor lesions of endometrial carcinoma. In: Kurman 
RJ, Ellenson LH, Ronnett BM, editors. Blaustein’s Pathology of the Female Genital Tract. 
Boston, MA: Springer; 2011:p 359-391. 
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, 
Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and letrozole in 
advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. 
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto 
A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. 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._Available at: https://seer.cancer.gov/csr/1975_2016/. 
Accessed November 22, 2021. 
Approved on 08 Sep 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLK (a) 
66 
Nardone A, Weir H, Delpuech O, Brown H, De Angelis C, Cataldo ML, Fu X, Shea MJ, 
Mitchell T, Veeraraghavan J, Nagi C, Pilling M, Rimawi MF, Trivedi M, Hilsenbeck SG, 
Chamness GC, Jeselsohn R, Osborne CK, Schiff R. 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. 
[NCCN] Abu-Rustum NR, Yashar CM, Bean S, Bradley K, Campos SM, Chon HS, Chu C, 
Clinton L, Cohn D, Crispens MA, Damast S, Fisher CM, Frederick P, Gaffney DK, George S, 
Giuntoli R 2nd, Han E, Huh WK, Mariani A, Mutch D, Nagel C, Nekhlyudov L, Fader AN, 
Remmenga SW, Reynolds RK, Sisodia R, Tillmanns T, Ueda S, Urban R, Wyse E, McMillian N, 
Motter A. NCCN Clinical Practice Guidelines in Oncology Uterine Neoplasms, Version 1.2020 - 
March 2020. 
[NCCN] Gradishar WJ, Anderson BO, Aft R, Balassanian R, Blair SL, Burnstein HJ, Cyr A, 
Dang C, Elias AD, Farrar WB, Forero A, Giordano SH, Goetz MP, Goldstein LJ, Isakoff SJ, 
Lyons J, Marcom PK, Mayer IA, McCormick B, Moran MS, O’Regan RM, Patel SA, Pierce 
LJ, Reed EC, Schwartzberg LS, Sitapati A, Smith KL, Smith ML, Soliman H, Somlo G, Telli 
ML, Ward JH, Kumar R, Shead DA. 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. Available at: 
https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq. Accessed November 22, 
2021. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Bartlett CH, Zhang K, 
Giorgetti C, Randolph S, Koehler M, Cristofanilli M, PALOMA3 Study Group. Palbociclib in 
hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219. 
van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M, Kema IP, 
Brown M, Schröder CP, de Vries EF, Hospers GA. Measuring residual estrogen receptor 
availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 
2015;5(1):72-81. 
Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288-300. 
Weatherman RV, Fletterick RJ, Scanlan TS. Nuclear-receptor ligands and ligand-binding 
domains. Annu Rev Biochem. 1999;68:559-581. 
Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 
testing in breast cancer: American Society of Clinical Oncology/College of American 
Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. 
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