The Effect of Imlunestrant on CYP2C8, CYP2C19, CYP2D6, P-gp, and BCRP Activity and the Effect of P-gp Inhibition on Imlunestrant Pharmacokinetics in Healthy Women of Non-childbearing Potential
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
Protocol J2J-MC-JZLI (a)  
 
 
The Eﬀect of Imlunestrant on CYP2C8, CYP2C19, CYP2D6, P-gp, and BCRP AcƟvity and the Eﬀect of P-
gp InhibiƟon on Imlunestrant PharmacokineƟcs in Healthy Women of Non-childbearing PotenƟal 
 
 
NCT05444556 
 
 
Approval Date: 26-Jun-2022 

CONFIDENTIAL 
Protocol number J2J-MC-JZLI (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 
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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 Imlunestrant on CYP2C8, CYP2C19, CYP2D6, P-gp, and BCRP Activity and the 
Effect of P-gp Inhibition on Imlunestrant Pharmacokinetics in Healthy Women of 
Non-childbearing Potential  
Protocol Number: J2J-MC-JZLI 
Amendment Number: (a) 
Compound: Imlunestrant (LY3484356) 
Brief Title: A study to investigate imlunestrant CYP and Transporter DDIs 
Study Phase: 1 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana 46285, USA 
Regulatory Agency Identifier Number(s) 
IND: 145311 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-062530 
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Protocol number J2J-MC-JZLI (a) 
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Medical Monitor Name and Contact Information will be provided separately. 
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Protocol number J2J-MC-JZLI (a) 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
12-April-2022 
Amendment (a)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis and 
Section 4.1.2 
Treatment and 
Assessment 
Period 
For Cohort 3, clarified that 
participants will not be in the 
CRU on Days 9 to 13, and will 
not dose at home. 
 
For Cohort 3, Clarified that in 
order for AEs to be reported 
spontaneously, that participants 
will call the CRU in the event of 
an AE. 
 
For Cohort 4, added that 
participants will attend the CRU 
as outpatients on Days 6 
through 8. 
For accuracy. 
 
 
 
 
For clarity 
 
 
 
 
For accuracy 
Section 1.2 
Schema 
Screening window updated. 
 
For Cohort 4, added that 
participants will attend the CRU 
as outpatients on Days 6 
through 8. 
For consistency with the Schedule of 
Assessments. 
For accuracy. 
Section 1.3 
Schedule of 
Assessments 
Added that ECGs taken on 
Day -1 in Cohorts 1 and 4 may 
be taken any time after 
check-in. 
Added posture of supine for all 
ECG assessments in all cohorts. 
For clarity. 
 
 
For clarity. 
 
 
 
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Protocol number J2J-MC-JZLI (a) 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Added timing of genetic sample 
(to be taken at Day 1 predose) 
for all cohorts. 
Weight separated from physical 
examination into a new row for 
each cohort. 
For Cohort 3, clarified that in 
order for AEs to be reported 
spontaneously on Days 9 to 13, 
that participants will call the 
CRU in the event of an AE. 
For Cohort 4, added row for 
outpatient visits. 
For Cohort 4, the genetic 
sample was moved from Day -1 
to Day 1. 
For clarity. 
 
 
For clarity. 
 
 
For clarity. 
 
 
 
For accuracy. 
Section 6.1 Study 
Interventions 
Administered 
Dose formulation for 
dextromethorphan was updated 
from capsule to oral suspension, 
and number of capsules 
required, and the unit dose 
strength was removed.  
Dextromethorphan oral suspension will 
now be used instead of the capsule 
formulation. An oral suspension is 
being used due to difficulty in acquiring 
the capsule formulation. 
Section 6.1.1 
Administration 
Details 
Clarified that the oral 
suspension of dextromethorphan 
will be administered via oral 
dosing syringe instead of an oral 
capsule, alongside the number 
and volume of rinses for the oral 
dosing syringe. Also clarified 
the timing of dosing with 
imlunestrant, omeprazole, and 
dextromethorphan on Day 3.  
In alignment with the change in 
formulation of dextromethorphan. 
Section 8 Study 
Assessments and 
Procedures 
The order of assessments at 
individual timepoints was 
added. 
For clarity. 
Section 8.4 
Pharmacokinetics 
Blood and urine sampling 
information split out into 
separate bullet points. 
For clarity 
Section 9.4 
Interim Analysis 
Clarified that the interim 
analysis will be performed after 
Cohort 2. 
For accuracy. 
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Protocol number J2J-MC-JZLI (a) 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
2. 
Introduction ...................................................................................................................33 
2.1. 
Study Rationale ...............................................................................................................33 
2.2. 
Background .....................................................................................................................33 
2.2.1. 
Pharmacokinetics of Imlunestrant...................................................................................34 
2.3. 
Benefit/Risk Assessment ................................................................................................34 
3. 
Objectives and Endpoints ............................................................................................37 
4. 
Study Design ..................................................................................................................38 
4.1. 
Overall Design ................................................................................................................38 
4.1.1. 
Screening.........................................................................................................................38 
4.1.2. 
Treatment and Assessment Period ..................................................................................38 
4.1.3. 
Follow-up ........................................................................................................................39 
4.2. 
Scientific Rationale for Study Design ............................................................................39 
4.3. 
Justification for Dose ......................................................................................................40 
4.3.1. 
Imlunestrant ....................................................................................................................40 
4.3.2. 
Repaglinide .....................................................................................................................40 
4.3.3. 
Omeprazole and Dextromethorphan ...............................................................................40 
4.3.4. 
Quinidine.........................................................................................................................40 
4.3.5. 
Rosuvastatin and Digoxin ...............................................................................................40 
4.4. 
End of Study Definition ..................................................................................................40 
5. 
Study Population ...........................................................................................................42 
5.1. 
Inclusion Criteria ............................................................................................................42 
5.2. 
Exclusion Criteria ...........................................................................................................43 
5.3. 
Lifestyle Considerations .................................................................................................44 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................44 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................45 
5.3.3. 
Activity ...........................................................................................................................45 
5.3.4. 
Other ...............................................................................................................................46 
5.4. 
Screen Failures ................................................................................................................46 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................46 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................47 
6.1. 
Study Interventions Administered ..................................................................................47 
6.1.1. 
Administration Details ....................................................................................................49 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................50 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................51 
6.4. 
Study Intervention Compliance ......................................................................................51 
6.5. 
Dose Modification ..........................................................................................................51 
6.6. 
Continued Access to Study Intervention After the End of the 
Study ...............................................................................................................................51 
6.7. 
Treatment of Overdose ...................................................................................................51 
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Protocol number J2J-MC-JZLI (a) 
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6.8. 
Concomitant Therapy .....................................................................................................51 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................53 
7.1. 
Discontinuation of Study Intervention ............................................................................53 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................53 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................54 
7.3. 
Lost to Follow-up............................................................................................................54 
8. 
Study Assessments and Procedures.............................................................................55 
8.1. 
Efficacy Assessments .....................................................................................................55 
8.2. 
Safety Assessments .........................................................................................................55 
8.2.1. 
Physical Examinations ....................................................................................................55 
8.2.2. 
Vital Signs .......................................................................................................................55 
8.2.3. 
Electrocardiograms .........................................................................................................56 
8.2.4. 
Clinical Laboratory Tests ................................................................................................56 
8.2.5. 
Safety Monitoring ...........................................................................................................57 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................59 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................59 
8.4. 
Pharmacokinetics ............................................................................................................61 
8.4.1. 
Bioanalysis ......................................................................................................................61 
8.5. 
Pharmacodynamics .........................................................................................................62 
8.6. 
Genetics ..........................................................................................................................62 
8.7. 
Biomarkers ......................................................................................................................62 
8.8. 
Immunogenicity Assessments.........................................................................................62 
8.9. 
Health Economics ...........................................................................................................62 
9. 
Statistical Considerations .............................................................................................63 
9.1. 
Statistical Hypotheses .....................................................................................................63 
9.2. 
Analyses Sets ..................................................................................................................63 
9.2.1. 
Study Participant Disposition .........................................................................................63 
9.2.2. 
Study Participant Characteristics ....................................................................................63 
9.2.3. 
Treatment Compliance ....................................................................................................63 
9.3. 
Statistical Analyses .........................................................................................................63 
9.3.1. 
Safety Analyses ...............................................................................................................64 
9.3.2. 
Pharmacokinetic Analyses ..............................................................................................64 
9.3.3. 
Pharmacodynamic Analyses ...........................................................................................65 
9.3.4. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................65 
9.4. 
Interim Analysis ..............................................................................................................65 
9.5. 
Sample Size Determination ............................................................................................65 
10. 
Supporting Documentation and Operational Considerations ..................................66 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................66 
10.1.1. Regulatory and Ethical Considerations ...........................................................................66 
10.1.2. Informed Consent Process ..............................................................................................67 
10.1.3. Data Protection................................................................................................................67 
10.1.4. Dissemination of Clinical Study Data.............................................................................68 
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10.1.5. Data Quality Assurance ..................................................................................................68 
10.1.6. Source Documents ..........................................................................................................70 
10.1.7. Study and Site Start and Closure ....................................................................................70 
10.1.8. Publication Policy ...........................................................................................................71 
10.1.9. Investigator Information .................................................................................................71 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................72 
10.2.1. Blood Sampling Summaries ...........................................................................................74 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...............................................................................................77 
10.3.1. Definition of AE .............................................................................................................77 
10.3.2. Definition of SAE ...........................................................................................................78 
10.3.3. Definition of Product Complaints ...................................................................................79 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................79 
10.3.5. Reporting of SAEs ..........................................................................................................81 
10.3.6. Regulatory Reporting Requirements ...............................................................................81 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................83 
10.4.1. Definitions.......................................................................................................................83 
10.5. 
Appendix 5: Genetics......................................................................................................84 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................85 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................87 
11. 
References ......................................................................................................................91 
 
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Protocol number J2J-MC-JZLI (a) 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
The Effect of Imlunestrant on CYP2C8, CYP2C19, CYP2D6, P-gp, and BCRP Activity and the 
Effect of P-gp Inhibition on Imlunestrant Pharmacokinetics in Healthy Women of 
Non-childbearing Potential  
Brief Title: A study to investigate imlunestrant CYP and Transporter DDIs 
Rationale: 
Study J2J-MC-JZLI (JZLI) is a Phase 1 open-label, 4-cohort study of imlunestrant administered 
to healthy females of non-childbearing potential. In vitro data indicates that imlunestrant has the 
potential to inhibit cytochrome P450 (CYP)2C8, CYP2C19, CYP2D6, P-glycoprotein (P-gp), 
and breast cancer resistance protein (BCRP) and clinical studies are required to quantify this 
potential effect. The FDA guidance on drug-drug interactions (DDIs) recommend repaglinide, 
omeprazole, and dextromethorphan as sensitive probes of CYP2C8, CYP2C19, and CYP2D6, 
respectively. Similarly, digoxin and rosuvastatin are recommended probes for quantify inhibition 
of P-gp and BCRP. Therefore, the purpose of this study is to investigate the effect of 
imlunestrant on CYP2C8, CYP2C19, and CYP2D6, and P-gp and BCRP activity by use of 
repaglinide, omeprazole, dextromethorphan, and digoxin and rosuvastatin, respectively. In vitro 
data also identified imlunestrant as a substrate of P-gp. The FDA recommends quinidine as a 
relatively selective inhibitor of P-gp when compared to other P-gp inhibtors that target CYP3A4 
in addition to P-gp. Therefore, to investigate the effect of P-gp inhibition on imlunestrant this 
study will employ repeat dosing of quinidine to inhibit both intestinal and central P-gp activity 
(liver, kidney, or both). The results of this study will inform dosing instructions in ongoing 
patient trials. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 Cohort 1: Evaluate the effect of 
imlunestrant on the pharmacokinetics 
(PK) of repaglinide (CYP2C8 
substrate) in healthy women of 
non-childbearing potential. 
 
 
 
 Cohort 2: Evaluate the effect of 
imlunestrant on the PK of omeprazole 
 Cohort 1: Area under the 
concentration versus time curve from 
zero to infinity (AUC[0-∞]), 
maximum observed drug 
concentration (Cmax) of repaglinide 
administered alone and in the presence 
of imlunestrant. 
 
 Cohort 2: AUC(0-∞), Cmax of 
omeprazole, 5-hydroxyomeprazole, 
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Protocol number J2J-MC-JZLI (a) 
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(CYP2C19 substrate) and 
dextromethorphan (CYP2D6 
substrate) in healthy women of 
non-childbearing potential. 
 
 Cohort 3: Evaluate the effect of 
quinidine (P-gp inhibitor) on the PK 
of imlunestrant in healthy women of 
non-childbearing potential. 
 
 Cohort 4: Evaluate the effect of 
imlunestrant on the PK of rosuvastatin 
(BCRP substrate) and digoxin (P-gp 
substrate) in healthy women of 
non-childbearing potential. 
dextromethorphan and dextrorphan 
administered alone and in the presence 
of imlunestrant. 
 
 
 Cohort 3: AUC(0-∞), Cmax of 
imlunestrant administered alone and in 
the presence of quinidine. 
 
 
 Cohort 4: AUC(0-∞), Cmax of 
rosuvastatin and digoxin administered 
alone and in the presence of 
imlunestrant. 
Secondary 
 
 To evaluate the safety and tolerability 
of 400 and 800 mg imlunestrant in 
healthy females of non-childbearing 
potential. 
 Incidence and severity of adverse 
events (AEs) and serious AEs 
Overall Design 
Brief Summary: 
Study JZLI is an open-label, 4-cohort, study comprising 4 fixed-sequence crossover cohorts. 
Cohorts 1 to 4 are in healthy females of non-childbearing potential to investigate the effect of 
imlunestrant on the PK of repaglinide (Cohort 1), omeprazole and dextromethorphan (Cohort 2), 
and rosuvastatin and digoxin (Cohort 4), and to investigate the effect of quinidine on the PK of 
imlunestrant (Cohort 3). Additionally, the safety and tolerability of imlunestrant will be 
evaluated when administered as a single 800-mg oral dose in the presence of repaglinide or 
omeprazole and dextromethorphan, and as a single oral 400-mg dose in the presence of quinidine 
or rosuvastatin and digoxin. 
Safety assessments, including AEs, concomitant medications, physical examination, clinical 
laboratory tests, vital signs, and electrocardiograms, and blood sampling for PK, will be 
performed. 
Study Population: 
Participants will be healthy women not of childbearing potential, aged between 18 and 65 years, 
inclusive. 
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Protocol number J2J-MC-JZLI (a) 
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Number of Participants: 
In Cohorts 1, 2, and 4, approximately 27 participants should be enrolled to ensure that at least 
22 evaluable participants in each of these cohorts complete the study. In Cohort 3, approximately 
32 participants should be enrolled to ensure that at least 26 evaluable participants in this cohort 
complete the study. 
Intervention Groups and Duration: 
Screening  
All participants will be screened within 28 days prior to enrollment. 
Treatment and Assessment Period 
Cohort 1 – imlunestrant on CYP2C8 activity 
Cohort 1 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
CYP2C8. Participants will be admitted to the clinical research unit (CRU) on Day -1. All 
participants will receive: 
 Day 1: 0.5 mg repaglinide alone 
 Day 3: 800 mg imlunestrant + 0.5 mg repaglinide 
There will be a washout period of 2 days between doses of repaglinide. All participants will 
remain resident in the CRU until discharge on Day 4. 
Cohort 2 – imlunestrant on CYP2C19 and CYP2D6 activity 
Cohort 2 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
CYP2C19 and CYP2D6. Participants will be admitted to the CRU on Day -1. All participants 
will receive: 
 Day 1: 20 mg omeprazole and 30 mg dextromethorphan 
 Day 3: 800 mg imlunestrant + 20 mg omeprazole and 30 mg dextromethorphan 
There will be a washout period of 2 days between doses of omeprazole and dextromethorphan. 
All participants will remain resident in the CRU until discharge on Day 5. 
Cohort 3 – P-gp inhibition on imlunestrant 
Cohort 3 will be an open-label, fixed-sequence design evaluating the effect of P-gp on 
imlunestrant. Eligible participants will take part in 2 treatment periods. Participants will be 
admitted to the CRU on Day -1. All participants will receive: 
 Day 1: 400 mg imlunestrant 
 Days 15 to 17: 200 mg quinidine twice daily (BID) alone 
 Day 18: 400 mg imlunestrant + 200 mg quinidine BID 
 Day 19 to Day 24: 200 mg quinidine bid alone 
There will be a washout period of 17 days between doses of imlunestrant. All participants will 
remain resident in the CRU until discharge on Day 8, then will be re-admitted to the CRU on 
Day 14 until Day 25. 
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Protocol number J2J-MC-JZLI (a) 
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On Days 9 to 13, participants will not be in the CRU. During this time, AEs and concomitant 
medications will be reported spontaneously by the participant. Participants will be instructed to 
call the CRU in the event of an AE. If the participant does need to take concomitant medication, 
they must contact the CRU so that the PI and CP may consult and approve the concomitant 
medication prior to the participant taking it.  
Cohort 4 – imlunestrant on BCRP and P-gp activity 
Cohort 4 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
BCRP and P-gp activity. Eligible participants will take part in 2 treatment periods. Participants 
will be admitted to the CRU on Day -1. All participants will receive: 
 Day 1: 10 mg rosuvastatin and 0.25 mg digoxin 
 Day 10: 400 mg imlunestrant + 10 mg rosuvastatin and 0.25 mg digoxin 
There will be a washout period of 9 days between doses of 10 mg rosuvastatin and 0.25 mg 
digoxin. All participants will remain resident in the CRU until discharge on Day 5, attend the 
CRU as outpatients on each of Days 6 through 8, then will be re-admitted to the CRU on Day 9 
until Day 15. 
Follow-up 
Participants will attend a follow-up visit 5 to 7 days after final discharge from the CRU. 
Data Monitoring Committee: No 
 
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Protocol number J2J-MC-JZLI (a) 
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1.2. 
Schema 
 
 
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Protocol number J2J-MC-JZLI (a) 
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Abbreviations:  BCRP = breast cancer resistance protein; BID = twice daily; CRU =   clinical research unit; CYP = cytochrome P450; P-gp = P-glycoprotein.
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Protocol number J2J-MC-JZLI (a) 
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1.3. 
Schedule of Activities (SoA) 
Cohort 1: Effect of Imlunestrant on CYP2C8 Activity 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1 
1 
2 
3 
4 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Physical examination 
including height 
X 
X 
 
 
 
X 
X 
X 
Full physical examination will occur at 
screening, follow-up, and early 
termination (if applicable). A symptom-
directed physical examination will be 
performed at all other scheduled times 
and as needed at the discretion of the PI. 
Height to be measured at screening only. 
Weight 
X 
 
 
 
 
 
X 
X 
 
Medical history (includes 
substance usage [and 
family history of 
premature 
cardiovascular disease]) 
X 
 
 
 
 
 
 
 
 
Past and current medical 
conditions 
X 
 
 
 
 
 
 
 
 
FSH test (if applicable) 
X 
 
 
 
 
 
 
 
 
Urine or breath ethanol 
test 
X 
X 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
Human 
immunodeficiency virus, 
hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
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Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1 
1 
2 
3 
4 
 
 
 
Clinical laboratory tests 
X 
X 
 
 
 
X 
X 
X 
. 
12-lead ECG (supine) 
X 
X 
 
 
P, 6h 
 
X 
X 
On Day -1, ECG may be performed any 
time after check-in. 
On Day 3, timepoints are relative to 
imlunestrant dosing time. 
Vital signs (supine) 
X 
X 
X 
X 
X 
X 
X 
X 
Timepoints will be defined as follows: 
Day-1 = Anytime after check-in 
Day 1 = 2h±1h after repaglinide 
Day 2 = 24h±4h after repaglinide 
Day 3 = 4h±1h after imlunestrant 
Day 4 = prior to discharge 
Genetic sample 
 
 
X 
 
 
 
 
 
To be collected predose. 
Check-in 
 
X 
 
 
 
 
 
 
 
Discharge from clinic 
 
 
 
 
 
X 
 
 
 
Outpatient visit 
 
 
 
 
 
 
X 
 
 
Trial treatment 
(repaglinide 0.5 mg 
orally) 
 
 
X 
 
X 
 
 
 
On Day 3, repaglinide will be dosed 
approximately 2 h after dosing with 
imlunestrant. 
Trial treatment 
(imlunestrant 800 mg 
orally) 
 
 
 
 
X 
 
 
 
 
Plasma PK evaluation of 
repaglinide  
 
 
P, 0.5h, 
1h, 2h, 3h, 
4h, 6h, 8h, 
12h 
24
h 
P, 0.5h, 1h, 
2h, 3h, 4h, 
6h, 8h, 12h 
24h 
 
 
Sample times are relative to repaglinide 
dosing times. 
Plasma PK evaluation of 
imlunestrant 
 
 
 
 
P, 0.5h, 1h, 
2h, 3h, 4h, 
6h, 8h, 12h 
24h 
 
 
Sample times are relative to imlunestrant 
dosing time. 
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Protocol number J2J-MC-JZLI (a) 
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Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1 
1 
2 
3 
4 
 
 
 
Blood sample for 
Coproporphyrin 1 
 
 
P, 0.5h, 
1h, 2h, 3h, 
4h, 6h, 8h, 
12h 
24
h 
P, 0.5h, 1h, 
2h, 3h, 4h, 
6h, 8h, 12h 
24h 
 
 
Sample times are relative to repaglinide 
dosing times. 
Adverse event/Serious 
adverse event review 
X 
X 
==========================→ 
X 
X 
 
Concomitant medication 
review 
X 
X 
==========================→ 
X 
X 
 
Abbreviations: CYP = cytochrome P450; ECG = electrocardiogram; ET = early termination; FSH = Follicle-stimulating hormone; h = hour(s); P = predose; 
PI = principal investigator; PK = pharmacokinetic. 
 
 
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Protocol number J2J-MC-JZLI (a) 
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Cohort 2: Effect of Imlunestrant on CYP2C19 and CYP2D6 Activity 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
including height  
X 
X 
 
 
 
 
X 
X 
X 
Full physical examination will occur at 
screening, follow-up, and early 
termination (if applicable). A symptom-
directed physical examination will be 
performed at all other scheduled times 
and as needed at the discretion of the 
PI. Height to be measured at 
screening only. 
Weight 
X 
 
 
 
 
 
 
X 
X 
 
Medical history 
(includes substance 
usage [and family 
history of premature 
cardiovascular 
disease]) 
X 
 
 
 
 
 
 
 
 
 
Past and current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone test (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
Urine or breath 
ethanol test 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
18 
Procedure 
Screening 
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1
1 
2 
3 
4 
5 
Human 
immunodeficiency 
virus, hepatitis B and 
C screen 
X 
Clinical laboratory 
tests 
X 
X 
X 
X 
X 
12-lead ECG (supine)
X 
P, 6h 
X 
X 
Vital signs (supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timepoints will be defined as follows: 
Day-1 = Anytime after check-in 
Day 1 = 2h±1h after omeprazole + 
dextromethorphan 
Day 2 = 24 h±4h after omeprazole + 
dextromethorphan 
Day 3 = 4h±1h after imlunestrant 
Day 4 = 24h±4h after imlunestrant 
Day 5 = prior to discharge 
Genetic sample 
X 
To be collected predose. 
Check-in 
X 
Discharge from clinic 
X 
Outpatient visit 
X 
Trial treatment 
(omeprazole [20 mg] + 
dextromethorphan 
[30 mg] orally) 
X 
X 
Trial treatment 
(imlunestrant 800mg 
orally) 
X 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
19 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
 
 
 
Plasma PK evaluation 
of omeprazole, 
5-hydroxyomeprazole, 
dextromethorphan, 
dextrorphan  
 
 
P, 0.5h, 
1h, 2h, 3h, 
4h, 6h, 8h, 
12h 
24
h 
P 
(48h), 
0.5h, 
1h, 
2h, 
3h, 
4h, 
6h, 
8h, 
12h 
24h, 
36h 
48h 
 
 
 
Plasma PK evaluation 
of imlunestrant  
 
 
 
 
P, 
0.5h, 
1h, 
2h, 
3h, 
4h, 
6h, 
8h, 
12h 
24h, 
36h 
48h 
 
 
 
Adverse event/Serious 
adverse event review 
X 
X 
===========================→ 
X 
X 
 
Concomitant 
medication review 
X 
X 
===========================→ 
X 
X 
 
Abbreviations: CYP = cytochrome P450; ECG = electrocardiogram; ET = early termination; h = hour(s); P = predose; PI = principal investigator; 
PK = pharmacokinetic. 
 
 
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Protocol number J2J-MC-JZLI (a) 
20 
Cohort 3: Effect of P-glycoprotein Inhibition on Imlunestrant 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 13 
(participant 
not in CRU 
at this 
time) 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
including 
height 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Full physical examination 
will occur at screening, 
Day 8, and early 
termination (if applicable). 
A symptom-directed 
physical examination will 
be performed at all other 
scheduled times and as 
needed at the discretion 
of the PI. Height to be 
measured at screening 
only. 
Weight 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Medical history 
(includes 
substance 
usage [and 
family history 
of premature 
cardiovascular 
disease]) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Past and 
current medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
21 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 13 
(participant 
not in CRU 
at this 
time) 
 
 
Human 
immunodeficie
ncy virus, 
hepatitis B and 
C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-
stimulating 
hormone test 
(if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or breath 
ethanol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory tests 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Day 8 assessment should 
be prior to discharge. 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from 
clinic 
 
 
 
 
 
 
 
 
 
X 
 
 
 
12-lead ECG 
(supine) 
X 
 
P, 6h 
 
 
 
 
 
 
X 
 
X 
On Day 1, timepoints are 
relative to imlunestrant 
dosing time. Day 8 
assessment should be 
prior to discharge. 
Approved on 26 Jun 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
22 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 13 
(participant 
not in CRU 
at this 
time) 
 
 
Vital signs 
(supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Timepoints will be as 
follows: 
Day-1: Any time after 
check-in 
Day 1 = 4h±1h after 
imlunestrant 
Day 2 = 24h±4h after 
imlunestrant 
Day 3 = 48h±4h after 
imlunestrant 
Day 4 = 72h±4h after 
imlunestrant 
Day 5 = 96h±4h after 
imlunestrant 
Day 6 = 120h±4h after 
imlunestrant 
Day 7 = 144h±4h after 
imlunestrant 
Day 8 = prior to discharge 
Genetic 
sample 
 
 
X 
 
 
 
 
 
 
 
 
 
To be collected predose. 
Trial treatment 
(imlunestrant 
400 mg orally) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
evaluation of 
imlunestrant  
 
 
P, 1h, 2h, 
3h, 4h, 
5h,6h, 8h, 
12h 
24h, 
36h 
48h 
72h 
96h 
120h 
144h 
168h 
 
 
 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
23 
Procedure 
Screening  
(up to 28 
days 
before 
Day 1) 
Treatment period 
 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 13 
(participant 
not in CRU 
at this 
time) 
 
 
Adverse 
event/Serious 
adverse event 
review 
X 
X 
=============================→ 
X 
X 
On Days 9 to 13, AEs will 
be reported 
spontaneously by the 
participant. Participants 
will be instructed to call 
the CRU in the event of 
an AE.  
Concomitant 
medication 
review 
X 
X 
=============================→ 
X 
X 
On Days 9 to 13, 
concomitant medications 
will be reported 
spontaneously by the 
participant. If the 
participant does need to 
take concomitant 
medication, they must 
contact the CRU so that 
the PI and CP may 
consult and approve the 
concomitant medication 
prior to the participant 
taking it. 
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; h = hour(s); P = predose; PI = principal investigator; 
PK = pharmacokinetic. 
 
 
Approved on 26 Jun 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
24 
Procedure 
Treatment Period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
14 
15 
16 
17 
18 
19 
20 
21 
22-25 
 
 
 
Physical 
examination  
 
 
 
 
 
 
 
 
 
X 
X 
Full physical examination will 
occur at follow-up, and early 
termination (if applicable). A 
symptom-directed physical 
examination may be performed 
as needed at the discretion of 
the PI. 
Weight 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical laboratory 
tests 
X 
 
 
X 
 
 
 
 
Day 25 
prior to 
discharge 
X 
X 
 
Urine or breath 
ethanol test 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from 
clinic 
 
 
 
 
 
 
 
 
Day 25 
 
 
 
Outpatient visit 
 
 
 
 
 
 
 
 
 
X 
 
 
12-lead ECG 
(supine) 
X 
X 
 
 
P, 6h 
 
 
 
Day 25 
prior to 
discharge 
X 
X 
On Day 18, timepoints will be 
relative to imlunestrant dosing 
time. 
Approved on 26 Jun 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
25 
Procedure 
Treatment Period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
14 
15 
16 
17 
18 
19 
20 
21 
22-25 
 
 
 
Vital signs 
(supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timepoints will be as follows: 
Day 14 = anytime after 
check-in 
Day 15 = 2h±1h after quinidine 
Day 16 = 2h±1h after quinidine 
Day 17 = 2h±1h after quinidine 
Day 18 = 4h±1h after 
imlunestrant 
Day 19 = 24h±4h after 
imlunestrant 
Day 20 = 48h±4h after 
imlunestrant 
Day 21 = 72h±4h after 
imlunestrant 
Day 22 = 96h±4h after 
imlunestrant 
Day 23 = 120h±4h after 
imlunestrant 
Day 24 = 144 h±4h after 
imlunestrant  
Day 25 = prior to discharge 
Trial treatment 
(quinidine 200 mg 
twice daily) 
 
X 
X 
X 
X 
X 
X 
X 
Days 22  
to 24 
 
 
 
Trial treatment 
(imlunestrant 
400 mg orally) 
 
 
 
 
X 
 
 
 
 
 
 
 
Plasma PK 
evaluation of 
imlunestrant 
 
 
 
 
P, 1h, 2h, 
3h, 4h, 
5h, 6h, 
8h, 12h 
24h, 
36h 
48h 
72h 
96h, 120h, 
144h, 168h 
 
 
 
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CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
26 
Procedure 
Treatment Period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
14 
15 
16 
17 
18 
19 
20 
21 
22-25 
 
 
 
Blood sample for 
Coproporphyrin 1 
 
 
 
 
P, 1h, 2h, 
3h, 4h, 
5h, 6h, 
8h, 12h 
24h 
 
 
 
 
 
Sample times are relative to 
imlunestrant dosing times. 
Adverse 
event/Serious 
adverse event 
review 
X 
=============================→ 
X 
X 
 
Concomitant 
medication review 
X 
=============================→ 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; h = hour(s); P = predose; PK = pharmacokinetic. 
 
 
Approved on 26 Jun 2022 GMT

CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
27 
Cohort 4: Effect of Imlunestrant on Breast Cancer Reactive Protein and P-glycoprotein Activity 
Procedure 
Screening  
(up to 28 
days 
before  
Day 1) 
Treatment period 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6-8 
9 
10 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
including height 
X 
X 
 
 
 
 
 
 
 
X 
X 
Full physical examination will occur at 
screening, Day 10, and early termination. 
A symptom-directed physical 
examination will be performed at all other 
scheduled times and as needed at the 
discretion of the PI. Height to be 
measured at screening only. 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
Medical history 
(includes 
substance usage 
[and family history 
of premature 
cardiovascular 
disease]) 
X 
 
 
 
 
 
 
 
 
 
 
 
Past and current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
FSH test (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine or breath 
ethanol test 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Human 
immunodeficiency 
virus, hepatitis B 
and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
28 
Procedure 
Screening  
(up to 28 
days 
before  
Day 1) 
Treatment period 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6-8 
9 
10 
 
 
Clinical laboratory 
tests 
X 
X 
 
 
 
 
X 
 
X 
 
X 
At screening, Day -1, and at each 
check-in and discharge from the CRU. 
12-lead ECG 
(supine) 
X 
X 
 
 
 
 
X 
 
X 
P, 6h 
X 
On Day -1, ECG may be performed any 
time after check-in 
On Day 10, timepoints will be relative to 
imlunestrant dosing time. 
Vital signs (supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Timepoints will be as follows: 
Day-1 = Any time after check-in 
Day 1 = 4h±1h after rosuvastatin and 
digoxin 
Day 2 = 24h±4h after rosuvastatin and 
digoxin 
Day 3 = 48h±4h after rosuvastatin and 
digoxin 
Day 4 = 72h±4h after rosuvastatin and 
digoxin 
Day 5 = 96h±4h after rosuvastatin and 
digoxin 
Day 6 = 120h±4h after rosuvastatin and 
digoxin 
Day 7 = 144h±4h after rosuvastatin and 
digoxin 
Day 8 = 168±4h after rosuvastatin and 
digoxin 
Day 9 = 192±4h after rosuvastatin and 
digoxin  
Day 10 = 4h±1h after imlunestrant 
Genetic sample 
 
 
X 
 
 
 
 
 
 
 
 
To be collected predose. 
Check-in 
 
X 
 
 
 
 
 
 
X 
 
 
 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
29 
Procedure 
Screening  
(up to 28 
days 
before  
Day 1) 
Treatment period 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6-8 
9 
10 
 
 
Discharge from 
clinic 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient visit 
 
 
 
 
 
 
 
X 
 
 
 
Participants will attend the CRU on each 
of Days 6 through 8 for an outpatient 
visit. 
Trial treatment 
rosuvastatin 
(10 mg) and 
digoxin (0.25 mg) 
 
 
X 
 
 
 
 
 
 
X 
 
 
Trial treatment 
(imlunestrant 
400 mg orally) 
 
 
 
 
 
 
 
 
 
X 
 
 
Plasma PK 
evaluation of 
rosuvastatin, 
digoxin  
 
 
P, 
0.5h
, 1h, 
2h, 
3h, 
4h, 
5h, 
6h, 
8h, 
12h 
24h, 
36h 
48h 
72h 
96h 
 
 
P, 0.5h, 
1h, 2h, 
3h, 4h, 
5h, 6h, 
8h, 12h 
 
 
Plasma PK 
evaluation of 
imlunestrant 
 
 
 
 
 
 
 
 
 
P, 0.5h, 
1h, 2h, 
3h, 4h, 
5h,6h, 
8h, 12h 
 
 
Urinary PK 
evaluation of 
digoxin 
 
 
0 to 
12h 
 
 
 
 
 
 
0 to 12h 
 
Sample times are relative to digoxin 
dosing times. 
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CONFIDENTIAL 
Protocol number J2J-MC-JZLI (a) 
30 
Procedure 
Screening  
(up to 28 
days 
before  
Day 1) 
Treatment period 
ET 
Notes 
-1 
1 
2 
3 
4 
5 
6-8 
9 
10 
 
 
Blood sample for 
Coproporphyrin 1 
 
 
 
 
 
 
 
 
 
P, 0.5h, 
1h, 2h, 
3h, 4h, 
5h, 6h, 
8h, 12h 
 
Sample times are relative to imlunestrant 
dosing times. 
Adverse 
event/Serious 
adverse event 
review 
X 
X 
=============================→ 
X 
 
Concomitant 
medication review 
X 
X 
=============================→ 
X 
 
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating hormone; h = hour(s); P = predose; PI 
= principal investigator; PK = pharmacokinetic. 
 
 
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Protocol number J2J-MC-JZLI (a) 
31 
Procedure 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
 
11 
12 
13 
14 
15 
 
 
 
Physical 
examination 
including height 
 
 
 
 
 
X 
X 
Full physical examination will occur at follow-up, and early 
termination (if applicable). A symptom-directed physical 
examination may be performed as needed at the discretion of the 
PI. 
Weight 
 
 
 
 
 
X 
X 
 
Clinical laboratory 
tests 
 
 
 
 
X 
X 
X 
 
12-lead ECG 
(supine) 
 
 
 
 
X 
X 
X 
 
Vital signs 
(supine) 
X 
X 
X 
X 
X 
X 
X 
Timepoints will be defined as: 
Day 11 = 24h±4h after imlunestrant 
Day 12 = 48h±4h after imlunestrant 
Day 13 = 72h±4h after imlunestrant 
Day 14 = 96h±4h after imlunestrant 
Day 15 = 120h±4h after imlunestrant 
Discharge from 
clinic 
 
 
 
 
X 
 
 
 
Outpatient visit 
 
 
 
 
 
X 
 
 
Plasma PK 
evaluation of 
rosuvastatin, 
digoxin  
24h, 
36h 
48h 
72h 
96h 
120h 
 
 
 
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Protocol number J2J-MC-JZLI (a) 
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Procedure 
Treatment period 
Follow-up 
(5-7 days 
post 
discharge) 
ET 
Notes 
 
11 
12 
13 
14 
15 
 
 
 
Plasma PK 
evaluation of 
imlunestrant  
24h, 
36h 
48h 
72h 
96h 
120h 
 
 
 
Adverse 
event/Serious 
adverse event 
review 
========================→ 
X 
X 
 
Concomitant 
medication review 
========================→ 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; h = hour(s); PI = principal investigator; PK = pharmacokinetic. 
 
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Protocol number J2J-MC-JZLI (a) 
33 
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 endometrial cancer), in patients where the disease has 
become less responsive to ET and options are often limited to chemotherapy. 
Full details of the nonclinical safety, efficacy, and PK may be found in the IB. 
2.1. 
Study Rationale 
Study J2J-MC-JZLI (JZLI) is a Phase 1 open-label, 4-cohort study of imlunestrant administered 
to healthy females of non-childbearing potential. In vitro data indicates that imlunestrant has the 
potential to inhibit CYP2C8, CYP2C19, CYP2D6, P-gp, and BCRP, and clinical studies are 
required to quantify this potential effect. The FDA guidance on DDIs recommend repaglinide, 
omeprazole, and dextromethorphan as sensitive probes of CYP2C8, CYP2C19, and CYP2D6, 
respectively. Similarly, digoxin and rosuvastatin are recommended probes to quantify inhibition 
of P-gp and BCRP, respectively. Therefore, the purpose of this study is to investigate the effect 
of imlunestrant on CYP2C8, CYP2C19 and CYP2D6, and P-gp and BCRP activity by use of 
repaglinide, omeprazole, dextromethorphan, and digoxin and rosuvastatin, respectively. In vitro 
data also identified imlunestrant as a substrate of P-gp. The FDA recommends quinidine as a 
relatively selective inhibitor of P-gp when compared to other P-gp inhibitors that target CYP3A4 
in addition to P-gp. Therefore to investigate the effect of P-gp inhibition on imlunestrant this 
study will employ repeat dosing of quinidine to inhibit both intestinal and central P-gp activity 
(liver, kidney, or both). The results of this study will inform dosing instructions in ongoing 
patient trials. 
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).  
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 
(Nardone et al. 2019). In addition, several studies have shown that with the current maximum 
feasible dose, fulvestrant treatment is not able to completely degrade ER in patients and can be 
associated with early progression (van Kruchten et al. 2015). Thus, there is unmet medical need 
Approved on 26 Jun 2022 GMT

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Protocol number J2J-MC-JZLI (a) 
34 
to develop oral SERDs with higher bioavailability, greater ER targeting, and degradation 
efficiency (Nardone et al. 2019).  
EC, while less frequently diagnosed than breast cancer, is increasing worldwide. In the United 
States, the incidence of EC has increased by approximately 12,000 cases between 2013 and 2019 
(Howlader et al. 2019). Endometrioid EC represents about 80% of EC cases, and over expression 
of estrogen may contribute to tumor proliferation (Ellenson et al. 2011). Standard of care for EC, 
regardless of subtype, consists of the surgery followed by adjuvant radiotherapy, chemotherapy, 
or both. In the advanced setting, a variety of endocrine therapy, such as megestrol acetate, 
tamoxifen, aromatase inhibitors, fulvestrant, are commonly used (NCCN 2020; NCI 2019). 
2.2.1. 
Pharmacokinetics of Imlunestrant 
As of 01 November 2021, imlunestrant PK parameters were available from 85 patients in study 
J2J-MC-JZLA (JZLA) across a 200- to 1200-mg QD dose range. After single oral 
administration, maximum plasma concentrations of imlunestrant were reached approximately 
4 hours postdose. The mean t1/2 was approximately 25 to 30 hours and exposures of imlunestrant 
increased with dose.
 
 
2.3. 
Benefit/Risk Assessment 
Imlunestrant is a potent antagonist and degrader of ERα and has demonstrated significant activity 
in nonclinical models against ER wild-type and mutant tumors. There is no anticipated benefit 
for the women of non-childbearing potential in this study. 
Due to the early stage of the development of imlunestrant, the clinical safety profile has not been 
fully established. There are currently ongoing clinical studies in healthy participants (JZLD and 
J2J-MC-JZLE [JZLE]). As of 01 November 2021, study JZLD has a total of 38 healthy female 
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Protocol number J2J-MC-JZLI (a) 
35 
participants. In this study, participants receive 2 × single doses of 400 mg imlunestrant 
(Cohorts 1, 2, and 4), or 2 × single doses of 200 mg imlunestrant (Cohort 3). Study JZLE has 
5 healthy female participants that are receiving a single dose of 400 mg imlunestrant (Parts 1 
or 2). These studies are still ongoing.  
Imlunestrant has also been administered to patients in ongoing clinical studies JZLA (200 to 
1200 mg QD for a 28 day cycle) and J2J-MC-JZLB a window of opportunity study (400 and 
800 mg) for a period of 15 to 22 days.  
As described in the IB, imlunestrant has been evaluated in a comprehensive set of nonclinical 
safety studies including good laboratory practice repeat-dose studies of approximately 3 months 
in rats and monkeys. Single doses of imlunestrant have been generally well tolerated in rats and 
monkeys. The primary toxicity associated with single doses of imlunestrant was gastrointestinal 
upset, characterized by vomitus in monkeys and abnormal feces in both species. The most 
significant adverse findings in repeat-dose toxicity studies with imlunestrant to date occur in the 
female reproductive tract and are attributable to exaggerated pharmacology of imlunestrant at the 
ER. There have been no adverse non-reproductive findings up to the highest dose tested in 
monkeys or up to the highest tolerated dose in rats. Imlunestrant has not been associated with 
cardiovascular, central nervous, or respiratory system toxicities.  
 
The potential risks associated with exposure to imlunestrant in nonclinical toxicity studies 
include: 
• 
effects on female reproductive organs, including ovarian follicular cysts, cessation of 
estrous cycling, and atrophy of the epithelium of the uterus, cervix, and vagina 
• 
maternal and embryofetal toxicity (embryo lethality, teratogenicity) 
• 
hematological changes 
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Protocol number J2J-MC-JZLI (a) 
36 
• 
decreased lymphoid cellularity in lymphoid organs 
• 
renal effects, such as tubular degeneration  
• 
evidence of phospholipidosis 
• 
gastrointestinal effects, such as abnormal feces and vomiting 
• 
hepatic effects, such as increased liver enzymes lacking morphological correlates 
• 
phototoxicity, based on an in vitro study, and  
• 
chromosomal damage, based on an in vitro study (not observed in the in vivo study), at 
levels of imlunestrant higher than patients will receive.  
Non-reproductive imlunestrant-related toxicities have demonstrated partial to full reversibility. 
As the pharmacologic mechanism of imlunestrant is to degrade the ER, effects on female 
reproductive organs are expected. Similar female reproductive tract findings have been observed 
with other approved agents, known to antagonize or degrade the ER, including tamoxifen 
(Nolvadex) and fulvestrant (Faslodex®). Therefore, this trial will enroll only women of 
non-childbearing potential, defined as postmenopausal or infertile due to surgical sterilization or 
alternate medical cause/congenital anomaly as outlined in Appendix 4 (Section 10.4).  
Potential toxicities will be regularly monitored during this study through ongoing assessment of 
participant symptoms, hematological and chemistry levels, and ECG readings, as detailed in 
Section 8.2. Participants will also be advised to use sunscreen and to wear clothing such as long 
sleeve tops that cover the arms, pants, or other garments that cover the legs, and hats to cover the 
head if out in direct sunlight, to reduce the possibility of phototoxicity that may result from 
imlunestrant exposure based on an in vitro phototoxicity study. 
Genotoxicity  
Imlunestrant was negative for mutagenicity in the Ames assay. It was positive for chromosomal 
damage in vitro in the presence of metabolic activation at ≥14 μg/mL via a mixed, predominantly 
aneugenic mechanism. The chromosomal damage observed in vitro occurred at levels of 
imlunestrant higher than participants will receive. In vivo, imlunestrant did not induce 
chromosomal damage in rats at systemic Cmax and AUC over the last 24-hour dosing interval 
exposures that are approximately 25- to 55-fold higher than clinical exposures at 800 and 
400 mg, respectively, based on single dose clinical PK data. The high threshold concentration for 
in vitro aneugenicity and the lack of chromosomal damage in vivo represent a weight of 
evidence indicating that the risk of imlunestrant in vivo genotoxicity is low, in accordance with 
ICH S2, and establishes safe exposures for clinical trial participants, including healthy 
participants. The risk to healthy participants in the present study is further reduced by 
administration of 1 or 2 doses of imlunestrant.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of imlunestrant may be found in the IB. 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
 Cohort 1: Evaluate the effect of 
imlunestrant on the PK of repaglinide 
(CYP2C8 substrate) in healthy women 
of non-childbearing potential. 
 
 Cohort 2: Evaluate the effect of 
imlunestrant on the PK of omeprazole 
(CYP2C19 substrate) and 
dextromethorphan (CYP2D6 substrate) 
in healthy women of non-childbearing 
potential. 
 
 Cohort 3: Evaluate the effect of 
quinidine (P-gp inhibitor) on the PK of 
imlunestrant in healthy women of 
non-childbearing potential. 
 
 Cohort 4: Evaluate the effect of 
imlunestrant on the PK of rosuvastatin 
(BCRP substrate) and digoxin (P-gp 
substrate) in healthy women of 
non-childbearing potential. 
 Cohort 1: AUC(0-∞), Cmax of 
repaglinide administered alone and in 
the presence of imlunestrant. 
 
 
 Cohort 2: AUC(0-∞), Cmax of 
omeprazole, 5-hydroxyomeprazole, 
dextromethorphan and dextrorphan 
administered alone and in the 
presence of imlunestrant. 
 
 
 Cohort 3: AUC(0-∞), Cmax of 
imlunestrant administered alone and 
in the presence of quinidine. 
 
 
 Cohort 4: AUC(0-∞), Cmax of 
rosuvastatin and digoxin administered 
alone and in the presence of 
imlunestrant. 
Secondary 
 
 To evaluate the safety and tolerability 
of 400 and 800 mg imlunestrant in 
healthy females of non-childbearing 
potential. 
 Incidence and severity of AEs and 
SAEs. 
 
 
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4. 
Study Design 
4.1. 
Overall Design 
Study JZLI is an open-label, 4-cohort, study comprising 4 fixed-sequence crossover cohorts. 
Cohorts 1 to 4 are in healthy females of non-childbearing potential to investigate the effect of 
imlunestrant on the PK of repaglinide (Cohort 1), omeprazole and dextromethorphan (Cohort 2), 
and rosuvastatin and digoxin (Cohort 4), and to investigate the effect of quinidine on the PK of 
imlunestrant (Cohort 3). Additionally, the safety and tolerability of imlunestrant will be 
evaluated when administered as a single 800-mg oral dose in the presence of repaglinide or 
omeprazole and dextromethorphan, and as a single oral 400-mg dose in the presence of quinidine 
or rosuvastatin and digoxin. 
The schema in Section 1.2 illustrates the study design. 
Safety assessments, including AEs, concomitant medications, physical examination, clinical 
laboratory tests, vital signs, and ECGs, and blood sampling for PK, will be performed according 
to the SoA (Section 1.3). 
4.1.1. 
Screening  
All participants will be screened within 28 days prior to enrollment. 
4.1.2. 
Treatment and Assessment Period 
Cohort 1 – imlunestrant on CYP2C8 activity 
Cohort 1 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
CYP2C8. Participants will be admitted to the CRU on Day -1. All participants will receive: 
 Day 1: 0.5 mg repaglinide alone 
 Day 3: 800 mg imlunestrant + 0.5 mg repaglinide 
There will be a washout period of 2 days between doses of repaglinide. All participants will 
remain resident in the CRU until discharge on Day 4. 
Cohort 2 – imlunestrant on CYP2C19 and CYP2D6 activity 
Cohort 2 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
CYP2C19 and CYP2D6. Participants will be admitted to the CRU on Day -1. All participants 
will receive: 
 Day 1: 20 mg omeprazole and 30 mg dextromethorphan 
 Day 3: 800 mg imlunestrant + 20 mg omeprazole and 30 mg dextromethorphan 
There will be a washout period of 2 days between doses of omeprazole and dextromethorphan. 
All participants will remain resident in the CRU until discharge on Day 5. 
Cohort 3 – P-gp inhibition on imlunestrant 
Cohort 3 will be an open-label, fixed-sequence design evaluating the effect of P-gp on 
imlunestrant. Eligible participants will take part in 2 treatment periods. Participants will be 
admitted to the CRU on Day -1. All participants will receive: 
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 Day 1: 400 mg imlunestrant 
 Days 15 to 17: 200 mg quinidine twice daily (BID) alone 
 Day 18: 400 mg imlunestrant + 200 mg quinidine BID 
 Day 19 to Day 24: 200 mg quinidine BID alone 
There will be a washout period of 17 days between doses of imlunestrant. All participants will 
remain resident in the CRU until discharge on Day 8, then will be re-admitted to the CRU on 
Day 14 until Day 25. 
On Days 9 to 13, participants will not be in the CRU. During this time, AEs and concomitant 
medications on this day will be reported spontaneously by the participant. If the participant does 
need to take concomitant medication, they must contact the CRU so that the PI and CP may 
consult and approve the concomitant medication prior to the participant taking it.  
Cohort 4 - imlunestrant on BCRP and P-gp activity 
Cohort 4 will be an open-label, fixed-sequence design evaluating the effect of imlunestrant on 
BCRP and P-gp activity. Eligible participants will take part in 2 treatment periods. Participants 
will be admitted to the CRU on Day -1. All participants will receive: 
 Day 1: 10 mg rosuvastatin and 0.25 mg digoxin 
 Day 10: 400 mg imlunestrant + 10 mg rosuvastatin and 0.25 mg digoxin 
There will be a washout period of 9 days between doses of 10 mg rosuvastatin and 0.25 mg 
digoxin. All participants will remain resident in the CRU until discharge on Day 5, attend the 
CRU as outpatients on each of Days 6 through 8, then will be re-admitted to the CRU on Day 9 
until Day 15. 
4.1.3. 
Follow-up 
Participants will attend a follow-up visit 5 to 7 days after final discharge from the CRU. 
4.2. 
Scientific Rationale for Study Design 
The fixed-sequence, crossover design used in each of Cohorts 1 to 4 is typical for interaction 
studies where a relatively small number of participants are required, because it allows 
intraparticipant comparisons and eliminates interparticipant comparisons. In addition, a 
fixed-sequence design is consistent with FDA guidance. 
This study will be open label because the study endpoints are not considered subjective. 
Conducting studies in healthy participants mitigates the potential confounding effects of the 
disease state and concomitant medications, and avoids non-beneficial drug exposures in cancer 
patients. Healthy females of non-childbearing potential have been selected as the study 
population since the pharmacologic mechanism of imlunestrant is to degrade the ER, and effects 
on the female reproductive organs are expected. 
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4.3. 
Justification for Dose 
4.3.1. 
Imlunestrant 
The proposed efficacious dose of imlunestrant is 400 mg daily and upon multiple dosing there is 
approximately a 2-fold accumulation at steady state. Therefore, to evaluate the inhibition of 
CYP2C8 (repaglinide), CYP2C19 (omeprazole) and CYP2D6 (dextromethorphan), which are 
expressed only in the liver, a single dose of 800 mg imlunestrant will be used to approximate 
steady-state plasma concentrations. To evaluate the inhibition of P-gp (digoxin) and BCRP 
(rosuvastatin), which are expressed in the intestinal wall, a single dose of 400 mg imlunestrant 
will be used to reproduce expected intestinal concentrations. To evaluate the effect of inhibiting 
P-gp (quinidine) on imlunestrant exposure we will use a single dose of 400 mg to reproduce 
expected intestinal concentrations in clinical use.  
4.3.2. 
Repaglinide 
The selected dose of 0.5 mg for repaglinide is based on typical doses (0.5 to 4 mg) for this drug 
and is considered to be high enough to provide sufficient plasma concentrations to achieve the 
objectives of the study. 
4.3.3. 
Omeprazole and Dextromethorphan 
A drug cocktail containing oral doses of 40 mg omeprazole, and 30 mg dextromethorphan has 
been studied previously (Ishii et al. 2018), with no safety concerns or DDIs between the 2 drugs 
raised. Therefore, the drug cocktail proposed in the current study, which contains 20 mg 
omeprazole, and 30 mg dextromethorphan is expected to be safe and well tolerated. 
4.3.4. 
Quinidine 
The selected dose of 200 mg BID of quinidine for 10 days is within the therapeutic dose range 
for this drug.  
4.3.5. 
Rosuvastatin and Digoxin 
Rosuvastatin and digoxin are commonly used as probes in DDI studies to detect the interaction 
involving BCRP and P-gp, respectively, either alone or as a cocktail (FDA 2020; Ishii et 
al. 2018). Rosuvastatin is commonly administered to adults at an oral dose of 5 to 40 mg QD, 
with the majority of the clinical DDI or pharmacogenetic studies conducted using a 10- or 20-mg 
dose (Lee et al. 2015; Crestor Prescribing Information, 2020). The suggested 10-mg dose is as a 
good clinical probe for both hepatic and intestinal BCRP function (Lee et al. 2015). Digoxin 
recommended therapeutic concentration ranges from 0.5 to 2.0 ng/mL (LANOXIN [digoxin] 
package insert). However, digoxin may produce clinical benefits below this range therefore the 
selected dose of 0.25 mg is anticipated to produce Cmax values in that range (Ishii et al. 2018), 
and address the study objectives with minimal risk. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if she has completed all scheduled 
procedures shown in the SoA (Section 1.3). 
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The end of the study is defined as the date of the last visit of the last participant in the study. 
 
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5. 
Study Population 
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examinations, vital signs, clinical laboratory tests, and ECGs. All 
participants will be women of non-childbearing potential. 
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. Participant 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 and Contraceptive/Barrier Requirements 
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 ICF and in 
this protocol. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
 
Medical Conditions 
8. Have known allergies to imlunestrant, related compounds or any components of the 
formulation, repaglinide, omeprazole, dextromethorphan, quinidine, rosuvastatin, or 
digoxin, as appropriate, or history of significant atopy. 
9. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, 
respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or 
designee). 
10. Current or chronic history of liver disease or known hepatic or biliary abnormalities. 
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the investigator (or designee). 
12. Have a clinically significant abnormality of blood pressure, pulse rate, or both, as 
determined by the investigator. 
13. Have a history or presence of cardiovascular (for example, symptomatic bradycardia with 
resting heart rate of <60 beats per minute), respiratory, renal, gastrointestinal, endocrine, 
hematological, or neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the investigational 
product; or of interfering with the interpretation of data. Appendectomy, hernia repair, 
and cholecystectomy are considered as acceptable. 
14. History of alcoholism or drug/chemical abuse within 2 years prior to initial check-in to 
the CRU. 
15. Alcohol consumption of > 14 units per week. Number of units = [total volume of drink 
(mL) x alcohol by volume (%)]/1000. 
16. Positive ethanol breath/urine test result or positive urine drug screen at screening or each 
check-in to the CRU, where applicable. 
17. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive 
hepatitis B surface antigen at screening. 
A positive result for hepatitis B surface antigen or hepatitis C antibody will be confirmed 
by polymerase chain reaction test to determine active infection. 
18. Show evidence of hepatitis C or positive hepatitis C antibody at screening. 
19. Have evidence of HIV infection or positive human HIV antibodies at screening. 
20. Have donated blood of more than 500 mL within the previous 2 months of study 
screening. 
21. Have any medical conditions, medical history, or are taking any medications which are 
contraindicated in the omeprazole, repaglinide, dextromethorphan, quinidine, 
rosuvastatin or digoxin labels, as appropriate. 
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Prior/Concomitant Therapy 
22. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to 
first dose, unless deemed acceptable by the investigator (or designee). 
23. Use or intend to use any prescription medications/products within 14 days prior to first 
dose until completion of the follow-up visit, unless deemed acceptable by the investigator 
(or designee), including but not limited to medications that inhibit or induce CYP2C8, 
CYP2C19, CYP2D6, P-gp or BCRP. 
24. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to initial check-in, unless deemed acceptable by the investigator (or 
designee). 
25. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
check-in until completion of the follow-up visit, unless deemed acceptable by the 
investigator (or designee). 
Prior/Concurrent Clinical Study Experience 
26. Participation in a clinical study involving administration of an investigational drug (new 
chemical entity) in the past 30 days prior to first dose, or 5 half-lives; whichever is 
longer. 
27. Have previously completed or withdrawn from this study or any other study investigating 
imlunestrant, and have previously received imlunestrant. 
28. Have previously received a SERD in the past 30 days prior to first dose, or 5 half-lives; 
whichever is longer. 
Other Exclusions 
29. Smoke more than 10 cigarettes or use the equivalent tobacco, smoking-cessation 
products, nicotine-containing products, or e-cigarettes (nicotine and non-nicotine) per 
day. Participants must be willing to abstain from smoking whilst resident at the CRU. 
30. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages 
within 7 days prior to initial check-in. 
31. Receipt of blood products within 2 months prior to initial check-in. 
32. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to 
screening, or platelets from 6 weeks prior to screening. 
33. Participants who, in the opinion of the investigator (or designee), should not participate in 
this study. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
During the confinement period, participants will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (for example, breakfast, lunch, dinner, and 
snack) will be provided to the participants while resident at the CRU. 
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Imlunestrant will be dosed in the fasted state; participants will be fasted overnight (at least 
10 hours) prior to dosing and refrain from consuming water and food from 1 hour predose until 
2 hours postdose, excluding the amount of water consumed at dosing. 
In Cohort 1, repaglinide will be dosed approximately 2 hours after dosing with imlunestrant on 
Day 3. Approximately 15 minutes after dosing with repaglinide, a light breakfast will be 
administered. An example of a light breakfast is as follows: 
Example 1: 
 1 hard-boiled egg 
 1 small piece of toast with butter 
 1 small apple or banana. 
Example 2: 
 1 small bowl of cereal or 1 small bagel with cream cheese 
 1 small apple or banana. 
Where applicable in Cohorts 2, 3, and 4, imlunestrant may be dosed at the same time as 
omeprazole and dextromethorphan, quinidine, or rosuvastatin and digoxin in the fasted state. 
With the exception of dosing on Day 3 of Cohort 1 where imlunestrant is coadministered with 
repaglinide, food is allowed from 2 hours post dosing with imlunestrant. With the exception of 
the water restrictions described above, participants may consume water ad libitum. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to check-in until follow-up. In addition, all other citrus fruits and tomato-based 
products will not be allowed from the time of check-in until discharge from the CRU. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco 
1. During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (for example, coffee, tea, cola drinks, and chocolate) for 
48 hours before the start of dosing until after collection of the final PK sample. 
2. During each dosing session, participants will abstain from alcohol for 24 hours before the 
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 check-in 
and through discharge from the CRU. 
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). 
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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, 
or other garments that cover the legs and hats to cover the head if out in direct sunlight, to reduce 
the possibility of phototoxicity. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Individuals may be rescreened up to 1 time. The interval between re-screenings 
should be at least 1 week. Each time rescreening is performed, the individual must sign a new 
ICF and will be assigned a new identification number. 
If participants have minor deviations in screening assessments (for example, laboratory safety 
tests, vital signs) these may be repeated at the investigator’s discretion to confirm eligibility. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant 
Not applicable for this study. 
 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Interventions Administered 
Table JZLI.1. Study Interventions (IMPs) Administered 
ARM Name 
Cohorts 1 and 2  
Cohort 3 and 4 
Cohort 1 
Intervention 
Name 
imlunestrant  
imlunestrant  
repaglinide 
Type  
drug 
drug 
drug 
Dose 
Formulation 
tablet 
tablet 
tablet 
Unit Dose 
Strength(s) 
200 mg 
200 mg 
0.5 mg 
Dosage Level(s) 
800 mg (4 × 200 mg) 
400 mg (2 × 200 mg) 
0.5 mg 
Route of 
Administration 
oral 
oral 
oral 
Sourcing 
Provided centrally by 
the sponsor. 
Provided centrally by 
the sponsor. 
Provided locally by the 
trial site. 
Packaging and 
Labeling 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
 
 
 
 
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ARM Name 
Cohort 2 
Cohort 2 
Cohort 3 
Intervention 
Name 
omeprazole 
dextromethorphan 
quinidine 
Dose 
Formulation 
capsule 
oral suspension 
tablet 
Unit Dose 
Strength(s) 
20 mg 
 --- 
200 mg 
Dosage 
Level(s) 
20 mg 
30 mg 
200 mg BID 
Route of 
Administration 
oral 
oral 
oral 
Sourcing 
Provided locally by the 
trial site. 
Provided locally by the 
trial site. 
Provided locally by the 
trial site. 
Packaging and 
Labeling 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
Study Intervention will 
be provided in a bottle. 
Each bottle will be 
labeled as required per 
country requirement. 
Abbreviation: BID = twice daily. 
 
 
 
 
 
 
 
 
 
 
 
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ARM Name 
Cohort 4 
Cohort 4 
Intervention Name 
rosuvastatin 
digoxin 
Dose Formulation 
tablet 
tablet 
Unit Dose Strength(s) 
10 mg 
0.25 mg 
Dosage Level(s) 
10 mg 
0.25 mg 
Route of 
Administration 
oral 
oral 
Sourcing 
Provided locally by the trial site. 
Provided locally by the trial site. 
Packaging and 
Labeling 
Study Intervention will be 
provided in a bottle. Each bottle 
will be labeled as required per 
country requirement. 
Study Intervention will be 
provided in a bottle. Each bottle 
will be labeled as required per 
country requirement. 
6.1.1. 
Administration Details 
Imlunestrant tablets should be swallowed whole. Participants should not break, crush, or chew 
the study intervention. 
Participants will not be allowed to lie supine for 2 hours after each dosing occasion, unless 
clinically indicated or for study procedures. 
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1. 
Cohort 1 – imlunestrant on CYP2C8 activity 
A single dose of 0.5 mg repaglinide will be administered on Day 1. On Day 3, a single oral dose 
of 0.5 mg repaglinide will be administered approximately 2 hours after dosing with 800 mg 
imlunestrant. All doses of repaglinide and imlunestrant will be administered with approximately 
240 mL of room temperature water while in a sitting position.  
Repaglinide tablets should be swallowed whole. Participants should not break, crush, or chew the 
study intervention. 
Cohort 2 – imlunestrant on CYP2C19 and CYP2D6 activity 
A single oral dose of 20 mg omeprazole and 30 mg dextromethorphan will be administered in the 
morning of Day 1. A single oral dose of 800 mg imlunestrant will be administered in 
combination with 20 mg omeprazole and 30 mg dextromethorphan on Day 3 (imlunestrant 
should be dosed first, with omeprazole and dextromethorphan being dosed immediately after). 
Doses of dextromethorphan will be administered via an oral dosing syringe which will be rinsed 
with approximately 10 mL of room temperature water two times, with each rinse being 
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administered.  All doses of omeprazole and dextromethorphan will be administered with 
approximately 240 mL of room temperature water while in a sitting position. No additional water 
is required when omeprazole and dextromethorphan are dosed in combination with imlunestrant. 
Omeprazole capsules should be swallowed whole. Participants should not break, crush, chew, or 
empty the study intervention. 
Cohort 3 – P-gp on imlunestrant 
A single oral dose of 400 mg imlunestrant will be administered in the morning of Day 1. Twice 
daily oral doses of 200 mg quinidine will be administered alone on Days 15 to 17, and on 
Days 19 to 24, and in combination with 400 mg imlunestrant on Day 18.  
All doses of imlunestrant and quinidine will be administered with approximately 240 mL of 
room temperature water while in a sitting position when dosed alone. No additional water is 
required when quinidine is dosed in combination with imlunestrant. 
Quinidine tablets should be swallowed whole. Participants should not break, crush, or chew the 
study intervention. 
Cohort 4 – imlunestrant on BCRP and P-gp activity 
A single oral dose of 10 mg rosuvastatin and 0.25 mg digoxin will be administered in the 
morning of Day 1. A single oral dose of 400 mg imlunestrant will be administered in 
combination with 10 mg rosuvastatin and 0.25 mg digoxin on Day 10. All doses of rosuvastatin 
and digoxin will be administered with approximately 240 mL of room temperature water while 
in a sitting position. No additional water is required when rosuvastatin and digoxin are dosed in 
combination with imlunestrant. 
Rosuvastatin and digoxin tablets should be swallowed whole. Participants should not break, 
crush, or chew the study intervention. 
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. 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Cohorts 1 to 4 will not be randomized. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and will be provided to the sponsor as requested.  
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 
Imlunestrant will not be made available to participants after completion of the study. 
6.7. 
Treatment of Overdose 
Any dose of imlunestrant greater than 800 mg (Cohorts 1 and 2), or >2 doses of 400 mg 
(Cohorts 3 and 4) within a 24-hour time period will be considered an overdose. 
In the event of an overdose, the investigator or treating physician should: 
1. contact the Lilly CP immediately 
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. 
6.8. 
Concomitant Therapy 
For all participants, any medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, phytotherapeutic/plant-derived preparations 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 
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ongoing medical problem. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Lilly CP/CRP, or designee. 
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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, or will remain in the study and follow procedures for 
remaining study visits, as shown in the SoA (Section 1.3). 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study, or 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons 
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, 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, 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: 
 CK 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 investigational product, 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 she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures 
● Study procedures and their timing are summarized in the SoA (Section 1.3).  
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
 The priority of assessments at individual timepoints should be as follows: vital 
signs > ECGs > PK blood collection (at nominal timepoint) > clinical laboratory 
assessments. 
8.1. 
Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
Physical examinations 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 SoA (Section 1.3). 
 Blood pressure and pulse rate should be measured singly after at least 5 minutes 
supine. For each individual participant, the same cuff size should be used 
throughout the study for the measurements of blood pressure. The cuff should be 
attached to the 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. 
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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. 
 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 physician (the investigator 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, and must document his/her review of the ECG printed at 
the time of collection. Any new clinically relevant finding should be reported as 
an AE. 
8.2.4. 
Clinical Laboratory Tests 
● See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed and the SoA (Section 1.3) for the timing and frequency. 
● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant's condition. 
● 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. 
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○ All protocol-required clinical laboratory tests, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA and standard 
collection requirements. 
● If laboratory values from non-protocol specified clinical laboratory tests 
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. 
8.2.5. 
Safety Monitoring 
8.2.5.1. 
Hepatic Safety 
Close hepatic monitoring 
Laboratory tests (Appendix 6, Section 10.6), including ALT, AST, ALP, TBL, direct 
bilirubin, gamma-glutamyl transferase, and CK, should be repeated within 48 to 72 hours 
to confirm the abnormality and to determine if it is increasing or decreasing, if 1 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 laboratory 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 1 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, 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 patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for HDV, CMV, 
EBV, 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. 
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 cause 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 informed 
consent form 
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 paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC 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 occurring after participant has completed the study 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.  
 In Cohort 1, blood samples of approximately 5 mL will be collected for measurement of 
concentrations of repaglinide. In Cohort 2, blood samples of 5 mL will be collected for 
measurement of concentrations of omeprazole, 5-hydroxyomeprazole, dextromethorphan, 
and dextrorphan. In Cohort 4, blood samples of approximately 5 mL will be collected for 
the measurement of rosuvastatin, digoxin.  
 Urinary samples of approximately 10 mL will be collected to determine the urinary 
concentrations of digoxin in Cohort 4. Samples will be collected at the time points 
specified in the SoA (Section 1.3). Up to 3 samples may be collected at additional time 
points during the study if warranted and agreed upon between both the investigator and 
sponsor. 
 Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded, 
as well as the date and time of each imlunestrant, rosuvastatin and digoxin, quinidine, 
omeprazole and dextromethorphan, and repaglinide dose. 
8.4.1. 
Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Plasma concentrations of imlunestrant, dextromethorphan, dextrorphan, omeprazole, 
5-hydroxyomeprazole, repaglinide, rosuvastatin will be assayed using a validated liquid 
chromatography mass spectrometry method. The unbound concentration in plasma may also be 
measured. Urinary digoxin concentration will be assayed using a validated liquid 
chromatography mass spectrometry method. Plasma coproporphyrin 1 will be assayed using a 
validated liquid chromatography mass spectrometry method. Samples collected for the analysis 
of plasma and urine concentrations may be stored and analyzed for future exploratory analysis 
related to drug disposition. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last participant visit for the study. During this time, 
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samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.  
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics 
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3), where local regulations allow. 
8.7. 
Biomarkers 
Venous blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of Coproporphyrin I in Cohorts 1, 3, and 4, as specified in the SoA (Section 1.3). 
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 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 DDI between imlunestrant and 
repaglinide, omeprazole and dextromethorphan, or rosuvastatin and digoxin, and to assess the 
effect of P-gp inhibition in imlunestrant by use of quinidine.  
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 IMP, or if they take the correct treatment. 
Safety 
All participants who take at least 1 dose of IMP.  
Pharmacokinetic Analysis 
All participants who received at least 1 dose of IMP and have 
evaluable PK. 
9.2.1. 
Study Participant Disposition 
A detailed description of participant disposition will be provided at the end of the study. 
9.2.2. 
Study Participant Characteristics 
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 IMP 
and have evaluable PK. 
Safety analyses will be conducted for all enrolled participants who received at least 1 dose of 
IMP, whether or not they completed all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
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Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.1. 
Safety Analyses 
9.3.1.1. 
Clinical Evaluation of Safety 
All IMP 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 
IMP 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 
PK parameter estimates will be calculated by standard noncompartmental methods. The primary 
PK parameters for analysis of imlunestrant, repaglinide, omeprazole and 5-hydroxyomeprazole, 
dextromethorphan and dextrorphan, rosuvastatin and digoxin will be: Cmax, AUC(0-∞), and 
tmax. The AUC (0-∞) and Cmax ratio of 5-hydroxyomeprazole to omeprazole and dextrorphan to 
dextromethorphan will be calculated. 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. Plasma concentrations of Coproporphyrin I in Cohorts 1, 3, and 4 will be 
summarized by descriptive statistics as appropriate. 
In Cohort 4, digoxin renal clearance (CLr) will be calculated on Days 1 and 10 by dividing the 
cumulative amount excreted in urine collected for 12 hours by the plasma AUC(0-12). 
9.3.2.2. 
PK Statistical Inference 
PK parameters will be evaluated to estimate DDIs in all cohorts. The treatment differences will 
be back-transformed to present the ratios of geometric means and the corresponding 90% CI.  
To estimate the effect of: 
 imlunestrant with repaglinide (Cohort 1), 
 imlunestrant with omeprazole and dextromethorphan (Cohort 2), 
 quinidine with imlunestrant (Cohort 3), and 
 imlunestrant with rosuvastatin and digoxin (Cohort 4). 
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Log-transformed Cmax and AUC(0-∞) parameters for repaglinide (Cohort 1), omeprazole and 
5-hydroxyomeprazole, dextromethorphan and dextrorphan (Cohort 2), imlunestrant (Cohort 3) 
and rosuvastatin and digoxin (Cohort 4) 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, PK parameters will be summarized using descriptive statistics. 
9.3.3. 
Pharmacodynamic Analyses 
Not applicable for this study. 
9.3.4. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable for this study. 
9.4. 
Interim Analysis  
An interim analysis will be conducted after the completion of Cohorts 1 and 2 (that is, after 
Cohort 2). If an unplanned interim analysis is deemed necessary for reasons other than a safety 
concern, the protocol must be amended. 
The SAP will describe the planned interim analyses in greater detail. 
The timing of dissemination of data summaries based on interim analyses is addressed in 
Appendix 10.1 (Section 10.1.4). 
9.5. 
Sample Size Determination 
In Cohorts 1, 2, and 4, approximately 27 participants should be enrolled to ensure that at least 
22 evaluable participants in each of these cohorts complete the study. The sample size (N=22) 
will provide at least 80% power that the 90% CI of the ratio is included in the acceptance interval 
between 0.8 and 1.25, assuming that the expected geometric mean ratio is 1.05 and the 
intra-subject CV is 22% for AUC. In Cohort 3, approximately 32 participants should be enrolled 
to ensure that at least 26 evaluable participants in this cohort completes the study. The sample 
size (N=26) will provide at least 85% power that the 90% CI of the ratio is included in the 
acceptance interval between 0.8 and 1.25, assuming that the expected geometric mean ratio is 
1.05 and the intra-subject CV is 22% for AUC. 
 
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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 GCP guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ 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 
o Reporting significant issues related to participant safety, participant rights, or data 
integrity. 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
 
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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. 
● 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(s). 
● 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 plans for 
appropriate and timely response in the event of a data security breach. 
 
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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, 
email, or both) as soon as possible. It will be a requirement that investigators respond 
upon receipt to confirm that they understand the communication and have taken the 
appropriate action prior to further dosing any participants with study intervention. Any 
investigator not responding will be followed up by Lilly personnel prior to any further 
planned dosing. If a dose is planned imminently, Lilly personnel will immediately, and 
continually, use all efforts to reach investigators until contact is made and instructions 
verified.  
Reports  
The sponsor will disclose a summary of study information, including tabular study 
results, on publicly available websites where required by local law or regulation.   
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data  
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for 
access to Phase 1 clinical trial data are evaluated on a case-by-case basis taking into 
consideration the ability to anonymize the data and the nature of the data collected. 
10.1.5. 
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. 
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● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals (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 application unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
● In addition, 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. 
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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. Current medical records must also be 
available. 
● Definition of what constitutes source data can be found in Section 10.1.4. 
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 
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 IRBs/IECs, 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. 
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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 
Uric acid  
International normalized ratio 
Total protein 
 
Albumin 
 
Total bilirubin 
Differential White Blood Cells (Absolute Counts) 
Alkaline phosphatase 
Neutrophils 
Aspartate aminotransferase 
Lymphocytes 
Alanine aminotransferase 
Monocytes 
Creatinine 
Eosinophils 
Lipase 
Basophils 
Amylase 
 
 
Urinalysis 
 
Specific gravity 
 
pH 
 
Protein 
 
Glucose 
Ethanol testinga 
Ketones 
Urine drug screena 
Bilirubin 
Hepatitis B surface antigenb,c 
Urobilinogen 
Hepatitis B core antibodyb 
Blood 
Hepatitis C antibodyb,c 
Nitrite 
Human immunodeficiency virus antibodiesb 
 
Follicle-stimulating hormone (if applicable)b 
 
 
 
 
a Performed at screening and each check-in, where appropriate. 
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 Summaries 
These tables summarize the approximate number of venipunctures and blood volumes for all 
blood sampling during the study.  
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Protocol J2J-MC-JZLI Sampling Summary – Cohort 1 
 
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 
3 
33 
Pharmacokinetics - imlunestrantb 
2 
10 
20 
Pharmacokinetics - repaglinideb 
5 
20 
100 
Coproporphyrin 1 
3 
20 
60 
Genetic sample 
10 
1 
10 
Total 
 
 
241.8 
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. 
Protocol J2J-MC-JZLI Sampling Summary – Cohort 2 
 
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 
3 
33 
Pharmacokinetics - imlunestrantb 
2 
12 
24 
Pharmacokinetics – omeprazole, 5-
hydroxyomeprazole, 
dextromethorphan, dextrophan 
5 
22 
110 
Genetic sample 
10 
1 
10 
Total 
 
 
195.8 
Total for clinical purposes  
200 
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. 
Protocol J2J-MC-JZLI Sampling Summary – Cohort 3 
 
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 
6 
66 
Pharmacokinetics - imlunestrantb 
2 
34 
68 
Coproporphyrin 1 
3 
10 
30 
Genetic sample 
10 
1 
10 
Total 
 
 
192.8 
Total for clinical purposes  
200 
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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Protocol J2J-MC-JZLI Sampling Summary – Cohort 4 
 
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 
5 
55 
Pharmacokinetics - imlunestrantb 
2 
16 
32 
Pharmacokinetics – rosuvastatin, 
digoxin 
5 
31 
155 
Coproporphyrin 1 
3 
10 
30 
Genetic sample 
10 
1 
10 
Total 
 
 
300.8 
Total for clinical purposes  
310 
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, ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency 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 DDI. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
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. 
 Situations in which an untoward medical occurrence did not occur (social or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (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 
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 
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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 participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a 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 PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 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. 
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 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 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 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 in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
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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, evaluations, or both, as medically indicated or as requested by sponsor 
or designee to elucidate the nature, causality, or both 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 Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the SAE report. 
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
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● 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, bilateral tubal occlusion, 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 at least 40 years of age and up to 55 years of age with an intact uterus, not on 
hormone therapy*, who has had cessation of menses for at least 12 consecutive months 
without an alternative medical cause, AND with a follicle-stimulating hormone 
>40 mIU/mL; or 
3. A woman 55 years of age or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea; or  
4. A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone-replacement therapy. 
* Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
 
 
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10.5. 
Appendix 5: 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; 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/endometrial cancer and related diseases. They may also be used to develop 
tests/assays including diagnostic tests related to imlunestrant and 
breast/endometrial cancer. 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). 
● 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, international normalized ratio 
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 is available. 
 
 
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10.7. 
Appendix 7: Abbreviations and Definitions 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC(0-∞) 
area under the concentration versus time curve from zero to infinity 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
Cmax 
maximum observed drug concentration 
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 (GCP), and applicable regulatory 
requirements. 
CP 
clinical pharmacologist 
CRF 
case report form. A printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRU 
clinical research unit 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
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EC 
endometrial cancer 
ECG 
electrocardiogram 
EDC 
electronic data capture system 
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 
GCP 
good clinical practice 
HIV 
human immunodeficiency virus 
HSA 
human serum albumin 
HER2 
human epidermal growth factor receptor 2 
HR 
hormone receptor 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
IEC 
independent ethics committee 
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. 
INR 
international normalized ratio 
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. 
IRB 
institutional review board 
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medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription. 
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 
P-gp 
P-glycoprotein 
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 
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. 
tmax 
time of maximum observed drug concentration 
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ULN 
upper limit of normal 
 
 
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11. 
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