EMBER-2: A Phase 1, Open-Label, Preoperative Window Study Evaluating the Biological Effects of LY3484356 in Post-menopausal Women With Stage I-III Estrogen Receptor-Positive, HER2-Negative Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Eli Lilly and Company

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

CONFIDENTIAL 
Protocol J2J-MC-JZLB(b) 
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 LY3484356, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.   
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title:  EMBER-2: A Phase 1, Open-Label, Preoperative Window Study evaluating the 
Biological Effects of LY3484356 in Post-menopausal Women with Stage I-III Estrogen 
Receptor-Positive, HER2-Negative Breast Cancer 
Protocol Number: J2J-MC-JZLB 
Compound: LY3484356 (imlunestrant) 
Amendment: (b) 
Study Phase: Phase 1 
Short Title: EMBER-2: A Preoperative Window Study of LY3484356 in Stage I-III Estrogen 
Receptor-Positive Breast Cancer  
Acronym: JZLB 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 145311 
EudraCT:  2020-002810-42 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 

CONFIDENTIAL 
Protocol J2J-MC-JZLB(b) 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 

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Protocol J2J-MC-JZLB(b) 
 
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Protocol Amendment Summary of Changes  
DOCUMENT HISTORY
Document 
Date
Amendment a
10-Dec-2020
Protocol J2J-MC-JZLB
31-Aug-2020 
Amendment (b) 
This amendment is considered to be nonsubstantial.  
Overall Rationale for the Amendment: 
This amendment incorporates an additional dose level (200mg) cohort, at the dose level below 
the recommended Phase 2 dose (RP2D) of LY3484356.  
The RP2D of LY3484356 was determined as 400 mg in the EMBER study, a Phase 1a/1b dose 
escalation and dose expansion study of LY3484356 in advanced breast and endometrial cancer 
participants. Occasionally, dose reduction of LY3484356 to 200 mg is necessary due to AEs 
observed at the RP2D (400 mg).  
Therefore, in this study amendment (b), we aim to determine the biologic effects of this lower 
dose level (200 mg) through evaluation of changes in ER (primary objective), PR and Ki67 
(secondary objectives) expression at the 200 mg dose.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 1.2 Schema; 2.1 
Study Rationale; 4.1 Overall 
Design; 4.3 Justification for 
Dose; 6.1 Study 
Intervention(s) Administered 
Addition of Cohort C to study design 
Added cohort to evaluate ER, PR, 
and Ki67 change in expression at 
200 mg dose level 
1.3 Schedule of Activities 
Added Visit 1 window to vital signs, 
hematology, clinical chemistry, whole 
blood (PGx) 
Added for flexibility 
1.3 Schedule of Activities 
Moved window for biomarker plasma to 
Day 1 
Operational 
1.3 Schedule of Activities 
Added concomitant medication collection 
to short-term follow-up visit 
Operational 
2.2 Study Background 
Updated background to incorporate new 
information 
Updated to include most recent 
information on LY3484356 from 
EMBER and EMBER-2 trials 
2.3 Benefit/Risk Assessment 
Updated section with most recent safety 
information on LY3484356 
Emerging safety information 
5.2 Exclusion Criteria 
Added Exclusion #28 
Criterion was erroneously omitted 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
Added description for the 200 mg cohort 
(Cohort C) 
Updated to reflect changes to 
study design 

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Protocol J2J-MC-JZLB(b) 
 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5 Concomitant Therapy; 
10.7 Appendix 7: Other CYP-
sensitive Substrates; 10.8 
Appendix 8: Examples of 
strong clinical inhibitors and 
inducers of UGT1A1 
Updated concomitant therapy guidance; 
updated appendices, removed appendix of 
P-gp inhibitors 
Alignment with current guidance 
for LY3484356 
9.2 Sample Size 
Determination; 1.1 Synopsis 
Updated total sample size 
Updated to reflect changes to 
study design 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Clarified reporting of abnormal values; 
specified discrepancies between local and 
central laboratory results will not be 
considered protocol deviations  
Clarification 
10.9 Appendix 9: Provisions 
for Changes in Study Conduct 
During Exceptional 
Circumstances 
Added appendix 
Added to provide flexibility for 
study participants during 
exceptional circumstances 
Throughout the protocol 
Minor editorial and formatting changes 
Minor; therefore, not detailed 

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Protocol J2J-MC-JZLB(b) 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities .....................................................................................................12 
1.3.1. 
Sampling Schedule for Pharmacokinetics ......................................................................18 
2. 
Introduction ...................................................................................................................19 
2.1. 
Study Rationale ...............................................................................................................19 
2.2. 
Study Background...........................................................................................................19 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
3. 
Objectives and Endpoints ............................................................................................24 
4. 
Study Design ..................................................................................................................25 
4.1. 
Overall Design ................................................................................................................25 
4.1.1. 
Dose-Limiting Toxicity Definition .................................................................................25 
4.2. 
Scientific Rationale for Study Design ............................................................................26 
4.3. 
Justification for Dose ......................................................................................................27 
4.4. 
End of Study Definition ..................................................................................................27 
5. 
Study Population ...........................................................................................................28 
5.1. 
Inclusion Criteria ............................................................................................................28 
5.2. 
Exclusion Criteria ...........................................................................................................29 
5.3. 
Lifestyle Considerations .................................................................................................31 
5.4. 
Screen Failures ................................................................................................................31 
6. 
Study Intervention ........................................................................................................32 
6.1. 
Study Intervention(s) Administered................................................................................32 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................32 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................33 
6.4. 
Study Intervention Compliance ......................................................................................33 
6.5. 
Concomitant Therapy .....................................................................................................33 
6.5.1. 
Photosensitivity ...............................................................................................................34 
6.6. 
Dose Modification ..........................................................................................................34 
6.7. 
Intervention after the End of the Study ...........................................................................34 
6.7.1. 
Treatment after Study Completion..................................................................................34 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................35 
7.1. 
Discontinuation of Study Intervention ............................................................................35 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................35 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................36 
7.3. 
Lost to Follow up ............................................................................................................36 
8. 
Study Assessments and Procedures.............................................................................37 
8.1. 
Efficacy Assessments .....................................................................................................37 
8.2. 
Safety Assessments .........................................................................................................37 
8.2.1. 
Electrocardiograms .........................................................................................................37 
8.2.2. 
Clinical Safety Laboratory Assessments ........................................................................37 

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Protocol J2J-MC-JZLB(b) 
 
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8.2.3. 
Safety Surveillance .........................................................................................................39 
8.3. 
Adverse Events and Serious Adverse Events .................................................................39 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................39 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................40 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................40 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................40 
8.3.5. 
Pregnancy ........................................................................................................................41 
8.3.6. 
Events or Outcomes ........................................................................................................41 
8.3.7. 
Adverse Events of Special Interest .................................................................................41 
8.3.8. 
Complaint Handling ........................................................................................................41 
8.4. 
Treatment of Overdose ...................................................................................................41 
8.5. 
Pharmacokinetics ............................................................................................................41 
8.6. 
Pharmacodynamics .........................................................................................................41 
8.7. 
Genetics ..........................................................................................................................42 
8.7.1. 
Whole Blood Sample for Pharmacogenetic Research ....................................................42 
8.8. 
Biomarkers ......................................................................................................................42 
8.9. 
Medical Resource Utilization and Health Economics ....................................................44 
9. 
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Hypotheses .....................................................................................................45 
9.2. 
Sample Size Determination ............................................................................................45 
9.3. 
Populations for Analyses ................................................................................................45 
9.4. 
Statistical Analyses .........................................................................................................45 
9.4.1. 
General Considerations ...................................................................................................45 
9.4.2. 
Primary Objective Analysis ............................................................................................46 
9.4.3. 
Secondary Objectives Analyses ......................................................................................46 
9.4.4. 
Safety Analyses ...............................................................................................................46 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................46 
9.4.6. 
Other Analyses ................................................................................................................47 
9.5. 
Interim Analyses .............................................................................................................47 
10. 
Supporting Documentation and Operational Considerations ..................................48 
10.1. 
Appendix 1: Regulatory and Ethical Considerations ......................................................48 
10.1.1. Informed Consent Process ..............................................................................................48 
10.1.2. Data Protection................................................................................................................49 
10.1.3. Dissemination of Clinical Study Data.............................................................................49 
10.1.4. Data Quality Assurance ..................................................................................................49 
10.1.5. Source Documents ..........................................................................................................50 
10.1.6. Study and Site Start and Closure ....................................................................................51 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................52 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................54 
10.3.1. Definition of AE .............................................................................................................54 
10.3.2. Definition of SAE ...........................................................................................................55 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................56 
10.3.4. Reporting of SAEs ..........................................................................................................57 

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Protocol J2J-MC-JZLB(b) 
 
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10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................58 
10.5. 
Appendix 5:  Inducers and Strong Inhibitors of CYP3A ................................................60 
10.6. 
Appendix 6: CYP3A Sensitive Substrates ......................................................................62 
10.7. 
Appendix 7: Other CYP-sensitive Substrates .................................................................63 
10.8. 
Appendix 8: Examples of strong clinical inhibitors and inducers 
for UGT1A1 ....................................................................................................................64 
10.9. 
Appendix 9: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................65 
10.10. 
Appendix 10: Abbreviations ...........................................................................................68 
10.11. 
Appendix 10: Protocol Amendment History ..................................................................71 
11. 
References ......................................................................................................................74 
 

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Protocol J2J-MC-JZLB(b) 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  EMBER-2: A Phase 1, Open-Label, Preoperative Window Study evaluating the 
Biological Effects of LY3484356 in Post-menopausal Women with Stage I-III Estrogen 
Receptor-Positive, human epidermal growth factor receptor 2 negative (HER2-) Breast Cancer  
Short Title: EMBER-2: A Preoperative Window Study of LY3484356 in Stage I-III Estrogen 
Receptor-Positive Breast Cancer 
Rationale:  
Study J2J-MC-JZLB (JZLB) is designed to assess pharmacodynamics (PD), pharmacokinetic 
(PK), and biologic effects and safety of the selective estrogen receptor degrader (SERD), 
LY3484356, in patients with estrogen receptor-positive (ER+), HER2- early stage (Stage I to 
Stage III) breast cancer, in order to compare the biologic activity of different doses of the drug. 
Patients will be randomized to one of multiple dose levels of LY3484356 with study objectives 
compared across each treatment arm. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 Determine PD effect of each dose level of 
LY3484356 on ER expression, in patients 
with ER+ early stage breast cancer. 
 Change in ER expression (as measured by 
IHC and quantified by H-score) between 
pre- and on-treatment tumor samples, at 
each dose level of LY3484356
Secondary 
 
 Assess PD effect of each dose level of 
LY3484356 on Tumor cell proliferation. 
 Change in Ki-67 (as measured by IHC 
and expressed by % positive 
scoring) between pre- and on-treatment 
tumor samples, at each dose level of 
LY3484356 
 Assess PD effect of each dose level of 
LY3484356 on PR expression. 
 Change in PR expression (as measured by 
IHC and quantified by H score) between 
pre- and on-treatment tumor samples, at 
each dose level of LY3484356
 Evaluate safety and tolerability of each 
dose level of LY3484356. 
 Incidence of investigator assessed AEs 
per NCI CTCAE v5.0, at each dose level 
of LY3484356 
 Evaluate PK effect of each dose level of 
LY3484356. 
 Plasma concentrations of LY3484356, at 
each dose level of LY3484356

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Protocol J2J-MC-JZLB(b) 
 
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Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ER = estrogen 
receptor; IHC = immunohistochemistry; NCI = National Cancer Institute; PD = pharmacodynamics;  
PK = pharmacokinetics; PR = progesterone receptor. 
 
 
 
Exploratory 
 

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Protocol J2J-MC-JZLB(b) 
 
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Overall Design:  Study JZLB is a Phase 1 open-label, randomized pre-operative window study 
of LY3484356 in post-menopausal women with Stage I to Stage III ER+, HER2- breast cancer 
who are scheduled for surgery with curative intent. Patients will consent to provide tumor 
samples obtained at the time of diagnosis and at the time of scheduled surgery or repeat biopsy, 
for the purpose of biomarker analyses. Patients will then be randomized to either 400 or 800 mg 
LY3484356 or directly assigned to the 200 mg dose and receive treatment for approximately 15 
days, up to and including the day of scheduled surgery or repeat biopsy (if neoadjuvant therapy 
is subsequently planned). Tumor samples taken pre- and on-treatment with LY3484356, at the 
time of diagnosis and scheduled surgery/repeat biopsy, respectively, will then be evaluated for 
biologic effects, as outlined in the study objectives. 
Disclosure Statement: This is a biomarker study in patients with early stage ER+ breast cancer 
with multiple treatment arms of LY3484356. 
Number of Participants: 
Approximately 90 participants with early stage ER+ breast cancer will be enrolled in this study. 
Patients will be randomized to either 400 or 800 mg LY3484356 or directly assigned to the 200 
mg dose, with approximately 30 patients assigned to each dose level cohort. 
Intervention Groups and Duration: 
Patients enrolled in this Phase 1 open-label, preoperative study will receive 200 mg, 400 mg or 
800 mg of LY3484356 as shown in the table below. Patients will start LY3484356 on Day 1 and 
continue it daily, up to and including the day of surgery or repeat biopsy on Day 15 (with an 
allowable window of -2 to +7 days). This pre-surgery/biopsy dose of LY3484356 will be the last 
dose of LY3484356 treatment on this study.  
Study Drug 
Cohort 
Proposed Doses 
Dose Schedule, Route of 
Administration, Duration
LY3484356 
A  
400 mg 
QD, PO, administered for 15 daysa 
LY3484356 
B  
800 mg 
QD, PO, administered for 15 daysa 
LY3484356 
C  
200 mg 
QD, PO, administered for 15 daysa 
Abbreviations: PO = orally; QD = once daily. 
a Allowable window to facilitate scheduling of on-treatment surgery/biopsy: Day 15 (- 2 to + 7 days, [ie, a range of 
13 to 22 days of LY3484356 treatment will be permissible]). Patients should continue to dose study drug 
continuously through the day of surgery/biopsy, with the last dose of LY3484356 administered on the morning of 
surgery/biopsy.  
Data Monitoring Committee: No 
 
 

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Protocol J2J-MC-JZLB(b)
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1.2.
Schema
Abbreviations:  BC = breast cancer; ER+ = estrogen receptor positive; HER2- = human epidermal growth factor 
receptor 2 negative; R = randomize.
*
Baseline (pre-treatment) tumor tissue collection:
Adequate archival tissue, as defined in Section 8.8, from diagnostic biopsy is acceptable if collected within 
6 weeks prior to consent.
Fresh biopsy:
o
Required if archival tissue is unavailable/exhausted or was collected >6 weeks prior to consent or 
while the patient was taking Hormone Replacement Therapy
o
Optional for the purpose of Oncotype DX testing
See Section 8.8 for specifics regarding both baseline (pretreatment) and Day 15 (on-treatment) breast tumor tissue 
collections.
** Allowable treatment window to facilitate scheduling of on-treatment surgery/biopsy: 15 days (- 2 to + 7 days [ie,
a range of 13 to 22 days of LY3484356 treatment will be permissible.])

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Protocol J2J-MC-JZLB(b)
 
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1.3. 
Schedule of Activities 
Screening, On-Study, and Post-Treatment Schedule of Activities 
 
Screening 
On-Treatment 
Duration ~15 days  
(-2 to +7 days) 
Post-Treatment 
 
 
(Day 
Relative to 
Day 1) 
Start of 
Treatment 
Pre-
Surgery/Biopsy 
Visita 
Surgery or 
Biopsy 
Short-term 
follow-upb 
 
28 
Day 1 
Within 7 days 
prior to 
Surgery/Biopsy 
Day 15  
(-2 to +7 days) 
30 days post-
surgery/biopsy 
(±14 days)  
Visit 
Screening 
V1 
V2 
V3 
V4 
Instructions 
Procedure 
 
 
 
 
  
  
Informed consent 
X 
 
 
 
 
ICF must be signed before any protocol-
specific procedures are performed 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Medical history 
and description of 
primary breast 
cancer 
X 
 
 
 
 
 Complete assessment of prior medical, 
surgical and social history (such as 
tobacco and alcohol use). 
 From pathology report, record primary 
diagnosis, tumor grade, and any 
additional biomarker testing including 
receptor status (ER/PR/HER2) and Ki-
67 (if reported) from the invasive 
breast cancer. 
Clinical Tumor 
Measurement 
X 
 
 
 
 
Record estimated size of tumor and 
clinical stage (per AJCC) from pre-
operative imaging study (mammogram, 
MRI or equivalent). 
Vital signs 
X 
X 
X 
 
X 
Measure vital signs (temperature, blood 
pressure, pulse rate, and pulse oximetry) 
may be performed 3 days prior to V1.  
V1&V2 vital signs should be measured 
before first dose. At V1, vital signs 
measurement will be also collected 
3-4 hours post-dose.   

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Protocol J2J-MC-JZLB(b)
 
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Screening, On-Study, and Post-Treatment Schedule of Activities 
 
Screening 
On-Treatment 
Duration ~15 days  
(-2 to +7 days) 
Post-Treatment 
 
 
(Day 
Relative to 
Day 1) 
Start of 
Treatment 
Pre-
Surgery/Biopsy 
Visita 
Surgery or 
Biopsy 
Short-term 
follow-upb 
 
28 
Day 1 
Within 7 days 
prior to 
Surgery/Biopsy 
Day 15  
(-2 to +7 days) 
30 days post-
surgery/biopsy 
(±14 days)  
Visit 
Screening 
V1 
V2 
V3 
V4 
Instructions 
ECOG 
performance status 
X 
X 
X 
 
X 
During study treatment, perform during 
clinic visits 
Physical 
examination 
X 
X 
 
 
X 
Collect height and weight at baseline; 
weight only thereafter 
ECG 
X 
X 
X 
 
 
Single local ECG: V1&V2 ECG should 
be collected before first dose. At V1, an 
ECG will also be collected 3-4 hours 
post-dose.  For all visit ECGs, participant 
should be recumbent or semi-recumbent 
for 5 to 10 minutes before collection and 
during study. 
Hematology 
X 
X 
X 
 
X 
See Appendix 2 (Section 10.2). May be 
performed 3 days prior to V1 
Clinical chemistry 
X 
X 
X 
 
X 
See Appendix 2 ( Section 10.2). May be 
performed 3 days prior to V1 
Pharmacokinetics 
 
X 
X 
 
 
See Section 1.3.1 for time points. 
Whole blood 
(PGx) 
 
X 
 
 
 
Collect on Day 1/V1 or may be 
performed 3 days prior to V1 
Biomarker plasma  
 
X (pre-dose) 
X 
 
 
Plasma to be collected on V1 pre-dose or 
may be performed 3 days prior to V1.  
The V2 plasma can be collected anytime 
during the clinic visit  
Follicle 
Stimulating 
Hormone (FSH) & 
estradiol 
X 
 
 
 
 
Only for patients who are <60 years of 
age 

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Protocol J2J-MC-JZLB(b)
 
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Screening, On-Study, and Post-Treatment Schedule of Activities 
 
Screening 
On-Treatment 
Duration ~15 days  
(-2 to +7 days) 
Post-Treatment 
 
 
(Day 
Relative to 
Day 1) 
Start of 
Treatment 
Pre-
Surgery/Biopsy 
Visita 
Surgery or 
Biopsy 
Short-term 
follow-upb 
 
28 
Day 1 
Within 7 days 
prior to 
Surgery/Biopsy 
Day 15  
(-2 to +7 days) 
30 days post-
surgery/biopsy 
(±14 days)  
Visit 
Screening 
V1 
V2 
V3 
V4 
Instructions 
Hepatitis B and C  
X 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
See Appendix 2 (Section 10.2). Perform 
at baseline and as clinically indicated 
Urinalysis 
X 
 
X 
 
 
See Appendix 2 (Section 10.2). Perform 
as clinically indicated. 

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Protocol J2J-MC-JZLB(b)
 
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Screening, On-Study, and Post-Treatment Schedule of Activities 
 
Screening 
On-Treatment 
Duration ~15 days  
(-2 to +7 days) 
Post-Treatment 
 
 
(Day 
Relative to 
Day 1) 
Start of 
Treatment 
Pre-
Surgery/Biopsy 
Visita 
Surgery or 
Biopsy 
Short-term 
follow-upb 
 
28 
Day 1 
Within 7 days 
prior to 
Surgery/Biopsy 
Day 15  
(-2 to +7 days) 
30 days post-
surgery/biopsy 
(±14 days)  
Visit 
Screening 
V1 
V2 
V3 
V4 
Instructions 
Breast tumor tissue 
X 
 
 
X 
 
At baseline (pre-treatment): 
 Adequate archival tissue, from the 
diagnostic biopsy is acceptable if 
collected within 6 weeks. 
 Fresh baseline biopsy: 
o 
Required: If archival tissue is 
unavailable/exhausted or was 
collected >6 weeks prior to 
consent or while the patient was 
taking Hormone Replacement 
Therapy 
o 
Optional: For the purpose of 
Oncotype DX testing 
See Section 8.8 for specifics regarding 
both baseline (pre-treatment) and Day 15 
(on-treatment) breast tumor tissue 
collections. 
Surgical Pathology 
Report 
 
 
 
 
X 
Record size of lesion (L×W×D), primary 
diagnosis, pathological stage, tumor 
grade, complete histologic description, 
and any additional biomarker testing 
including receptor status (ER/PR/HER2) 
and Ki-67 (if reported) from the invasive 
breast cancer. 

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Screening, On-Study, and Post-Treatment Schedule of Activities 
 
Screening 
On-Treatment 
Duration ~15 days  
(-2 to +7 days) 
Post-Treatment 
 
 
(Day 
Relative to 
Day 1) 
Start of 
Treatment 
Pre-
Surgery/Biopsy 
Visita 
Surgery or 
Biopsy 
Short-term 
follow-upb 
 
28 
Day 1 
Within 7 days 
prior to 
Surgery/Biopsy 
Day 15  
(-2 to +7 days) 
30 days post-
surgery/biopsy 
(±14 days)  
Visit 
Screening 
V1 
V2 
V3 
V4 
Instructions 
This is only required for patients who 
provide surgical resection for on-
treatment tissue collection. 
Administer 
LY3484356 
 
See Instructions 
 
Administer according to Section 6.1. 
Patient diary 
 
See Instructions 
 
Provide patient diary Day 1. Completed 
daily by patient until day of surgery. 
Review at each study visit.  Collection of 
diary and reconciliation of study drug can 
occur at V3 or V4. 
Concomitant 
medication 
X 
See Instructions 
X 
 At baseline, record prior and 
concurrent medications. 
 Record all premedication, supportive 
care, and concomitant medication 
continuously at every visit and 
throughout the study. 
AE collection 
 
See Instructions 
X 
Collect continuously at every visit and 
throughout the study using CTCAE 
Version 5.0 
Abbreviations:  AE = adverse event; AJCC = American Joint Committee on Cancer; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; ICF = informed consent form; L×W×D = length times width times depth; PGx = 
pharmacogenomics; PK = pharmacokinetic; PR = progesterone receptor; V = visit. 

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Protocol J2J-MC-JZLB(b)
 
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a Pre-op (V2) study assessments must occur within 7 days of the scheduled surgical/biopsy date (V3). These assessments may be coordinated with routine 
preoperative assessments or may occur, if necessary, on the morning of surgery/biopsy (V3), provided all V2 assessments (including 3 to 4 hour post-dose PK 
draw) are performed and the results of the clinical investigations are reviewed prior to surgery/biopsy. 
b Short-term follow- up visit must occur 30 days ±14 days after surgery/biopsy or after resolution of all treatment related adverse effects whichever comes later.

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Protocol J2J-MC-JZLB(b) 
 
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1.3.1. 
Sampling Schedule for Pharmacokinetics 
Differences from the time specified in the protocol are not considered protocol deviations if 
samples are collected, and accurate dates and times are recorded in a timely manner on the 
appropriate forms. 
Visit 
Sample time 
Relative to Dose 
LY3484356 PK Sampling 
V1 & V2a 
Predoseb 
Plasma PK Sample 
3 to 4 hours post-doseb 
Plasma PK Sample 
 +/- V3 
Post-dose 
Tumor PK Samplec 
Abbreviations:  PK = pharmacokinetic; V = visit. 
a Pre-op (V2) study assessments may occur, if necessary, on the morning of surgery/biopsy (V3).  
b Pre-dose and 3 to 4 hours post-dose PK sampling to be drawn on the same day. 
c Optional but strongly encouraged. See Section 8.8 for specifics regarding the V3 (on-treatment) tumor tissue 
collections. 
 

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Protocol J2J-MC-JZLB(b) 
 
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2. 
Introduction 
2.1. 
Study Rationale 
Selective estrogen receptor degraders are one of the treatment options for ER+/human epidermal 
growth factor receptor 2 negative (HER2-) breast cancer patients. In a recent large retrospective 
clinicopathologic study, Li and colleagues reported that 70.4% of breast cancers are ER+ (Li et 
al. 2019). Fulvestrant is currently the only regulatory agency-approved SERD for the treatment 
of ER+ metastatic breast cancer (mBC) (Nardone et al. 2019; Soleja et a. 2019). Its efficacy is 
highly dose-dependent, where increasing the administered dose has led to improved survival 
(Robertson et al. 2004; Robertson and Harrison 2004; Di Leo et al. 2014). However, even though 
doses higher than 500 mg per month may lead to better ER degradation, the intramuscular (IM) 
administration route limits the amount of fulvestrant that can be given to patients (Nardone et al. 
2019). In addition, several studies have shown that with the current maximum feasible dose, 
fulvestrant treatment is not able to completely degrade ER in patients and can be associated with 
early progression (van Kruchten et al. 2015). Thus, there is unmet medical need to develop oral 
SERDs with higher bioavailability, greater ER targeting, and degradation capabilities (Nardone 
et al. 2019). 
Study J2J-MC-JZLB (JZLB) is a short-term, preoperative, randomized Phase 1 study comparing 
the biologic activity of different doses of the SERD, LY3484356. The purpose of this study is to 
assess PD, PK, and biologic effects and safety of LY3484356, in patients with ER+ early stage 
(Stage I to Stage III) breast cancer. Patients will be randomized to either 400 mg or 800 mg dose 
levels of LY3484356 with study objectives compared across the treatment arms. No 
randomization will occur for the 200 mg level as this dose level will open after the 400 and 800 
mg dose levels are closed. 
2.2. 
Study 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 breast cancer considers multiple clinical factors such as ER/HER2 status, age, 
comorbidities, and patient preference. More specifically, treatment options for women with 
breast cancer are largely determined by tumor ER and HER2 status (NCCN 2018; Waks and 
Winer 2019).   
Over two-thirds of breast cancers express ER, which is a key driver of breast cancer initiation 
and progression. Endocrine therapies aim to reduce ER activity and include strategies such as 
direct ER modulation (tamoxifen), systemic prevention of the conversion of androgens to 
estrogens using aromatase inhibitors (AIs; letrozole, anastrozole, and exemestane), and SERDs 
(fulvestrant) that block and degrade the ER.   
Currently, fulvestrant is the only regulatory agency-approved SERD (Soleja et al. 2019) for the 
treatment of ER+ mBC in patients who are endocrine therapy naïve or after progression on 
tamoxifen or aromatase inhibitors. However, it has several limitations. Due to its insoluble nature 
with poor oral bioavailability and a short intravenous half-life, fulvestrant needs to be given IM 
and is highly dose-dependent (Robertson and Harrison 2004; Robertson et al. 2004). An 

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Protocol J2J-MC-JZLB(b) 
 
20 
improved response and overall survival were observed in patients receiving a dose of 500 mg IM 
compared to 250 mg IM.  
Developing a SERD with better oral bioavailability that could overcome the dose limitation of 
fulvestrant is highly desired. However, challenges with such development have complicated the 
path. Despite the disclosure of several agents in the past (Lai et al. 2015; Weir et al. 2016; Guo et 
al. 2018; Hamilton et al. 2018; Tria et al. 2018), few have progressed into clinical testing and 
none have demonstrated activity in large randomized studies to date. Several of these challenges 
were associated with lack of competitive bioavailability to guide further development. However, 
recently, several small studies with heterogeneous group (variable prior therapies and presence 
or absence of ESR1 mutations) of patients with ER+/HER2- mBC reported promising activity 
(Bardia et al. 2017, 2019). 
LY3484356 is an oral SERD. It is a potent degrader and selective pure antagonist of wild type 
E
cancer cells. LY3484356 selectively inhibits the proliferation of ER+ breast cancer cell lines and 
has equivalent potency in both wild type and mutant ESR1 breast cancer cell lines. In in vivo 
target inhibition studies, LY3484356 has shown sustained and prolonged inhibition of gene 
PD 
biomarker in ESR1 wild type xenograft or ESR1 (Y537S) mutant patient-derived xenograft 
(PDX) tumor models in mice. The exposure in the tumors is 12 to 175× higher than plasma in 
mice. In in vivo efficacy studies, LY3484356 has demonstrated robust single-agent activity and 
tumor regressions in ESR1-wild type (MCF7, T47D, ZR-75-1, HCC1428) xenograft models and 
ESR1-mutant (Y537S) patient-derived xenograft models. LY3484356 is also brain penetrant and 
inhibits the growth of MCF7-fLuc breast cancer cells implanted orthotopically in the mouse 
brain.  
LY3484356 is currently under evaluation in the EMBER trial (Phase 1a/1b Study of LY3484356 
Administered as Monotherapy and in Combination with Anticancer Therapies for Patients with 
ER+ Locally Advanced or Metastatic Breast Cancer and Other Select Non-Breast Cancers). 
Phase 1a is a dose escalation of LY3484356 to determine the recommended Phase 2 dose 
(RP2D); followed by Phase 1b, randomized dose-expansion of LY3484356 as monotherapy and 
in combination with other anticancer therapies. Based on the totality of safety, PK and efficacy 
data from the EMBER study, the RP2D of LY3484356 was determined to be 400 mg once daily 
(QD). 
 134 patients received LY3484356 monotherapy in the EMBER (J2J-
MC-JZLA) trial. Patients have received LY3484356 as monotherapy at each of the following 
daily doses: 
 
LY3484356 was well tolerated across dose levels in dose escalation, with no dose-limiting 
toxicities reported during the dose escalation and a maximum tolerated dose was not reached. 
The most frequently reported treatment-emergent adverse events (TEAEs) at the RP2D (
 
n=64) were nausea (
), fatigue (
), and diarrhea (
). Most TEAEs 
were Grade 1 or 2 in severity.  Treatment-related adverse events (TRAEs) at the RP2D were 
observed in 
 patients, most frequently nausea (
), diarrhea (
), 
and fatigue (
. Two (
) patients treated at the RP2D required a dose reduction to 

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21 
 due to a TRAE (
). No dose reductions occurred at 
 dose level. 
 45 female patients were enrolled in the EMBER-2 trial (J2J-MC-
JZLB), and 2 dose levels (
) were evaluated in patients with early-stage breast 
cancer with a treatment period of 15 to 22 days. TEAEs were observed in 
 patients. 
Most TEAEs were Grade 1 or 2, with the most common TEAEs observed at each dose level
 
Additional details can be found in the LY3484356 IB. 
Window of opportunity trial designs in early stage breast cancer have been utilized to permit the 
evaluation of in vivo downstream effects of treatment with a specific compound with 
corresponding samples that otherwise might be difficult to obtain. Ultimately these presurgical 
studies provide insights into drug-mechanism of action, biologic effects, and dose-PD 
relationships in order to better inform the development of that drug in the clinic (Arnedos et al. 
2019).   
Measurement of ER modulation through an immunohistochemistry (IHC) assessment of change 
in percentage and intensity of ER staining by a H-score is clinically validated (Cohen et al. 
2012). Indeed, the degree of target (ER) modulation of fulvestrant was successfully captured 
utilizing IHC-based assessments of change in both ER and progesterone receptor (PR) 
expression following treatments ranging from 2 to 6 weeks (Kuter et al. 2012; Robertson et al. 
2013; Agarwal et al. 2016). 
Change in Ki-67 expression following administration of standard or investigational preoperative 
endocrine therapy is also a well-established PD marker and study endpoint in clinical studies 
(Dowsett et al. 2011). The tumor cell proliferation protein, Ki-67, is validated as a prognostic 
and predictive biomarker in ER+ breast cancer (Stuart Harris et al. 2008; Yerushalmi et al. 
2010). Indeed, several trials have shown that the degree of suppression of Ki-67 correlates with 
clinical outcome, and that this change can be reliably assessed as early as 2 weeks after therapy 
initiation (Dowsett et al. 2011). Notably, short-term presurgical treatment with fulvestrant has 
also demonstrated measurable changes in Ki-67 (Agarwal et al. 2016; Kuter et al. 2012; 
Robertson et al. 2013). 
Given the mechanism of action of LY3484356 as a degrader and pure antagonist of ER, an 
assessment of change in ER expression in tumor in response to LY3484356 treatment provides 
direct measurement of the PD modulation of the intended drug target. 
Therefore, in this presurgical, window of opportunity study, the biological effects of 3 different 
doses of LY3484356 will be evaluated by measuring tumor changes in ER (primary endpoint), 
PR (secondary endpoint), and Ki-67 (secondary endpoint) in response to short term treatment 
with LY3484356. Additional parameters will include standard safety assessments and PK 
measurements along with exploratory analyses as detailed in Section 3. 

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22 
2.3. 
Benefit/Risk Assessment 
Selective estrogen receptor degraders as a class of drugs are promising given the demonstrated 
clinical activity and benefit of fulvestrant, currently the only approved SERD, in multiple large 
randomized studies. However, a need still exists to develop oral SERDs, such as LY3484356, 
with potentially improved bioavailability and enhanced biological activity.  
The clinical safety experience of LY3484356 in advanced breast and endometrial cancer patients 
from the EMBER study is described in Section 2.2 with additional details described in the IB. 
LY3484356 monotherapy was well tolerated with the majority of observed AEs being low grade, 
reversible, monitorable and manageable, and the safety profile is consistent with that expected 
based on LY3484356 mechanism of action and the patient population being treated.  
Nonclinical LY3484356 toxicology studies demonstrate an acceptable safety profile, with 
toxicities that are generally monitorable and/or reversible.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Non-reproductive in vivo toxicology findings demonstrated partial to full reversibility after a 2-
week recovery period (evaluated in rats). Female reproductive tract findings have similarly been 
observed with other approved agents, known to antagonize or degrade the ER, including 
tamoxifen and fulvestrant. To mitigate the risk of pharmacologically mediated reproductive and 
developmental toxicity, women of childbearing potential are not eligible for this study. 
Potential toxicities will be regularly monitored during this study through ongoing assessment of 
patient symptoms, hematological and chemistry levels, and electrocardiogram (ECG) readings, 
as detailed in Section 8.2. Patients will also be advised to use sunscreen if out in direct sunlight, 
to reduce the possibility of phototoxicity. 
In this study, LY3484356 will be administered for 15 days (-2 days to +7 days) to patients with 
early stage (I to III) ER+ breast cancer, awaiting a curative intent resection. This presurgical 
treatment course of LY3484356 is not expected to result in therapeutic benefit. However, given 
the short duration of treatment on this study and the lack of the additional mandatory research 
biopsies, for the majority of enrolled patients, the potential areas of concern for LY3484356 are 

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23 
considered acceptable. More detailed information about the known and expected benefits and 
risks, SAEs, and reasonably anticipated AEs of LY3484356 can be found in the IB. 

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24 
3. 
Objectives and Endpoints 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ER = estrogen 
receptor; IHC = immunohistochemistry; NCI = National Cancer Institute; PD = pharmacodynamics; PK = 
pharmacokinetic; PR = progesterone receptor. 
Objectives 
Endpoints 
Primary 
 
 Determine PD effect of each dose level of 
LY3484356 on ER expression, in patients 
with ER+ early stage breast cancer. 
 Change in ER expression (as measured by 
IHC and quantified by H-score) between 
pre- and on-treatment tumor samples, at 
each dose level of LY3484356
Secondary 
 
 Assess PD effect of each dose level of 
LY3484356 on Tumor cell proliferation. 
 Change in Ki-67 (as measured by IHC 
and expressed by % positive 
scoring) between pre- and on-treatment 
tumor samples, at each dose level of 
LY3484356 
 Assess PD effect of each dose level of 
LY3484356 on PR expression. 
 Change in PR expression (as measured by 
IHC and quantified by H score) between 
pre- and on-treatment tumor samples, at 
each dose level of LY3484356
 Evaluate safety and tolerability of each 
dose level of LY3484356. 
 Incidence of investigator assessed AEs) 
per NCI CTCAE v5.0, at each dose level 
of LY3484356 
 Evaluate PK effect of each dose level of 
LY3484356. 
 Plasma concentrations of LY3484356, at 
each dose level of LY3484356
Exploratory 
 

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25 
4. 
Study Design 
4.1. 
Overall Design 
Study EMBER-2 is a Phase 1, open-label, randomized, pre-operative window study of 
LY3484356 in post-menopausal women with Stage I to III ER+, HER2- breast cancer who are 
scheduled for surgery with curative intent. Patients will consent to provide tumor samples 
obtained at the time of diagnosis and at the time of scheduled surgery or repeat biopsy, for the 
purpose of biomarker analyses. Patients will then be randomized to either 400 or 800 mg 
LY3484356 or directly assigned to the 200 mg dose (see table in Section 6.1) and receive 
LY3484356 for 15 days, up to and including the day of scheduled surgery or repeat biopsy (if 
neoadjuvant therapy is subsequently planned). Tumor samples taken pre- and on-treatment with 
LY3484356, at the time of diagnosis and scheduled surgery/repeat biopsy, respectively, will then 
be evaluated for biologic effects, as outlined in the study objectives. (See Section 8.8 for 
specifics regarding tumor tissue collections). 
For the 400 and 800 mg doses, randomization will be stratified by tumor histology (infiltrating 
ductal carcinoma [IDC] versus infiltrating lobular carcinoma [ILC]; as locally determined from 
the diagnostic tumor biopsy). No stratification will occur for the 200 mg dose level. 
A treatment window of 15 days (-2 to +7 days [ie, a range of 13 to 22 days of LY3484356 
treatment] will be permissible to facilitate flexibility in scheduling of the on-treatment 
surgery/biopsy. The last dose of LY3484356 will be taken on the morning of surgery/biopsy.  
The primary endpoint for this study is to determine change in ER expression (between pre- and 
on-treatment tumor samples) following LY3484356 treatment at each dose level. These changes 
will be measured utilizing an immunohistochemistry (IHC) H-score (0 to 300) that captures the 
change in the number of positive cells and intensity of ER staining. 
Secondary endpoints include assessment of change in PR expression by IHC H-score (0 to 300); 
change in the percentage of Ki-67 staining positive tumor cells (Ki-67 index); and safety and 
tolerability and PK evaluation of LY3484356.  
Taken together, these data will be used to describe the comparative biologic effects of each dose 
level of LY3484356 on early stage, treatment naïve ER+ breast tumors.  
In addition, and in patients with sufficiently large tumors to permit additional sample provision 
for exploratory endpoint analyses, LY3484356 tumor biodistribution and further LY3484356 
biologic effects (on ER and/or other cancer related biomarkers at both doses) will be evaluated at 
each dose level. 
In the absence of toxicities, patients will remain on study treatment for a minimum of 13 days 
and until the day of surgery. 
Please refer to Section 1.2 for a study schema. 
4.1.1. 
Dose-Limiting Toxicity Definition 
A DLT is defined as an AE that fulfills any 1 of the following DLT criteria from the Phase 1a/1b 
EMBER study of LY3484356 using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0. 

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26 
 
-hematological toxicity.  Exceptions will be made for:  
o Nausea, vomiting, diarrhea, or constipation that lasts for <72 hours and can be 
controlled with treatment and does not require hospitalization and 
o Grade 3 rash that resolves or improves to a Grade 2 or less within 7 days and 
remains tolerable may not be considered a DLT if agreed by the study investigator 
and Lilly clinical research physician (CRP)/clinical research scientist (CRS).   
 Grade 4 neutropenia, anemia, or leukopenia of >7 days duration; anemia that requires 
packed red blood cell transfusion; or neutropenia that requires granulocyte-colony 
stimulating factor. 
 Grade 4 thrombocytopenia of any duration or thrombocytopenia that requires platelet 
transfusion. 
 Grade 3 thrombocytopenia with bleeding.  
 Any febrile neutropenia.  
 Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose-limiting (eg, any toxicity that is possibly related to the 
study medication that requires the discontinuation of LY3484356 during the 
approximately 15-day [+7/-2] treatment period).  
 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
the upper limit 
of normal (ULN), irrespective of baseline values 
 
values) 
 
Due to the short-term (15 days [+7/-2]) window of treatment with LY3484356, no dose 
modifications will be undertaken. If patients experience a DLT or AE as defined in Appendix 3 
(Section 10.3), that is deemed dose limiting (eg, any significant toxicity possibly related to the 
study medication), per medical guidance and the opinion of the primary investigator, patients 
will discontinue LY3484356.  
Ongoing and overall safety review will be performed by the study sponsor and the investigators. 
The rates of AEs and DLTs will be monitored in an ongoing basis as each patient enrolls. If at 
any time the cumulative incidence of either DLTs or AEs that result in postponement of the 
, the Bayesian posterior Pr (toxicity rate >20%)), 
patient accrual will be temporarily halted while a safety data review is triggered and a re-
evaluation of dose may occur. Specifically, intermediate or lower doses may be explored in 
subsequently enrolled patients, that ensure patient safety while maintaining adequate target 
engagement. 
4.2. 
Scientific Rationale for Study Design 
The overall rationale for the study design is described in Section 2.1 (Study Rationale), 
Section 2.2 (Background), and Section 9 (Statistical Considerations). Dose selection and 
justification details can be found in Section 4.3 (Justification for Dose). 

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27 
4.3. 
Justification for Dose 
The clinical doses used in this study will be 200 mg, 400 mg, or 800 mg given orally once daily 
(see table in Section 6.1). 
As outlined in Section 2.2 (Study Background), LY3484356 is under evaluation in the EMBER 
trial (Phase 1a/1b Study of LY3484356 Administered as Monotherapy and in Combination with 
Anticancer Therapies for Patients with ER+ Locally Advanced or Metastatic Breast Cancer and 
Other Select Non-Breast Cancers). Dosing, safety, PK, and efficacy data generated from the 
ongoing EMBER study forms the basis and justification for the doses used in this window of 
opportunity trial. Specifically, the clinical, PK, and pre-clinical PK observations described in 
Section 2.2 provide justification for the dose selection of 200 mg, 400 mg, and 800 mg. 
The RP2D of LY3484356 has been determined as 400 mg. This pre-surgical pharmacodynamic 
trial permits evaluation of the biologic activity of LY3484356 at its RP2D (400 mg) and at the 
dose levels above (800 mg) and below (200 mg) the RP2D. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last follow-up visit of the last global participant 
in the study as shown in the Schedule of Activities (SoA) (Section 1.3). Biomarker data will be 
evaluated on an interval batched basis. Upon evidence of evaluable primary and secondary 
endpoint data for 20 patients in each cohort, the study sponsor will have the option to end the 
trial. 

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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Age 
(1) 
Participant must be at least 18 years of age. 
Type of Participant and Disease Characteristics 
(2) 
Histologically confirmed invasive breast carcinoma with the following characteristics: 
a) Clinical Stage I to III according to the American Joint Committee on Cancer (AJCC) 
Staging Manual, 8th Edition (Amin et al. 2017). 
b) 
 
c) ER+ (>50% of tumor cell nuclei from the invasive component, that is 
immunoreactive by immunohistochemistry or Allred Score >5 [Harvey et al.1999]), 
and HER2- (according to American Society of Clinical Oncology (ASCO)/Clinical 
Practice Guideline (CAP) guidelines for HER2 testing [Wolff et al. 2018]), per local 
laboratory tumor testing.   
d) Deemed appropriate for curative surgical resection.  
e) Multifocal disease is allowed if confined to 1 breast, and if each tumor is ER+, 
HER2- 
 
(3) 
Participant may be scheduled for definitive neoadjuvant therapy after participating in this 
study but must be willing to undergo a biopsy for Day 15 of study tissue collection (as 
specified in Section 1.3 and Section 8.8), before commencing subsequent neoadjuvant 
therapy. 
(4) 
Participant must be willing and able to provide pre- and on-treatment tumor samples, as 
specified in Section 1.3 and Section 8.8.  
(5) 
Have a performance status of 0 or 1 on the ECOG scale (Oken et al. 1982). 
(6) 
Have adequate organ function, as defined in the table below: 
System 
Laboratory Value 
Hematologic 
ANC 
1.5×109/L
Platelets 
100×109/L
Hemoglobin 
8 g/dL
Abbreviations:  ANC = absolute neutrophil count; G-CSF = granulocyte colony-
stimulating factor. 
Note:  
erythropoietin or G-CSF therapy to meet enrollment criteria are not allowed in the 
14 days preceding the first dose of study drug.
 
 

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29 
 
Hepatic 
Total bilirubin 
syndrome with a total bilirubin 
bilirubin within normal limits are 
permitted.
Serum albumin 
g/dL 
ALT and AST 
2.5×ULN 
Renal 
Serum creatinine OR
<1.5×ULN OR
Measured creatinine clearance OR 
50 mL/min/1.73 m2
Calculated creatinine clearance
 
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ULN = upper limit of normal. 
 
(7) 
Participants must be able to swallow capsules. 
(8) 
Are able and willing to be available for the duration of the study and are willing to follow 
study procedures. 
Sex 
(9) 
Participants must be female. 
(10) 
Postmenopausal women due to the natural cessation of ovarian function, surgery, or 
therapeutic radiation, defined by at least 1 of the following criteria: 
a) Prior bilateral oophorectomy, or 
b) 
 
c) Age <60 years, amenorrheic for at least 12 months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression), and follicle-stimulating hormone and 
estradiol levels in the postmenopausal range. 
Informed Consent 
(11) 
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
(12) 
Bilateral invasive breast cancer. 
(27) 
Occult primary breast cancer. 
(13) 
Metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is 
permitted). 

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30 
(14) 
Inflammatory breast cancer, defined as the presence of erythema or induration involving 
one third or more of the breast (Hortobagyi et al. 2017). 
(15) 
Plan to receive concurrent neoadjuvant therapy with any other nonprotocol anti-cancer 
therapy. 
(16) 
Prior therapy (of any kind) for an invasive or non-invasive breast cancer (ductal 
carcinoma in situ or lobular carcinoma in situ).  
(17) 
Prior radiotherapy to the ipsilateral chest wall for any malignancy. 
(18) 
Prior anti-estrogen therapy with raloxifene, tamoxifen, aromatase inhibitor, or other 
selective estrogen receptor modulator, either for osteoporosis or prevention of breast 
cancer.   
(19) 
Prior hormone-replacement therapy within 4 weeks of the start of study treatment. 
(20) 
Have a serious concomitant systemic disorder (eg, active infection or a gastrointestinal 
disorder causing clinically significant symptoms such as nausea, vomiting, diarrhea, or 
profound immune suppression) that, in the opinion of the investigator, would 
following: 
a) Have uncontrolled human immunodeficiency virus (HIV) 1/2 infection. Controlled 
HIV infection is defined as: 
(i) Compliance with highly active anti-retroviral therapy 
(ii) No evidence of autoimmune deficiency syndrome-defining opportunistic 
infections within the last 2 years 
(iii) CD4 count >350 cells/µL, and 
(iv) Required anti-retroviral therapy is not prohibited based on predicted dose-
dose interactions with investigational medical product (see Section 6.5). 
b) Active hepatitis B or C virus infection (screening required). 
c) Severe renal impairment, interstitial lung disease (ILD), severe dyspnea at rest or 
requiring oxygen therapy, history of major surgical resection involving the stomach 
or small bowel, or pre
chronic condition resulting in clinically significant diarrhea. 
(21) 
Have a serious cardiac condition, such as  
a) Congestive heart failure 
b) New York Heart Association Class III/IV heart disease 
c) Unstable angina pectoris 
d) Myocardial infarction within the last 3 months 
e) Valvulopathy that is severe or moderate, or deemed clinically significant 
f) Arrhythmias that are symptomatic or require treatment (not including patients with 
rate-controlled atrial fibrillation) 
g) Cerebrovascular accident (stroke) within the last 3 months 
h) 
 

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31 
i) Baseline bradycardia with resting heart rate <60 beats per minute  
(22) 
Have had major surgery within 28 days prior to randomization to allow for post-operative 
healing of the surgical wound and site(s). 
(23) 
Criterion (23) has been removed. 
(24) 
Known allergic reaction against any of the components of the study treatment. 
(28) 
Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ 
of the cervix), unless in complete remission with no therapy for a minimum of 3 years. 
 
Prior/Concurrent Clinical Study Experience 
(25) 
Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
(26) 
Have participated, within the last 30 days (3 months for studies conducted in the United 
Kingdom), in a clinical study involving an investigational product.  If the previous 
investigational product has a known long half-life, 5 half-lives or 30 days (3 months for 
studies conducted in the UK), whichever is longer, should have passed. 
5.3. 
Lifestyle Considerations 
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products and avoid medications considered to be strong inducers and inhibitors of cytochrome 
P450 3A4 (CYP3A4), P-glycoprotein 1 (P-gp), and uridine 5'-diphospho-glucuronosyltransferase 
1A1 (UGT1A1) (see examples in Appendix 6, Section 10.5) while on study and 2 weeks prior to 
the start of LY3484356, which is an in vitro substrate of CYP3A4, P-gp and UGT1A1. 
Caution should be used with concomitant medications that are sensitive substrates of CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or substrates of these CYPs with a 
narrow therapeutic index. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment and 
safety follow up should be performed as outlined in Section 1.3 (Schedule of Activities), 
Section 8.2 (Safety Assessments) and Section 8.3 (Adverse Events and Serious Adverse Events) 
of the protocol. 

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32 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
The investigator or his/her designee is responsible for the following: 
 
treatment to the patient/study site personnel/legal representative 
 verifying that instructions are followed properly 
 maintaining accurate records of study treatment dispensing and collection 
 returning all unused medication at the end of the study to Lilly, or its designee, unless 
Lilly and sites have agreed all unused medication is to be destroyed by the site, as 
allowed by local law 
 Patients enrolled in this Phase 1 open-label, randomized, pre-operative study will receive 
LY3484356 at one of the dose levels, shown in the table below. 
 Patients will start LY3484356 on Day 1 and continue it daily, up to and including the day 
of surgery or repeat biopsy on Day 15 (-2 to +7 days). 
 Doses will be administered at approximately the same times on each day. Patients should 
not consume any food at least 1 hour before and at least 2 hours after administration of 
LY3484356. 
 
Study Drug 
Cohort 
 
Proposed 
Doses 
Dose Schedule, Route of Administration, 
Duration 
LY3484356 
A 
400 mg 
QD, PO, administered for 15 daysa 
LY3484356 
B 
800 mg 
QD, PO, administered for 15 daysa 
LY3484356 
C 
200 mg 
QD, PO, administered for 15 daysa 
Abbreviations:  PO = orally; QD = once daily.  
a Allowable window to facilitate scheduling of on-treatment surgery/biopsy: Day 15 (- 2 to + 7 days, [a range of 13 
to 22 days of LY3484356 treatment will be permissible]). Patients should continue to dose study drug 
continuously through the day of surgery/biopsy, with the last dose of LY3484356 administered on the morning of 
surgery/biopsy.  
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature 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 and only 
authorized site staff may supply or administer study intervention. All study intervention 

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must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
5. Investigators should consult the site training, Pharmacy Manual, or label for specific 
study drug information. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study that will implement a 1:1 randomization design for the 400 mg and 
800 mg to mitigate the selection bias in allocating patients to each dose level of LY3484356. For 
the 200 mg cohort, no randomization will occur, as this cohort will open once the 400 mg and 
800 mg cohorts are closed. 
Randomization will be stratified by tumor histology (IDC versus ILC versus Other; as locally 
determined from the diagnostic tumor biopsy) to ensure appropriate distribution of these 
histologies across each dose level cohort.  
6.4. 
Study Intervention Compliance 
Patient compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning and by counting returned tablets and/or capsules. Patients must 
receive 80% of assigned doses to be considered compliant with study. Deviation(s) from the 
prescribed dosage regimen should be recorded in the electronic case report form (eCRF). 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates 
The Lilly CRP/CRS should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The information in this section is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
CYP Substrates 
In vitro assays indicated that LY3484356 is a time-dependent inhibitor of CYP2C8, CYP2C9, 
CYP2C19, and CYP3A. LY3484356 is also predicted to be a clinically relevant reversible 
inhibitor of CYP2B6, CYP2C19, CYP2C8, CYP2C9, and CYP2D6. As a result, caution should 
be used with concomitant medications that are sensitive substrates of CYP2B6, CYP2C8, 

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CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or substrates of these CYPs with a narrow 
therapeutic index. A week of washout time following LY3484356 treatment is advised before 
starting sensitive substrates of CYP2C8, CYP2C9, CYP2C19, and CYP3A (Section 10.5 
Appendix 5, Section 10.6 Appendix 6, and Section 10.7 Appendix 7). 
UGT1A1, P-gp and BCRP 
According to preclinical studies, UGT1A1 is involved in the metabolism of LY3484356. As a 
precaution, strong inducers and inhibitors of UGT1A1 should be avoided (Section 10.8 
Appendix 8). 
Due to limitations of in vitro assessments, the impact of LY3484356 as an inhibitor to P-gp and 
the Breast Cancer Resistance Protein (BCRP) in the gut wall cannot be ruled out. Therefore, 
caution should be exercised when co-administrating LY3484356 with narrow therapeutic index 
substrates of P-gp and BCRP (i.e. digoxin). 
Consult the IB for additional information. 
6.5.1. 
Photosensitivity 
Based on an in vitro study, exposure to LY3484356 may result in photosensitivity. Patients are 
advised to avoid direct sun exposure and the use of tanning beds during study administration 
period and at least 5 days after the last dose.  If patients must be exposed to the sun, they should 
be advised to wear sunscreen, appropriate sun-blocking clothing, and sunglasses. 
6.6. 
Dose Modification 
Due to the short-term (15 days [+7/-2]) window of treatment with LY3484356, no dose 
modifications will be accepted. If any AEs as defined in Appendix 3 (Section 10.3) are deemed 
as dose limiting (eg, any significant toxicity possibly related to the study drug) per medical 
guidance and the opinion of the primary investigator, the recommendation will be to discontinue 
LY3484356. 
6.7. 
Intervention after the End of the Study 
The end of study definition is provided in Section 4.4. Investigators will continue to follow the 
SoA (Section 1.3) until notified by Lilly that the end of study has occurred. 
6.7.1. 
Treatment after Study Completion 
Study completion will occur following the final analysis of primary and secondary objectives, 
which will be performed no more than 3 months after the last patient is randomized/enrolled. 
Investigators will continue to follow the SoA (Section 1.3) for all patients until notified by Lilly 
that study completion has occurred. 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
Possible reasons leading to permanent discontinuation of investigational product: 
 Subject decision 
o 
 (eg, parents or legal guardian, 
requests to discontinue investigational product). 
 The patient is significantly noncompliant with study procedures and/or treatment. 
 Unacceptable toxicity or DLT toxicity requiring dose discontinuation. 
 The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  Discontinuation 
from study treatment will occur prior to introduction of the new agent. 
 The investigator decides that the patient should be discontinued from study treatment. 
 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using 
) after enrollment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study:  
 
participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP) 
 
at any time at his/her own request  
 
at the request of his/her designee (for example, parents or legal guardian) 
 
at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 
if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
 
if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent 

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Discontinuation is expected to be uncommon. At the time of discontinuing from the study, if 
possible, an early discontinuation visit should be conducted, as shown in the SoA (Section 1.3). 
See the SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. The participant will be permanently 
discontinued both from the study intervention and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor Clinical Research Physician 
(CRP) agree it is medically appropriate to continue, the investigator must obtain documented 
approval from the sponsor CRP to allow the inadvertently enrolled participant to continue in the 
study with or without treatment with investigational product. Safety follow up is as outlined in 
Section 1.3 (Schedule of Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse 
Events and Serious Adverse Events) of the protocol. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel 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. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 

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8. 
Study Assessments and Procedures 
 
Unless otherwise stated in the subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.  
Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards. 
 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
 
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 
(Section 1.3), is essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1. 
Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Electrocardiograms 
Electrocardiograms are to be single ECGs as indicated in the SoA (Section 1.3). 
8.2.2. 
Clinical Safety Laboratory Assessments 
 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. 
 
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the case 
report form (CRF). The laboratory reports must be filed with the source documents. 
 
 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or during the short-term follow-up period after the last dose of 
study intervention should be repeated until the values return to normal or baseline or are 
no longer considered clinically significant by the investigator or medical monitor. 

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38 
o 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. 
o All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the laboratory manual and 
the SoA. 
o If laboratory values from non-protocol specified laboratory assessments 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.2.2.1. 
Hepatic Safety Monitoring 
Liver testing (Appendix 4, Section 10.4), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine phosphokinase, should be repeated within 2 to 4 days 
to confirm the abnormality and to determine if it is increasing or decreasing, if one or more of 
these conditions occur: 
 
 
 
 
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), history of concomitant 
medications (including over the counter, herbal and dietary supplements, history of alcohol 
drinking and other substance abuse). In addition, the evaluation should include a blood test for 
prothrombin time test-international normalized ratio; serological tests for viral hepatitis A, B, C, 
E, autoimmune hepatitis; and an abdominal imaging study (eg, ultrasound or computed 
tomography scan). 
in consultation with the Lilly designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
ssessment of the 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, and/or a liver biopsy. 
Additional Hepatic Safety Collection 
Additional safety data should be collected via the CRF if 1 or more of the following conditions 
occur: 
 
 

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39 
 
 
values) 
In all study participants: 
 Discontinuation from study treatment due to a hepatic event or abnormality of liver tests. 
 Occurrence of a hepatic event considered to be an SAE. 
8.2.3. 
Safety Surveillance 
Lilly has systematic and robust internal processes in place that ensure safety surveillance of 
development compounds in line with expectations of regulatory agencies. This includes 
processes with clearly described roles and responsibilities th
Patient Safety organization. These processes are designed to monitor the evolving safety profile 
(ie, review of cumulative SAEs and other important safety information) by designated cross-
functional teams in a timely manner at predefined intervals or on an ad-hoc basis. In addition, a 
dedicated process may be used to perform unblinded comparisons of event rates for SAEs, as 
necessary. 
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program are reviewed on a regular basis and that important new safety 
information such as the need for protocol modification or other relevant safety-related material is 
identified and communicated to regulators and investigators appropriately and in a timely 
fashion. An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate. Any serious adverse reactions (SARs) are reported within the required 
timeline for expedited reporting. 
In addition to annual periodic safety updates and to further inform investigators, a line listing 
reports of suspected unexpected serious adverse reactions is created and distributed to 
investigators on a twice-yearly) basis. Any significant potential risk/safety concerns that are 
being monitored, as well as any results being reported in other periodic reports for the 
compound, SAC decisions, and other significant safety data (for example, nonclinical, clinical 
findings, and removal of SARs) are included in the report. 
8.3. 
Adverse Events and Serious Adverse Events 
Adverse 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 the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs will be collected from the signing of the ICF until participation in study has ended. 
All AEs will be collected from the signing of the ICF until the 30-day short-term follow-up visit. 

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Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the Adverse Event CRF. Although all AEs, after signing of the ICF, are recorded 
by the site in the CRF/electronic data entry, SAE reporting to the sponsor begins after the 
participant has signed the ICF and has received study drug.  However, if an SAE occurs after 
signing the ICF, but prior to receiving LY3484356, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. Serious adverse events, including death, caused by disease progression should not be 
reported unless the investigator deems them to be possibly related to study treatment.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and adverse events of special interest (AESI; as defined 
in Section 8.3.7), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Appendix 3 (Section 10.3).
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 

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41 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
Not applicable. 
8.3.6. 
Events or Outcomes 
Not applicable. 
8.3.7. 
Adverse Events of Special Interest 
Not applicable. 
8.3.8. 
Complaint Handling 
Lilly collects product complaints on investigational products used in clinical studies in order to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
8.4. 
Treatment of Overdose 
Refer to the IB of LY3484356 for available information on the signs, symptoms, and treatment 
of overdose. 
8.5. 
Pharmacokinetics 
 
Venous blood and tumor samples will/may be collected for measurement of 
plasma/tumor concentrations of LY3484356 as specified in the SoA (Section 1.3).  
 
Samples may be removed or collected at additional time points during the study if 
warranted and agreed upon between the investigator and the 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. 
 
Bioanalytical samples collected to measure investigational product concentration will 
be retained for a maximum of 1 year following last participant visit for the study. 
8.6. 
Pharmacodynamics 
Samples collected to measure PD biomarkers will be identified by the participant number 
(coded) and retained at a facility selected by Lilly or its designee for a maximum of 15 years 
following last participant visit for the study at a facility selected by Lilly or its designee. See 
Section 8.8 for biomarker information. 

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8.7. 
Genetics 
8.7.1. 
Whole Blood Sample for Pharmacogenetic Research 
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to LY3484356 and to 
investigate genetic variants thought to play a role in cancer. Assessment of variable response 
may include evaluation of AEs or differences in efficacy. Samples may be used to determine the 
somatic or germline origin of tumor-associated genetic alterations. 
All samples will be coded with the patient number. These samples and any data generated can be 
linked back to the patient only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
Ethical Review Boards (ERBs)/IRBs impose shorter time limits. This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of LY3484356 or after LY3484356 
becomes commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies. Regardless of 
technology utilized, data generated will be used only for the specific research scope described in 
this section. Samples may also be used to determine the somatic or germline origin of tumor-
associated genetic alterations. 
8.8. 
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid, 
ribonucleic acid, proteins, lipids, and other cellular elements. 
Breast tumor tissue and plasma samples for biomarker research will be collected at the times 
specified in the SoA (Section 1.3) where local regulations allow. It is recommended that the cold 
ischemia time be kept to 1 hour or less for all tissue specimens as per the ER and PgR IHC 
Testing Guideline recommendations (ASCO/CAP; Yildiz-Aktas et al. 2012). 

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Collection of the following tumor tissue samples are requested for all patients in order to 
participate in this study: 
1. Pre-treatment (Required) 
 
 Archival tissue from a diagnostic tumor biopsy will be sufficient provided it was taken 
no more than 6 weeks prior to consent.  
o The tumor block or a total of 20 unstained slides should be submitted along with a 
copy of the pathology report confirming viable tumor sufficient to make the 
diagnosis, along with the requisite biomarker profile (ER+, HER2-) for eligibility 
outlined in Section 5.1.   
 If the diagnostic tumor block is close to exhaustion, case by case 
consideration will be given after consultation with the CRP or CRS to 
accept less than 20 unstained slides. 
 Fresh on-study biopsy (16-gauge core needle or wider is suggested with a minimum of 
3 cores obtained) performed prior to treatment initiation, will be: 
o Required: If archival tissue unavailable/exhausted or was collected >6 weeks prior 
to consent, or while on Hormone Replacement Therapy 
o Optional: For the purpose of Oncotype DX test
discretion. 
o Cores 1 through 3 are to be Formalin-Fixed 
 
2. On-treatment (Required) 
 
 Tumor tissue can be obtained either from: 
o A Core needle biopsy (16 gauge or wider is suggested with a minimum 4 cores 
obtained), if the patient is scheduled for subsequent neoadjuvant therapy.  
 Cores 1 through 3 are to be Formalin-Fixed  
 Core 4 is to be flash frozen with the weight of this core recorded where 
possible. 
o The resected surgical specimen in patients scheduled directly for surgery.  
 Standard local pathology practices will be acceptable. Surgical specimens 
need to be placed in formalin immediately following gross inspection and 
tissue procurement.   
 Following completion of the surgical pathology report the tumor block or 
a total of 20 unstained slides should be submitted along with a copy of the 
pathology report confirming viable tumor sufficient to make the diagnosis.   
 
2.1 On-treatment (Optional but strongly encouraged) 
 
 For sufficiently large tumor resection specimens (deemed to contain sufficient tumor for 
research purposes), the following samples should be obtained where possible. 
1. Tumor sample and a sample of adjacent normal tissue from the resection specimen of 
at least 0.5 cm3 each, for immediate flash freezing to support PK assessment. 
Importantly, the weight of each specimen should be recorded prior to freezing.   

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2. Tumor sample and a sample of adjacent normal tissue of approximately 0.5 
cm×0.5cm each, to be immediately placed in formalin tissue block for exploratory 
research. 
 
As described above, unstained archival tumor tissue sample of sufficient quantity and quality 
must be confirmed by the site to be available to allow for retrospective central ER, PR, and Ki-
67 assessments. Due diligence should be used to ensure that sample contains sufficient viable 
tumor cells (not a normal adjacent or a tumor margin sample) prior to shipment to central 
laboratory.  
All accompanying pathology reports must be coded with the patient number. Personal identifiers, 
and initials, must be removed from the institutional pathology report 
prior to submission.   
Sponsor/Lilly has a right to retain a portion of the submitted tissue. Archival blocks will be 
sectioned and returned to the study site. Slides and tissue samples collected on-study will not be 
returned. 
This study will analyze biomarkers relevant to LY3484356, mechanism of action of LY3484356, 
the variable response to study drug, tumor cell biology, immune function, tumor 
microenvironment, angiogenesis, and pathways associated with cancer. These samples may also 
be used to develop related research methods or to validate diagnostic tools or assays. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3484356 or after LY3484356 becomes commercially available. 
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named. Existing approaches, including mutation profiling, copy number variability 
analysis, gene expression assays, multiplex assays, and/or immunohistochemistry may be 
performed on these tissue samples to assess potential associations between these biomarkers and 
clinical outcomes. 
It is possible that biomarker data for patients in the study has already been generated from 
samples that were collected and analyzed prior to enrolling in this study. This may include data 
generated from genetic analyses. If available, these data may be requested from medical records 
for use in the research described above in this biomarker section. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization parameters and Health Economics will not be evaluated in this 
study. 

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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
No formal statistical hypotheses and no formal statistical hypothesis testing will be performed. 
9.2. 
Sample Size Determination 
Approximately 90 participants will be assigned equally to the different dose-level cohorts in this 
study to ensure that conservatively 20 participants, with evaluable biomarker data are ultimately 
available for analysis from each cohort. The sponsor may elect to continue accrual until 
sufficient biomarker data is generated. Participants will be randomized to either 800 mg or 
400 mg once daily oral dosing, or directly assigned to the 200 mg dose. See details about 
randomization in Section 6.3. 
 
 
 
9.3. 
Populations for Analyses 
The following analysis sets will be defined for this study: 
Intention-to-Treat (ITT) analysis set:  will include all enrolled/randomized participants. The 
ITT analysis of biomarker data will consider allocation of participants to treatment groups as 
assigned/randomized and not by actual treatment received. This analysis set will be used for all 
baseline and post-treatment analyses.  
Safety analysis set:  will include all enrolled/randomized participants who received any quantity 
of study treatment, regardless of their eligibility for the study. The safety evaluation will be 
performed based on the first dose of study treatment a participant actually received, regardless of 
and safety analyses. 
Pharmacokinetic analysis set:  will include all enrolled/randomized participants who received 
at least 1 full dose of LY3484356 and have at least 1 postbaseline evaluable PK sample. 
Biomarker analysis set:  will include the subset of participants from the ITT analysis set from 
whom a valid assay result has been obtained. 
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
All CIs will be given at a 2-sided 95% level, unless otherwise stated. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 

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methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan and the clinical study report. Additional exploratory analyses of the 
data will be conducted as deemed appropriate. 
9.4.2. 
Primary Objective Analysis 
Change in ER expression is defined as the change from the pre-treatment to on-treatment 
sample. The geometric mean of change in the ER H-score, the percent change in H-score of ER 
expression, and the 90% CI (based on t statistic) will be summarized for each cohort. 
9.4.3. 
Secondary Objectives Analyses 
Change in Ki-67 index is defined as the change from the pre-treatment to on-treatment. The 
geometric mean of change in Ki-67 expressing positive cells, the percent change in Ki-67 
expressing positive cells, and its 90% CI (based on t statistic) will be summarized for each 
cohort, per international guidelines (Dowsett et al. 2011). Subgroup analyses will be performed 
in patients with higher (>5%) baseline Ki-67%. 
Change in PR expression is defined as the change from the pre-treatment to on-treatment. The 
geometric mean of change in the ER H-score, the percent change in H-score of PR expression, 
and the 90% CI (based on t statistic) will be summarized for each cohort. 
9.4.4. 
Safety Analyses 
All participants who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity. 
Safety analyses will include summaries of  
 adverse events, including severity and possible relationship to study drug  
 serious adverse events, including possible relationship to study drug  
 adverse events leading to dose adjustments  
 discontinuations from study treatment due to AEs or death  
 treatment-emergent abnormal changes in laboratory values, and 
 treatment-emergent abnormal changes in vital signs and ECGs. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Plasma and tumor concentrations of LY3484356 will be summarized. 
In addition, PK parameter estimates for LY3484356 may be calculated by population PK 
analysis methods using NONMEM, data allowing.   
Pharmacokinetic/PD analyses may be conducted to explore exposure-response relationships 
between LY3484356 concentrations in systemic circulation and various PD measures as a second 
step if the dose-response relationship is positively assessed. 

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9.4.6. 
Other Analyses 
9.4.6.1. 
Participant Disposition 
A detailed description of participant disposition will be provided, including a summary of the 
number and percentage of participants entered into the study, enrolled/randomized in the study, 
treated in the study, completing the study (patients who complete the required treatment period), 
and discontinued from the study (overall and by reason for discontinuation). 
9.4.6.2. 
Participant Characteristics 
Demographic data are collected and reported to demonstrate that the study population represents 
the target participant population. 
9.4.6.3. 
Concomitant Therapy 
A summary of prior and concomitant medications by dose/treatment cohort will be reported. 
9.4.6.4. 
Treatment Compliance 
The number of doses received, dose omissions, dose reductions, and dose intensity will be 
summarized for all treated participants by dose/treatment cohort. 
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments. Study 
treatment taken will be derived from the difference between the total number of pills dispensed 
 
9.5. 
Interim Analyses 
No interim analyses are planned for this study. However, each cohort will be continuously 
monitored for safety. Enrollment to a cohort will be temporarily halted and a safety data review 
will be triggered 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with: 
o consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, and 
o applicable laws and regulations. 
 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
The investigator will be responsible for  
o providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and 
o providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.1. 
Informed Consent Process 
 
The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study. 
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act 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. 

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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 par
authorized representative and is kept on file. 
10.1.2. 
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 his/her 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 his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.3. 
Dissemination of Clinical Study Data 
Dissemination of study data will be performed according to all applicable Lilly and international 
policies. 
10.1.4. 
Data Quality Assurance 
 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the 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 (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the monitoring plan. 
 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 

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Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
 
In addition, 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 electronic data capture system (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 will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive 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 results will be provided to the investigator for 
review and retention. Data will subsequently be transferred from the central vendor to the Lilly 
data warehouse. 
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.5. 
Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate 
 
 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 

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explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.6. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
 
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 of participants by the investigator, and 
 
discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed below will be performed as indicated in the table. 
 
If there is an abnormal laboratory value or abnormal value for any other diagnostic or 
screening test (eg, blood pressure increased, neutrophils decreased, etc.) and it is 
associated to a diagnosis of an AE, then the AE should be entered in the CRF. 
 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are 
used to make either a study intervention decision or response evaluation, the results 
must be entered into the CRF. Discrepancies between local and central laboratory 
results will not be considered protocol deviations. 
 
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 each laboratory safety report. 
 
Clinical Laboratory Tests 
Hematologya,b 
Clinical Chemistrya,b 
Leukocytes (WBC) 
Serum Concentrations of: 
Neutrophilsb 
Alanine aminotransferase (ALT) 
Lymphocytes 
Albumin 
Monocytes 
Alkaline phosphatase 
Eosinophils 
Aspartate aminotransferase (AST) 
Basophils 
Bilirubin, direct 
Erythrocytes (RBC) 
Bilirubin, total 
Hemoglobin (HGB) 
Blood urea nitrogen (BUN) or blood urea 
Hematocrit (HCT) 
Calcium 
Platelets (PLT) 
Creatinine  
 
Glucose (random 
Urinalysisb 
Potassium 
Blood 
Protein 
Glucose 
Sodium 
Ketones 
 
pH 
Coagulationb 
Protein 
PT/INR 
Specific gravity 
aPTT 
Urine leukocyte esterasec 
 
Blood Testsa,b 
 

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Hepatitis B surface antigen 
 
Hepatitis C antibody 
 
Follicle Stimulating Hormone (FSH)
Estradiol
 
 
 
Abbreviations: aPTT = activated partial thromboplastin time; CRF = case report form; INR = international 
normalized ratio; PT = prothrombin time; RBC = red blood cells; WBC = white blood cells. 
a Treatment and enrollment decisions will be based on local laboratory results. 
b Local or investigator-designated laboratory. 
c Urine microscopy may be used in place of the urine leukocyte esterase assessment to test for the presence of 
WBC. 
 
Note:  Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms.  When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands. 
 
 
 

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10.3. 
Appendix 3: 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 patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

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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 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term life-threatening  in the definition of serious  refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent disability/incapacity 
 
ty to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

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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. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The investigator will then record all relevant AE/SAE information in the CRF. 
 It is not 
ical 
records to Sponsor or designee in lieu of completion of the AE/SAE CRF page. 
 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 use CTCAE v5.0 (NCI 2018) to assign AE severity grades. 
 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to 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 his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 New or updated information will be recorded in the originally completed CRF. 
 The investigator will submit any updated SAE data to Sponsor or designee within 
24 hours of receipt of the information.
10.3.4. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
Contacts for SAE reporting can be found in the SAE form.
SAE Reporting via Paper CRF 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor. 
 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 form.
 
 

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10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the Lilly CRP/CRS. 
Hepatic Evaluation Testing Refer to protocol Hepatic Safety Monitoring Section 8.2.2.1 for guidance on 
appropriate test selection. 
 
 
For testing selected, analysis is required to be completed by the Lilly designated central laboratory 
except for Microbiology. 
 
Local testing may be performed in addition to central testing when required for immediate patient 
management. 
 
Results will be reported if a validated test or calculation is available.
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - Red Blood Cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry 
Basophils 
Acetaminophen 
Eosinophils 
Acetaminophen Protein Adducts 
Platelets 
Alkaline Phosphatase Isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl Alcohol (EtOH) 
Prothrombin Time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin A (IgA [Quantitative]) 
Hepatitis A Virus (HAV) Testing: 
Immunoglobulin G (IgG [Quantitative]) 
HAV Total Antibody 
Immunoglobulin M (IgM [Quantitative]) 
HAV IgM Antibody 
Phosphatidylethanol (PEth) 
Hepatitis B Virus (HBV) Testing: 
Urine Chemistry 
Hepatitis B surface antigen (HBsAg) 
Drug Screen 
Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG) 
Hepatitis B core total antibody (Anti-HBc) 
Other Serology 
Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 

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Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
HBV DNAb 
Anti-actin antibodyc 
Hepatis C Virus (HCV) Testing: 
Epstein-Barr Virus (EBV) Testing: 
HCV antibody 
EBV antibody 
HCV RNAb 
EBV DNAb 
Hepatitis D Virus (HDV) Testing: 
Cytomegalovirus (CMV) Testing: 
HDV antibody 
CMV antibody 
Hepatitis E Virus (HEV) Testing: 
CMV DNAb 
HEV IgG antibody 
Herpes Simplex Virus (HSV) Testing: 
HEV IgM antibody 
HSV (Type 1 and 2) antibody 
HEV RNAb 
HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture: 
 
Blood 
 
Urine 
 
Abbreviations:  CRF = case report form; CRP = clinical research physician; CRS = clinical research scientist; DNA 
= deoxyribonucleic acid; Ig = immunoglobulin; INR = international normalized ratio; RNA = ribonucleic acid.  
a This is not required if Anti-Actin Antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
c This is not required if Anti-smooth muscle antibody (ASMA) is tested. 
d Assayed by Investigator-designated local laboratory ONLY; no Central Testing available.   
 
 
 
 

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10.5. 
Appendix 5:  Inducers and Strong Inhibitors of CYP3A 
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
Strong Inducers of CYP3A 
Aminoglutethimide
Apalutamide
Avasimibe
Carbamazepine
Enzalutamide 
Fosphenytoin 
Ivosidenib
Lumacaftor
Mitotane 
Phenobarbital/phenobarbitone
Phenytoin
Rifabutin 
Rifampicin 
Rifapentine
 
Moderate Inducers of CYP3A
Almorexant 
Bosentan
Cenobamate
Dabrafenib 
Daclatasvir and asunaprevir and beclabuvir
Danshen
Efavirenz
Encorafenib
Etravirine
Faldaprevir and efavirenz 
Genistein
Lersivirine
Lesinurad
Lopinavir (alone) 
Lorlatinib
Modafinil
Nafcillin (intravenous)
Pentobarbital 
Primidone 
Telotristat ethyl
Thioridizine
Tipranavir and ritonavir
Tocilizumab
 
 

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Strong Inhibitors of CYP3A
Boceprevir 
Clarithromycin
Cobicistat
Conivaptan
Danoprevir and ritonavir 
Diltiazem 
Elvitegravir and ritonavir
Grapefruit juice
Idelalisib
Indinavir and ritonavir
Itraconazole
Ketoconazole 
Lopinavir and ritonavir
Nefazodone 
Nelfinavir
Posaconazole 
Ribociclib 
Ritonavir 
Saquinavir and ritonavir 
Telithromycin
Tipranavir and ritonavir
Viekira Pak
Voriconazole
 
 
 

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10.6. 
Appendix 6: CYP3A Sensitive Substrates 
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
abemaciclib 
lomitapide
acalabrutinib
lopinavir
alectinib 
lovastatin
alfentanil 
lumefantrine
aprepitant (also fosaprepitant)
lurasidone
atazanavir
maraviroc
atorvastatin
midazolam
avanafil
midostaturin
avapritinib
naloxegol
bosutinib
neratinib
brotizolam
nisoldipine
budesonide
paritaprevir
buspirone 
quetiapine
cobimetinib 
quinidine
conivaptan
saquinavir
darifenacin 
sildenafil
darunavir
simeprevir
dasatinib 
simvastatin
dronedarone 
sirolimus
ebastine (OUS only)
tacrolimus
elighlustat 
ticagrelor
elvitegravir
tipranavir
entrectnib
tolvaptan
eplerenone
triazolam
everolimus
ulipristal
felodipine
uprogepant
ibrutinib 
vardenafil
indinavir 
venetoclax
isavuconazole (prodrug is isavuconazonium sulfate)
vinblastine
ivabradine
zanubrutinib
ivacaftor (also ivacaftor with lumacaftor, ivacaftor with 
tezacaftor)
 
Source: University of Washington Drug Interaction Solutions List of CYP3A Sensitive Substrates accessed 14 May 2020. 
 
 
 

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10.7. 
Appendix 7: Other CYP-sensitive Substrates 
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
  
Sensitive substrates 
CYP2C8 
repaglinide 
CYP2C9 
celecoxib 
CYP2C19
S-mephenytoin, omeprazole
CYP2D6 
atomoxetine, desipramine, dextromethorphan , 
eliglustat(e), nebivolol, nortriptyline, 
perphenazine, tolterodine, R-venlafaxine 
Note: Sensitive substrates are drugs that demonstrate an increase in area under the concentration time curve 
(AUC) 
-fold with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction 
studies. 
 
 
 

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10.8. 
 Appendix 8: Examples of strong clinical inhibitors and inducers for 
UGT1A1 
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
Inhibitors 
Inducers
UGT1A1
ombitasvir and paritaprevir and ritonavir 
and dasabuvir, faldaprevir 
telaprevir
Source: University of Washington Drug Interactions Database accessed August 2020.  
-fold with a UGT1A1 
substrate in clinical DDI studies and/or pharmacogenetics data.  
 
 

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10.9. 
Appendix 9: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
 sites may 
implement changes if permitted by local regulations.  
After approval by local ERBs, regulatory bodies, and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific conditions in which notification is required 
(for example, upon implementation and suspension of changes). All approvals and notifications 
must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study, and maintaining the integrity of the study.  
Informed Consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section 
 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in Study Conduct During Exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 

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Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments.  
Other alternative locations: Procedures that may be done at an alternate location in exceptional 
circumstances. 
Data captures 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
 
 When delivering supplies to a location other than the study site (for example, 
par
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Adjustments to visit windows 
should complete the usual Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, the windows for visits may be adjusted, upon further guidance 
from the sponsor. This minimizes missing data and preserves the intended conduct of the study. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
 
 

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Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
manner. 
 
 

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10.10. 
Appendix 10: Abbreviations 
Term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
CAP 
Clinical Practice Guideline 
CI 
confidence interval 
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. 
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. 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome P450 3A4 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
enroll 
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ER+ 
estrogen receptor-positive 
ER  
 
EDC 
electronic data capture system 
ERB 
Ethical Review Board 
G 
grade 
HER2- 
human epidermal growth factor receptor 2 negative 

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Term 
Definition 
IB 
 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDC 
infiltrating ductal carcinoma 
IEC 
Independent Ethics Committee 
ILC 
infiltrating lobular carcinoma 
IM 
intramuscular 
Informed consent 
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
documented by means of a written, signed and dated informed consent form. 
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 
ITT 
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
mBC 
metastatic breast cancer 
NCI 
National Cancer Institute 
participant 
Equivalent to CDISC term 
either as recipient of an investigational medicinal product or as a control 
P-gp 
P-glycoprotein 1 
PK/PD 
pharmacokinetics/pharmacodynamics 
PR 
progesterone receptor 
SAE 
serious adverse event 
SAR 
serious adverse reaction 

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Term 
Definition 
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 
TBL 
total bilirubin 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
 
 

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10.11. 
Appendix 10: Protocol Amendment History 
Amendment (a) 
This amendment is considered to be not substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
This amendment incorporates changes to address feedback from the Voluntary Harmonisation 
Procedure for Clinical Trials of Medicinal Products.  In addition, this amendment includes 
changes made to correct and clarify information for sites.  This amendment also corrects 
typographical errors and inconsistencies that were noted in the JZLB protocol. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3.  Schedule of Activities 
Biomarker Plasma 
Biomarker plasma to be collected 
To better understand the 
mutational burden of early stage 
disease and whether changes 
occur with study drug 
administration 
1.3.  Schedule of Activities 
Vital Signs 
More details about how to collect vital 
signs for Visits 1 and 2 
To provide guidance on when 
vital signs are to be collected 
1.3.  Schedule of Activities 
ECG 
Additional ECG added 3-4 hours after 
dose at Visit 1 
To provide clarity on need for 
additional ECG collection 
timepoint 
1.3.  Schedule of Activities 
Follicle Stimulating 
Hormone/estradiol 
Added collection for patients less than 60 
To align with inclusion criterion 
10 
1.3.  Schedule of Activities 
Hepatitis B & C 
 
Added testing for screening for hepatitis B 
& C 
To align with requirement that 
patients with hepatitis B & C be 
excluded from trial 
1.3.  Schedule of Activities 
Surgical Pathology Report 
Added that this is only required for 
patients who provide surgical resection for 
on-treatment tissue collection. 
To clarify that only some patients 
will be required to do this  
1.3.  Schedule of Activities 
Patient diary 
Collection of diary can occur at visit 3 or 
visit 4 
To provide flexibility  
4.1.1.  Dose Limiting 
Toxicities 
8.2.2.1.  Hepatic Safety 
Monitoring 
Additional Hepatic Safety 
Collection 
Changed levels of ALT or AST that 
qualify as a DLT  
To satisfy concerns about hepatic 
safety 

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Section # and Name 
Description of Change 
Brief Rationale 
5.2.  Exclusion Criteria  
Criterion 20 iv. 
Changed to say hepatitis B&C testing is 
required 
To align with requirement that 
patients with hepatitis B & C be 
excluded from trial 
5.2.  Exclusion Criteria  
Criterion 23 
breastfeeding, or expecting to conceive 
children within the projected duration of 
the trial, starting with the screening visit 
through 180 days after the last dose of 
 
Because only post-menopausal 
women can be in the study, this 
criterion was considered 
unnecessary and deleted 
5.2.  Exclusion Criteria 
Criterion 25 
Added new criterion that occult breast 
cancer is not allowed 
To clarify that patients with occult 
breast cancer are not eligible for 
the study 
5.3.  Lifestyle Considerations 
6.5.  Concomitant Medications 
Added and uridine 5'-diphospho-
glucuronosyltransferase 1A1 (UGT1A1) 
added to substances to avoid while on 
study medicine 
In vitro, UGT enzymes were 
shown to be involved in the 
metabolism of LY3484356  
 
5.4.  Screen Failures 
Added that any participant who does not 
meet enrollment criteria and was 
inadvertently enrolled will be discontinued 
from study treatment and safety follow up 
should be performed.  
So that this process applies to all 
participants 
6.3.  Measures to Minimize 
Bias: Randomization and 
Blinding 
Added 
stratification 
To give more information about 
the randomization process, 
i
third stratification level 
6.5.  Concomitant Medications 
10.7.  Appendix 8: Other 
CYP-sensitive Substrates 
CYP2B6 added to list of substances to be 
cautious with 
LY3484356 reversibly inhibits the 
metabolism of CYP2B6 
6.5.1.  Photosensitivity 
Added more guidance about sun avoidance 
To help ensure investigators and 
participants are aware of this risk 
and to provide guidance on how to 
manage the risk 
7.2.  Participant 
Discontinuation/Withdrawal 
from the Study 
Removed pregnancy as reason for 
withdrawal 
Because only post-menopausal 
women can be in the study, this 
statement was considered 
unnecessary and deleted 
8.8.  Biomarkers 
Plasma collection added 
To better understand the 
mutational burden of early stage 
disease and whether changes 
occur with study drug 
administration 

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Section # and Name 
Description of Change 
Brief Rationale 
9.5.  Interim Analysis 
Addition of >50% 
To remedy an accidental deletion 
and match the SAP 
10.2.  Appendix 
Inclusion of additional blood tests  
To clarify these blood tests should 
be conducted as part of Eligibility 
confirmation 
10.1.1. 
Removed need for rescreened patients to 
sign new ICF 
Rescreening is not permitted in 
this study 
10.5.1.  Discontinuation of 
Inadvertently Enrolled 
Patients in the United 
Kingdom  
Deleted 
So that this process applies to all 
participants 
10.8.  Appendix 8: Clinical 
inhibitors for P-gp 
10.9.  Appendix 9: Examples 
of strong clinical inhibitors 
and inducers for UGT1A1 
(Aug 2020) 
Addition of tables for conmeds 
To add more information about 
conmeds 
 

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11. 
References 
Agrawal A, Robertson JFR, Cheung KL, et al. Biological effects of fulvestrant on estrogen 
receptor positive human breast cancer: short, medium and long-term effects based on 
sequential biopsies. Int J Cancer. 2016;138(1):146-159. https://doi.org/10.1002/ijc.29682 
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, 
Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch 
CM. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint 
Commission on Cancer; 2017. 
Arnedos M, Roulleaux Dugage M, Perez-Garcia J, Cortes J. Window of opportunity trials for 
biomarker discovery in breast cancer. Curr Opin Oncol. 2019;31(6):486-492. 
https://doi.org/10.1097/CCO.0000000000000583 
Bardia A, Kabos P, Elledge R, et al. Evaluation of RAD1901, a novel investigational, selective 
estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast 
cancer [abstract]. J Clin Oncol. 2017;35(15_suppl):1014. 
https://doi.org/10.1200/JCO.2017.35.15_suppl.1014 
Bardia A, Linden HM, Ulaner GA, et al. Dose-escalation study of SAR439859, an oral selective 
estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- 
metastatic breast cancer (mBC) [abstract]. J Clin Oncol. 2019;37(suppl 15):1054. 
https://doi.org/10.1200/JCO.2019.37.15_suppl.1054 
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 
2018;68(6):394-424. https://doi.org/10.3322/caac.21492 
Cohen DA, Dabbs DJ, Cooper KL, Amin M, Jones TE, Jones MW, Chivukula M, Trucco GA, 
Bhargava R. Interobserver agreement among pathologists for semiquantitative hormone 
receptor scoring in breast carcinoma. Am J Clin Pathol. 2012;138(6):796-802. 
https://doi.org/10.1309/AJCP6DKRND5CKVDD 
Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg 
in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337 
Dowsett M, Nielsen TO, 
JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, 
Smith IE, Viale G, Zujewski JA, Hayes DF. Assessment of Ki67 in breast cancer: 
recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer 
Inst. 2011;103(22):1656-1664. https://doi.org/10.1093/jnci/djr393 
Giuliano AE, Edge SB, Hortobagyi GN. Eighth edition of the AJCC Cancer Staging Manual: 
breast cancer. Ann Surg Oncol. 2018;25:1783-1785. https://doi.org/10.1245/s10434-018-6486-
6 
Guo S, Zhang C, Bratton M, et al. ZB716, a steroidal selective estrogen receptor degrader 
(SERD), is orally efficacious in blocking tumor growth in mouse xenograft models. 
Oncotarget. 2018;9(6):6924-6937. https://doi.org/10.18632/oncotarget.24023 

CONFIDENTIAL 
Protocol J2J-MC-JZLB(b) 
 
75 
Hamilton EP, Patel MR, Armstrong AC, et al. A first-in-human study of the new oral selective 
estrogen receptor degrader AZD9496 for ER+/HER2- advanced breast cancer. Clin Cancer 
Res. 2018;24(15):3510-3518. https://doi.org/10.1158/1078-0432.CCR-17-3102 
Harvey JM, Clark JM, Osborne CK, Allred DC. Estrogen receptor status by 
immunohistochemistry is superior to the ligand-binding assay for predicting response to 
adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474-1481. 
https://doi.org/10.1200/JCO.1999.17.5.1474 
 
DL, Winchester DJ, Giuliano A. AJCC Cancer Staging Handbook: From the AJCC Cancer 
Staging Manual. 8th ed. Springer; 2017. 
Kuter I, Gee JMW, Hegg R, et al. Dose-dependent change in biomarkers during neoadjuvant 
endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. 
Breast Cancer Res Treat. 2012;133(1):237-246. https://doi.org/10.1007/s10549-011-1947-7 
Lai A, Kahraman M, Govek S, et al. Identification of GDC-0810 (ARN-810), an orally 
bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in 
tamoxifen-resistant breast cancer xenografts. J Med Chem. 2015;58(12):4888-4904. 
https://doi.org/10.1021/acs.jmedchem.5b00054 
Li S, Yang J, Shen Y, et al. Clinicopathological features, survival and risk in breast cancer 
survivors with thyroid cancer: an analysis of the SEER database. BMC Public Health. 
2019;19(1):1592. https://doi.org/10.1186/s12889-019-7947-y 
Nardone A, Weir H, Delpuech O, et al. The oral selective oestrogen receptor degrader (SERD) 
AZD9496 is comparable to fulvestrant in antagonizing ER and circumventing endocrine 
resistance. Br J Cancer. 2019;120(3):331-339. https://doi.org/10.1038/s41416-018-0354-9 
[NCCN] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology (NCCN Guidelines). Breast Cancer. Version 1.2018. Accessed August 25, 2020. 
https://www.nccn.org/professionals/physician_gls/default.aspx 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Robertson JF, Dixon JM, Sibbering DM, et al. A randomized trial to assess the biological 
activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 
500 mg alone or anastrozole alone on primary breast cancer. Breast Cancer Res. 
2013;15(2):R18. https://doi.org/10.1186/bcr3393 
Robertson JF, Errikstein B, Osborne KC, et al. Pharmacokinetic profile of intramuscular 
fulvestrant in advanced breast cancer. Clin Pharmacokinet. 2004;43(8):529-538. 
https://coi.org/10.2165/00003088-200443080-00003 
Robertson JFR, Harrison M. Fulvestrant: pharmacokinetics and pharmacology. Br J Cancer. 
2004;90(suppl 1):S7-S10. https://doi.org/10.1038/sj.bjc.6601630 
Stuart-Harris R, Caldas C, Pinder SE, Pharoah P. Proliferation markers and survival in early 
breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast. 
2008;17(4):323-334. https://doi.org/10.1016/j.breast.2008.02.002 

CONFIDENTIAL 
Protocol J2J-MC-JZLB(b) 
 
76 
Soleja M, Raj GV, Unni N. An evaluation of fulvestrant for the treatment of metastatic breast 
cancer. Expert Opin Pharmacother. 2019;20(15):1819-1829. 
https://doi.org/10.1080/14656566.2019.1651293 
Tria GS, Abrams T, Baird J, et al. Discovery of LSZ102, a potent, orally bioavailable selective 
estrogen receptor degrader (SERD) for the treatment of estrogen receptor positive breast 
cancer. J Med Chem. 2018;61(7):2837-2864. https://doi.org/10.1021/acs.jmedchem.7b01682 
van Kruchten M, de Vries EG, Glaudemans AW, et al. Measuring residual estrogen receptor 
availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 
2015;5(1):72-81. https://doi.org/10.1158/2159-8290.CD-14-0697 
Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288-300. 
https://doi.org/10.1001/jama.2018.1932 
Weir HM, Bradbury RH, Lawson M, et al. AZD9496: an oral estrogen receptor that blocks the 
growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 
2016;76(11):3307-3318. https://doi.org/10.1158/0008-5472.CAN-15-2357 
Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 
testing in breast cancer: American Society of Clinical Oncology/College of American 
Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. 
https://doi.org/10.1200/JCO.2018.77.8738 
Yerushalmi R, Woods R, Ravdin PM, et al. Ki67 in breast cancer: prognostic and predictive 
potential. Lancet Oncol. 2010;11(2):174-183. https://doi.org/10.1016/S1470-2045(09)70262-1 
Yildiz-Aktas IZ, Dabbs DJ, Bhargava R. The effect of cold ischemic time on the 
immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 
expression in invasive breast carcinoma. Mod Pathol. 2012;25(8):1098-1105. 
https://doi.org/0.1038/modpathol.2012.59