EMBER-3: A Phase 3, Randomized, Open-Label Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Patients With Estrogen Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer Previously Treated With Endocrine Therapy
Phase: PHASE3
Conditions: Breast Neoplasms, Neoplasm Metastasis
Sponsor: Eli Lilly and Company

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Clinical Protocol J2J-OX-JZLC(d) 
LY3484356; LY2835219 
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CLINICAL PROTOCOL J2J-OX-JZLC 
EMBER-3: A Phase 3, Randomized, Open-Label Study of 
Imlunestrant, Investigator’s Choice of Endocrine Therapy, and 
Imlunestrant plus Abemaciclib in Patients with Estrogen Receptor 
Positive, HER2 Negative Locally Advanced or Metastatic Breast 
Cancer Previously Treated with Endocrine Therapy
Investigational Product: 
imlunestrant (LY3484356); abemaciclib (LY2835219) 
Protocol Number: 
J2J-OX-JZLC 
Development Phase: 
3 
IND #: 
EudraCT#: 
145311 
2021-000079-35 
EU trial number: 
2023-506786-63-00 
Sponsor: 
Eli Lilly and Company 
Indianapolis, IN, USA 46285 
Current Version: 
Amendment (d) 
Document ID: 
VV-CLIN-074716
Confidentiality Statement 
This document contains confidential information that is the property of Eli Lilly and Company and may not be 
disclosed to anyone other than the recipient Clinical Investigator, research staff, and respective members of the 
Institutional Review Board/Independent Ethics Committee. This information cannot be used for any purpose other 
than the evaluation of conduct of the clinical investigation without the prior written consent of Eli Lilly and 
Company. 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment c 
11-Nov-2022 
Amendment b 
17-Aug-2022 
Amendment a 
08-Oct-2021 
Original Protocol 
15-Mar-2021 
Amendment [d]  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary rationale of this amendment is to change the initial alpha split for PFS for Arm A 
versus Arm B in the ITT population and PFS for Arm A versus Arm B in the ESR1-mutation 
detected population due to external SERD data. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added 
 Regulatory Agency Identifier Number(s) 
 Study Population 
 Ethical Considerations of Benefit/Risk 
 “Yes” for Data Monitoring Committee 
For EU-CTR compliance 
1.3. Schedule of 
Activities 
To “Survival Information” row, added “Date of 
progression on the FIRST post-discontinuation anticancer 
treatment should be collected”  
For clarification 
2. Introduction 
Added “Introduction/Rationale for Amendment (d): 
Updating initial alpha allocation for PFS between Arm A 
and Arm B” paragraph 
Addition 
6. Study 
Intervention 
Updated the definition of study intervention 
For EU-CTR compliance 
6.1. Study 
Intervention(s) 
Administered 
 
Added 
 Last row to the table 
 Packaging and labeling 
For EU-CTR compliance 
9.2. Sample Size 
Determination 
Updated third, fourth, and fifth paragraphs 
Update due to external SERD 
data 
9.4.1. General 
Considerations 
Added the last paragraph regarding handling of missing, 
unused, and spurious data 
For EU-CTR compliance 
9.4.3.1. Primary 
Analyses 
Updated second and third paragraphs. 
Update due to external SERD 
data 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.5.2. Efficacy 
Interim Analyses 
Description of the efficacy interim analyses plan was 
updated in first paragraph, deleted second paragraph, 
updated third paragraph, and updated the table “Stopping 
Boundaries for Each Analysis between Arm A and Arm 
B in the ITT Population Based on the Initial Allocation of 
Alpha for Illustration” 
Update due to external SERD 
data 
10.1.1. Regulatory 
and Ethical 
Considerations 
Added a bullet point regarding reporting of significant 
issues related to participant’s safety, rights, and data 
integrity  
For EU-CTR compliance 
10.1.4. Data 
Protection 
Updated the language 
For EU-CTR compliance 
10.1.5. 
Dissemination of 
Clinical Study 
Data 
Added this section and section numbers of subsequent 
sections are changed 
For EU-CTR compliance 
10.6.1. Definition 
of AE 
Replaced the fifth bullet point of “Events Meeting the AE 
Definition” 
For EU-CTR compliance 
10.6.6. Regulatory 
Reporting 
Requirements 
Updated the language in second bullet point 
For EU-CTR compliance 
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Table of Contents  
1 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities .....................................................................................................15 
1.3.1. 
Schedule of Assessments for Patient-Reported Outcomes .............................................27 
1.3.2. 
Sampling Schedules for Pharmacokinetics .....................................................................29 
2. 
Introduction ...................................................................................................................30 
2.1. 
Study Rationale ...............................................................................................................33 
2.2. 
Background .....................................................................................................................34 
2.3. 
Benefit/Risk Assessment ................................................................................................34 
2.3.1. 
Risk Assessment .............................................................................................................34 
2.3.2. 
Benefit Assessment .........................................................................................................36 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................36 
3. 
Objectives and Endpoints ............................................................................................37 
4. 
Study Design ..................................................................................................................39 
4.1. 
Overall Design ................................................................................................................39 
4.2. 
Scientific Rationale for Study Design ............................................................................40 
4.3. 
Justification for Dose ......................................................................................................40 
4.4. 
End of Study Definition ..................................................................................................41 
5. 
Study Population ...........................................................................................................43 
5.1. 
Inclusion Criteria ............................................................................................................43 
5.2. 
Exclusion Criteria ...........................................................................................................45 
5.3. 
Lifestyle Considerations .................................................................................................47 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................47 
5.4. 
Screen Failures ................................................................................................................47 
6. 
Study Intervention ........................................................................................................48 
6.1. 
Study Intervention(s) Administered................................................................................48 
6.1.1. 
Selection and Timing of Doses .......................................................................................49 
6.1.2. 
Arm A Imlunestrant: General Dosing Instructions .........................................................49 
6.1.3. 
Arm B Investigator’s Choice of Endocrine Therapy of 
Fulvestrant or Exemestane: General Dosing Instructions ...............................................49 
6.1.4. 
Arm C Imlunestrant + Abemaciclib: General Dosing Instructions ................................50 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................50 
6.2.1. 
Arm A Preparation/Handling/Storage: Imlunestrant ......................................................50 
6.2.2. 
Arm B Preparation/Handling/Storage: Investigator’s Choice of 
Endocrine Therapy of fulvestrant or exemestane ...........................................................50 
6.2.3. 
Arm C Preparation/Handling/Storage: Imlunestrant + 
Abemaciclib ....................................................................................................................50 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................50 
6.4. 
Study Intervention Compliance ......................................................................................52 
6.5. 
Concomitant Therapy .....................................................................................................52 
6.5.1. 
Palliative Medicine and Supportive Care .......................................................................54 
6.5.2. 
Supportive Management for Diarrhea ............................................................................54 
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6.5.3. 
Photosensitivity ...............................................................................................................55 
6.6. 
Dose Modification ..........................................................................................................55 
6.6.1. 
Imlunestrant Dose Adjustments for Treatment-Emergent, 
Related*, and Clinically Significant Adverse Events .....................................................56 
6.6.2. 
Dose Modifications for Endocrine Therapy of Investigator’s 
Choice .............................................................................................................................58 
6.6.3. 
Dose Modifications for Abemaciclib ..............................................................................58 
6.6.4. 
Re-escalation Criteria......................................................................................................61 
6.7. 
Intervention after the End of the Study ...........................................................................61 
6.7.1. 
Continued Access............................................................................................................61 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................62 
7.1. 
Participant Discontinuation/Withdrawal from Study Treatment ....................................62 
7.1.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................62 
7.2. 
Discontinuation from the Study ......................................................................................63 
7.3. 
Lost to Follow-Up ...........................................................................................................63 
8. 
Study Assessments and Procedures.............................................................................64 
8.1. 
Efficacy Assessments .....................................................................................................64 
8.1.1. 
Efficacy Assessments at Baseline and during Study Treatment .....................................64 
8.1.2. 
Efficacy Assessments during Post-discontinuation Follow-Up ......................................65 
8.1.3. 
Primary Efficacy Measure ..............................................................................................66 
8.2. 
Safety Assessments .........................................................................................................66 
8.2.1. 
Electrocardiograms .........................................................................................................66 
8.2.2. 
Clinical Safety Laboratory Assessments ........................................................................66 
8.2.3. 
Safety Surveillance .........................................................................................................68 
8.2.4. 
Guidance for Monitoring Renal Function .......................................................................69 
8.2.5. 
Guidance for Venous Thromboembolic Events ..............................................................69 
8.2.6. 
Guidance for Interstitial Lung Disease/Pneumonitis ......................................................69 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................70 
8.3.1. 
Follow-Up of AEs and SAEs ..........................................................................................71 
8.3.2. 
Regulatory Reporting Requirements for SAEs ...............................................................72 
8.3.3. 
Pregnancy ........................................................................................................................72 
8.3.4. 
Cardiovascular and Death Events ...................................................................................72 
8.3.5. 
Complaint Handling ........................................................................................................72 
8.4. 
Treatment of Overdose ...................................................................................................73 
8.5. 
Pharmacokinetics ............................................................................................................73 
8.6. 
Pharmacodynamics .........................................................................................................74 
8.7. 
Genetics ..........................................................................................................................74 
8.7.1. 
Whole Blood Sample for Pharmacogenetic Research ....................................................74 
8.8. 
Biomarkers ......................................................................................................................74 
8.9. 
Health Outcomes and Medical Resource Utilization ......................................................75 
8.9.1. 
Patient-Reported Outcomes ............................................................................................75 
8.9.2. 
EORTC QLQ-C30 ..........................................................................................................76 
8.9.3. 
EORTC IL19: Physical Function ....................................................................................76 
8.9.4. 
EQ-5D-5L .......................................................................................................................77 
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8.9.5. 
PGIS (Patient’s Global Impression of Severity) - Cancer 
Symptoms .......................................................................................................................77 
8.9.6. 
mBPI-sf ...........................................................................................................................77 
8.9.7. 
Worst Pain NRS ..............................................................................................................77 
8.9.8. 
PRO-CTCAE Items for Diarrhea and Injection Site Pain and 
Swelling ..........................................................................................................................77 
8.9.9. 
Medical Resource Utilization .........................................................................................78 
9. 
Statistical Considerations .............................................................................................79 
9.1. 
Statistical Hypotheses .....................................................................................................79 
9.2. 
Sample Size Determination ............................................................................................79 
9.3. 
Populations for Analyses ................................................................................................80 
9.4. 
Statistical Analyses .........................................................................................................81 
9.4.1. 
General Considerations ...................................................................................................81 
9.4.2. 
Treatment Group Comparability .....................................................................................81 
9.4.3. 
Efficacy Analyses ...........................................................................................................82 
9.4.4. 
Patient-Reported Outcomes and Medical Resource Utilization .....................................85 
9.4.5. 
Safety Analyses ...............................................................................................................85 
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................85 
9.4.7. 
Other Analyses ................................................................................................................86 
9.5. 
Interim Analyses .............................................................................................................87 
9.5.1. 
Safety Interim Analyses ..................................................................................................87 
9.5.2. 
Efficacy Interim Analyses...............................................................................................88 
10. 
Supporting Documentation and Operational Considerations ..................................90 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................90 
10.1.1. Regulatory and Ethical Considerations ...........................................................................90 
10.1.2. Financial Disclosure........................................................................................................90 
10.1.3. Informed Consent Process ..............................................................................................91 
10.1.4. Data Protection................................................................................................................91 
10.1.5. Dissemination of Clinical Study Data.............................................................................92 
10.1.6. Data Quality Assurance ..................................................................................................92 
10.1.7. Source Documents ..........................................................................................................94 
10.1.8. Study Closure ..................................................................................................................94 
10.2. 
Appendix 2: Protocol JZLC ECOG Performance Status ................................................95 
10.3. 
Appendix 3: Protocol JZLC RECIST Criteria 1.1 ..........................................................96 
10.4. 
Appendix 4: Clinical Laboratory Tests .........................................................................103 
10.5. 
Appendix 5: Creatinine Clearance Formula .................................................................105 
10.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting ......................................................106 
10.6.1. Definition of AE ...........................................................................................................106 
10.6.2. Definition of SAE .........................................................................................................107 
10.6.3. Definition of Product Complaints .................................................................................108 
10.6.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ....................................................................................................................109 
10.6.5. Reporting of SAEs ........................................................................................................110 
10.6.6. Regulatory Reporting Requirements .............................................................................111 
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10.7. 
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................112 
10.8. 
Appendix 8: Genetics....................................................................................................115 
10.9. 
Appendix 9: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................116 
10.10. 
Appendix 10: Country-specific Requirements .............................................................118 
10.10.1. Belgium .........................................................................................................................118 
10.10.2. Czech Republic .............................................................................................................122 
10.10.3. France ............................................................................................................................125 
10.10.4. Germany ........................................................................................................................127 
10.10.5. Italy ...............................................................................................................................132 
10.10.6. Spain .............................................................................................................................135 
10.11. 
Appendix 11: Inducers and Strong Inhibitors of CYP3A .............................................136 
10.12. 
Appendix 12: CYP3A Sensitive Substrates ..................................................................138 
10.13. 
Appendix 13: Other CYP-Sensitive Substrates ............................................................139 
10.14. 
Appendix 14: Inhibitors and inducers of UGT1A1 .......................................................140 
10.15. 
Appendix 15: Provisions for Changes in Study Conduct during 
Exceptional Circumstances ...........................................................................................141 
10.16. 
Appendix 16: Abbreviations .........................................................................................144 
10.17. 
Appendix 17: Protocol Amendment History ................................................................151 
11. 
References ....................................................................................................................161 
 
 
 
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List of Tables 
Table 
Page 
Table 1: Imlunestrant Dose Reduction Guidelines ....................................................................... 56 
Table 2: Time Point Response: Patients with Target (± Nontarget) Disease ............................. 100 
Table 3: Time Point Response: Patients with Nontarget Disease Only ...................................... 101 
 
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1 
Protocol Summary  
1.1. Synopsis  
Protocol Title: EMBER-3: A Phase 3, Randomized, Open-Label, Study of Imlunestrant, 
Investigator’s Choice of Endocrine Therapy, and Imlunestrant plus Abemaciclib in Patients with 
Estrogen Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer 
Previously Treated with Endocrine Therapy 
Short Title: EMBER-3: A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, 
and Imlunestrant plus Abemaciclib in Patients with ER+, HER2- Advanced Breast Cancer 
Regulatory Agency Identifier Number(s): 
IND #:145311 
EudraCT#: 2021-000079-35 
EU trial number: 2023-506786-63-00 
Rationale: 
The incorporation of CDK4/6 inhibitors into the first line of ET for locally advanced or 
metastatic ER+, human epidermal growth factor receptor 2 negative (HER2-) breast cancer has 
dramatically improved patient outcomes. However, these therapies are not curative, and 
progression eventually occurs in nearly all patients. Outcomes for subsequent second-line ET are 
unfortunately poor and remain an area of unmet need (Chia et al. 2008). Orally bioavailable 
SERDs with improved bioavailability were designed to overcome the PK and pharmacodynamic 
liabilities of fulvestrant, an intramuscularly administered agent and the only currently approved 
SERD. 
Imlunestrant (LY3484356) is an oral SERD with antitumor activity within multiple preclinical 
models, including ESR1-mutant models, and an acceptable toxicity profile in nonclinical species. 
Imlunestrant is a potent degrader and selective pure antagonist of both wild type and mutant ERα 
(encoded for by the gene ESR1). Imlunestrant’s antitumor activity is enhanced by the 
combination with abemaciclib, including in ESR1-mutant models and palbociclib-resistant cells. 
Furthermore, imlunestrant has demonstrated tolerability along with preliminary evidence of 
clinical activity, alone and in combination with abemaciclib.  
Study J2J-OX-JZLC (henceforth referred to as EMBER-3) is a Phase 3, randomized, 3-arm study 
of imlunestrant, Investigator’s Choice of Endocrine Therapy of either fulvestrant or exemestane, 
and imlunestrant plus abemaciclib in patients with ER+, HER2- locally advanced or metastatic 
breast cancer previously treated with an AI, with or without a CDK4/6 inhibitor. This study will 
evaluate 2 comparisons: imlunestrant vs Investigator’s Choice of Endocrine Therapy; and 
imlunestrant plus abemaciclib vs imlunestrant. 
 
 
 
 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 To compare the PFS of imlunestrant (Arm A) to the 
standard comparator of Investigator’s Choice 
Endocrine Therapy of either fulvestrant or 
exemestane (Arm B) in the ITT population 
 To compare the PFS of Arm A to Arm B in the 
ESR1-mutation detected population 
 To compare the PFS of imlunestrant plus 
abemaciclib (Arm C) to imlunestrant (Arm A) in 
the ITT population 
 Investigator-assessed PFS (between Arm A and Arm 
B) in the ITT population 
 Investigator-assessed PFS (between Arm A and Arm 
B) in the ESR1-mutation detected population 
 Investigator-assessed PFS (between Arm C and Arm 
A) in the ITT population 
 
Secondary 
 
 To compare OS of Arm A to Arm B in the ITT 
population  
 To compare OS of Arm A to Arm B in the ESR1-
mutation detected population 
 To compare OS of Arm C to Arm A in the ITT 
population 
 To compare other efficacy objectives of Arm A to 
Arm B, and Arm C to Arm A 
 
OS between Arm A and Arm B in the ITT 
population (key secondary endpoint)  
 
OS between Arm A and Arm B in the ESR1-
mutation detected population (key secondary 
endpoint) 
 
OS between Arm C and Arm A in the ITT 
population (key secondary endpoint) 
 
Investigator-assessed ORR, DoR, and CBR 
 
PFS by blinded Independent Review Committee 
(BIRC) 
 To assess the safety and tolerability of each 
treatment arm  
 Including but not limited to AEs, serious AEs, deaths, 
and clinical laboratory abnormalities per NCI CTCAE 
v5.0 
 To evaluate the effectiveness of Arm A compared 
to Arm B and Arm C compared to Arm A based on 
PROs of pain using the Worst Pain NRS 
 Time to sustained worsening of the “worst pain” as 
measured by Worst Pain NRS  
 To assess the PK of imlunestrant (Arm A and Arm 
C) 
 To assess the PK of abemaciclib and its metabolites 
(Arm C) 
 Plasma concentrations of imlunestrant and 
abemaciclib  
Abbreviations: AE = adverse event; BIRC = blinded Independent Review Committee; CBR = clinical benefit rate; 
CTCAE = Common Terminology Criteria for Adverse Events; DoR = duration of response; ITT = Intention to 
treat; NCI = National Cancer Institute; NRS = numeric rating scale; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetics; PROs = patient-reported outcomes. 
Overall Design 
EMBER-3 is a Phase 3 global, randomized, open-label, 3-arm study of imlunestrant as 
continuous monotherapy (Arm A) Investigator’s Choice Endocrine Therapy of either fulvestrant 
or exemestane (Arm B), and imlunestrant plus abemaciclib (Arm C) in patients with ER+, 
HER2- locally advanced (not amenable to curative treatment by surgery) or metastatic breast 
cancer. The study will enroll patients who have been treated with an AI, alone or in combination 
with a CDK4/6 inhibitor. Prior treatment with a CDK4/6 inhibitor is expected if this treatment is 
approved and reimbursed, and the Sponsor may elect to limit the enrollment of participants who 
have NOT received prior treatment with a CDK4/6 inhibitor. 
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The study will consist of a 28-day screening phase; followed by a treatment phase; and a post-
treatment phase, which includes safety, efficacy, and survival follow-up. Investigator’s Choice 
Endocrine Therapy (fulvestrant or exemestane) must be selected prior to randomization.  
Patients will be randomized 1:1:1 between the 3 treatment arms of imlunestrant (Arm A), 
Investigator’s Choice Endocrine Therapy (Arm B), or imlunestrant plus abemaciclib (Arm C). 
Arm C was added to the study (amendment a) after first patient visit for Arms A and B. 
Randomization of patients will continue in Arms A and B (1:1) until amendment a is approved 
and implemented, at which point patients will be randomized 1:1:1 (A:B:C) until the target 
enrollment for Arm A and Arm B (n=640 in total) is met. 
Patients will be randomized using the following stratification factors:  
 Previous treatment with any CDK4/6 inhibitor (yes versus no) 
 Presence of visceral metastases (yes versus no); visceral includes lung, liver, brain, pleural, 
and peritoneal involvement 
 Region (East Asia versus North America/Western Europe versus Others) 
The primary study objectives are to 
 compare the PFS of Arm A to Arm B in the ITT population, 
 compare the PFS of Arm A to Arm B in the ESR1-mutation detected population, and 
 compare the PFS of Arm C to Arm A in the ITT population.  
To control the overall type I error rate, the PFS hypotheses will be tested hierarchically using a 
graphical approach. Initially, the overall 1-sided alpha level of 0.025 will be split between PFS 
for Arm A versus Arm B in the ITT population and PFS for Arm A versus Arm B in the ESR1-
mutation detected population. PFS for Arm C versus Arm A in the ITT population will be 
inferentially tested only if the PFS for Arm A versus Arm B in either the ITT population or in the 
ESR1-mutation detected population is statistically significant. 
Disclosure Statement: This is a randomized, active treatment study with 3 arms where the patient 
and investigator will not be blinded. 
Study Population: 
 Participants must be at least 18 years of age 
 Have a diagnosis of ER+, HER2- breast cancer, as defined in the relevant ASCO/CAP 
Guidelines 
 Have locally advanced (not amenable to curative treatment by surgery) or metastatic 
disease with disease recurrence or progression on an adjuvant AI with or without a CDK-
4/6 inhibitor. 
 Must be deemed appropriate for treatment with ET. 
 
Number of Participants: 
Approximately 860 participants will be enrolled to this study. 
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Intervention Groups and Duration: 
  
Arm A 
Imlunestrant 
Arm B 
Investigator’s Choice Endocrine Therapy 
Arm C 
Imlunestrant + Abemaciclib 
Treatment 
Imlunestrant 
Fulvestrant 
Exemestane 
Imlunestrant 
Abemaciclib 
Dose 
400 mg 
500 mg 
25 mg 
400 mg 
150 mg 
Schedule 
QD in 28-day 
continuous 
cycles 
500 mg on C1D1 and 
C1D15 and then on Day 
1 of a 28-day cycle 
starting at Cycle 2  
QD in 28-day 
continuous 
cycles 
QD in 28-day 
continuous 
cycles 
BID in 28-day 
continuous 
cycles 
Route 
Oral 
Intramuscular injection 
of two 250 mg injections 
 
Oral 
Oral 
Oral 
Abbreviations: BID = twice daily; C = cycle; D = day; QD = once daily. 
Duration of treatment: 
Patients will be treated until disease progression or other discontinuation criteria are met 
(Section 7.1).  
Ethical Considerations of Benefit/Risk: 
Given the key anticipated benefits for patients with ER+, HER2- mBC, an incurable disease with 
a poor prognosis, and limited non-cytotoxic therapeutic options, the potential risks are considered 
acceptable to evaluate this novel therapy, imlunestrant, as monotherapy or in combination with 
abemaciclib, in this patient population within this global Phase 3 study.  
 
Data Monitoring Committee: Yes 
A DMC will be utilized to assess aggregate efficacy and safety data for this study. Please refer to 
the DMC charter and Section 6.3 for further information. 
 
 
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1.2. 
Schema  
 
 
Note: ESR1 mutation status will be centrally determined in plasma by Guardant 360 ctDNA assay from a blood draw at baseline. 
Treatment administration instructions are detailed in Section 6.1. 
Abbreviations: AI = aromatase inhibitor; CDK = cyclin-dependent kinase; ctDNA = Circulating tumor DNA; ER+ = estrogen receptor positive; FPV = first patient 
visit; HER2- = human epidermal growth factor receptor 2 negative; mTOR = mammalian target of rapamycin; n = number of participants; PI3K = 
phosphoinositide 3-kinase; PO = orally; QD = once daily; R = randomization; SERD = selective estrogen receptor degrader.
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1.3. 
Schedule of Activities  
 
 
Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Study Entry/ 
Enrollment 
Informed consent 
form signed 
X 
 
 
 
 
 
 
Section 10.1.3 
Informed consent form must be signed prior 
to performance of any protocol-specific 
tests or procedures and prior to 
randomization 
Inclusion/exclusion 
evaluation 
X 
 
 
 
 
 
 
Sections 5.1 
and 5.2 
 
Medical History 
Medical history 
X 
 
 
 
 
 
 
Section 9.4.2.2 
 All conditions ongoing and relevant past 
surgical and medical history should be 
collected 
 Malignancy history should be collected 
regarding disease being assessed for this 
study, prior cancer treatments, and any 
history of other malignancy 
Physical 
Examination 
Physical exam 
X 
X 
 
X 
X 
X 
 
Section 9.4.2.2 
 Complete PE including height (at 
screening only), weight, and review of 
relevant symptoms at screening 
 Screening results obtained within 3 days 
of C1D1 can be used for C1D1 results 
Vital signs  
X 
X 
 
X 
X 
X 
 
Section 8.2 
 Include systolic and diastolic blood 
pressure, heart rate, respiratory rate, and 
body temperature 
 Screening results obtained within 3 days 
of C1D1 can be used for C1D1 results 
ECOG PS 
X 
X 
 
X 
X 
X 
 
Section 10.2 
Appendix 2 
Screening results obtained within 3 days of 
C1D1 can be used for C1D1 results 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Clinical Tumor 
Assessment 
Tumor 
measurement 
(palpable or visible) 
X 
 
 
See Instructions 
 
 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Visible tumor (such as skin lesions) 
should be documented by photography, 
and each photographic image of the 
tumor should include a ruler. If 
measurable, caliper measurements should 
be recorded. Images will be collected for 
central storage for BIRC review 
 Perform at RECIST response assessment 
intervals outlined below 
Tumor 
Assessment 
Radiologic imaging 
according to 
RECISTb 
X 
 
 
See Instructions 
 
 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Required for all patients  
 Perform according to RECIST v1.1 
criteria by the same method used at 
baseline 
 CT or MRI scan of the chest, abdomen, 
and pelvis performed with IV contrast 
when possibleb 
 Response assessments should occur at 
baseline and then at the following 
intervals relative to Cycle 1 Day 1: every 
8 weeks (±4 days) for the first 12 months 
and then every 12 weeks (±4 days) 
thereafter, until radiographic disease 
progression, death, start of a new 
anticancer therapy or study completion, 
whichever occurs first.  
 Perform as scheduled, regardless of any 
treatment delays or interruptions 
 Perform within 14 days of clinical 
progression 
 A central radiology vendor will be used 
to collect and store images for BIRC 
review 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
  
X-ray or CT scan 
with bone windows 
or MRI 
X 
 
 
See Instructions 
 
 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Required only for patients with RECIST 
non-measurable bone-only disease, for 
any lesions identified on bone 
scintigraphy that are not visible on the 
chest, abdomen, and pelvis CT or MRI 
 All such bone lesions are evaluated by 
directed imaging (X-ray, CT scan with 
bone windows, or MRI) to enable serial 
assessment 
 One or more of these studies (X-ray, CT 
scan with bone windows, or MRI), 
identical to the study obtained at 
baseline, should be performed at the 
RECIST response assessment intervals 
outlined above 
 For patients with new lesions identified 
by postbaseline bone scintigraphy, 
targeted assessments by X-ray, CT scan 
with bone windows, or MRI will be 
performed to confirm findings 
 A central radiology vendor will be used 
to collect and store images for BIRC 
review 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Brain imaging 
X 
 
 
See Instructions 
 
 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Required at baseline for patients without 
a history of brain metastases: Either a 
brain CT or brain MRI. Contrast is 
recommended. 
 Required at baseline for patients with 
treated brain metastases: Contrast-
enhanced brain MRI is preferred; 
however, if MRI contrast is 
contraindicated, then the following are 
acceptable: MRI (without contrast) or 
brain CT (recommended with contrast).  
 Patients with a history of brain 
metastases must have imaging repeated 
at the RECIST response assessment 
intervals outlined above. 
 A central radiology vendor will be used 
to collect and store images for BIRC 
review. 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Tumor 
Assessment 
Bone scintigraphy 
X 
 
 
 
See 
Instructions 
 
 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Required for all patients (testing up to 45 
days prior to C1D1 may be used for 
baseline assessment) 
 Postbaseline bone scintigraphy should 
occur every 24 weeks (±4 days), with 
first assessment relative to Cycle 1 Day 
1, until radiographic disease progression, 
death, start of a new anticancer therapy, 
or study completion, whichever occurs 
first 
 Perform as scheduled, regardless of any 
treatment delays or interruptions 
 Perform within 14 days of clinical 
progression 
 Importantly, RECIST v1.1 emphasizes 
bone scintigraphy is not adequate to 
measure bone lesions; however, bone 
scintigraphy can be used to confirm the 
presence or disappearance of bone 
lesions 
 A central radiology vendor will be used 
to collect and store images for BIRC 
review 
Patient Diary 
(Arms A and C) 
 
 
X 
 
X 
X 
 
 
 
 Provide patient drug diary on Day 1 of 
each cycle for patients randomized to 
Arms A or C. Completed daily by patient 
 Review at each study visit 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Survival 
Information 
 
 
 
 
 
 
X 
X 
Section 8.1 and 
Section 10.3 
Appendix 3 
 Survival information is collected during 
both study treatment and at post-
discontinuation follow-up  
 During long-term follow-up, survival 
information is collected approximately 
every 12 weeks (±14 days) for the 
duration of this period. Survival 
information may be collected in clinic 
or by contacting the patient or family 
directly (for example, via telephone). 
Long-term follow-up data collection 
may include post-discontinuation 
anticancer therapies. Date of 
progression on the FIRST post-
discontinuation anticancer treatment 
should be collected. 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Adverse Event 
Collection/ 
CTCAE Grading 
 
X 
X 
 
X 
X 
X 
X 
Section 8.3 
 Collect continuously at every visit and 
throughout the study 
 CTCAE Version 5.0  
 For long-term follow-up: all SAEs 
regardless of relationship to study 
treatment and adverse events possibly 
related to study treatment will be 
collected  
 All adverse events possibly related to 
study drugs or protocol procedures 
should be followed until they resolve, 
are no longer considered to be possibly 
related, become stable or return to 
baseline, the patient starts a new 
therapy, the patient expires, or the 
patient becomes lost to follow-up. The 
frequency of evaluation is determined 
according to the judgment of the 
investigator 
Concomitant 
Medications 
 
X 
X 
 
X 
X 
X 
 
Section 6.5 
 At baseline, record prior and concurrent 
medications 
 Record all pre-medications, supportive 
care, and concomitant medication 
continuously at every visit and 
throughout study 
Lab/Diagnostic 
Tests 
Coagulation 
X 
 
 
 
 
 
 
Section 10.4 
Appendix 4 
 Perform at baseline and as clinically 
indicated 
 Local testing  
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Hematology 
X 
X 
X 
X 
X 
X 
 
Section 10.4 
Appendix 4 
 Assessments may be performed up to 3 
days prior to Day 1 of each cycle  
 Local testing 
 Cycles 1 and 2 Day 15 hematology 
required for Arms A, C only 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
Section 10.4 
Appendix 4 
 Assessments may be performed up to 3 
days prior to Day 1 of each cycle 
Central testing 
 Cycles 1 and 2 Day 15 clinical 
chemistry required for Arms A, C only 
FSH and estradiol 
levels 
X 
 
 
 
X 
X 
 
See Section 5.1 
and 
Section 10.4 
 For Screening: local FSH/E2 testing for 
women <60 years when needed to 
confirm post-menopausal status  
 For On study: local estradiol every 3 
cycles, starting on Day 1 of Cycle 4 and 
again at STFU visit, for women whose 
postmenopausal status is due to GnRH 
agonist treatment 
Pregnancy test 
X 
 
 
 
 
X 
 
Section 10.7 
Appendix 7 
 Local testing 
 For Screening: serum pregnancy test 
required for women of child-bearing 
potential 
 For on Study: per local regulations 
and/or institutional guidelines  
 For Short-Term Follow-Up: local 
testing for women of child bearing 
potential 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Fasting lipid testing 
X 
 
 
X 
X 
 
 
Section 10.4 
Appendix 4 
 Perform at baseline, then every 3 cycles 
starting on Cycle 3 Day 1 
 May be performed ±7 days in relation to 
Day 1 of relevant cycles  
 Central testing 
Lab/Diagnostic 
Tests 
Local ECG 
X 
X 
 
 
X 
X 
 
Section 1.3.2 
 A local ECG (no replicates required) 
should be obtained at baseline in all 
patients 
 For patients receiving treatment with 
imlunestrant (Arms A & C): collect 
single local ECG on Day 1 of Cycles 1, 
2, 4 and at the STFU at the time points 
specified in Section 1.3.2 
 Patients must be supine for 
approximately 5 to 10 minutes before 
ECG collection and remain supine but 
awake during ECG collection 
Biomarker, 
Pharmacokinetic, 
Pharmacogenetic, 
Tissue Collection 
PK sample 
 
X 
 
X 
X 
 
 
Section 1.3.2 
 For patients receiving treatment with 
imlunestrant (Arms A & C): collect PK 
samples on Day 1 of Cycles 1, 2, 3 and 
4 at the time points specified in Section 
1.3.2 
Pharmacogenetic 
whole blood sample 
 
X 
 
 
 
 
 
Section 8.7 
 Collect once. Sample may be collected 
anytime if not collected on C1D1 to 
reduce burden of blood draws on C1D1  
Biomarker plasma 
sample 
X 
X 
 
X 
X 
X 
 
Section 8.8 
 Collected during screening; pre-dose on 
C1D1 and at any time on C2D1; then at 
any time on Day 1 of each odd cycle 
beginning with Cycle 3; and lastly at 
STFU Visit 801 
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Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Tumor tissue 
X 
 
 
 
 
 
 
Section 8.8 
 Required for all patients if available  
 See Section 8.8 for additional 
instructions 
Health 
Outcomes 
PRO 
 
See Instructions  
X 
 
Section 1.3.1 
 Performed at the time points specified 
in Section 1.3.1 
 See Section 1.3.1 for details of 
assessment for each instrument 
Hospitalization and 
ED visits 
X 
X 
X 
 
Section 8.9.9  
 
SRE assessment 
X 
X 
X 
 
Sections 8.9.9 
& 9.4.7.1 
 
Study Drug 
Administration 
Imlunestrant 
 
PO QD on Days 1 through 28 of every 
cycle 
 
 
Section 6.1 
 See Section 6.1 for administration 
instructions  
Fulvestrant 
 
IM Days 1 and 15 (±3 days) of Cycle 1, then Day 
1 (±3 days) of Cycle 2 and beyond  
 
 
Section 6.1 
 Administer per approved label 
 See Section 6.1 for administration 
instructions 
Exemestane 
 
PO QD on Days 1 through 28 of every 
cycle 
 
 
Section 6.1 
 Administered per approved label 
 See Section 6.1 for administration 
instructions 
Abemaciclib 
 
PO BID on Days 1 through 28 of every cycle 
 
 
Section 6.1 
 See Section 6.1 for administration 
instructions  
Abbreviations: BID = twice daily; BIRC = blinded independent review committee; C = cycle; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ED = emergency department; FSH = follicular 
stimulating hormone; IM = intramuscular; MRI = magnetic resonance imaging; PE = physical exam; PK = pharmacokinetics; PO = orally; PRO = patient-
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reported outcome; PS = performance status; QD = once daily; RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; SRE 
= skeletal-related event: STFU = short-term follow-up.  
a Short-term follow-up period begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures should be performed once at the end of the short-term follow-up period (approximately 30 days after 
the last dose of study drug). Long-term follow-up period begins the day after the short-term follow-up visit is completed and continues until the patient’s death 
or overall study completion; the associated study procedures are performed approximately every 12 weeks (± 14 days) for the duration of this period beginning 
12 weeks after the short-term follow-up visit. 
b For patients with inoperable locally advanced breast cancer: MRI scan of the breast should occur at baseline and then at the following intervals relative to Cycle 
1 Day 1: every 8 weeks (±4 days) for the first 12 months and then every 12 weeks (±4 days) thereafter. For all patients: Tumor assessments, including 
measurement of visible lesions, CT or MRI scan of the chest, abdomen, and pelvis, should occur at baseline and then at the following intervals with first 
assessment relative to Cycle 1 Day 1: every 8 weeks (±4 days) for the first 12 months and then every 12 weeks (±4 days) thereafter. It is recommended that CT 
imaging of the abdomen and pelvis be performed with IV contrast whenever possible. If this is not feasible due to hypersensitivity or other conditions, then 
gadolinium-enhanced MRI is preferred. For patients with known serious allergic reactions to CT contrast material, a CT of the chest without contrast and 
gadolinium-enhanced MRI of the abdomen/pelvis are encouraged. For patients who discontinue study treatment without objectively measured progressive 
disease, continue to evaluate tumor response at the following intervals relative to Cycle 1 Day 1: approximately every 8 weeks for the first 56 weeks and 
thereafter approximately every 12 weeks until radiographic disease progression, death, start of a new anticancer therapy or study completion, whichever occurs 
first.  
c Cycle 1 Day 15: For patients assigned to Arms A or C, this visit is only for obtaining protocol-specified laboratory studies. For patients assigned to Arm B who 
are receiving fulvestrant, this visit is only for administration of the fulvestrant. Cycle 2 Day 15: For patients assigned to Arms A or C, this visit is only for 
obtaining protocol-specified laboratory studies. 
 
 
 
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Continued Access SoA for All Patients (see also Section 6.7.1) 
 
Study 
Treatment 
Extension Period 
30-Day Follow-Upa 
 
 
Visit 
501-5XX 
901 
 
 
Duration (days) 
28 
30 ±5 
 
 
Procedure 
 
 
Protocol Reference 
Instructions 
AE Collection 
X 
X 
Section 8.3 
Per CTCAE v5.0, for post follow-up, the investigator should 
only be made aware of collected SAEs related to study 
regimen or protocol procedures. 
Collect throughout the study. 
Administer study 
intervention 
X 
 
Section 6.1 
See Section 6.1 for Study Intervention administration details 
and guidelines.  
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event. 
a The extension period begins after study completion and ends at the end of trial. 
 
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1.3.1. 
Schedule of Assessments for Patient-Reported Outcomes  
Instrument 
Screening 
Cycle 1 
Completed at Home during All Cycles until Last 
Visit (SFU) 
Short-Term 
Follow-Up 
Instructions 
Visit Window 
 
Day 1 
Every 
Day 
Every 
Week 
Every 4 
Weeks 
Every 8 
Weeks 
 
 
Worst Pain 
NRS 
 
X 
X 
 
 
 
X 
Completed at home daily by patient on ePRO patient 
hand-held device, except on C1D1 and STFU visits 
when it will be administered in the clinic 
mBPIsf 
 
X 
 
 
X 
 
X 
Completed at home every 4 weeks on ePRO patient 
hand-held device, except on C1D1 and STFU when it 
will be administered in the clinic. 
PRO-CTCAE: 
Diarrhea 
 
X 
 
X 
 
 
X 
Completed at home weekly on ePRO patient hand-held 
device, except on C1D1 and STFU when it will be 
administered in the clinic. 
PRO-CTCAE: 
Injection site 
pain and 
swelling 
 
 
 
X 
 
 
X 
Screening /Logic question completed electronically 
weekly by the patients receiving fulvestrant only. 
PRO CTCAE Injection site pain and swelling item will 
be administered only if the patient has responded “yes” 
to receiving fulvestrant injection during the 2 weeks 
prior. 
Administered at home on ePRO patient hand-held 
device, except on STFU when it will be administered in 
the clinic. 
EORTC QLQ-
C30a 
 
X 
 
 
 
X 
X 
Completed at home every 8 weeks on ePRO patient 
hand-held device, except on C1D1 and STFU when it 
will be administered in the clinic. 
EORTC QLQ-C30 and EORTC IL 19 instruments will 
be administered on an alternating schedule such that 
these are scheduled about 4 weeks apart from each other 
due to the overlapping items for physical function. The 
second administration of EORTC QLQ C-30 will occur 
on C3D1 and then continue every 8 weeks thereafter. 
During the SFU visit, EORTC QLQ-C30 will be 
administered. 
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Instrument 
Screening 
Cycle 1 
Completed at Home during All Cycles until Last 
Visit (SFU) 
Short-Term 
Follow-Up 
Instructions 
Visit Window 
 
Day 1 
Every 
Day 
Every 
Week 
Every 4 
Weeks 
Every 8 
Weeks 
 
 
EORTC IL 19 a  
 
 
 
 
 
X 
 
The first administration of EORTC IL-19 will occur on 
C2D1, completed electronically by the patient at home, 
not site-administered, and then every 8 weeks thereafter. 
EORTC IL 19 will not be administered during the STFU 
visit. 
 
EORTC QLQ-C30 and EORTC IL 19 instruments will 
be administered on an alternating schedule such that 
these are scheduled about 4 weeks apart from each other 
due to the overlapping items for physical function.  
PGIS 
 
X 
 
 
X 
 
X 
Completed at home every 4 weeks on ePRO patient 
hand-held device, except on C1D1 and SFU when it will 
be administered in the clinic. 
EQ-5D-5L 
 
X 
 
 
 
X 
X 
Completed electronically every 8 weeks by the patient. 
Administered at home on ePRO patient hand-held 
device, except on C1D1 and SFU when it will be 
administered in the clinic. 
Abbreviations: C = cycle; D = day; EORTC IL 19 = European Organization for Research and Treatment of Cancer Item Library 19; EORTC QLQ-
C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-5D-5L = 5-level-EuroQol; 
mBPIsf = modified Brief Pain Inventory-short form; NRS = numeric rating scale; PGIS= Patient’s Global Impression of Symptoms; PROs = patient-reported 
outcomes; PRO-CTCAE = Patient Reported Outcomes - Common Terminology Criteria for Adverse Events; STFU = short-term follow-up. 
a EORTC IL 19 will not be administered during the weeks that EORTC QLQ-C30 is administered due to overlapping items.
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1.3.2. 
Sampling Schedules for Pharmacokinetics  
The schedule for PK sampling for patients receiving treatment with imlunestrant (Arm A) or 
imlunestrant plus abemaciclib (Arm C) on study is summarized in the table below. PK samples 
collected in Arm A will be analyzed for imlunestrant concentrations. PK samples collected in 
Arm C will be analyzed for concentrations of both imlunestrant and abemaciclib (and its 
metabolites). See also fasting requirements for imlunestrant dosing in Section 6.1. 
On all PK sampling days (with the exception of Cycle 3 Day 1), patients should take the study 
drug at the clinic. The date and exact time of collection for each venous blood sample should be 
documented on the laboratory requisition. 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. 
Pharmacokinetic Sampling Schedule for Arm A and Arm C 
Cycle 
Day 
PK Sample 
Number 
ECG Sample 
Numbera 
PK Sampling Time Relative to 
Imlunestrant Dosing  
Screening 
Day -28 to Day -1 
 
1 
 
Cycle 1 
Day 1 
1 
2 
2 to 4 hours postdose 
Cycle 2 
Day 1 
2 
3 
Predoseb 
Cycle 3 
Day 1c 
3 
 
PK draw should occur approximately 3 
hours after study drug dose. For 
flexibility, the patient may take C3D1 
dose at home prior to arrival at site. 
Day 1c 
4 
 
2 ± 0.5 hours after PK Sample Number 
3 (at least 5 ± 0.5 hours after taking 
study drug dose at home)  
Cycle 4 
Day 1 
5 
4 
Predoseb 
Short-term 
follow-up 
30-Day follow-up 
 
5 
 
Abbreviations: ECG = electrocardiogram; PK = pharmacokinetic. 
a A local ECG (no replicates required) should be obtained at baseline in all patients, 2 to 4 hours after the imlunestrant 
dose on Cycle 1 Day 1, pre-imlunestrant dose on Cycle 2 Day 1, and Cycle 4 Day 1, and at the short-term follow-
up visit. Predose ECGs should be taken at either 90 (-90) minutes, 60 (-60) minutes, or 30 (-30) minutes. Predose 
time points are flexible for site convenience. 
b Predose PK samples should be taken within 90 minutes prior to next dose. 
c On Cycle 3 Day 1 only, patient may take study drug dose at home before arrival at site. The time of study drug 
dose intake must be recorded by the patient that day. 
 
 
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2. 
Introduction  
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). Treatment options for women with breast 
cancer are largely determined by tumor hormone receptor (HR) and HER2 status (Gradishar et 
al. 2020; Waks and Winer 2019). 
Over two-thirds of breast cancers express the ER, which is a key driver of breast cancer initiation 
and progression. ER+ mBC is incurable and therefore considered a serious and life-threatening 
disease, with a median OS of only 2 to 3 years (Cardoso et al. 2012; Sledge 2020). For patients 
with HR+, HER2- status, treatment options include ET given alone or in combination with a 
CDK4/6 inhibitor (abemaciclib, palbociclib, ribociclib); an mTOR inhibitor (everolimus), or a 
PI3K inhibitor (alpelisib, for the subset of tumors also harboring select PIK3CA mutations). 
Alternatively, some patients may receive chemotherapy (for example, capecitabine, docetaxel, 
paclitaxel, nab-paclitaxel (Waks and Winer 2019; Gradishar et al. 2020) as initial therapy based 
on aggressiveness at initial presentation, or as salvage therapy following failure of ET-based 
interventions. However, in most ER+ breast cancers, ER remains an important therapeutic target 
even after the development of resistance to initial ET and changing the ET backbone has led to 
improved outcomes, either alone or with other anticancer therapies (Weatherman et al. 1999; 
Baselga et al. 2012; Turner et al. 2015; Finn et al. 2016; André et al. 2019). 
Multiple means of inhibition of ER signaling are already available. These include strategies such 
as direct ER modulation (tamoxifen), systemic prevention of the conversion of androgens to 
estrogens using AIs, and SERDs (fulvestrant) that block and degrade the ER. While ET is 
typically highly effective initially, especially with the incorporation of CDK4/6 inhibitors (Finn 
et al. 2016; Hortobagyi et al. 2016; Goetz et al. 2017), most patients ultimately relapse and 
develop acquired ET resistance (Lei et al. 2019). Outcomes for subsequent second-line ET, often 
with fulvestrant or exemestane, are unfortunately poor and remain an area of unmet need 
(Chia et al. 2008).  
It is now understood that an important mechanism to the development of ET resistance is the 
acquisition of somatic mutations in the ER gene (ESR1) (Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014). These mutations result in a ligand-independent constitutively activated 
ER, leading to proliferation and decreased sensitivity to ET. These mutations in ESR1 have been 
observed in anywhere up to 50% of mBC patients with the rate highest in patients treated with 
multiple lines of ET (Zundelevich et al. 2020). Importantly, both preclinical and clinical data 
demonstrate that SERDs can continue to exert antagonistic effects even in the presence of select 
ESR1 mutations (Toy et al. 2017, Turner et al. 2020), ultimately leading to downregulation of the 
constitutively active receptor.  
Fulvestrant is currently the only regulatory agency-approved SERD for the treatment of ER+ 
mBC (Nardone et al. 2019). However, it has limitations. Due to its insoluble nature with poor 
oral bioavailability and a short intravenous (IV) half-life, fulvestrant needs to be given IM and is 
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highly dose dependent (Robertson and Harrison 2004; Robertson et al. 2004). Certainly, 
improved outcomes were observed in patients receiving a dose of 500 mg IM compared to 
250 mg IM (Di Leo et al. 2014). Even though doses higher than 500 mg per month may lead to 
better ER degradation, the IM administration route of fulvestrant limits the amount of fulvestrant 
that can be given to patients. Moreover, studies have shown that the maximum administrable 
dose of 500 mg remains insufficient for maximal ER downregulation in patients. Certainly, 
patients with inadequate ER downregulation to fulvestrant do appear to do significantly worse 
than those with a greater decrease in ER, as measured by reduction in ER availability on FES-
PET (van Kruchten et al. 2015). 
Therefore, there is unmet medical need to develop novel ETs, such as oral SERDs to overcome 
both the resistance and the PK limitations of fulvestrant, to offer improved bioavailability, 
greater ER-targeting and -degradation capabilities (Nardone et al. 2019). 
Introduction/Rationale for Amendment (a): Addition of Study Arm C (Imlunestrant plus 
Abemaciclib) 
The incorporation of CDK4/6 inhibitors with ET into first line treatment of HR+, HER2- MBC 
has dramatically improved outcomes (Finn et al. 2016, Tripathy et al. 2018, Johnston et al. 
2019). Additionally, the monarchE trial demonstrated significant and clinically meaningful 
improvement in IDFS and DRFS with the addition of abemaciclib to adjuvant endocrine therapy 
(ET) (Johnston et al. 2020).  
However, resistance mechanisms to CDK4/6 inhibitor regimens are not well understood and may 
be multifactorial, including resistance to the ET backbone and/or the CDK4/6 inhibitor. 
Specifically, tumors that have developed endocrine resistance (e.g., through an ESR1 mutation, a 
common mechanism of acquired ET resistance), may still have continued dependence on 
inhibition of the CDK4 and 6 pathway. Given the safety and tolerability of CDK4/6 inhibitors in 
combination with ET, there is growing interest in testing the continuation of a CDK4/6 inhibitor 
beyond progression while switching the ET backbone. In fact, some randomized Phase 2 studies 
of continued CDK4/6 inhibition are ongoing to address this question (NCT02632045, 
NCT03147287, NCT03809988). Supporting this hypothesis, there is preclinical data 
demonstrating synergy of abemaciclib plus fulvestrant in cell lines resistant to CDK4/6 inhibitors 
(data on file) along with real-world retrospective clinical studies suggesting the benefit of 
abemaciclib following disease progression on a CDK4/6 inhibitor (Wander et al. 2020, Mariotti 
et al. 2020, Martin et al. 2020).  
Study J2J-OX-JZLC (henceforth referred to as EMBER-3) is a Phase 3, randomized, 3-arm study 
of imlunestrant, Investigator’s Choice of Endocrine Therapy of either fulvestrant or exemestane, 
and Imlunestrant plus Abemaciclib for patients with ER+, HER2- locally advanced or metastatic 
breast cancer previously treated with an AI, with or without a CDK4/6 inhibitor. This study will 
evaluate 2 comparisons: Imlunestrant vs Investigator’s Choice of Endocrine Therapy; and 
Imlunestrant plus Abemaciclib vs Imlunestrant. 
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Introduction/Rationale for Amendment (b): Addition of the PFS of Arm A to Arm B in the 
ESR1-mutation detected population as a primary endpoint 
The primary goals of this trial are to determine whether: imlunestrant prolongs PFS compared to 
Investigator’s Choice of Endocrine Therapy in patients with ER+, HER2- locally advanced or 
mBC previously treated with an AI with or without a CDK4/6 inhibitor; AND if imlunestrant 
plus abemaciclib prolongs PFS compared to imlunestrant monotherapy (inferentially tested 
ONLY if the PFS between Arm A and Arm B is statistically significant).  
It is well understood that a proportion (up to approximately 50%) of the unselected enrolled 
population (ITT population) will have an ESR1-mutation detected at baseline (ESR1-mutation 
detected population) (Zundelevich et al. 2020). Analyses in this subpopulation were already 
prespecified in the initial study protocol. However, with this amendment (amendment b), the 
analysis of PFS in the ESR1-mutation detected population now will be elevated to a primary 
endpoint, based on evolving data among the novel SERD class showing increased clinical benefit 
with ESR1-mutation enrichment (Bidard et al. 2022). With the proposed statistical methodology 
to adjust for multiplicity, the trial will be considered to have met its primary objective (for the 
Arm A to Arm B comparison) if imlunestrant is superior to Investigator’s Choice of Endocrine 
Therapy in PFS in either all patients (ITT) OR in patients with an ESR1-mutation detected 
(ESR1-mutation detected population). 
Introduction/Rationale for Amendment (c): Increasing the sample size for PFS between 
Arm A and Arm B 
In this amendment, the total sample size for Arm A and Arm B has been increased to 
approximately 640 participants (320 in each arm). The primary analysis of PFS between Arm A 
and Arm B in the ITT population will be conducted when approximately 480 events have been 
observed (maintaining the same censoring rate of 25% as before). With a total of 480 events, the 
statistical power has been increased from 80% to 89% assuming a target hazard ratio of 0.74. 
Correspondingly, the required number of events for PFS between Arm A and Arm B in the 
ESR1-mutation detected population has also been increased from approximately 150 to 192, 
resulting in increased statistical power (from 80% to 90%) for this endpoint as well.  
Additionally, all three arms will be closed at the same time (once the target enrollment for 
Arm A and Arm B is met). The estimated total sample size across all three arms has increased 
from approximately 800 to 860 under the updated enrollment assumptions.  
Introduction/Rationale for Amendment (d): Updating initial alpha allocation for PFS 
between Arm A and Arm B 
In this amendment, the initial alpha allocation for PFS between Arm A and Arm B in the ITT 
population (H1) and PFS between Arm A and Arm B in the ESR1-mutation detected population 
(H2) is updated from 0.02 and 0.005 to 0.005 and 0.02, respectively. This update is based on the 
external data of oral SERDs in patients with recurrent ER+ HER2 negative breast cancer where 
clinically and statistically meaningful improvement in PFS has been primarily driven by the 
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ESR1-mutation detected population (Bidard et al. 2022). In addition, the second interim analysis 
for efficacy for H1 (interim 2) has been removed since the timing of interim 2 is projected to be 
closer to the timing of the final analysis based on the updated enrollment projection. 
2.1. 
Study Rationale  
Imlunestrant (Arm A) 
Imlunestrant is an orally bioavailable, pure ER antagonist, and potent ER degrader, developed to 
address the limitations of existing SERD therapy. Specifically, imlunestrant has favorable 
pharmacologic and PK properties designed to support continuous ER inhibition throughout the 
dosing period, with a large volume of distribution and high intratumoral accumulation compared 
to plasma (exposures 12- to 56-fold higher in tumor than plasma in preclinical models). 
Imlunestrant has shown antitumor activity within multiple preclinical models, including 
ESR1-mutant models, along with an acceptable toxicity profile in nonclinical species (see the IB 
for further details on the preclinical package).  
In the Phase 1a/1b study (J2J-MC-JZLA, NCT04188548, EMBER), imlunestrant has shown 
acceptable safety with the most common TEAEs possibly related to study drug including nausea, 
fatigue, and diarrhea. Importantly, imlunestrant has demonstrated preliminary evidence of 
clinical activity with a clinical benefit rate of 48% in patients with ER+ HER2- mBC, including 
in those previously treated with fulvestrant and CDK4/6 inhibitors (Jhaveri et al. 2021). 
Additional information pertaining to nonclinical and clinical safety, efficacy, and PK of 
imlunestrant may be found in the IB. 
Imlunestrant plus Abemaciclib (Arm C) 
Abemaciclib is a CDK4/6 inhibitor with proven benefit in PFS and OS in CDK4/6-naïve patients 
with ER+ HER2- MBC when combined with ET (Spring et al. 2019; Sledge et al. 2020). Along 
with this, preclinical and limited clinical data also suggest benefit of abemaciclib in a CDK4/6-
pre-treated context. (Wander et al. 2020, Mariotti et al. 2020, Martin et al. 2020).  
Imlunestrant’s antitumor activity is enhanced by the combination with abemaciclib. Importantly, 
imlunestrant has shown strong synergy or additivity in in vitro combination studies with 
abemaciclib, along with good tolerability and enhanced efficacy with abemaciclib in MCF7 and 
T47D ESR1-wild type breast cancer xenograft model and in an ESR1-mutant Y537S breast 
cancer PDX model. Additionally, the combination of abemaciclib plus imlunestrant 
synergistically inhibits growth in palbociclib-resistant cells, accompanied by decreased Ki-67 (a 
marker of proliferation) and increased senescence and apoptosis (data on file). 
In the EMBER (J2J-MC-JZLA) study, 4 cohorts of the phase 1b included imlunestrant plus 
abemaciclib combination treatment regimens. The combination, at the proposed doses, has 
shown an acceptable safety profile. The overall safety profile was generally consistent with 
expectations for an abemaciclib plus ET combination, with the most common TEAEs observed 
including diarrhea, nausea, vomiting, fatigue, decreased appetite and neutropenia. 
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Additional information pertaining to the clinical safety, efficacy, and PK of imlunestrant plus 
abemaciclib may be found in the imlunestrant IB. 
2.2. 
Background  
As described in Section 2, there remains an unmet medical need for novel, improved, and 
tolerable ETs for the management of ER+, HER2- mBC, that can overcome the PK and 
resistance limitations of ETs currently used in the clinic. To this end, promising clinical data 
have been observed with the oral SERD, imlunestrant, in heavily pretreated ER+ mBC patients. 
Along with this, abemaciclib has well established clinical benefit in CDK4/6-naïve patients in 
the 1st and 2nd line setting and has the potential for benefit in CDK4/6-pre-treated patients 
(Sections 2 & 2.1). The clinical and the preclinical results outlined in Section 2.1 support further 
investigation of imlunestrant and imlunestrant plus abemaciclib for patients with ER+, HER2- 
locally advanced or mBC.  
The purpose of this study, in patients with ER+, HER2- locally advanced or mBC previously 
treated with an AI with or without a CDK4/6 inhibitor, is to determine whether: imlunestrant 
prolongs PFS compared to Investigator’s Choice of Endocrine Therapy; and if imlunestrant plus 
abemaciclib prolongs PFS compared to imlunestrant monotherapy. 
Patient randomization within this study will be stratified by known prognostic factors (see 
Section 4.1 for further details) to reduce the potential for bias and improve the power of the 
analyses. Randomization minimizes systematic bias in the selection and assignment of patients to 
study therapy and provides justification for inferential statistical methods to be used on data from 
this study. Using an appropriate concurrent control arm enables direct statistical estimation of 
benefits and harms due to study therapy and minimizes bias in the assessment and interpretation 
of observed treatment effects. See Sections 6.2.3 and 9.4.2 for further description. 
2.3. 
Benefit/Risk Assessment  
2.3.1. 
Risk Assessment  
The clinical safety experience from the EMBER study is described in Section 2.1 with additional 
details described in the IB. Imlunestrant 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 imlunestrant mechanism of action and the patient 
population being treated. Similarly, available clinical data for imlunestrant plus abemaciclib have 
shown the combination to have a manageable safety profile with the majority of observed events 
being low grade and expected based on prior abemaciclib plus ET combination experience. 
Imlunestrant toxicology studies demonstrate an acceptable safety profile, with toxicities that are 
generally monitorable and/or reversible and are clinically manageable in the EMBER-3 patient 
population. The toxicity of imlunestrant has been evaluated in a comprehensive series of 
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nonclinical safety studies, including repeat-dose toxicology studies in Sprague-Dawley rats and 
cynomolgus monkeys, genetic toxicity, and phototoxicity studies. 
Potential toxicities identified in nonclinical studies include 
 effects on female reproductive organs, including ovarian follicular cysts and atrophy of the 
epithelium of the uterus, cervix, and vagina 
 hematological changes, namely increased white blood cells 
 decreased lymphoid cellularity in lymphoid organs 
 renal effects, such as tubular degeneration at non-tolerated doses in rats 
 hepatic effects, such as increased liver enzymes lacking morphological correlation 
 gastrointestinal effects including abnormal feces  
 phototoxicity, based on an in vitro study 
 chromosomal damage, based on an in vitro study (not observed in the in vivo study). 
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 (WOCBP) that enroll in EMBER-3 will: 
 Have a negative pregnancy test prior to starting study 
 Agree to use highly effective contraception prophylaxis for up to 6 months after the last 
dose of imlunestrant (also applies to male participants) 
 Agree to use hormone suppression initiated at least 28 days prior to study treatment with 
a gonadotropin-releasing hormone agonist such as goserelin or leuprolide 
 Receive guidance regarding potential reproductive and developmental toxicities in 
informed consent documents 
Assessment of the potential overlapping toxicities of the combination regimen imlunestrant and 
abemaciclib based on current non-clinical and clinical data are considered to be: 
 increased liver enzymes 
 gastrointestinal effects  
 increased susceptibility to infections 
 reproductive and developmental toxicity 
The potential overlapping toxicities identified are expected to be reversible on discontinuation of 
study drug and/or investigational product and, therefore, readily managed in clinical practice.  
The risk to subjects in this Phase 3 trial will be minimized by compliance with the eligibility 
criteria, study procedures, close clinical monitoring (including regular hematological and 
chemistry testing), recommendations for concomitant medications, guidance for prohibited 
medications, and dose adjustments. Patients will be monitored using clinical safety laboratory tests 
as described in Section 8.2. Appropriate AE management, safety assessments, and on-study 
monitoring are detailed in Sections 6.6, 8.2, and 1.3 (SoA), respectively. Hepatic and renal function 
are regularly monitored throughout the study by means of measurement of chemistry values. 
Increased susceptibility to infection will be monitored through regular hematology monitoring. 
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Patients will also be advised to use sunscreen if out in direct sunlight, to reduce the possibility of 
phototoxicity. 
These activities will enable appropriate investigator oversight, including identification and 
management of AEs. Should the risk profile change as more information becomes available, 
additional testing and/or evaluations, and adjustments to the dose of  may be implemented. Refer 
to Section 4.3 for the justification of the selected therapy doses.  
More detailed information about the known and expected benefits, risks, reasonably expected 
adverse events, SAEs, and safety profiles of imlunestrant and abemaciclib can be found in the 
latest versions of the respective IBs. 
Detailed information about the known and expected benefits and risks of the SOC approved agents, 
fulvestrant and exemestane, may be found in the following: Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics. 
2.3.2. 
Benefit Assessment  
In patients with ER+, HER2- locally advanced or mBC previously treated with an AI, with or 
without a CDK4/6 inhibitor, treatment with imlunestrant may result in an improved clinical 
benefit compared to Investigator’s Choice of Endocrine Therapy (fulvestrant or exemestane); 
and treatment with imlunestrant plus abemaciclib may result in an improved clinical benefit 
compared to imlunestrant. All patients enrolled in this trial will receive an active therapy, either 
the investigational agent, imlunestrant alone or in combination with abemaciclib or an approved 
ET that is SOC (Section 2, Introduction).  
Based on preclinical and preliminary clinical data (see Sections 2.1 and 2.2), treatment with 
imlunestrant is expected to be well tolerated and to delay disease progression compared to 
Investigator’s Choice of ET; and treatment with imlunestrant plus abemaciclib is expected to 
further improve upon the benefit seen with imlunestrant as a single agent and to be well 
tolerated. 
Patients receiving imlunestrant may also benefit from increased convenience and less pain 
associated with monthly IM fulvestrant injections. 
2.3.3. 
Overall Benefit: Risk Conclusion  
Given the key anticipated benefits for patients with ER+, HER2- mBC, an incurable disease with 
a poor prognosis and limited non-cytotoxic therapeutic options, the potential risks are considered 
acceptable to evaluate this novel therapy, imlunestrant, as monotherapy or in combination with 
abemaciclib, in this patient population within this global Phase 3 study.  
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 To compare the PFS of imlunestrant (Arm A) to the 
standard comparator of Investigator’s Choice 
Endocrine Therapy of either fulvestrant or 
exemestane (Arm B) in the ITT population 
 To compare the PFS of Arm A to Arm B in the 
ESR1-mutation detected population 
 To compare the PFS of imlunestrant plus 
abemaciclib (Arm C) to imlunestrant (Arm A) in 
the ITT population 
 Investigator-assessed PFS (between Arm A and Arm 
B) in the ITT population 
 Investigator-assessed PFS (between Arm A and Arm 
B) in the ESR1-mutation detected population 
 Investigator-assessed PFS (between Arm C and Arm 
A) in the ITT population 
 
 
Secondary 
 To compare OS of Arm A to Arm B in the ITT 
population 
 To compare OS of Arm A to Arm B in the ESR1-
mutation detected population 
 To compare OS of Arm C to Arm A in the ITT 
population 
 To compare other efficacy objectives of Arm A to 
Arm B, and Arm C to Arm A 
 OS between Arm A and Arm B in the ITT population 
(key secondary endpoint) 
 OS between Arm A and Arm B in the ESR1-mutation 
detected population (key secondary endpoint) 
 OS between Arm C and Arm A in the ITT population 
(key secondary endpoint) 
 Investigator-assessed ORR, DoR, and CBR 
 PFS by blinded Independent Review Committee 
(BIRC) 
 To assess the safety and tolerability of each 
treatment arm  
 Including but not limited to AEs, serious AEs, deaths, 
and clinical laboratory abnormalities per NCI CTCAE 
v5.0 
 To evaluate the effectiveness of Arm A compared 
to Arm B and Arm C compared to Arm A based on 
PROs of pain using the Worst Pain NRS 
 Time to sustained worsening of the “worst pain” as 
measured by Worst Pain NRS  
 
To assess the PK of imlunestrant (Arm A and Arm 
C) 
 
To assess the PK of abemaciclib and its metabolites 
(Arm C)  
 Plasma concentrations of imlunestrant and 
abemaciclib 
Exploratory 
 
To assess exploratory clinical parameters of Arm A 
compared to Arm B, and Arm C compared to Arm 
A 
 
 Time to progressive bone metastases 
 Time to first SRE (defined as either pathological 
fracture, spinal cord compression, radiation to the 
bone, or surgery to the bone) 
 TTC 
 CFS 
 PFS2 (from randomization to disease progression on 
the next line of treatment or death) 
 Time to worsening of ECOG PS of ≥2 
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Objectives 
Endpoints 
 To explore other PRO and HRQOL parameters of 
Arm A compared to Arm B, and Arm C compared 
to Arm A 
  
 Time to worsening of physical function as measured 
by the physical function score of EORTC IL 19 
 Change from baseline as measured by EORTC QLQ-
C30 and EQ-5D-5L 
 Incidence of AE using the PRO-CTCAE item for 
diarrhea 
 Change from baseline as measured by the PGIS-
Cancer Symptoms  
 To compare clinical efficacy parameters of Arm C 
to Arm B 
 PFS 
 OS 
 To explore potential biomarkers related to the ER 
pathway and/or the pathogenesis of breast cancer  
 Biomarker results and efficacy outcomes 
Abbreviations: AE = adverse event; BIRC = blinded Independent Review Committee; CBR = clinical benefit rate; 
CFS = chemotherapy-free survival; CTCAE = Common Terminology Criteria for Adverse Events; 
ctDNA = Circulating tumor DNA; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; 
EORTC IL 19 = European Organization for Research and Treatment of Cancer Item Library 19; EORTC QLQ-
C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-
5D-5L = 5-level-EuroQol; ER = estrogen receptor; HRQOL = Health Related Quality of Life; ITT = Intention to 
treat; NCI = National Cancer Institute; NRS = numeric rating scale; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PGIS = Patient’s Global Impression of Symptoms; 
PK = pharmacokinetics; PROs = patient-reported outcomes; PS = performance status; SRE = skeletal-related 
event; TTC = time to chemotherapy. 
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4. 
Study Design  
4.1. 
Overall Design  
EMBER-3 is a Phase 3 global, randomized, open-label confirmatory study for patients with ER+, 
HER2- locally advanced (not amenable to curative treatment by surgery) or mBC, who have 
been treated with an AI, alone or in combination with a CDK4/6 inhibitor. Prior treatment with a 
CDK4/6 inhibitor is expected if this treatment is approved and reimbursed and the Sponsor may 
elect to limit the enrollment of participants who have NOT received prior treatment with a 
CDK4/6 inhibitor. 
Participants will be randomized 1:1:1 between 3 treatment arms (Arm A: Arm B: Arm C) and 
will be treated until disease progression or other discontinuation criteria are met (Section 
7.1).See also schema (Section 1.2) 
 
Arm A: Imlunestrant 400 mg orally QD on Days 1 to 28 of a 28-day cycle  
 
Arm B: Investigator’s Choice Endocrine Therapy  
o Exemestane 25 mg orally QD on Days 1 to 28 of a 28-day cycle OR 
o Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 
of Cycle 2 and beyond 
 
Arm C: Imlunestrant + Abemaciclib 
o Imlunestrant 400 mg orally QD on Days 1 to 28 of a 28-day cycle 
o Abemaciclib 150 mg orally BID on Days 1 to 28 of a 28-day cycle 
Arm C was added to the study (amendment a) after first patient visit for Arms A and B. 
Randomization of participants will continue in Arms A and B (1:1) until amendment a is 
approved and implemented, at which point participants will be randomized 1:1:1 (A:B:C) until 
the target enrollment for Arms A and B (a total number of approximately 640 participants) is 
met. 
The study will consist of a 28-day screening phase; followed by a treatment phase; and a post-
treatment phase, which includes safety, efficacy, and survival follow-up. Investigator’s Choice 
Endocrine Therapy (fulvestrant or exemestane) must be selected prior to randomization. 
Participants will be randomized using the following stratification factors: 
 previous treatment with any CDK4/6 inhibitor (yes versus no)  
 presence of visceral metastases (yes versus no); visceral includes lung, liver, brain, 
pleural, and peritoneal involvement, and 
 region (East Asia versus North America/Western Europe versus Others). 
The primary study objectives are to  
 compare the PFS of Arm A to Arm B in the ITT population 
 compare the PFS of Arm A to Arm B in the ESR1-mutation detected population, and  
 compare the PFS of Arm C to Arm A in the ITT population.  
To control the overall type I error rate, a graphical approach will be applied to test these PFS 
hypotheses hierarchically. Initially, the overall 1-sided alpha level of 0.025 will be split between 
PFS for Arm A versus Arm B in the ITT population and PFS for Arm A versus Arm B in the 
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ESR1-mutation detected population. PFS for Arm C versus Arm A in the ITT population will be 
inferentially tested only if the PFS for Arm A versus Arm B in either the ITT population or the 
ESR1-mutation detected population is statistically significant. Further details are provided in 
Section 9 . 
 The primary analysis of PFS between Arm A and Arm B in the ITT population will be 
performed after approximately 480 investigator-assessed PFS events have been observed 
in Arm A and Arm B.  
 The primary analysis of PFS between Arm A and Arm B in the ESR1-mutation detected 
population will be performed after approximately 192 investigator-assessed PFS events 
have been observed in the ESR1-mutation detected subset (or 80% of the participants in 
this subset have experienced an event, whichever is earlier) in Arm A and Arm B.  
 The primary analysis of PFS between Arm C and Arm A will be performed after 
approximately 248 investigator-assessed PFS events have been observed among the 
participants concurrently randomized to Arm A and Arm C.  
Under the enrollment assumptions, it is estimated that a total of approximately 860 participants 
(320 in Arm A, 320 in Arm B, and 220 in Arm C) will be enrolled to this study. Details on 
sample size determination (including the enrollment assumptions) and statistical considerations 
are described in Section 9.  
Please refer to Section 1.2 for a study schema. 
4.2. 
Scientific Rationale for Study Design  
The overall rationale for the study design is described in Section 2.2, and statistical considerations 
are described in Section 9. Dose selection and justification details can be found in Section 4.3 
(Justification for Dose). 
4.3. 
Justification for Dose  
Imlunestrant 
The dose of imlunestrant monotherapy and in combination with abemaciclib used in this study 
will be 400 mg given orally once daily (see table in Section 6.1).  
Preclinical data supporting the selection of the starting dose of imlunestrant for the EMBER 
study is detailed in the imlunestrant IB. In short, in in vivo target inhibition studies, imlunestrant, 
dosed at 10 mg/kg in mice, showed sustained and prolonged inhibition of PGR α expression, a 
transcriptional target and pharmacodynamic biomarker of Erα, of more than 75% inhibition of 
PGR for up to 96 hours. Based upon the preclinical PK and pharmacodynamic modeling 
performed in both wildtype and ESR1 mutant xenograft models, the in vivo plasma EC80 range 
for PGR inhibition was predicted to be 17-28 ng/mL. Clinical doses for the Phase 1a dose 
escalation study (EMBER) were based on predicted human PK, assuming similar PK and 
pharmacodynamic relationships between species. Average clinical doses of 200 mg QD (80% 
prediction interval of 100–750 mg QD) were thus predicted to achieve 80% PGR inhibition, the 
level of inhibition associated with efficacious doses in mouse xenograft studies. 
During Phase 1 dose escalation, imlunestrant was administered at doses ranging from 200 mg 
QD to 1200 mg QD. PK data obtained during dose escalation demonstrated that at doses of 
200 mg QD or higher, steady-state plasma concentrations of imlunestrant exceeded the EC80 
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range calculated from xenograft efficacy models, suggesting that predicted efficacious 
concentrations would be reached at these doses. Based on the totality of efficacy, clinical PK, 
and safety data of all enrolled patients (detailed in the IB), the Sponsor determined that the 
recommended Phase 2 dose of imlunestrant is 400 mg QD. 
As previously described in Section 2.1, the proposed doses of imlunestrant 400 mg QD and 
abemaciclib 150 mg BID demonstrated an acceptable safety profile. In addition, despite the 
potential for a drug-drug interaction between abemaciclib and imlunestrant based on in vitro data 
(see Section 6.5), preliminary PK data from EMBER indicate that abemaciclib concentrations are 
within the normal range of those in monotherapy studies (Patnaik et al 2016).  
Therefore, the imlunestrant dose of 400 mg QD in combination with abemaciclib 150 mg BID 
has been selected as the dose in this study. 
Fulvestrant 
The dose of fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 of a 28-day cycle, 
then on Day 1 of Cycle 2 and beyond) was selected for this study, as this is the recommended 
doses in patients with mBC based on tolerability, efficacy, and PK (fulvestrant package insert). 
Further justification for dose may be found in the corresponding Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics. 
Exemestane 
The QD dose of 25 mg of exemestane was selected for this study, as this is the recommended 
doses in patients with mBC based on tolerability, efficacy, and PK (exemestane US package 
insert). Further justification for dose may be found in the corresponding Patient Information 
Leaflet, Package Insert, or Summary of Product Characteristics. 
Abemaciclib 
For the approved indication in HR+, HER2- MBC, the recommended starting dose of 
abemaciclib in combination with fulvestrant is 150 mg BID. This is based on the pivotal Phase 3 
study, MONARCH 2 (Sledge et al. 2017), in which abemaciclib 150 mg BID in combination 
with fulvestrant exhibited a manageable safety profile and resulted in clinically meaningful PFS 
and OS benefit compared to fulvestrant/placebo in patients with HR+, HER2- advanced or 
metastatic breast cancer (Verzenio® package insert, 2019). Further support of the abemaciclib 
dose in combination with imlunestrant can be found in Section 2.1 and the imlunestrant IB. 
Refer to the abemaciclib IB for additional details. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA (Section 1.3) for the last participant in the trial 
globally. This study will be considered complete (that is, the scientific evaluation will be 
complete [study completion]) following the evaluation of final OS data (see Study Period and 
Extension Period Diagram below) as determined by the Sponsor. Investigators will continue to 
follow the study schedule for all patients until notified by the Sponsor that study completion has 
occurred. 
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“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient. 
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed continued access period follow-up (Figure below). 
Study Period and Extension Period Diagram 
 
Abbreviations: OS = overall survival; PFS = progression-free survival. 
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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  
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant must be at least 18 years of age 
2. Have a diagnosis of ER+, HER2- breast cancer 
a. to fulfill the requirement for ER+ disease, a breast cancer must express the ER by 
immunohistochemistry, as defined in the relevant ASCO/CAP Guidelines (Allison 
et al. 2020) 
b. to fulfill the requirement of HER2- disease, a breast cancer must not demonstrate, 
at initial diagnosis or upon subsequent biopsy, overexpression of HER2 by either 
immunohistochemistry (IHC) or in-situ hybridization as defined in the relevant 
ASCO/CAP Guidelines (Wolff et al. 2018). Although not required as a protocol 
procedure, a patient with a new metastatic lesion should be considered for biopsy 
whenever possible to reassess HER2 status prior to study entry if clinically 
indicated 
3. Have locally advanced (not amenable to curative treatment by surgery) or metastatic 
disease and fulfill 1 of the following criteria (3a-c) below.  
Note 1: Patients are expected to have received prior treatment with a CDK4/6 inhibitor if this 
treatment is approved and can be reimbursed.  
Note 2: During the course of the trial, the Sponsor may elect to limit the enrollment of participants 
who have NOT received prior treatment with a CDK4/6 inhibitor. 
a. relapsed with evidence of progression while on or within 12 months of completion 
of (neo)adjuvant aromatase inhibitor (AI), alone or in combination with a CDK4/6 
inhibitor, with no treatment for advanced disease. 
Note: Patients relapsing on or within 12 months of completion of (neo)adjuvant 
tamoxifen, alone or in combination with a CDK4/6 inhibitor are not eligible. 
b. relapsed with evidence of progression >12 months from completion of 
(neo)adjuvant ET (ET, tamoxifen, or AI), with subsequent progression on or after 
only 1 line of therapy with an AI, alone or in combination with a CDK4/6 inhibitor.  
Note 1: Patients should not have relapsed on or within 12 months of completion of 
(neo)adjuvant ET (with tamoxifen or an AI). 
Note 2: Patients may not have received any other prior therapy (other than the 
aforementioned: AI, alone or in combination with a CDK4/6 inhibitor) in the 
advanced/metastatic setting. 
c. presented de novo with metastatic disease, with subsequent progression on or after 
only 1 line of therapy with an AI, alone or in combination with a CDK4/6 inhibitor.  
Note: Patients may not have received any other prior therapy (other than the 
aforementioned: AI, alone or in combination with a CDK4/6 inhibitor) in the 
advanced/metastatic setting. 
4. Must be deemed appropriate for treatment with ET. 
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5. If female, have a postmenopausal status due either surgical/natural menopause or ovarian 
function suppression (OFS) with a gonadotropin-releasing hormone (GnRH) agonist such 
as goserelin or leuprolide (received monthly and initiated at least 28 days prior to Cycle 1 
Day 1).  
Note: Participants established on a less frequent (i.e. 3-month) GnRH agonist administration 
schedule will be permitted, if considered by the investigator to have adequate OFS based on serial 
estradiol assessments.  
Postmenopausal due to surgical/natural menopause requires at least 1 of the following: 
a. prior bilateral oophorectomy 
b. age ≥60 years 
c. age <60 years, amenorrheic for at least 12 months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression), and FSH and estradiol levels in the 
postmenopausal range using local laboratory thresholds. 
6. If female and postmenopausal status is due to ovarian suppression, participants must have 
a negative serum pregnancy test at baseline (within 14 days prior to enrollment) and agree 
to use highly effective, medically approved precautions to prevent pregnancy (see 
Section 10.7 Appendix 7) during the study and for 6 months (2 years for patients receiving 
fulvestrant) following the last dose of study treatment 
7. If male, must agree to use the following: 
a. hormone suppression (initiated at least 28 days prior to Cycle 1 Day 1) with a 
gonadotropin-releasing hormone agonist such as goserelin or leuprolide 
Note: Participants established on a less frequent (i.e. 3-month) GnRH agonist 
administration schedule will be permitted, if considered by the investigator to have 
adequate hormone suppression.  
b. highly effective methods of birth control and to not donate sperm during the study 
and for at least 6 months (2 years for patients receiving fulvestrant) following the 
last dose of study drug(s), or for the duration specified in country requirements, 
whichever is longer 
8. Have one of the following as defined by RECIST v1.1 (Eisenhauer et al. 2009; Section 10.3 
Appendix 3): 
 Measurable disease 
 Non-measurable bone-only disease. Non-measurable bone-only disease may 
include any of the following: 
i. 
Blastic bone lesions (also known as sclerotic bone lesions) 
ii. 
Lytic bone lesions without a measurable soft tissue component 
iii. 
Mixed lytic-blastic bone lesions without a measurable soft tissue 
component 
9. Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale 
(Oken et al. 1982) 
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10. Have adequate organ function as defined in table below 
System 
Laboratory Value 
Renal 
Serum creatinine or, 
<1.5× ULN OR 
Measured creatinine clearance or, 
≥50 mL/min
  
Calculated creatinine clearance  
 (See Section 10.5 Appendix 5) 
Hematologic 
 
ANC 
≥1.5 × 109/L 
Platelets 
≥100 × 109/L 
Hemoglobin 
≥9 g/dL 
Note: transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or G-CSF therapy to 
meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug. 
 
Hepatic 
Total bilirubin 
≤1.5× ULN  
 (Patients with Gilbert’s syndrome with a total bilirubin ≤2.0 times ULN and 
direct bilirubin within normal limits are permitted.) 
ALT and AST 
≤3× ULN  
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = 
granulocyte colony stimulating factor; ULN = upper limit of normal. 
11. Have discontinued previous therapies for cancer prior to receiving study drug, and 
recovered from the acute effects of therapy to at least Grade 1, except for residual alopecia 
and peripheral neuropathy, with the following therapy washout periods required prior to 
receiving study drug:  
a. for myelosuppressive agents (for example, CDK4/6 inhibitors): at least 21 days  
b. for nonmyelosuppressive agents (for example, Endocrine Therapy): 7 days or 
5 half-lives, whichever is shorter 
c. for investigational agents: 28 days or 5 half-lives, whichever is shorter 
12. Patients must be able to swallow capsules/tablets  
13. Are willing to participate for the duration of the study and to follow study procedures 
14. Capable of giving signed informed consent as described in Section 10.1 Appendix 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 applies: 
15. Have received prior treatment with chemotherapy (except for neoadjuvant/adjuvant 
chemotherapy), fulvestrant, any investigational-ER-directed therapy (including SERDs 
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and non-SERDs), any PI3K-, mTOR-, or AKT-inhibitor. Patients who have progressed on 
prior exemestane treatment must not receive exemestane if randomized to the control arm. 
16. Are currently receiving an investigational drug in a clinical trial or participating in any 
other type of medical research judged not to be scientifically or medically compatible with 
this study 
17. Have inflammatory breast cancer 
18. Patients with known pathogenic germline mutations who are appropriate for treatment with 
a PARP inhibitor, in regions where these therapies are approved and available, are not 
eligible for this study. 
19. Have visceral crisis, lymphangitic spread within the lung, or any evidence of 
leptomeningeal disease. Visceral crisis is not the mere presence of visceral metastases but 
implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, 
and rapid progression of the disease 
20. Have symptomatic or untreated brain metastasis. Patients with treated brain metastases are 
eligible for this study if they completed prior therapy (including radiation and/or surgery) 
≥28 days prior to first dose of study treatment and are not receiving corticosteroids and/or 
anticonvulsants for at least 14 days prior to first dose of study treatment, and their disease 
is asymptomatic and radiographically stable for at least 28 days prior to randomization by 
repeat imaging (repeat imaging should be performed during study screening) 
21. Have had major surgery within 28 days prior to randomization 
22. Have had wide-field radiotherapy ≤4 weeks (defined as involving ≥25% of the bone 
marrow), or limited field radiation for palliation ≤1 week prior to randomization. Patients 
must also have recovered to grade 1 or better from related side effects of such therapy (with 
the exception of alopecia) 
23. 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. a mean QT interval corrected for heart rate of ≥470 msec on screening ECG, as 
calculated using the Fridericia’s formula at several consecutive days of assessment 
i. baseline bradycardia with resting heart rate <60 beats per minute at several 
consecutive days of assessment 
24. Have serious preexisting medical conditions that, in the judgment of the investigator, 
would preclude participation in this study (such as severe renal impairment [for example, 
estimated creatinine clearance <30 mL/min], pre-existing medical condition of 
ILD/pneumonitis, severe dyspnea at rest or requiring oxygen therapy, history of major 
surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or 
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ulcerative colitis or a preexisting chronic condition resulting in clinically significant 
diarrhea). 
25. 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 
26. Have received an autologous or allogeneic stem cell transplant 
27. Have active bacterial or fungal infection, or detectable viral infection (for example, human 
immunodeficiency virus [HIV] or viral hepatitis). Screening is not required for enrollment 
28. Pregnant, breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 180 days after the last dose of 
study intervention 
29. Have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for 
example, denosumab) <7 days prior to randomization 
30. Known allergic reaction against any of the components of the study treatment. 
5.3. 
Lifestyle Considerations  
5.3.1. 
Meals and Dietary Restrictions  
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study. 
5.4. 
Screen Failures  
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized to a study treatment due to inability to complete or meet the criteria for 
participation (Sections 5.1 and 5.2) within the 28-day baseline screening period. Patients who are 
determined to be screen failures can be rescreened at an interval of ≥1 week. Patients may be 
rescreened up to 2 times after the initial screening. Each time rescreening is performed, the patient 
must sign a new ICF and will be assigned a new identification number. All required tests (see 
Schedule of Activities, Section 1.3) must be repeated for patients who are rescreened in a new 28-
day baseline screening.  
Repeating laboratory tests that did not meet eligibility criteria during the 28-day baseline screening 
period does not constitute rescreening. However, laboratory tests may not be repeated more than 
twice.  
The following patients may be eligible for rescreening: 
 patients who have become eligible to enroll in the study as the result of a protocol 
amendment 
 patient status has changed such that the eligibility criterion that caused the patient to screen 
fail would no longer cause the patient to screen fail again, and 
 patients who complete screening and meet all inclusion and exclusion requirements but are 
unable to be enrolled due to extenuating circumstances (such as, severe weather, death in 
family, child illness). 
The investigator should contact the Sponsor CRP prior to rescreening a patient. 
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6. 
Study Intervention  
Study intervention is defined as any medicinal product(s) or medical device(s) intended to be 
administered to/used by a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
 
  
Arm A 
Imlunestrant 
Arm B 
Investigator’s Choice Endocrine Therapy 
Arm C 
Imlunestrant + Abemaciclib 
Treatment 
Imlunestrant 
Fulvestrant 
Exemestane 
Imlunestrant 
Abemaciclib 
Dose 
400 mg 
500 mg 
25 mg 
400 mg 
150 mg 
Schedule 
QD in 28-day 
continuous 
cycles 
500 mg on C1D1 and 
C1D15 and then on Day 
1 of a 28-day cycle 
starting at Cycle 2  
QD in 28-day 
continuous 
cycles 
QD in 28-day 
continuous 
cycles 
BID in 28-day 
continuous cycles 
Route 
Oral 
Intramuscular injection 
of two 250 mg injections 
 
Oral 
Oral 
Oral 
Authorized 
as defined 
by EU 
Clinical 
Trial 
Regulation 
Not authorized 
in EU 
 
Authorized and used 
according to EU 
authorization 
 
Authorized and 
used according 
to EU 
authorization 
 
Not authorized 
in EU 
 
Authorized and 
used according to 
EU authorization 
 
Abbreviations: BID = twice daily; C = cycle; D = day; QD = once daily. 
Imlunestrant will be administered orally, 400 mg QD on Days 1 to 28 on a 28-day cycle. The 
imlunestrant 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 
imlunestrant. Fasting requirements are also described in the patient diary.  
The Investigator’s Choice of Endocrine Therapy will be limited to fulvestrant or exemestane. 
Fulvestrant will be administered 500 mg intramuscularly into the buttocks slowly as two 250 mg 
injections, one in each buttock on Days 1 and 15 of Cycle 1 of a 28-day cycle, then on Day 1 of 
Cycle 2 and beyond. However, for patients with moderate hepatic impairment (defined as Child-
Pugh Class B), including any patient who develops moderate hepatic impairment during study 
treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock slowly as 
one 250-mg injection. See local approved label for additional instructions. 
Exemestane will be supplied as 25 mg and administered orally, 25 mg QD. See local approved 
label for additional instructions. 
Abemaciclib will be administered orally, 150 mg BID on Days 1 to 28 on a 28-day cycle. The 
abemaciclib doses will be administered at approximately the same times on each day (see 
Section 6.1.4).  
Packaging and labeling 
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Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Selection and Timing of Doses  
A cycle is defined as an interval of 28 days during treatment period. The 28-day cycle length 
should be maintained throughout the treatment phase regardless of dose interruptions. Patients 
will begin dosing assigned treatment on C1D1.  
Treatment will continue until progression, unacceptable toxicity, or other discontinuation criteria 
are met (Section 7.1).  
Patients with documented progressive disease (PD) as determined by the investigator may be 
allowed to continue study treatment if the patient is tolerating study drug and, in the opinion of 
the investigator, the patient is deriving clinical benefit from continuing study treatment and 
continuation of treatment is approved by the Sponsor. In addition to the permitted protocol 
windows (see Schedule of Activities, Section 1.3), a delay for a maximum of 7 days of a cycle 
start not due to an AE, but due to holiday, weekend, bad weather, or other unforeseen 
circumstances, will be permitted and not counted as a protocol deviation. Response assessments 
should remain on the original schedule (see Schedule of Activities, Section 1.3). 
6.1.2. 
Arm A Imlunestrant: General Dosing Instructions  
Each cycle will consist of 28 days. Imlunestrant will be given as 400 mg QD administered at 
approximately the same time on each day (refer to Section 6.1).  
For imlunestrant administration, patients should follow the fasting guidance provided in the 
patient diary. 
See Section 6.5 for concomitant medication guidance. 
Patients randomized to imlunestrant treatment arms must keep a daily diary to record dosing 
compliance of oral study treatment, which will also be assessed at each clinic visit by means of a 
tablet count in the returned bottle(s). Late doses (that is, 4 or more hours after scheduled time) 
should be noted in the diary. Doses that are late by more than 6 hours should not be made up and 
recorded in the dosing diary as missed. Reasons should be recorded for any missed dose. 
Vomiting after dosing should be noted in the diary, and a vomited dose should not be re-dosed or 
replaced. Assessment of treatment compliance is described in Section 6.4.  
Effects of imlunestrant on coagulation in humans are unknown. In rats, imlunestrant produced 
minimal to mild decreases in platelets and increases in prothrombin time that were partially to 
fully reversible. Thus, patients undergoing major surgical procedures should have imlunestrant 
held at least 3 days prior and 3 days post procedure; the Sponsor should be notified of the 
planned procedure and planned dose hold. 
6.1.3. 
Arm B Investigator’s Choice of Endocrine Therapy of Fulvestrant or Exemestane: 
General Dosing Instructions  
Patients randomized to Arm B will begin dosing with investigator’s choice of either fulvestrant or 
exemestane on C1D1, as outlined above in Section 6.1. Refer to local prescribing information for 
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additional administration details. Handling and administration of fulvestrant or exemestane should 
be in accordance with instructions per locally approved labelling or institutional standards.  
6.1.4. 
Arm C Imlunestrant + Abemaciclib: General Dosing Instructions  
Each cycle will consist of 28 days. Abemaciclib will be given at a starting dose of 150 mg BID 
and should be taken twice daily (with at least approximately 6 hours separating doses) at the 
same time each day with 6-8 ounces of water. Participants should be instructed to swallow 
tablets whole and not chew or crush them. 
See Section 6.5 for concomitant medication guidance. 
6.2. 
Preparation/Handling/Storage/Accountability  
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study interventions. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.2.1. 
Arm A Preparation/Handling/Storage: Imlunestrant  
Imlunestrant will be provided as tablets for oral administration and should be stored according to 
the product label, and not opened, crushed, or dissolved. Investigators should instruct patients to 
store the study drug in the original package and in a location inaccessible to children.  
6.2.2. 
Arm B Preparation/Handling/Storage: Investigator’s Choice of Endocrine 
Therapy of fulvestrant or exemestane  
Preparation, storage, and handling for fulvestrant or exemestane will be according to instructions 
provided in the local label for the individual product. 
6.2.3. 
Arm C Preparation/Handling/Storage: Imlunestrant + Abemaciclib  
Abemaciclib will be provided as tablets for oral administration and should be stored according to 
the product label, and not crushed or dissolved. Investigators should instruct patients to store the 
study drug in the original package and in a location inaccessible to children. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is a randomized, open-label study. The route of administration for the anti-cancer agents in 
the study justifies an open-label design. Upon obtaining informed consent, site personnel should 
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access the IWRS, which will assign a patient number. Participants who meet all criteria for 
enrollment will be randomly assigned to the treatment arm. Assignment to treatment groups will 
be determined by a computer-generated random sequence using the IWRS. Sites will be 
prompted to enter the specific Arm B ET of choice at time of randomization until the enrollment 
to Arm B is stopped. Each participant in this study will be aware of his or her own assigned 
treatment group. At each investigative site, all staff involved in treating and caring for study 
participants will have full knowledge of treatment assignments for the participants under their 
care.  
In order to maintain the scientific integrity of the trial, access to study data will be strictly 
controlled prior to the interim and final analyses. Access to the EDC will be limited to those who 
require this information for their role and all access will be documented. 
For the accumulated aggregate database to which Sponsor statisticians (or those of its designee) 
have access, treatment assignment, and other parameters that can disclose treatment assignment 
will be scrambled or masked. Therefore, the Sponsor and all investigative sites will remain 
blinded to treatment group assignments for the aggregate database until the database lock for the 
final analysis. Scrambled treatment assignments will be used in the reporting database until the 
study reaches its final analysis or the study is determined to be positive or futile by the DMC. 
During this time, analyses using unblinded treatment codes will be performed only at the interim 
analysis points specified in the protocol/SAP. 
Participants will be randomized 1:1:1 between the 3 treatment arms, of either imlunestrant (Arm 
A), Investigator’s Choice Endocrine Therapy (Arm B), or imlunestrant plus abemaciclib (Arm 
C), using the following stratification factors:  
 previous treatment with any CDK4/6 inhibitor (yes versus no)  
 presence of visceral metastases (yes versus no); visceral includes lung, liver, brain, 
pleural, and peritoneal involvement, and 
 region (East Asia versus North America/Western Europe versus Others). 
Arm C was added to the study (amendment a) after first patient visit for Arms A and B. 
Randomization of participants will continue in Arms A and B (1:1) until amendment a is 
approved and implemented, at which point participants will be randomized 1:1:1 (A:B:C) until 
the target enrollment for arms A and B (a total number of approximately 640 participants) is met. 
Interim analyses for safety and efficacy will be conducted under the guidance of an independent 
DMC. The DMC will consist of at least 3 members, including at least 1 clinician and 1 
statistician. The DMC will communicate any recommendations based on interim analysis to the 
Sponsor Senior Management Designee (SMD). If necessary, the SMD may form an Internal 
Review Committee (IRC) to review and act upon the recommendations of the DMC. Details will 
be specified in a separate DMC charter.  
For those safety and efficacy analyses assigned to the DMC, only the designated Statistical 
Analysis Center (SAC), which is independent of the Sponsor, will perform analyses on 
unblinded data, that is, an aggregate database with correct treatment assignments. At the request 
of the Sponsor, the SAC may provide pooled summary reports of the data to the Sponsor (for 
example, a summary of AEs across the study). These reports will not include treatment arms. 
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6.4. 
Study Intervention Compliance  
Treatment compliance information for study treatment will be collected through patient dosing 
diaries and/or solid oral dosage unit counts at each visit, with the number of dosage units taken 
relative to the number expected to be taken summarized for each cycle. The patient must take 
≥80% of the planned doses for study treatment in a cycle to be deemed compliant. Dose 
suspensions or delays may occur and will not result in a patient being considered as 
noncompliant. A patient may be considered noncompliant if judged by the investigator to have 
intentionally or repeatedly taken ≥125% of the planned doses of study treatment in a cycle. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and in the CRF.  
6.5. 
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 and after the last dose of study treatment at the short-term follow-up Visit (See 
Schedule of Activities, Section 1.3) must be recorded in the eCRF and should be updated 
throughout the patient’s participation in the study along with 
 reason for use, and 
 dates of administration, including start and end dates. 
The Sponsor CRP/CRS should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Medications not permitted (All Arms) 
Anticancer therapies for cancer (including ET, chemotherapy, immunotherapy) will not be 
permitted while patients are on study treatment. Use of megestrol acetate as an appetite stimulant 
is not permitted. 
Strong inducers of CYP3A4 should also be avoided in patients receiving exemestane on-study. 
Imlunestrant Guidance  
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 imlunestrant is a time-dependent inhibitor of CYP2C8, CYP2C9, 
CYP2C19, and CYP3A. Imlunestrant 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, 
CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or substrates of these CYPs with a narrow 
therapeutic index. A week of washout time following imlunestrant treatment is advised before 
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starting sensitive substrates of CYP2C8, CYP2C9, CYP2C19, and CYP3A (Section 10.11 
Appendix 11, Section 10.12 Appendix 12, and Section 10.13 Appendix 13). 
UGT1A1, P-gp and BCRP 
According to preclinical studies, UGT1A1 is involved in the metabolism of imlunestrant. As a 
precaution, strong inducers and inhibitors of UGT1A1 should be avoided (Section 10.14 
Appendix 14). 
Due to limitations of in vitro assessments, the impact of imlunestrant 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 imlunestrant with narrow therapeutic index 
substrates of P-gp and BCRP (i.e. digoxin). 
Consult the IB for additional information. 
Abemaciclib Guidance  
The information in this section is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
Modulators of CYP3A 
Abemaciclib is extensively metabolized through oxidation by CYP3A. In clinical drug interaction 
studies,  
 coadministration of clarithromycin, a strong CYP3A inhibitor, increased exposure (AUC) 
of abemaciclib by 3.4-fold (Study I3Y-MC-JPBE), and  
 coadministration of rifampin, a strong CYP3A inducer, decreased exposure of abemaciclib 
by 95% (Study I3Y-MC-JPBF). 
Strong inhibitors of CYP3A (given via non-topical routes of administration) should be substituted 
or avoided if possible (Appendix 11, Section 10.11). This includes grapefruit or grapefruit juice. 
In particular, avoid oral administration of the very strong CYP3A inhibitor, ketoconazole. 
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib by 50 mg at the start of CYP3A inhibitor treatment. That is, for patients 
receiving 150 mg twice daily, reduce the dose to 100 mg twice daily. For patients who have 
already had dose reduced to 100 mg twice daily for tolerability, reduce the dose further to 50 mg 
twice daily. Alternatively, the investigator may consider suspending abemaciclib for the duration 
of the CYP3A inhibitor medication.  
Upon discontinuation of the strong CYP3A inhibitor, the dose of abemaciclib may be re-
escalated to the dose that was used before starting the strong inhibitor after a sufficient washout 
period (3 to 5 half-lives of the strong inhibitor). Re-escalation of the abemaciclib dose requires 
review and approval from the Sponsor CRP/CRS. 
Inducers of CYP3A should be substituted or avoided if possible (Appendix 11, Section 10.11). 
Coadministration with a CYP3A inducer ≥28 days must be discussed with the Sponsor 
CRP/CRS. 
Transporter Substrates 
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Abemaciclib inhibits the transporters P-glycoprotein, breast cancer resistance protein, organic 
cation transporter 2, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. The 
observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition 
of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K. In vivo interactions of 
abemaciclib with narrow therapeutic index substrates of these transporters, such as digoxin and 
dabigatran, may occur. 
6.5.1. 
Palliative Medicine and Supportive Care  
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care as judged by their treating physician. If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Sponsor CRP. Use of any 
supportive care therapy should be reported in the eCRFs. 
Palliative radiation therapy is permitted after discussion with and agreement of the Sponsor 
CRP/CRS or designee for irradiating small areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics. Such areas must not be an identified target lesion 
and must not constitute progressive disease or meet RECIST v1.1 criteria for progressive 
disease. Any symptomatic deterioration or clinical disease progression requiring, in the opinion 
of the investigator, other forms of specific antitumor systemic therapy, will be cause for 
discontinuation of study therapy. 
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate discontinuation from the study. Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the CRF. 
The use of granulocyte-colony stimulating factor is permitted at the discretion of the investigator 
based on ASCO (Smith et al. 2015) and European Society for Medical Oncology (Crawford et al. 
2009) guidelines. 
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013). 
Patients with bone metastases present on baseline imaging should be appropriately treated with 
bisphosphonates or RANK-L targeted agents (for example, denosumab), per respective approved 
labels. Initiation of treatment with bone-modifying agents must begin at least 7 days prior to 
randomization. Patients receiving bisphosphonates or RANK-L targeted agents should not switch 
treatments (for example, replace a bisphosphonate with denosumab) while on study treatment. 
However, exceptional cases without evidence of PD may be considered in consultation with the 
Lilly CRP. These exceptional cases will not incur a protocol deviation. 
6.5.2. 
Supportive Management for Diarrhea  
Patients should receive instructions on the management of diarrhea. In the event of diarrhea, 
supportive measures should be initiated as early as possible. These include  
 At the first sign of loose stools, the patient should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator or site personnel for further instructions 
and appropriate follow-up. 
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 Patients should also be encouraged to drink fluids (that is, 8 to 10 glasses of clear liquids 
per day). 
 Site personnel should assess response within 24 hours. 
 Follow dose modification guidance for imlunestrant (Section 6.6.1) and/or abemaciclib 
(Section 6.6.3), including dose suspension and/or reduction as appropriate. 
 For severe cases of diarrhea, or any diarrhea associated with severe nausea or vomiting, 
consider 
o IV fluids with electrolyte replacement 
o measurement of absolute neutrophil counts 
o monitor patients for fever 
 If diarrhea is associated with fever or severe neutropenia, consider broad-spectrum 
antibiotics. 
6.5.3. 
Photosensitivity  
Based on an in vitro study, exposure to imlunestrant may result in photosensitivity. Patients are 
advised to avoid direct sun exposure and the use of tanning beds during study administrations 
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  
General Considerations for Dose Delays. 
In addition to the permitted protocol windows (see Schedule of Activities, Section 1.3), treatment 
cycles may be delayed up to 7 days due to holidays, weekends, bad weather, or other unforeseen 
circumstances and will not be deemed a protocol violation. 
In exceptional cases, for planned delays (including but not limited to vacation or holidays), 
additional study drug may be dispensed. 
When a study drug is delayed, if possible and appropriate, patients should resume study 
treatment within 1 treatment cycle and, if not possible, then every effort should be made to start 
on the first day of the next dosing cycle. In rare circumstances, a delay of >28 days may be 
permitted before permanent treatment discontinuation, as long as the patient has clinical benefit 
without objective disease progression and is recovering from the toxicity. Such circumstances 
must be discussed with the Sponsor CRP/CRS. All dose modifications should be documented, 
including the approach taken and a clear rationale for the need for modification.  
Dose Modifications for Imlunestrant  
Management of some adverse reactions may require dose interruption and/or dose reduction. If 
dose reduction is necessary, decrease the dose by 200 mg. Discontinue imlunestrant for patients 
unable to tolerate 200 mg QD. In the event that imlunestrant must be discontinued, a participant 
may continue to receive abemaciclib (Arm C only).  
Refer to the tables below for further details on dose modification and management. 
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Table 1: Imlunestrant Dose Reduction Guidelines  
Dose Adjustment 
Oral Dose Imlunestrant 
Frequency 
0 
400 mg 
QD 
1 
200 mg 
QD 
Abbreviation: QD = once daily. 
6.6.1. 
Imlunestrant Dose Adjustments for Treatment-Emergent, Related*, and 
Clinically Significant Adverse Events  
Treatment-emergent laboratory abnormalities of neutrophil count decreased and/or ALT/AST 
increased, regardless of clinical significance, must follow the dose adjustment table below.  
*Related means there is a reasonable causal relationship with imlunestrant. 
 
Toxicity Type 
Toxicity Profile and Severity 
Dose Suspension 
Dose Reduction 
Hematologic 
toxicity 
Grade 3 
Dose MUST be suspended 
until toxicity resolves to at 
≤Grade 2 
Not required 
Grade 4 or Recurrent Grade 3 
Dose MUST be suspended 
until toxicity resolves to at 
≤Grade 2 
Resume at next lower dose 
level 
If Patient Requires 
Administration of 
Blood Cell Growth 
Factors 
 
Regardless of severity 
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2 and a 
minimum of 48 hours after 
growth factor administration 
Resume at next lower dose 
unless the dose was already 
reduced for the toxicity that 
led to the use of the growth 
factor (that is, second dose 
reduction not required) 
Febrile 
neutropenia 
Regardless of severity 
Dose MUST be suspended 
until toxicity resolves 
Resume at next lower dose 
level 
Nonhematologic 
toxicity (except 
diarrhea, alopecia, 
and 
hepatotoxicity)a 
 
Persistent or recurrent Grade 2 
that does not resolve with 
maximal supportive measures 
within 7 days to baseline or 
Grade 1 
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1 
Not required 
Grade 3 or 4 (except non-
hepatic asymptomatic 
laboratory changes) 
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1 
Resume at next lower dose 
level 
Hepatotoxicity 
AST/ALT >ULN - 5.0×ULN 
Not required 
Persistent or Recurrent: 
AST/ALT >3.0-5.0×ULN 
Dose MUST be suspended 
until toxicity resolves to 
baseline or to >ULN-
3.0×ULN 
Not required 
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Toxicity Type 
Toxicity Profile and Severity 
Dose Suspension 
Dose Reduction 
AST/ALT >5.0-20×ULN 
Or 
ALT or AST ≥ 3 × baseline (if 
ALT or AST ≥ 1.5 × ULN at 
baseline) or AST/ALT >8 × 
ULN (whichever is the lower 
threshold) 
Dose MUST be suspended 
until toxicity resolves to 
baseline or to 
ALT/AST>ULN - 3.0×ULN 
Resume at next lower dose 
level 
AST/ALT >20.0×ULN 
Or 
ALT or AST ≥ 3 × ULN 
concurrent with TBL ≥ 2 × 
ULN (if ALT or AST < 1.5 × 
ULN at baseline), in the 
absence of cholestasis 
Or 
ALT or AST ≥ 2 × baseline 
concurrent with TBL ≥ 2 × 
ULN (if ALT or AST ≥ 1.5 × 
ULN at baseline), in the 
absence of cholestasis 
Discontinue imlunestrant 
Diarrhea 
Grade 1 
Not required 
Grade 2 that does not resolve 
with maximal supportive 
measures within 24 hours to 
≤Grade 1 
Suspend until toxicity 
resolves to ≤Grade 1 
Not required 
Grade 2 that persists or recurs 
after resuming the same dose 
despite maximal supportive 
measures. 
Requires hospitalization or 
Grade 3 or 4 
Suspend until toxicity 
resolves to ≤Grade 1 
Resume at next lower dose 
level 
Bloody diarrhea 
Any grade 
Dose MUST be suspended 
until bloody diarrhea 
resolves and diarrhea 
resolves to Grade ≤1 
Resume at next lower dose 
level 
Abbreviations: ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal. 
a Events of diarrhea and hepatotoxicity should follow corresponding guidance listed in the table. 
Note: Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the first event. As a general 
guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences a new 
episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of the same Grade 3 
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hematological toxicity, the investigator may consider resuming the participant on the same drug dose should the 
participant satisfy the following conditions: 
 
The participant showed stable hematological counts (Grade ≤2) during that timeframe 
 
In the absence of any infectious sign or risk factor 
 
The participant is benefiting from study intervention. 
6.6.2. 
Dose Modifications for Endocrine Therapy of Investigator’s Choice  
Dose adjustments for control arm ET of exemestane are not allowed. 
Dose adjustments for control arm ET of fulvestrant will be determined by the investigator in 
accordance with the approved product labels. For patients with moderate hepatic impairment 
(defined as Child-Pugh Class B), including any patient who develops moderate hepatic 
impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly 
into the buttock slowly (1 to 2 minutes) as one 250-mg injection.  
Dose suspensions ≥28 days must be discussed with the Sponsor CRP/CRS. 
6.6.3. 
Dose Modifications for Abemaciclib  
Management of some adverse reactions may require dose interruption and/or dose reduction. If 
dose reduction is necessary, decrease the dose by 50 mg at a time. Discontinue abemaciclib for 
patients unable to tolerate 50 mg BID. In the event that abemaciclib must be discontinued, a 
patient may continue to receive imlunestrant. 
Refer to the tables below for further details on dose modification and management. 
Recommended Dose Reduction Guidelines for Abemaciclib 
Dose Adjustment 
Abemaciclib Dose  
Frequency 
Starting dose 
150 mg 
BID 
First dose reduction 
100 mg 
BID 
Second dose reduction 
50 mg 
BID 
Abbreviation: BID = twice daily. 
 
 
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The toxicity dose adjustments and delays table below provides guidance for the management of 
treatment-emergent, related (i.e., with reasonable causal relationship with abemaciclib), AEs. An 
investigator may suspend or reduce doses without meeting one of the criteria below and this 
would not be considered a protocol deviation. 
Abemaciclib Dose Adjustments for Treatment-Emergent, Related Adverse Events 
Toxicity Type 
Severity 
Dose Suspension 
Dose Reduction 
Hematologic Toxicity 
Grade 1 or 2 
Not required 
Grade 3 
Suspend until toxicity 
resolves to ≤Grade 2 
Not required 
Grade 4 or recurrent Grade 
3 
Suspend until toxicity 
resolves to ≤Grade 2 
Resume at next lower dose 
level 
If Patient Requires 
Administration of Blood 
Cell Growth Factors 
 
Additional guidance for use 
of growth factors is in 
Section 6.5.1.  
Regardless of severity 
Suspend until toxicity 
resolves to at least 
Grade 2 and a 
minimum of 48 hours 
after growth factor 
administration 
Resume at next lower dose 
unless the dose was already 
reduced for the toxicity that 
led to the use of the growth 
factor (that is, second dose 
reduction not required) 
Nonhematologic Toxicity 
Excluding Diarrhea, 
ALT/AST Increased, 
Interstitial Lung 
Disease/Pneumonitis, and 
VTE (see below) 
 
Additional guidance for renal 
monitoring is in Section 8.2.4 
and for VTE Section 8.2.5. 
Grade 1 or 2 
Not required 
Persistent or recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures within 
7 days to baseline or Grade 
1. 
 
Grade 3 or 4 
Suspend until toxicity 
resolves to baseline 
or Grade 1 
Resume at next lower dose 
level 
Diarrhea 
 
Additional guidance for 
diarrhea management is in 
Section 6.5.2.  
Grade 1 
Not required 
Grade 2 that does not 
resolve with maximal 
supportive measures within 
24 hours to ≤Grade 1 
Suspend until toxicity 
resolves to ≤Grade 1 
Not required 
Grade 2 that persists or 
recurs after resuming the 
same dose despite maximal 
supportive measures. 
Requires hospitalization or 
Grade 3 or 4 
 
Suspend until toxicity 
resolves to ≤Grade 1 
Resume at next lower dose 
level 
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Toxicity Type 
Severity 
Dose Suspension 
Dose Reduction 
ALT/AST Increased 
 
See Section 8.2.2.1 for 
additional guidance for 
hepatic monitoring.  
>ULN-5.0×ULN 
or 
1.5-5.0 × baseline (if 
baseline ≥1.5×ULN) 
Not required 
Persistent or recurrent >3.0-
5.0×ULN (or × baseline if 
baseline ≥1.5×ULN),  
or  
>5.0-20.0×ULN (or × 
baseline if baseline 
≥1.5×ULN) 
Suspend until toxicity 
resolves to baseline 
or >ULN-3.0×ULN 
Resume at next lower dose 
level 
>3.0×ULN (or × baseline if 
baseline ≥1.5×ULN)with 
total bilirubin >2×ULN, in 
the absence of cholestasis, 
or  
>20.0×ULN (or × baseline 
if baseline ≥1.5×ULN) 
 
Discontinue abemaciclib 
 
 
VTE 
 
Additional guidance for VTE 
monitoring is in 
Section 8.2.5. 
 
 
Grade 1 or 2 
 
Not required 
Grade 3 or 4 
 
Suspend and treat. 
Resume when the 
patient is clinically 
stable. 
Not required 
 
Interstitial Lung 
Disease/Pneumonitis 
 
Additional guidance for 
ILD/pneumonitis monitoring 
is in Section 8.2.6.  
Grade 1 or 2 
Not required 
Grade 2 that persists or 
recurs despite maximal 
supportive measures and 
does not return to baseline 
or Grade 1 within 7 days. 
Suspend until toxicity 
resolves to baseline 
or Grade ≤1 
Resume at next lower dose 
level 
Grade 3 or 4 
Discontinue abemaciclib 
Abbreviations: ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2017); ILD = interstitial 
lung disease; ULN = upper limit of normal; VTE = venous thromboembolic event.  
Note: Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the first event. As a general 
guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences a new 
episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of the same Grade 3 
hematological toxicity, the investigator may consider resuming the participant on the same drug dose should the 
participant satisfy the following conditions: 
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 
The participant showed stable hematological counts (Grade ≤2) during that timeframe 
 
In the absence of any infectious sign or risk factor 
 
The participant is benefiting from study intervention. 
6.6.4. 
Re-escalation Criteria  
If an imlunestrant and/or abemaciclib dose is reduced for apparent treatment-related toxicity, the 
dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. 
However, if the patient tolerates a reduced dose of imlunestrant and/or abemaciclib for ≥2 weeks, 
then the dose may be re-escalated to a prior dose level, at the discretion of the investigator and 
after consultation with the Sponsor CRP/CRS. After re-escalation, subsequent dose adjustments 
should be based on the dose that the patient is currently receiving.  
6.7. 
Intervention after the End of the Study  
The end of the study is defined in Section 4.4. Investigators will continue to follow the SoA 
provided in Section 1.3 until notified by the Sponsor that the end of the study has occurred. 
Study completion will occur following the final analysis of OS, as determined by the Sponsor. 
6.7.1. 
Continued Access  
Patients receiving study treatment and experiencing ongoing clinical benefit may continue to 
receive study treatment in the continued access period until 1 of the criteria for discontinuation is 
met (Section 7). The continued access period will apply to this study only if at least 1 patient is 
still receiving study intervention when study completion occurs. The Sponsor will notify 
investigators when the continued access period begins. The Sponsor may allow patients to enroll 
in a “rollover” protocol to provide long-term continued access for patients enrolled in this study. 
The continued-access period will begin after study completion and ends at the end of the study 
(Section 4.4). The patient’s continued access to study treatment will end when a criterion for 
discontinuation is met (Section 7). Continued-access follow-up will begin when the patient and 
the investigator agree to discontinue study treatment. Follow-up procedures will be performed as 
shown in the SoA (Section 1.3). 
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed. Long-term 
follow-up does not apply. 
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up. 
Investigators will perform any other standard procedures, and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion. 
Sponsor will not routinely collect the results of these assessments. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Participant Discontinuation/Withdrawal from Study Treatment  
Patients will be discontinued from study treatment in the following circumstances:  
 at any time at his or her own request 
 at the request of his or her designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 if the participant becomes pregnant during the study – See Section 8.3.2 regarding 
regulatory reporting requirements 
 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 
 if the participant is significantly noncompliant with study procedures and/or treatment 
 
 disease progression. Exceptions for continuing study treatment beyond confirmed 
radiographic progression may be made on a case-by-case basis for patients who are 
believed to be clinically benefiting from study treatment, and the investigator and the 
Sponsor agree that continuing study treatment is in the patient’s best interest, and 
 
 unacceptable toxicity. 
Participants who discontinued from the investigational product prematurely for any reason will 
remain in the study and have short-term and long-term follow-up procedures as outlined in the 
SoA, Section 1.3.  
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 or she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
7.1.1. 
Discontinuation of Inadvertently Enrolled Participants  
If the Sponsor or the investigator identifies a patient who did not meet enrollment criteria and 
was inadvertently enrolled, a decision on whether or not the patient may remain on treatment will 
be made between the Sponsor CRP/CRS and the investigator. If both agree that it is medically 
appropriate to continue, the investigator must obtain documented approval from the Sponsor 
CRP/CRS to allow the inadvertently enrolled patient to continue in the study with or without 
study treatment. Safety follow-up should be performed as outlined in Section 1.3 (Schedule of 
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Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events, Serious Adverse 
Events, and Product Complaints) of the protocol. 
7.2. 
Discontinuation from the Study  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for survival. See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed. 
Patients will be discontinued from the study in the following circumstances: 
 the Sponsor determines that participation in the study needs to be stopped for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
 the investigator decides the patient should be discontinued from the study 
 the patient requests to be withdrawn from the study, and 
 the study has been completed.  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula (QTcF)) 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 electrocardiogram printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an AE. 
7.3. 
Lost to Follow-Up  
A patient 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 patients who fail to return for a scheduled visit or were otherwise unable to 
be followed up by the site. 
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product. Public sources may be searched for vital status information. If vital 
status is determined, this will be documented, and the patient will not be considered lost to 
follow-up. 
The Sponsor personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
 
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8. 
Study Assessments and Procedures  
 Study procedures and their timing are summarized in the SOA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
 Appendix 4 (Section 10.4) provides a list of the laboratory tests that will be 
performed for this study. 
 Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the 
SOA, is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
 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. 
 Procedures conducted as part of the patient’s routine clinical management (for 
example, blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA (Section 1.3). 
8.1. 
Efficacy Assessments  
8.1.1. 
Efficacy Assessments at Baseline and during Study Treatment  
For all patients, imaging studies (CT, including spiral CT, or MRI scan of the chest, abdomen, 
and pelvis) will be performed locally at baseline and repeated per the SoA (Section 1.3). It is 
recommended that CT imaging of the abdomen and pelvis be performed with IV contrast, 
whenever possible. For patients with known hypersensitivity to CT contrast material, a CT scan 
of the chest without contrast and gadolinium-enhanced MRI of the abdomen and pelvis are 
encouraged. The CT portion of a PET-CT scan may be used as a method of response assessment 
if the site can document that the CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast). A PET scan alone or as part of a PET-CT may be performed as part of routine 
clinical care but cannot be used to assess response according to RECIST v1.1.  
All patients must have baseline brain imaging. For patients without a history of brain metastases, 
either a brain CT or brain MRI is required. Contrast is recommended. For patients without brain 
metastases as determined by baseline assessments, on-study brain imaging is not required, and 
sites may follow local/institutional standard of care guidelines. 
For patients with treated brain metastases, contrast-enhanced brain MRI is preferred; however, if 
MRI contrast is contraindicated, then MRI (without contrast) or brain CT (recommended with 
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contrast) is acceptable. Patients with a history of brain metastases must have imaging should be 
repeated at the RECIST response assessment intervals outlined in the Schedule of Activities 
(Section 1.3). 
For all patients, bone scintigraphy will be performed locally at baseline and repeated per the 
Study Schedule (Section 1.3). In addition, bone scans should be repeated if a CR in target disease 
is identified or progression in bone is suspected. For patients with new lesions identified by post-
baseline bone scintigraphy, targeted assessment by X-ray, CT scan with bone windows, or MRI 
will be performed to confirm findings. 
For only those patients with RECIST non-measurable bone-only disease, for any lesions 
identified on bone scintigraphy at baseline that are not visible on the chest, abdomen, and pelvis 
CT or MRI, all such lesions will be evaluated by directed imaging (X-ray, CT scan with bone 
windows, or MRI) to enable serial assessment. Directed imaging will be performed at baseline, 
per the Study Schedule (Section 1.3), and within 14 days of clinical progression. 
For patients with locoregionally recurrent breast cancer not amenable to curative treatment, MRI 
scan of the breast will be performed at baseline, per the Study Schedule (Section 1.3), and within 
14 days of clinical progression.  
For patients with visible tumor (such as skin lesions), photography will be performed at baseline 
and each photographic image of the tumor should include a ruler. Photography should be 
performed at baseline and then per the Study Schedule (Section 1.3) and within 14 days of 
progression. Photographic images may be taken more frequently based upon the discretion of the 
investigator or following the identification of new skin lesions post-baseline. 
For patients continuing treatment during the continued access period (after study completion), 
efficacy assessments (frequency and type of assessments) will be at the discretion of the 
investigator. 
8.1.2. 
Efficacy Assessments during Post-discontinuation Follow-Up  
Post-discontinuation follow-up during the study period will be conducted as described in the 
SoA (Section 1.3). For those patients who are randomized and never receive study treatment or 
those who discontinue study treatment without objectively measured PD, the investigative sites 
will continue to monitor patients and periodically evaluate tumor response approximately every 8 
weeks for the first 12 months with the first assessment relative to Cycle 1 Day 1 and thereafter 
approximately every 12 weeks by the same method used at baseline and throughout the study 
until the patient has objective disease progression, death, start of a new anticancer therapy or 
study completion. In addition, anticancer therapies initiated after study treatment discontinuation 
will be collected during this follow-up period. 
After the patient has objective disease progression, radiologic imaging and photographic images 
are no longer required and the patient will be followed up approximately every 12 weeks until 
the patient’s death or overall study completion. Lilly will continue to collect survival data on all 
patients but may reduce data collection for other efficacy data. Sponsor will notify investigators 
when this reduced data collection can begin. 
Tumor assessments will be performed for each patient at the times shown in the SoA 
(Section 1.3). 
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8.1.3. 
Primary Efficacy Measure  
Response Evaluation Criteria in Solid Tumors v1.1 (Eisenhauer et al. 2009; Section 10.3 
Appendix 3) will be applied as the primary criteria for assessment of tumor response and date of 
tumor progression. The method of tumor assessment used at baseline must be used consistently 
throughout the study. Local tumor imaging (investigator assessment with site radiological 
reading) will be used.  
Sponsor or its designee will collect and store all tumor assessment images on all randomized 
participants throughout the study to permit a blinded independent central review of patient scans. 
Please see the Site Imaging Manual for guidelines on how the various imaging studies should be 
performed. 
The PFS time is measured from the date of randomization to the date of first objective 
progression or the date of death due to any cause, whichever is earlier. For those patients with 
nonmeasurable bone-only disease (refer to Inclusion Criterion [8]), objective progression will be 
established if at least 1 of the following criteria is met: 
 the appearance of 1 or more new lesions (in bone or outside of bone), or 
 unequivocal progression of existing bone lesions. 
According to RECIST v1.1, the finding of a new lesion should be unequivocal and not 
attributable to findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions). Pathologic fracture, 
new compression fracture, or complications of bone metastases will not be considered as 
evidence of disease progression, unless at least 1 of the above criteria is met. 
See Section 9.4.3 for definitions of the efficacy endpoints. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
For each patient, ECGs, vital signs, laboratory tests, and other tests should be collected as shown 
in the SoA (Section 1.3). Results from any clinical laboratory test analyzed (refer to Section 10.4 
Appendix 4) will be provided to investigative sites by the Sponsor or its designee. 
Refer to Section 8.3 for details on the recording of AEs. 
8.2.1. 
Electrocardiograms  
Local ECG’s (no replicates required) should be obtained. Time points for ECG collection on-study 
are located in Section 1.3.2.  
8.2.2. 
Clinical Safety Laboratory Assessments  
See Appendix 4 (Section 10.4) for the list of clinical laboratory tests to be performed and see the 
SoA (Section 1.3) 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 CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
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laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or until the completion of Visit 801 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. 
 If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified, and the Sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 4 (Section 10.4), 
must be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
If there is an abnormal laboratory value or abnormal value for any other diagnostic or screening 
test (for example, blood pressure increased, neutrophils decreased) and it is known to be related 
to a disease diagnosis (for example, hypertension, neutropenia), this should be reported in the 
CRF as an AE. Do not enter the test abnormality; enter the disease diagnosis or categorical term. 
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the investigator (for example, SAE or AE or dose modification), then the event(s) 
must be reported in the CRF as AEs. 
8.2.2.1. 
Hepatic Safety Monitoring  
Liver testing (Section 10.9 Appendix 9), including ALT, AST, alkaline phosphatase, TBL, direct 
bilirubin, gamma-glutamyltransferase, and creatine phosphokinase, should be repeated (local 
testing acceptable) within 2 to 4 days to confirm the abnormality and to determine if it is 
increasing or decreasing, if 1 or more of these conditions occur: 
In participants with baseline ALT or AST <1.5 ULN 
 Elevation of serum ALT or AST to ≥5× ULN 
 The combination of elevated ALT or AST ≥3× ULN and elevated TBL ≥2× ULN  
In participants enrolled with baseline ALT or AST ≥1.5× ULN  
 Elevated ALT or AST ≥3× baseline  
 The combination of elevated ALT or AST ≥2× baseline and elevated TBL ≥2× ULN 
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Sponsor-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 PT-INR; 
serological tests for viral hepatitis A, B, C, E, autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or CT scan). 
Based on the patient’s history and initial evaluation results, further testing should be considered, 
in consultation with the Sponsor-designated medical monitor, including tests for hepatitis D 
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virus, cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein 
adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl 
glucuronide, and serum phosphatidylethanol. Based on the circumstances and the investigator’s 
assessment of the participant’s clinical condition, the investigator should consider referring the 
participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, and/or a liver biopsy. 
For patients that meet the criteria above, whenever possible and as clinically appropriate, continue 
monitoring after discontinuation of imlunestrant until values are back to baseline. 
Additional Hepatic Safety Collection 
Additional safety data outlined in Section 10.9 Appendix 9 should be collected via the CRF if 1 
or more of the following conditions occur: 
In participants with baseline ALT or AST <1.5 ULN 
 Elevation of serum ALT or AST to ≥5× ULN on 2 or more consecutive blood tests  
 The combination of elevated ALT or AST ≥3× ULN and elevated TBL ≥2× ULN  
In participants enrolled with baseline ALT or AST ≥1.5× ULN  
 Elevated ALT or AST ≥3× baseline on 2 or more consecutive tests 
 The combination of elevated ALT or AST ≥2× baseline and elevated TBL ≥2× ULN 
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 a SAE. 
8.2.3. 
Safety Surveillance  
The Sponsor 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 that are owned by the Sponsor’s 
Global Patient Safety organization. These processes are designed to monitor the evolving safety 
profile (that is, 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 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 SUSARs is created and distributed to investigators on a twice-yearly basis. Any 
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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. 
8.2.4. 
Guidance for Monitoring Renal Function  
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
transporters without affecting glomerular function (as measured by iohexol clearance). In clinical 
studies, increases in serum creatinine occurred within the first month of abemaciclib dosing, 
remained elevated but stable through the treatment period, were reversible upon treatment 
discontinuation, and were not accompanied by changes in markers of renal function, such as 
blood urea nitrogen, cystatin C, or calculated glomerular filtration rate (GFR) based on cystatin 
C. 
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function. If renal 
impairment is suspected per the investigator’s clinical assessment, measurement of serum 
cystatin C on a central chemistry laboratory sample may be performed to confirm renal function. 
Abemaciclib dose adjustment should follow the protocol guidance for non-hematological 
toxicities in Section 6.6.3. 
8.2.5. 
Guidance for Venous Thromboembolic Events  
In breast cancer, VTE has been identified as an adverse drug reaction (ADR) for abemaciclib in 
combination with ET. In the randomized Phase 3 studies in participants with breast cancer who 
received abemaciclib in combination with ET, a greater number of participants experienced 
VTEs in the abemaciclib plus ET arms than in the placebo plus ET arm or ET alone arm. The 
majority of participants who experienced VTEs were treated with anticoagulants. In studies with 
single-agent abemaciclib use in the metastatic breast cancer population or other tumor types, 
including non-small cell lung cancer, no increased rates of VTEs were observed as compared to 
the incidence of VTEs for these particular patient populations who were treated with other 
anticancer agents. At this time, the mechanism underlying the association between abemaciclib 
and the occurrence of VTEs is not known. 
Monitor participants for signs and symptoms of deep vein thrombosis and pulmonary embolism 
and treat as medically appropriate. Refer to Section 6.6.3 for guidance on dose adjustments of 
abemaciclib for patients with VTEs. 
8.2.6. 
Guidance for Interstitial Lung Disease/Pneumonitis  
Interstitial lung disease (ILD)/pneumonitis has been identified as an ADR for abemaciclib. The 
majority of events observed in clinical trials were Grade 1 or Grade 2 with serious cases and fatal 
events reported. Additional information is available in the IB. 
Ask participants to report any new or worsening pulmonary symptoms, such as dyspnea, cough, 
and fever, and investigate and treat as per local clinical practice (including corticosteroids as 
appropriate). If ILD/pneumonitis is suspected, investigations may include imaging, such as high-
resolution CT, bronchoalveolar lavage, and biopsy as clinically indicated. Refer to Section 6.6.3 
for guidance on dose adjustments or discontinuation of abemaciclib for patients with 
ILD/pneumonitis.  
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8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting the Sponsor or its designee to any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study. The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise explained. The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study. In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure, investigational product, via CRF.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
Abnormal laboratory values should ONLY be reported as an AE if they are clinically relevant 
(See Section 10.6, Appendix 6). 
If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to the Sponsor or its designee via CRF, clarifying if possible the circumstances 
leading to any dosage modifications, or discontinuations of treatment. 
The definitions of the following events can be found in Section 10.6, Appendix 6: 
 Adverse events 
 Serious adverse events, and 
 Product complaints. 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue study treatment. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.6 Appendix 6. 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. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs 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). For 
product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Section 10.6 Appendix 6.  
Timing and Mechanism for Collecting Events 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to the Sponsor begins after the patient has signed the ICF and has received study 
drug. However, if an SAE occurs after signing the ICF, but prior to receiving imlunestrant, it 
needs to be reported ONLY if it is considered reasonably possibly related to study procedures. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE CRF.  
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The investigator will submit any updated SAE data to 
the Sponsor within 24 hours of it being available. SAEs, 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 patient has been discharged from the study, and he or she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
Sponsor. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient and/or legal guardian is the preferred method to 
inquire about AE occurrences. 
8.3.1. 
Follow-Up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3).  
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8.3.2. 
Regulatory Reporting Requirements for SAEs  
 Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients 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, IRBs/IECs, and investigators. 
 Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (for example, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate, 
according to local requirements. 
8.3.3. 
Pregnancy  
 Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected. 
 If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.7 
Appendix 7. 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Additional requirements for pregnancy testing during and after study intervention are 
located in Section 10.7 Appendix 7. 
 The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
8.3.4. 
Cardiovascular and Death Events  
Events leading to the clinical outcome of death due to study disease that are part of the efficacy 
analyses for this study will not be reported to the Sponsor or its designee as SAEs unless the 
investigator believes the event may have been caused by the investigational product. 
8.3.5. 
Complaint Handling  
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
trial intervention. 
Sponsor collects product complaints on study intervention and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements. 
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Participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the intervention so that the situation can be assessed. 
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.1 and Section 10.6 Appendix 6 of the protocol. 
Time Period for Detecting Product Complaints 
Product complaints that result in an adverse event will be detected, documented, and reported to 
the sponsor during all periods of the study in which the intervention is used. 
If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to an intervention 
provided for the study, the investigator will promptly notify the sponsor. 
Prompt Reporting of Product Complaints to Sponsor 
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint. 
The Product Complaint Form will be sent to the sponsor by a method designated by the sponsor. 
Follow-up of Product Complaints 
Follow-up applies to all participants, including those who discontinue study intervention. 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product complaint. 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator and submitted to the sponsor. 
8.4. 
Treatment of Overdose  
In the event of an overdose, the investigator should: 
 Contact the Sponsor CRS/CRP immediately. 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
 Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
 Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 
Refer to the IB of imlunestrant and/or abemaciclib for available information on the signs, 
symptoms, and treatment of overdose. 
If an overdose of any control arm therapy is suspected, investigators should follow locally 
approved label recommendations and actions accordingly. 
8.5. 
Pharmacokinetics  
At the visits and times specified in the SoA (Section 1.3.2), venous blood samples will be 
collected to determine the plasma concentrations of imlunestrant, abemaciclib, and its 
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metabolites LSN3106726 and LSN2839567. Concentrations of imlunestrant and abemaciclib and 
its metabolites in plasma samples will be quantified using validated assay methodology in a 
laboratory designated by the Sponsor. Blood samples may also be used for exploratory 
metabolism work of imlunestrant and abemaciclib as deemed appropriate by the Sponsor. 
Samples may be removed or collected at additional time points during the study if warranted and 
agreed upon between both the investigator and Sponsor. Instructions for the collection and 
handling of blood samples will be provided by the Sponsor. The actual date and time (24-hour 
clock time) of each sampling will be recorded in the sample requisition form. 
Differences from the time specified in the protocol are not considered protocol deviations as long 
as samples are collected, and accurate dates and times are recorded in a timely manner on the 
appropriate forms. 
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  
Pharmacodynamic parameters are not evaluated in this study. 
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. See Section 10.8 Appendix 8 for information 
regarding genetic research.  
8.8. 
Biomarkers  
This study will analyze biomarkers relevant to study treatment, mechanism of action of 
imlunestrant, the variable response to study drug(s), immune function, tumor microenvironment, 
replication stress, angiogenesis, and pathways associated with cancer. Biomarker research may 
be performed to address questions of relevance to drug disposition, target engagement, PD, 
variability of participant response (including safety), and clinical outcome. Samples collected 
enable examination of these questions through the measurement of biomolecules, including 
DNA, ribonucleic acid, proteins, lipids, and other cellular elements. These samples may also be 
used to develop related research methods or to validate diagnostic tools or assays.  
Collection of samples for biomarker research is also part of this study. The following samples for 
biomarker research are required and will be collected from all participants in this study as 
specified in the SoA: 
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 tumor tissue (preferably from the most recently obtained nonbone biopsy) must be 
obtained for patients if available*. Tissue blocks are preferred, otherwise ~25 x 5 um 
unstained slides, with verification of at least 20% tumor content, should be provided. 
Patients who do not have adequate archival tumor tissue available may undergo a fresh 
tumor biopsy prior to treatment if it is considered safe to perform and with the patient’s 
consent. (*If archival tissue is not available and a fresh tumor biopsy cannot be 
performed, the patient may still be eligible to enroll if all other eligibility criteria are 
met.) 
 plasma at multiple time points as specified in SoA. 
The pathology report accompanying archival tissue may also be requested. The pathology report 
must be coded with the patient’s study subject number. Personal identifiers, including the 
patient’s name and initials, must be removed from the institutional pathology report prior to 
submission. The Sponsor has a right to retain a portion of the submitted tissue. Archival blocks 
will be sectioned and returned to the study site upon request. Slides and tissue samples collected 
on-study will not be returned. 
All samples will be coded with the participant study number. These samples and any data 
generated can only be linked to the participant’s study number. Personal identification 
information that can directly identify a patient will not be included with the sample.  
Samples will be retained at a facility selected by the Sponsor 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 imlunestrant or after imlunestrant 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, whole exome/genome sequencing, gene expression assays, multiplex protein assays, 
and/or immunohistochemistry may be performed on these samples to assess potential 
associations between these biomarkers and clinical outcomes. 
It is possible that biomarker data for patients in the study have 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 in Sections 8.7 and 8.8. 
8.9. 
Health Outcomes and Medical Resource Utilization  
8.9.1. 
Patient-Reported Outcomes  
Self-reported questionnaires will be administered using a provisioned electronic patient reported 
outcome (ePRO) device in countries where the questionnaires have been translated into the native 
language of the region and linguistically validated. Only patients that are literate in an available 
translation will complete the questionnaires. The device will use an alarm feature to remind the 
subject/patient to complete their questionnaire, if the patient has not yet completed their 
questionnaire on the day it is scheduled. This will be detailed in the eCOA operations manual. In 
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the event that a device does not work properly, the site will follow the mitigation plan specified in 
the eCOA operations manual for collecting this data. Since no paper version of the questionnaires 
are provided, patients with religious objections to using electronic devices are not required to 
complete these activities 
The patient-reported outcomes including pain, cancer-related symptoms, physical function, 
adverse effect of diarrhea, and other health-related quality of life (HRQoL) outcomes will be used 
to compare across three treatment arms and generate health utility data. See Section 1.3.1 for 
patient-reported outcome (PRO) SoA.  
All baseline assessment PRO questionnaires will be administered electronically on C1D1 prior to 
extensive interaction with site staff and study drug administration with the exception of the 
EORTC QLQ IL19 (not administered on C1D1 due to overlapping questions with EORTC QLQ-
C30) and PRO-CTCAE item for injection site pain and swelling. Subsequent assessments will be 
completed at home according to the SoA for patient reported outcomes (Section 1.3.1) to minimize 
the number of activities required during clinic visits, with the exception of the SFU visit. At the 
SFU visit, patients with complete the specified assessments on the patient’s ePRO device on site, 
therefore patients will be asked to bring their device with them for the SFU visit. While individual 
patients may vary in their response time, data from prior research among patients with advanced 
cancers suggest that 20 items can be completed in an average of less than 4 minutes using an 
electronic device. 
8.9.2. 
EORTC QLQ-C30  
Health-related quality of life will be assessed using the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30; 
Aaronson et al. 1993). Broadly used in cancer trials, validated, and available in over 80 different 
languages, EORTC QLQ-C30 is a reliable and validated tool that has supported quality-of-life 
claims in both Food and Drug Administration and European Medicines Evaluation Agency labels. 
The full EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covering 
3 dimensions regarding the patient’s experience in the past 7 days:  
 global health status/quality of life (2 items)  
 functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning), and  
 symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact). 
This assessment will be completed by patients on a handheld electronic device at home (at site on 
C1D1 and SFU visit) every 8 weeks per the SoA in Section 1.3.1. To minimize patient burden, this 
instrument will be administered on an alternating schedule with the EORTC IL 19 instrument due 
to overlapping items (physical function domain). Assessment completion time is typically 5-7 
minutes.  
8.9.3. 
EORTC IL19: Physical Function  
The EORTC IL19 consists of 5 items that are identical to the physical functioning subscale (items 
1-5) of the EORTC QLQ-C30. This assessment will be completed by patients at home on an 
electronic handheld device on an every 8-week schedule as described in Section 1.3.1. To 
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minimize patient burden, the EORTC IL 19 scale will be first administered on C2D1 and will be 
administered in an alternating schedule with the EORTC QLQ-C30 such that the 2 instruments are 
completed 4 weeks apart from each other. 
8.9.4. 
EQ-5D-5L  
Health status will be assessed using the EQ-5D-5L (Janssen et al. 2008). These utility measures 
are an important input for economic evaluations by global health technology assessment 
organizations that examine the value of treatment interventions. Patients will complete the 5-
dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and 5-
level (no problem, slight, moderate, severe, or extreme problem) assessment. Additionally, patients 
will indicate their current health status by marking on a visual analog scale ranging from 100 (best 
imaginable health state) to 0 (worst imaginable health state) as of “today.” The EQ-5D-5L is 
designed for self-completion by respondents, is cognitively simple, takes only a few minutes to 
complete, with a recall period of “today,” and will be completed by patient using an electronic 
device, every 8 weeks, according to the schedule described in Section 1.3.1. 
8.9.5. 
PGIS (Patient’s Global Impression of Severity) - Cancer Symptoms  
The PGIS-Cancer Symptoms is a single-item assessment whereby patients are asked to report the 
overall severity of their cancer-related symptoms in the past 7 days using a 5-level response scale 
ranging from “No Symptoms” to “Very Severe.” This assessment will be completed by the patient 
on an electronic device every 4 weeks as per the schedule described in Section 1.3.1. 
8.9.6. 
mBPI-sf  
The mBPI-sf (Cleeland 1991) is an 11-item instrument used as a multiple-item measure of cancer 
pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for patients to record 
the presence of pain in general, pain relief, and pain interference with function (general activity, 
mood, ability to walk, ability to perform normal work, relations with others, sleep, and enjoyment 
of life). Responses for the mBPI-sf items are captured through the use of 11-point NRS anchored 
at 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or 
completely interferes). The mBPI-sf recall period is 24 hours, and typical completion time for this 
instrument is less than 5 minutes. This pain instrument will be completed by the patient at home 
on an electronic PRO device provided every 4 weeks as per the schedule described in Section 1.3.1.  
8.9.7. 
Worst Pain NRS  
The Worst Pain NRS is a single-item, extracted from the mBPI-sf. This item is subject-
administered with an 11-point horizontal scale anchored at 0 (“no pain”) and 10 (“pain as bad as 
you can imagine”). The recall period is the last 24 hours and will be completed daily at home by 
the patient on an electronic PRO device provided. The daily assessments for worst pain NRS will 
be collected during the study period, started at C1D1 to capture the baseline pain data as per the 
schedule described in Section 1.3.1.  
8.9.8. 
PRO-CTCAE Items for Diarrhea and Injection Site Pain and Swelling  
The PRO-CTCAE is a PRO measurement system developed by the National Cancer Institute to 
collect symptomatic AEs from cancer patients enrolled in clinical trials (Basch et al. 2014; 
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Dueck et al. 2015). These items have been developed to assess symptomatic AEs from the patient 
perspective associated with cancer therapy, to complement the CTCAE data collected at the site 
level (Basch et al. 2014, Atkinson et al. 2016). The information from the PRO-CTCAE will be 
used strictly for the study objective and shall not be reviewed by the site nor used in AE reporting. 
A single question from the PRO-CTCAE item library was selected to characterize diarrhea. The 
single-item PRO-CTCAE will be completed weekly by the patient via the electronic device 
provided as per the SoA described in Section 1.3.1. 
A single question from the PRO-CTCAE item library was selected to characterize injection site 
pain and swelling if any, for the patients who receive fulvestrant IM injections. The single item 
PRO-CTCAE will be completed by the patient weekly for 2 weeks following each administration 
of fulvestrant injection as per the SoA described in section 1.3.1. 
8.9.9. 
Medical Resource Utilization  
Medical resource utilization will be collected in the eCRF by the investigator and study site 
personnel for all patients throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. The data collected will include hospitalization, emergency room visit, 
radiation, surgery, and analgesic use. 
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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
Hypothesis 1: the imlunestrant arm (Arm A) will provide a clinically meaningful increase in PFS 
over the Investigator’s Choice Endocrine Therapy (Arm B) in patients with ER+, HER2- locally 
advanced or mBC previously treated with ET in the ITT population. 
Hypothesis 2: the imlunestrant arm (Arm A) will provide a clinically meaningful increase in PFS 
over the Investigator’s Choice Endocrine Therapy (Arm B) in patients with ER+, HER2- locally 
advanced or mBC previously treated with ET in the ESR1-mutation detected population. 
Hypothesis 3: the imlunestrant plus abemaciclib (Arm C) will provide a clinically meaningful 
increase in PFS over the imlunestrant arm (Arm A) in patients with ER+, HER2- locally 
advanced or mBC previously treated with ET in the ITT population. 
9.2. 
Sample Size Determination  
Participants will be randomly assigned to Arm A, Arm B or Arm C in a 1:1:1 ratio until the 
target enrollment for arms A and B (a total number of approximately 640 participants) is 
reached. 
Though Arm C was added to the study (amendment a) after first patient visit for Arms A and B, 
all arms will be closed at the same time. Randomization of participants will continue in Arms A 
and B (1:1) until amendment a is approved and implemented, at which point participants will be 
randomized 1:1:1 (A:B:C) until the target enrollment for arms A and B (a total number of 
approximately 640 participants) is reached. 
To adjust for multiplicity and control the overall type I error rate at 0.025 (1-sided), the graphical 
approach (Maurer and Bretz 2013) will be used to test the 3 PFS hypotheses and the 3 OS 
hypotheses. Initially, the overall 1-sided alpha level of 0.025 will be split between PFS for Arm 
A versus Arm B in the ITT population (H1) and PFS for Arm A versus Arm B in the ESR1-
mutation detected population (H2), with H1 tested at the 1-sided alpha level of 0.005 and H2 
tested at the 1-sided alpha level of 0.02. No alpha level (alpha=0) is initially assigned to the PFS 
endpoint for Arm C versus Arm A in the ITT population (H3) and OS endpoints. The full graph 
including the OS endpoints and further details about the graphical approach will be provided in 
the SAP. 
As the overall alpha is initially split between H1 and H2, the study will be considered positive (for 
Arm A versus Arm B) if either PFS in the ITT population (H1) or PFS in the ESR1-mutation 
detected population (H2) is statistically significant. The power and associated sample sizes for H1 
and H2 are based on the initial allocation of alpha. The analysis population for the first primary 
hypothesis (PFS for Arm A versus Arm B in the ITT population) is all participants randomized 
to Arm A and Arm B. The primary analysis of PFS for Arm A versus Arm B in the ITT 
population will be performed when approximately 480 investigator-assessed events have been 
observed (that is, a 25% censoring rate) in Arm A and Arm B. Assuming a PFS hazard ratio of 
0.74, a total of 480 events yields at least 76% power to detect superiority of imlunestrant Arm A 
over Arm B with the 1-sided log-rank test at the initial significance level of 0.005. If H1 can be 
tested at the full alpha level of 0.025 after recycling per the graphical approach, the same number 
of events can yield at least 91% power with the 1-sided log-rank test. The median PFS of Arm B 
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is assumed to be 4.3 months, and the hazard ratio of 0.74 amounts to an approximate 1.5-month 
improvement in median PFS under the assumption of exponential survival distribution. The 
assumed median PFS of Arm B is estimated based on an unpublished meta-analysis of historical 
controls. 
The analysis population for the second primary hypothesis (PFS for Arm A versus Arm B in the 
ESR1-mutation detected population) is the ESR1-mutation detected subset in Arm A and Arm B. 
The primary analysis of PFS will be performed when approximately 192 investigator-assessed 
events have been observed in the ESR1-mutation detected subset. Assuming a PFS hazard ratio 
of 0.57, a total of 192 events yields approximately 97% power to detect superiority of Arm A 
over Arm B with the 1-sided log-rank test at the significance level of 0.02. Assuming the median 
PFS of Arm B in the subset is 3.6 months, the hazard ratio of 0.57 amounts to an approximate 
2.7-month improvement in median PFS under the assumption of exponential survival 
distribution. 
The power and sample size for H3 is based on the 1-sided alpha level of 0.025 assuming that both 
H1 and H2 are rejected. The analysis population of the third primary hypothesis (PFS for Arm C 
versus Arm A in the ITT population) is the participants concurrently randomized to Arm A and 
Arm C. The primary analysis of PFS will be performed when approximately 248 investigator-
assessed events have been observed in this analysis population. Assuming a PFS hazard ratio of 
0.7, a total of 248 events yields at least 80% power to detect superiority of Arm C over Arm A 
with the 1-sided log-rank test at the significance level of 0.025. If the median PFS of Arm A is 
assumed to be 5.8 months (assuming the target HR for Arm A versus Arm B in the ITT 
population is met), the hazard ratio of 0.7 then amounts to an approximate 2.5-month 
improvement in median PFS under the assumption of exponential survival distribution. 
Previous enrollment assumptions were based on hypothetical enrollment rates. Under current 
rates of 35-40 participants per month, it is estimated that a total number of 860 participants will 
be enrolled to this study. Specifically, approximately 320 participants will be enrolled in Arms A 
and B, respectively, and approximately 220 participants in Arm C. The analysis population for 
PFS between Arm A and Arm B in the ITT population is all approximately 640 participants 
randomized to Arm A and Arm B, and the analysis population for PFS between Arm C and Arm 
A in the ITT population is the approximately 440 participants concurrently randomized to Arm A 
and Arm C. More details about the enrollment assumptions will be provided in the SAP. 
9.3. 
Populations for Analyses  
Populations are defined as follows: 
Population 
Description 
ITT 
All participants randomly assigned to study treatment, regardless of whether they 
take any doses of study treatment, or if they took the correct treatment. 
Participants will be analyzed according to the treatment group to which they were 
assigned 
Safety 
All participants randomly assigned to study treatment and who take at least 1 dose 
of study treatment. Participants will be analyzed according to the study treatment 
they actually received 
Evaluable 
The subset of participants from the ITT population from whom a valid result has 
been obtained. Defined in the specific sections if applicable 
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9.4. 
Statistical Analyses  
Statistical analysis of this study will be the responsibility of Sponsor or its designee. 
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 methods 
described in the protocol, and the justification for making the change, will be described in the SAP 
and the CSR. Additional exploratory analyses of the data will be conducted as deemed appropriate. 
The SAP will include a more technical and detailed description of the statistical analyses described 
in this section.  
9.4.1. 
General Considerations  
Continuous variables will be summarized using descriptive statistics (that is, number of patients, 
mean, median, standard deviation, minimum, and maximum). Categorical variables will be 
summarized by frequency and its corresponding percentage. 
Efficacy analyses will be based on the ITT population, unless otherwise stated. Safety analyses 
will be based on the safety population. 
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.025, unless otherwise 
stated, and all CIs will be given at a 2-sided 95% level. 
The assumptions for each statistical method will be evaluated. If there is violation of assumptions, 
alternative statistical methods may be used. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. 
9.4.2. 
Treatment Group Comparability  
9.4.2.1. 
Participant Disposition  
A detailed description of patient disposition will be provided, including a summary of the number 
and percentage of participants entered into the study, enrolled in the study, and treated as well as 
number and percentage of patients completing the study, as defined in the SAP, or discontinuing 
(overall and by reason for discontinuation).  
9.4.2.2. 
Participant Characteristics  
A summary of participants demographic, baseline disease characteristics, historical diagnoses, 
preexisting conditions, and prior therapies will be provided.  
9.4.2.3. 
Concomitant Therapy  
A summary of preferred names of concomitant medications by treatment arm by decreasing 
frequency will be reported. 
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9.4.2.4. 
Post-Study Treatment Therapy  
The numbers and percentages of participants receiving poststudy anticancer therapies will be 
provided by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug class and/or 
name, overall and by line of therapy. 
9.4.2.5. 
Extent of Exposure  
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm. 
9.4.2.6. 
Treatment Compliance  
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 tablets dispensed and returned over the 
course of the patient’s treatment. Compliance will only be assessed for imlunestrant, exemestane, 
and abemaciclib. 
9.4.3. 
Efficacy Analyses  
9.4.3.1. 
Primary Analyses  
The primary endpoint is investigator-assessed PFS. PFS is defined as the time from randomization 
to the date of first documented progression of disease or death from any cause in the absence of 
disease progression using RECIST version 1.1. Participants known to be alive and without disease 
progression will be censored at the last known date of progression-free assessment. A detailed PFS 
event/censoring scheme is provided in the table below. The Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the PFS curves. Median PFS and PFS rates at various time 
points with 95% CIs will be estimated for each arm. The comparison of PFS curves between 
treatment arms will be conducted by a stratified log-rank test as the primary analysis, stratified by 
the randomization strata. The treatment effect will be estimated by hazard ratio with its 
corresponding 95% CIs using the stratified Cox proportional hazard model with treatment as the 
only covariate, stratified by the randomization strata.  
For the primary objective of PFS for Arm A versus Arm B in the ITT population, 1 interim PFS 
analysis is planned when approximately 192 investigator-assessed events have been observed to 
allow the trial to stop early due to futility, and the final analysis will be conducted when 
approximately 480 investigator-assessed events have been observed in the same population. 
Details about the interim analysis are provided in Section 9.5. 
For the primary objective of PFS for Arm A versus Arm B in the ESR1-mutation detected 
population, the final analysis will be conducted when approximately 192 investigator-assessed 
events have been observed. The comparison of PFS curves between treatment arms will be 
conducted by a stratified log-rank test as the primary analysis, stratified by the randomization strata. 
The treatment effect will be estimated by hazard ratio with its corresponding 95% CIs using the 
stratified Cox proportional hazard model with treatment as the only covariate. Strata may be 
collapsed to reduce the number of strata for the primary analysis. More details will be provided in 
the SAP. 
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For the primary objective of PFS for Arm C versus Arm A in the ITT population, one interim PFS 
analysis will be conducted when approximately 100 events have been observed among the 
approximately 440 participants concurrently randomized to Arm A and Arm C. This interim 
analysis will allow the trial (Arm A versus Arm C comparison) to stop early due to futility. Details 
are provided in Section 9.5. The final analysis will be conducted when approximately 248 events 
have been observed among the participants concurrently randomized to both arms. The PFS 
between Arm C and Arm A will only be tested hierarchically based on the graphical approach. 
More details will be provided in the SAP. 
Sensitivity analyses including PFS analyses using different censoring rules, using the full ITT 
population (all randomized participants to corresponding arms for Arm C versus Arm A 
comparison), using unstratified log-rank test and unstratified Cox model may also be performed at 
the time of the final PFS analysis. Further details about these sensitivity analyses will be described 
in the SAP. 
PFS Censoring Scheme 
Situation 
Event/Censor 
Date of Event or Censor 
Tumor progression or death 
Event 
Earliest date of PD or death 
No tumor progression and no death 
Censored 
Date of last adequate tumor assessment, 
per RECIST 1.1 criteria, or date of 
randomization (whichever is later) 
 
Unless 
 
No baseline radiologic tumor assessment available 
Censored 
Date of randomization 
No adequate postbaseline tumor assessment 
available and death reported after 2 scan intervals 
following randomization 
Censored 
Date of randomization 
New systemic anticancer therapy and no tumor 
progression or death  
Censored 
Date of adequate tumor assessment, per 
RECIST 1.1 criteria, prior to start of 
new therapy or date of randomization 
(whichever is later) 
Tumor progression or death documented 
immediately after 2 or more missing scan intervals 
following last adequate tumor assessment or 
randomization (whichever is later) 
Censored 
Date of last adequate tumor assessment 
prior to 2 or more missing scans, per 
RECIST 1.1 criteria, or date of 
randomization (whichever is later) 
Abbreviations: PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1. 
a Symptomatic deterioration (that is, symptomatic progression that is not radiologically confirmed per RECIST 1.1 
criteria) will not be considered as tumor progression. 
b  Adequate tumor assessment per RECIST 1.1 criteria refers to an assessment with 1 of the following responses: 
CR, PR, SD, or PD. 
c The 2-scan interval is counted from the date of last adequate tumor assessment to the date of next 2 scheduled 
tumor assessments plus 8 days (adjusted by tumor assessment window). 
d If there are multiple dates associated with 1 assessment, the assessment date will be set to the first date when the 
overall response is PD and the last date otherwise. 
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9.4.3.2. 
Key Secondary Analyses  
Overall survival between Arm A and Arm B in the ITT population, OS between Arm A and Arm 
B in the ESR1-mutation detected population and OS between Arm C and Arm A in the ITT 
population are the key secondary endpoints. To maintain the family-wise type I error rate, OS 
endpoints will be tested hierarchically based on the graphical approach. The full details about the 
graphical approach including OS endpoints will be provided in the SAP. Other secondary 
endpoints will not be error controlled. 
Overall survival (OS) is defined as the time from randomization until death from any cause. If 
the patient is alive or lost to follow-up at the time of analysis, OS data will be censored on the last 
date the patient is known to be alive. OS curves, median OS, and OS rates at 1 year, 2 years, and 
3 years with 95% CI for each treatment arm will be estimated using the Kaplan-Meier method. OS 
will be compared between treatment arms using a log-rank test, stratified by the same factors as 
PFS. The corresponding hazard ratio between treatment arms will be estimated using a stratified 
Cox regression model. The inferential analysis of OS will be based on the stratified analyses. 
Unstratified analyses will also be performed. For Arm A versus Arm B in the ESR1-mutation 
detected population, OS will be analyzed using the same methods as PFS. 
The analysis of each OS endpoint will be conducted in the same analysis populations for PFS as 
defined in Section 9.4.3.1. Interim analyses for each OS endpoint are also planned. Further details 
about the interim analyses for OS will be provided in the SAP. 
9.4.3.3. 
Other Secondary Analyses  
All other secondary analyses will be conducted for each comparison (Arm A versus Arm B in the 
ITT and ESR1-mutation detected populations and Arm C versus Arm A in the ITT population) per 
the prespecified analysis populations. 
Objective response rate (ORR) is defined as the number of participants who achieve a confirmed 
best overall response of CR or PR divided by the total number of participants randomized to the 
corresponding treatment arm. The ORR with 95% CIs will be summarized for each treatment arm 
and compared between treatment arms using the Cochran-Mantel-Haenszel test adjusting for the 
randomization strata. The analysis of ORR will be conducted in the ORR evaluable population, 
which is defined as all randomized participants who have measurable disease per RECIST v1.1 at 
baseline. 
Clinical benefit rate (CBR) is defined as the number of participants who achieve a best overall 
response of CR, PR, or SD ≥24 weeks divided by the total number of participants randomized to 
the corresponding treatment arm. The CBR with 95% CIs will be summarized for each treatment 
arm and compared between treatment arms using the Cochran-Mantel-Haenszel test adjusting for 
the randomization strata.  
Duration of response (DoR) is defined as the time from the date measurement criteria for CR or 
PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective 
progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence 
of objectively determined disease progression or recurrence. The DoR will be censored according 
to the same rules as PFS. Median DoR with 95% CI and curves for each treatment arm will be 
estimated using the Kaplan-Meier method. The analysis of DoR will be based on participants who 
achieve an objective response (CR or PR). 
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Progression-free survival by blinded independent review committee (BIRC) is defined the 
same way as the primary endpoint of PFS. For BIRC analysis, scans will be collected and reviewed 
in all randomized participants based on RECIST version 1.1. PFS as assessed by BIRC intends to 
evaluate the reliability of the treatment effect based on the investigator-assessed PFS. PFS as 
assessed by BIRC will be analyzed using the same methods as the investigator-assessed PFS. The 
evaluation for the potential bias in the investigator assessment will also be performed. Further 
details will be described in the SAP. 
9.4.4. 
Patient-Reported Outcomes and Medical Resource Utilization  
Time to sustained worsening of worst pain is defined from the randomization to the time of the 
first increase (≥2 points) in the weekly average of the worst pain score with confirmation in the 
next consecutive week. Time to sustained worsening of worst pain will be summarized for each 
arm by the Kaplan-Meier method and will be compared between the 2 arms using the stratified 
log-rank test. 
Time to worsening of physical function is defined as the time from randomization to the first ≥10-
point decrease from baseline with confirmation at the next cycle. Time to worsening of physical 
function will be summarized for each arm by the Kaplan-Meier method, and the stratified log-rank 
test will be used to compare between the 2 arms.  
For each participant with data from baseline and at least 1 post-baseline visit, the change from 
baseline at each time point, and maximum change from baseline score will be calculated for each 
scale of each instrument. The reason and number of missing and incomplete questionnaires and/or 
assessments by visit will be summarized for each instrument and arm.  
Frequency counts of hospitalizations, emergency room visits, radiation, surgery, transfusion, and 
analgesic use will be summarized descriptively for each arm. 
Full censoring rules for these endpoints will be described in the SAP. All the analyses will be 
conducted for each comparison (Arm A versus Arm B in the ITT and the ESR1-mutation detected 
populations and Arm C versus Arm A in the ITT population) per the prespecified analysis 
populations. Further analysis details will be described in the SAP. 
9.4.5. 
Safety Analyses  
Safety analyses will be based on the safety population, including the summaries of the following: 
 AEs, including severity and possible relationship to study drug 
 SAEs, including possible relationship to study drug 
 AEs leading to dose adjustments 
 discontinuations from study treatment due to AEs or death, and 
 treatment-emergent abnormal changes in laboratory values, vital signs, and ECGs. 
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses  
PK parameters for imlunestrant in plasma (for example, clearance, volume of distribution) and 
inter-individual PK variability will be computed using nonlinear mixed-effect modeling 
implemented in NONMEM. Covariate effects, such as age, weight, sex, and creatinine clearance, 
on the PK parameters of LY3484356 in plasma will also be investigated. 
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Concentrations of abemaciclib and its metabolites, LSN3106726 and LSN2839567 may be 
compared to previously established population PK models. 
Biomarker data collected in this study may be used in a population PK/pharmacodynamic model. 
9.4.7. 
Other Analyses  
9.4.7.1. 
Exploratory Analyses  
All the exploratory analyses will be conducted for each comparison (Arm A versus Arm B in the 
ITT and the ESR1-mutation detected populations and Arm C versus Arm A in the ITT population) 
per the prespecified analysis populations, unless otherwise stated. 
Time to progressive bone metastases is defined as the time from randomization to the date of 
earliest development of new bone metastases. Time to progressive bone metastases will be 
summarized for each treatment arm using the Kaplan-Meier method and will be compared between 
2 arms using the log-rank test. 
Time to first SRE is defined as the time from randomization to the first SRE event defined as either 
pathological fracture, spinal cord compression, radiation to the bone, or surgery to the bone. Time 
to first SRE will be summarized for each treatment arm using the Kaplan-Meier method and will 
be compared between 2 arms using the log-rank test. 
Time to chemotherapy is defined as the time from randomization to the initiation of first post-
discontinuation chemotherapy. TTC will be summarized for each treatment arm using the 
Kaplan-Meier method and will be compared between 2 arms using the log-rank test. 
Chemotherapy-free survival is defined as the time from randomization to the initiation of first post-
discontinuation chemotherapy or death, whichever is earlier. CFS will be summarized for each 
treatment arm using the Kaplan-Meier method and will be compared between 2 arms using the 
log-rank test. 
Progression-free survival 2 is defined as the time from randomization to disease progression on 
the next line of treatment or death, whichever is earlier. PFS2 will be summarized for each 
treatment arm using the Kaplan-Meier method and will be compared between 2 arms using the 
log-rank test. 
Time to worsening of ECOG PS of ≥2 is defined as the time from randomization to the date when 
ECOG PS score of ≥2 was observed for the first time. Time to worsening of ECOG PS of ≥2 will 
be summarized for each treatment arm using the Kaplan-Meier method and will be compared 
between 2 arms using the log-rank test. 
PFS and OS will be compared between Arm C and Arm B using the stratified log-rank test. The 
treatment effect will be estimated by hazard ratio with its corresponding 95% CIs using the 
stratified Cox proportional hazard model. The analysis population for Arm C versus Arm B is all 
concurrently randomized participants between two arms. Subgroup analyses will be conducted if 
deemed appropriate. 
Further analysis details will be described in the SAP. 
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9.4.7.2. 
Subgroup Analyses  
Subgroup analyses of PFS and OS will be performed for potential prognostic subgroup variables 
in each comparison, including but not limited to 
 all baseline stratification factors 
 ESR1 mutation status (mutation detected versus mutation not detected) for the analyses in 
the ITT population 
 measurable disease at baseline (yes versus no) 
 age (<65 years versus ≥65 years) 
 region (North America, Europe, Asia, and Other) 
 race (Caucasian, Asian, and Other) 
 PGR status (positive versus negative) 
 baseline ECOG PS (0 versus 1), and 
 number of organs involved (1 versus 2 versus 3+). 
If a level of a factor consists of fewer than 5% of total number of events, analysis within that level 
may be omitted. Other subgroup analyses may be performed as deemed appropriate. Details are 
included in the SAP. 
9.4.7.3. 
Biomarker Analyses  
Biomarkers related to treatment, mechanism of action, and/or cancer will be measured and 
analyzed. Baseline ESR1 mutation status (mutation detected versus mutation not detected) will be 
summarized. The association of biomarkers and clinical outcomes will be assessed via single-
marker and/or multi-marker analysis.  
9.5. 
Interim Analyses  
9.5.1. 
Safety Interim Analyses  
The DMC will monitor the overall safety of the study. An early safety analysis will be performed 
after approximately 100 participants have been randomized to all arms and had the opportunity to 
be treated for 1 cycle. The DMC will meet and review data approximately every 6 months 
thereafter. At the recommendation of the DMC, the frequency of safety interim analyses may be 
modified.  
At each interim analysis, the DMC may recommend the trial continue without modifications, 
continue with specific modifications, or be stopped for safety concerns. There will be no 
prespecified rules for stopping the trial due to safety concerns. The DMC members will review 
unblinded safety data at each interim analysis. If a significant safety signal is identified, the DMC 
may recommend a protocol amendment, termination of enrollment, and/or termination of study 
treatment. The recommendations of the DMC will be communicated to the Sponsor SMD. 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the treatment group level, members of the DMC can conduct additional analyses of the safety data. 
Additionally, unblinding of a limited number of the Sponsor representatives external to the study 
team may be required for evaluation of selected SAEs for determination of regulatory reporting. 
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9.5.2. 
Efficacy Interim Analyses  
One interim analysis is planned for the primary endpoint of PFS between Arm A and Arm B in the 
ITT population, when approximately 192  of the 480 events (40% information fraction) have been 
observed in the analysis population as defined in Section 9.2. The primary purpose of this interim 
is to allow the trial to stop early due to futility. The beta-spending function is determined by the 
gamma family. The DMC should recommend stopping the trial for futility if the hazard ratio is 
above 1.128. There is no intent to declare statistical significance for superior efficacy at this 
interim; therefore, there is no impact on the statistical significance levels for the final analysis.  
For PFS between Arm A and Arm B in the ESR1-mutation detected population, if the target 
number of events in this subset has not been reached at the time of final PFS analysis in the ITT 
population, one interim analysis for efficacy may be conducted in the subset at the time of final 
analysis in the ITT population. The Lan-DeMets spending function (O'Brien-Fleming type) will 
be used to determine the boundaries at the interim and final analyses for PFS in the ESR1-mutation 
detected population. 
Stopping Boundaries for Each Analysis between Arm A and Arm B in the ITT Population 
Based on the Initial Allocation of Alpha for Illustration 
Analysis 
Number 
of Events 
Information 
Fraction 
Critical 
P-value 
Boundary 
Critical 
Hazard 
Ratio 
Boundary 
Cumulative 
Type I 
Error Rate 
Boundary Crossing Probabilities a 
Hazard 
Ratio = 
0.74 
Hazard 
Ratio = 
1 
Hazard 
Ratio = 
1.25 
Interim  
192 
40% 
NA 
1.128 
NA 
0.002 
0.203 
0.757 
Final 
480 
100% 
0.005 
(efficacy) 
0.790 
0.005 
0.759 
0.005 
0 
a Boundary crossing probabilities under different hazard ratio assumptions. 
One interim analysis is planned for the primary endpoint of PFS between Arm C and Arm A when 
approximately 100 of the 248 events (40% information fraction) have been observed in the analysis 
population for this comparison as defined in Section 9.2. The purpose of the interim is to allow the 
trial comparison for Arm C versus Arm A to stop early due to futility. The beta-spending function 
is determined by the gamma family. Assuming the 1-sided alpha level of 0.025 will be used for 
testing this endpoint, the DMC should recommend stopping the trial (for Arm C versus Arm A) 
for futility if the hazard ratio is above 1.126. The boundary will be updated based on the actual 
number of observed events and the actual 1-sided alpha level that is used for this endpoint per the 
graphical approach. There is no intent to declare statistical significance for superior efficacy at this 
interim; therefore, there is no impact on the statistical significance levels for the final analysis.  
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Stopping Boundaries for Each Analysis between Arm C and Arm A in the ITT Population 
Based on the 1-sided Alpha Level of 0.025 for Illustration 
Analysis 
Number 
of Events 
Information 
Fraction 
Critical 
P-value 
Boundary 
Critical 
Hazard 
Ratio 
Boundary 
Cumulative 
Type I 
Error Rate 
Boundary Crossing Probabilities a 
Hazard 
Ratio = 0.7 
Hazard 
Ratio = 1 
Hazard 
Ratio = 
1.25 
Interim  
100 
40% 
NA 
1.126 
NA 
0.009 
0.279 
0.705 
Final 
248 
100% 
0.025 
(efficacy) 
0.779 
0.025 
0.794 
0.027 
0 
a Boundary crossing probabilities under different hazard ratio assumptions. 
 
Only the DMC is authorized to evaluate unblinded safety and efficacy interim analyses. Study sites 
will receive information about interim results only if they need to know for the safety of their 
participants.  
An interim analysis may be collapsed with any other analyses including a final analysis if they are 
expected to occur within a similar timeframe (e.g., within approximately 2 month). Additionally, 
the final analysis of PFS between Arm A and Arm B in the ITT population may be collapsed with 
the final analysis in the ESR1-mutation detected population or the final analysis between Arm C 
and Arm A in the ITT population if they are expected to occur within a similar timeframe.  
At the time of the final evaluation of PFS between Arm A and Arm B, the Sponsor will only have 
access to Arm A and Arm B data and will be blinded to Arm C if the final analysis between Arm 
A and Arm B is before the final analysis between Arm C and Arm A and is conducted by the 
Sponsor. Unblinding details are specified in a separate blinding and unblinding plan document. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
○ consensus ethical principles derived from international guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ applicable ICH GCP Guidelines, and 
○ applicable laws and regulations. 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (for example, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. 
 The investigator will be responsible for the following: 
o 
providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
o 
notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o 
providing oversight of study conduct for participants under their 
responsibility and adherence to requirements of 21 CFR, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations, and 
o 
reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity. 
 Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process  
 The investigator or his or her representative will explain a description of the 
investigational drug, the nature of the study, including the risks and benefits, to the 
participant or his or 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 (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file. Participants who are rescreened are 
required to sign a new ICF. 
10.1.4. 
Data Protection  
 Participants will be assigned a unique identifier by the sponsor to protect the 
participant’s personal data. Any participant information, such as records, datasets, 
or tissue samples that are transferred to the sponsor, will contain the identifier only. 
Participant names or any information which would make the participant identifiable 
will not be transferred. 
 The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The level 
of disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. This is done 
by the site personnel through the informed consent process. 
 The participant must be informed through the informed consent by the site 
personnel that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The sponsor has processes in place to ensure information security, data integrity, 
and data protection. These processes address management of data transfer, and 
prevention and management of unauthorized access, disclosure, dissemination, 
alteration or loss of information or personal data. These processes include 
appropriate contingency plan(s) for appropriate and timely response in the event of 
a data security breach. 
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 The transfer of personal data is subject to appropriate safeguards through 
contractual agreements and processes. The sponsor’s processes are compliant with 
local privacy laws and relevant legislations including the General Data Protection 
Regulation (GDPR). 
10.1.5. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data-sharing agreement. 
Data and documents, including the study protocol, statistical analysis plan, clinical study report, 
and blank or annotated case report forms, will be provided in a secure data-sharing environment 
for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.6. 
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 (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
 The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
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 Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality, such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
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 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. 
Additionally, eCOA data (questionnaires and scales) will be directly recorded by the patient, into 
an instrument (for example, an electronic device). The eCOA data will serve as the source 
documentation, and the investigator does not maintain a separate, written, or electronic record of 
these data.  
Data collected via the Sponsor-provided data capture system(s) will be stored at third party (at 
third parties). The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s). Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention. 
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Data managed by a central vendor, such as laboratory test data, will be stored electronically in the 
central vendor’s database system and will be provided to the investigator for review and retention. 
Data will subsequently be transferred from the central vendor to the Sponsor data warehouse. 
Data from complaint forms submitted to Sponsor will be encoded and stored in the global product 
complaint management system. 
10.1.7. 
Source Documents  
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
 Data reported on 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 explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
10.1.8. 
Study Closure  
Study site participation may be discontinued if the Sponsor or its designee, the investigator, or the 
ERB of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
 
 
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10.2. 
Appendix 2: Protocol JZLC ECOG Performance Status  
ECOG Performance Status 
Activity Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, for example, light housework and office work 
 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
 
5 
Dead. 
 
Source: Oken et al. 1982. 
 
 
 
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10.3. 
Appendix 3: Protocol JZLC RECIST Criteria 1.1  
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009). 
Measurability of Tumor at Baseline 
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable. 
Measurable disease is defined by the presence of at least 1 measurable lesion. 
Measurable 
Tumor lesions: measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of 
 10 mm by CT or MRI scan (slice thickness ≤5 mm)  
 10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers), and 
 20 mm by chest X-ray. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan thickness recommended to be 
≤5 mm). 
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly nonmeasurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special Considerations for Lesion Measurability 
Bone lesions: 
 Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques, such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Simple cysts should not be considered as malignant lesions (neither 
measurable nor nonmeasurable). 
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 Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurability. If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions. 
Lesions with Prior Local Treatment: 
 Tumor lesions situated at a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion. 
Baseline Documentation of Target and Non-Target Lesion 
Target Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Non-nodal 
target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements. 
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of <15 mm by 
CT scan. All measurements are to be recorded in the CRF in millimeters (or decimal fractions of 
centimeters [cm]). 
Nontarget Lesions 
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline. Measurement of these lesions are not required but should be 
followed as “present,” “absent,” or in rare cases “unequivocal progression.” In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as 1 liver lesion). 
Lymph nodes with short axis ≥10 mm but <15 mm should be considered nontarget lesions. 
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed. 
Specifications by Methods of Measurement 
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment (except for the 
baseline bone scintigraphy, which may be obtained up to 45 days prior to the beginning of the 
treatment). 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam. 
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An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient. If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and 
follow-up should be guided by the tumor type under investigation and the anatomic location of 
the disease. 
Clinical Lesions: clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (for example, skin nodules). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may be reviewed at the end of the 
study. 
Chest X-ray: chest CT is preferred over chest X-ray when progression is an important endpoint. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
CT and MRI: CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is ≤5 mm. When CT scan has slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (for example, for body scans). If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 
Ultrasound: ultrasound should not be used to measure lesion size. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date, and because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from 1 assessment to the next. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
Endoscopy, Laparoscopy: the utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following CR or 
surgical resection is an endpoint. 
Tumor Markers: tumor markers alone cannot be used to assess tumor response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in CR. 
Specific guidelines for both prostate-specific antigen response (in recurrent prostate cancer) and 
CA-125 response (in recurrent ovarian cancer) have been published. 
Cytology, Histology: these techniques can be used to differentiate between PRs and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (for example, with certain taxane compounds or 
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angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or SD in order to differentiate between response (or SD) and PD. 
Pet Scan (FDG-PET, PET CT): PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality. If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan. 
Bone Scan: If lesions measured by bone scan are reported at baseline, it is necessary to repeat the 
bone scan when trying to identify a CR or PR in target disease or when progression in bone is 
suspected. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker 
results must have normalized. 
Partial Response (PR): at least a 30% decrease in the sum of diameter of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): at least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. 
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Not Evaluable: when an incomplete radiologic assessment of target lesions is performed or there 
is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response. 
Evaluation of Nontarget Lesions 
Complete Response: disappearance of all nontarget lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological or normal in size (<10 mm short axis). 
Non-CR/ non-PD: persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits. 
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Progressive Disease: unequivocal progression of existing nontarget lesions. The appearance of 1 
or more new lesions is also considered progression. 
Not Evaluable: when a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation. The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions. The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial. 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs (when no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point). Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
Table 2: Time Point Response: Patients with Target (± Nontarget) Disease  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease.  
Table 3 is to be used when patients have nonmeasurable disease only. 
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Table 3: Time Point Response: Patients with Nontarget Disease Only  
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease. 
a non-CR/non-PD is preferred over SD for nontarget disease.  
Frequency of Tumor Reevaluation 
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor reevaluation while on and adapted to treatment should be protocol 
specific and adapted to the type and schedule of treatment. In the context of Phase 2 studies 
where the beneficial effect therapy is not known, follow-up every 6-8 weeks is reasonable. 
Normally, all target and non-target sites are evaluated at each assessment using the same method. 
However, bone scans may need to be repeated only when CR is identified in target disease or 
when progression in bone is suspected. 
Confirmatory Measurement/Duration of Response 
Confirmation 
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point. In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met. To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan. To confirm a PR or SD, a 
full assessment of target lesions that were present at baseline must occur; assessment of 
nontargets is not required. 
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required. But elimination of the requirement may 
increase the importance of central review to protect against bias, in particular for studies which 
are not blinded. 
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from randomization. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study). 
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD). 
Independent Review of Response and Progression 
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study. If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment. 
 
 
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10.4. 
Appendix 4: Clinical Laboratory Tests  
 
The tests detailed below will be performed as indicated in the table below. 
 
If there is an abnormal laboratory value or abnormal value for a diagnostic or screening 
test (for example, blood pressure increased, neutrophils decreased) and it is associated 
to a diagnosis of an AE, then the AE should be entered in the CRF. 
 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol. 
 
Enrollment and treatment decisions may be based on local chemistry laboratory results, 
but a specimen must also be sent to central laboratory. Discrepancies between local and 
central laboratory results will not be considered protocol deviations. 
 
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 
Hematology  
Leukocytes (WBC) 
Assayed by local laboratory 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Erythrocytes (RBC) 
Hemoglobin (HGB) 
Hematocrit (HCT) 
Platelets (PLT) 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Assayed by Central laboratory 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bilirubin, direct 
Bilirubin, total 
Blood urea nitrogen (BUN) or blood urea 
Calcium 
Creatinine  
Glucose (random) 
Potassium 
Protein 
Sodium 
Cystatin C (obtained as clinically indicated)d 
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Coagulation  
PT/INR 
Assayed by local laboratory 
aPTT 
Fasting Lipid Panel - central laboratory 
Cholesterol 
Assayed by central laboratory 
High-density lipoproteins 
Low-density lipoproteins 
Triglycerides 
Hormone Testing (Female) 
Serum Pregnancy test: For Screening - local 
laboratorya for women of childbearing potentialb 
Evaluated by local laboratory 
Follicle-stimulating hormone (FSH)a, c 
Estradiola, c 
Evaluated by local or investigator-designated 
laboratory  
Abbreviations: aPTT = activated partial thromboplastin time; INR = international normalized ratio; PT = prothrombin 
time; RBC = red blood cells; WBC = white blood cells. 
a Local or investigator-designated laboratory. 
b Local regulations and/or institutional guidelines may require additional testing. 
c  FSH and Estradiol are obtained at screening for women <60 years of age if needed to verify menopausal status; 
and Estradiol is monitored on study for women receiving GnRH agonist for ovarian function suppression. 
 
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. 
d See Section 8.2.4 
 
 
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10.5. 
Appendix 5: Creatinine Clearance Formula  
Note: this formula is to be used for calculating creatinine clearance (CrCl) from 
local laboratory results only. 
Cockcroft-Gault prediction of CrCl from serum creatinine (1976) 
For serum creatinine concentration in mg/dL: 
CrCl= 
(mL/min) 
(140 – agea)  (wt)  0.85 (if female), or  1.0 (if male) 
72  serum creatinine (mg/dL) 
 
For serum creatinine concentration in µmol/L: 
CrCl= 
(mL/min) 
 (140 – agea)  (wt)  0.85 (if female), or  1.0 (if male) 
0.81  serum creatinine (mol/L) 
a Age in years, weight (wt) in kilograms. 
Source: Cockcroft and Gault 1976. 
 
 
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10.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting  
10.6.1. 
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 (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug–drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
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.  
 
 
 
 
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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 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.6.2. 
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 (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
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 physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
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 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised 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 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
10.6.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o deficiencies in labeling information, and 
o use errors for device or drug–device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
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10.6.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and product 
complaint information is reported on the Product Complaint Form. 
Note: an event may meet the definition of both a product complaint and an AE/SAE. In 
such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will use CTCAE version 5.0 (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. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 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 or her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he or she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
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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 or her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 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. 
10.6.5. 
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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10.6.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 Prompt notification by the investigator to the Sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor has processes for safety reports for 
identification, recording, and expedited reporting of SUSARs according to local 
regulatory requirements. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/IECs), and investigators. 
 An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (for example, summary or listing of SAEs) from 
the Sponsor will review and then file it along with the Investigator’s Brochure 
and will notify the IRB/IEC, if appropriate according to local requirements.  
 
 
 
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10.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information  
Definitions: 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). If fertility is unclear (for example, amenorrhea in adolescents or 
athletes) and a menstrual cycle cannot be confirmed before first dose of study intervention, 
additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with at least 1 of the following: 
 Documented hysterectomy, or 
 documented bilateral salpingectomy, or 
 documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example, Müllerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note: determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female is defined as, women with 
 12 months of amenorrhea for women >60, with no need for FSH 
 12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and no other 
medical condition such as anorexia nervosa and not taking medications during the 
amenorrhea (for example, oral contraceptives, hormones, gonadotropin-releasing 
hormone, anti-estrogens, selective estrogen receptor modulators, or chemotherapy that 
induced amenorrhea). If fertility is unclear, then additional evaluation should be 
considered. 
Contraception Guidance: 
Patients with reproductive potential (that is, non-postmenopausal patients) are instructed to use 
highly effective contraceptive methods. The choice of the most effective and appropriate 
contraception method is up to the investigator’s judgment after discussion with the patient, taking 
into account age, pregnancy, and other gyneco-obstetrical history, sexual activity, patients’ 
preference, acceptance of the contraception method, and potential adherence. 
In patients with breast cancer, the use of estrogen-based hormonal contraception (includes the 
hormonal IUDs) is contraindicated, and the effect of progestin-based hormonal contraception 
remains unclear. 
The Clinical Trial Facilitation Group has defined highly effective methods of contraception.1 
Highly effective methods include 
• intrauterine device 
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• bilateral tubal occlusion 
• vasectomized partner2, and 
• sexual abstinence3. 
Due to the possible risk of human teratogenicity/fetotoxicity, non-highly effective methods (such 
as double-barrier methods) of contraception are not allowed. 
Local regulation/guidelines are to be followed with regard to highly effective birth control method, 
if more restrictive. 
1Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy testing in clinical trials. September 
2020. Accessed September 22, 2021. https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf. 
2Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomized partner has received medical assessment of the surgical success. 
3In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
 The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study drug. 
 After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant’s pregnancy.  
 The participant will be followed up to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the Sponsor. Generally, follow-up will not 
be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
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 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
 A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
 Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Sponsor as described in 
protocol Section 8.3.3. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. If the participant is discontinued from the study 
intervention, follow the standard discontinuation process and continue directly to 
the follow-up phase.  
 
 
 
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10.8. 
Appendix 8: Genetics  
Use/Analysis of DNA 
 Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Assessment of variable response may include evaluation of AEs 
or differences in efficacy. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
 DNA samples will be used for research related to imlunestrant or breast cancer and related 
diseases. They may also be used to develop tests/assays, including diagnostic tests related 
to study intervention and/or interventions of this drug class and indication. Genetic research 
may consist of the analysis of 1 or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate). 
 
Samples may also be used to determine the somatic or germline origin of tumor-associated 
genetic alterations. 
 Samples will not be used to conduct unspecified disease or population genetic research 
either now or in the future. 
 The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to imlunestrant or study interventions of this class to understand 
study disease or related conditions. 
 The results of genetic analyses may be reported in the CSR or in a separate study summary. 
 The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
 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 the Sponsor 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 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 imlunestrant or 
after imlunestrant become(s) 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 and 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.  
 
 
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10.9. 
Appendix 9: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
Hepatic Evaluation Testing 
See Section 10.4, Appendix 4 and Section 8.2.2.1 for guidance on appropriate test selection. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
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 Sponsor CRP/CRS. 
 
Hematology – local laboratory 
Clinical Chemistry – central laboratory 
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-glutamyltransferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry – central laboratory  
Basophils 
Acetaminophen 
Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Copper 
Coagulation – local laboratory 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Microbiology – local laboratory 
Immunoglobulin A (IgA [Quantitative]) 
Culture 
Immunoglobulin G (IgG [Quantitative]) 
Blood 
Immunoglobulin M (IgM [Quantitative]) 
Urine 
Phosphatidylethanol (PEth) 
Urine Chemistry – central laboratory  
Drug screen 
Ethyl glucuronide (EtG) 
Serology – local laboratory 
Other Serology – central laboratory  
Hepatitis A virus (HAV) testing: 
Anti-nuclear antibody (ANA) 
HAV total antibody 
Anti-smooth muscle antibody (ASMA)a 
HAV IgM antibody 
Anti-actin antibodyc 
Hepatitis B virus (HBV) testing: 
Epstein-Barr virus (EBV) testing: 
Hepatitis B surface antigen (HBsAg) 
EBV antibody 
Hepatitis B surface antibody (Anti-HBs) 
EBV DNAb 
Hepatitis B core total antibody (Anti-HBc) 
Cytomegalovirus (CMV) testing: 
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Hepatitis B core IgM antibody 
CMV antibody 
Hepatitis B core IgG antibody 
CMV DNAb 
HBV DNAb 
Herpes simplex virus (HSV) testing: 
Hepatis C virus (HCV) testing: 
HSV (Type 1 and 2) antibody 
HCV antibody 
HSV (Type 1 and 2) DNAb 
HCV RNAb 
Liver Kidney Microsomal Type 1 (LKM-1) antibody 
Hepatitis D virus (HDV) testing: 
 
HDV antibody 
 
Hepatitis E virus (HEV) testing: 
 
HEV IgG antibody 
HEV IgM antibody 
HEV RNAb 
Abbreviations: CRP = clinical research physician; CRS = clinical research scientist; DNA = deoxyribonucleic acid; 
Ig = immunoglobulin; INR = international normalized ratio.  
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.  
 
 
 
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10.10. 
Appendix 10: Country-specific Requirements  
The country-specific addenda reflected in this appendix must be performed in each of the 
respective countries, in addition, to all procedures required by current version of Protocol J2J-
OX-JZLC (JZLC) where applicable. The consolidation of these individual country-specific 
addenda into this appendix is to facilitate transition of this trial to the CTIS system under the new 
clinical trial regulation in Europe.  
10.10.1. 
Belgium  
This addendum will address feedback from the Federal Agency for Medicines and Health 
Products (FAMHP) in Belgium and the Ethics Committee (EC) regarding the request to amend 
the original EMBER-3 protocol. 
The following table describes the changes being made to Protocol JZLC for participants in 
Belgium: 
Protocol Section # and Name 
Description of Change 
1.3. Schedule of Activities  
10.4. Appendix 10.4: Clinical Laboratory Tests 
Revised to require FSH and estradiol testing during the 
on study treatment period.  
Note: this revision was added to the global protocol in 
amendment (a). 
1.3. Schedule of Activities  
10.4. Appendix 10.4: Clinical Laboratory Tests 
Revised to require pregnancy testing during the study 
treatment period and at short-term follow-up. 
5.1. Inclusion Criteria 
Modified criteria 6 and 7 to specify that patients that 
receive fulvestrant should use highly effective methods 
of contraception for 2 years after the last dose.  
Note: this revision was added to the global protocol in 
amendment (a). 
6.1.2. Arm A LY3484356: General Dosing Instructions 
General dosing instructions Section 6.1.2 was revised 
to reflect the most up to date limitations of in vitro 
assessments and the potential impact of imlunestrant as 
an inhibitor to P-gP and the Breast Cancer Resistance 
Protein (BCRP).  
Note: this revision was added to the global protocol in 
amendment (a). 
All additions have been identified by the use of underline, and deletions have been identified by 
strikethrough. 
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Section 1.3. Schedule of Activities (Belgium) 
 
 
  
Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 
2–3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1 
2 
3–4 
5 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a 
Cycle 
≤28 
Day 1 
 
Day 
15c 
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Lab/ 
Diagnostic 
Tests 
FSH and 
estradiol 
levels 
X 
 
 
X 
X 
 
 
Section 10.7 
Appendix 7  
 For Screening: local testing required only for 
women <60 years with amenorrhea for at 
least 12 months to confirm post-menopausal 
status 
 For on-study: Required every 3 months ( 5 
days) only for women < 60 years 
Pregnancy 
Tests 
X 
 
 
X 
X 
X 
 
Section 10.7 
Appendix 7  
 Local testing 
 For Screening: serum pregnancy test required 
for women of child-bearing potential 
 For On Study: local testing for women of 
child-bearing potential 
 For Short-Term Follow-Up: local testing for 
women of child-bearing potential 
Abbreviation: FSH = follicular stimulating hormone.  
a Short-term follow-up period begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures are performed once at the end of this period. Long-term follow-up period begins the day after short-
term follow-up visit is completed and continues until the patient’s death or overall study completion; the associated study procedures are performed 
approximately every 12 weeks ( 14 days) for the duration of this period beginning 12 weeks after the short-term follow-up visit. 
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Section 5.1. Inclusion Criteria 
6. If female and postmenopausal status is due to ovarian suppression, participants must have a 
negative serum pregnancy test at baseline (within 14 days prior to enrollment) and agree to use 
highly effective, medically approved precautions to prevent pregnancy (see Section 10.7 
Appendix 7) during the study and for 6 months (2 years for patients receiving fulvestrant) 
following the last dose of study treatment. 
7. If male, must agree to use the following: 
a. hormone suppression (received monthly and initiated at least 28 days prior to Cycle 1 
Day 1) with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide; 
b. highly effective methods of birth control and to not donate sperm during the study and for 
at least 6 months (2 years for patients receiving fulvestrant) following the last dose of 
study drug(s), or for the duration specified in country requirements, whichever is longer. 
Section 6.1.2. Arm A LY3484356: General Dosing Instructions 
Each cycle will consist of 28 days. LY3484356 will be given as 400 mg QD administered at 
approximately the same time on each day (refer to Section 6.1). 
For LY3484356 administration, patients should follow the fasting guidance provided in the 
patient diary. 
Because LY3484356 is metabolized by CYP3A4, patients should refrain from consuming 
grapefruit, grapefruit juice, and grapefruit-containing products and avoid medications considered 
strong inducers and inhibitors of CYP3A and P-glycoprotein (P-gp) 2 weeks prior to and while 
on study due to the effect on CYP3A4 and/or P-gp. 
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 could not be ruled out. Therefore, 
caution should be exercised when co-administering LY3484356 with narrow therapeutic index 
substrates of P-gp and BCRP (i.e. digoxin). 
Appendix 10.4: Clinical Laboratory Tests  
Clinical Chemistry - central laboratory  
Serum Concentrations of: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bilirubin, direct 
Bilirubin, total 
Blood urea nitrogen (BUN) or blood urea 
Calcium 
Creatinine  
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Estradiol 
Follicular Stimulating Hormone (FSH) 
Glucose (random) 
Potassium 
Protein 
Sodium 
Pregnancy Test (for female patients of childbearing potential) 
For Screening- local laboratory a, b 
Serum pregnancy test 
On Study and Short-Term Follow-Up – local laboratory test a,b 
Abbreviations: aPTT = activated partial thromboplastin time; INR = international normalized ratio; PT = prothrombin 
time; RBC = red blood cells; WBC = white blood cells. 
a 
Local or investigator-designated laboratory. 
b Local regulations and/or institutional guidelines may require additional testing. 
 
 
 
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10.10.2. 
Czech Republic  
This addendum will address feedback from the Czech Republic regarding the request to amend 
the EMBER-3 protocol. The following table describes the changes being made to Protocol JZLC 
for participants in Czech Republic: 
Protocol Section # and Name 
Description of Change 
1.3. Schedule of Activities 
Added HIV and viral hepatitis screening and 
indicated that this screening will be conducted 
locally. 
5.1. Inclusion Criteria 
Adjusted hemoglobin laboratory value cutoff 
to ≥9 g/dL in criterion 10.  
Note: this was added to the global protocol in 
amendment (b). 
5.2. Exclusion Criteria 
Increased required interval since major 
surgery to 28 days in criterion 21.  
Note: this was added to the global protocol in 
amendment (b). 
Removed “screening is not required for 
enrollment” from criterion 27. 
 
All additions have been identified by the use of underline, and deletions have been identified by 
strikethrough. 
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Section 1.3 Schedule of Activities (Czech Republic) 
 
Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 and 2 
3 
4 and Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1, 3 
2, 4 
5 
6 and Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
Day 
15c 
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Lab/Diagnostic 
Tests 
HIV and viral 
hepatitis 
screening 
X 
 
 
 
 
 
 
 
 
Local testing 
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Section 5.1 Inclusion Criteria 
10. Have adequate organ function as defined in table below: 
System 
Laboratory Value 
Hematologic 
 
ANC 
≥1.5 × 109/L 
Platelets 
≥100 × 109/L 
Hemoglobin 
≥98 g/dL 
Note: transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or G-CSF 
therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug. 
 
 
Abbreviations: ANC = absolute neutrophil count; G-CSF = granulocyte colony stimulating factor. 
Section 5.2 Exclusion Criteria 
21. Have had major surgery within 2814 days prior to randomization 
27. Have active bacterial or fungal infection, or detectable viral infection (for example, human 
immunodeficiency virus [HIV] or viral hepatitis). Screening is not required for enrollment. 
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10.10.3. 
France  
This addendum will address feedback from France regarding the request to amend the EMBER-3 
protocol. The following table describes the changes being made to Protocol JZLC for 
participants in France: 
Protocol Section # and Name 
Description of Change 
5.1. Inclusion Criteria 
Modified criterion 3 to note that investigators 
must document in the patient records the basis 
for including participants that have not been 
treated with a CDK4/6 inhibitor prior to study 
enrollment, rather than treating with a 
CDK4/6 inhibitor. 
7.1. Participant Discontinuation/Withdrawal 
from Study Treatment 
Modified to discontinue, without exception, 
all patients that develop disease progression 
on study treatment. 
 
All additions have been identified by the use of underline, and deletions have been identified by 
strikethrough. 
Section 5.1. Inclusion Criteria 
3. Have locally advanced (not amenable to curative treatment by surgery) or metastatic 
disease and fulfill 1 of the following criteria below:. CDK4/6 inhibitors are a treatment 
option in these patients. Therefore, for patients who have not received treatment with a 
CDK4/6 inhibitor prior to enrollment into the trial, the investigator must document in the 
patient records the rationale for including them in this trial rather than treatment with a 
CDK4/6 inhibitor. 
a. relapsed with evidence of progression while on or within 12 months of 
completion of (neo)adjuvant AI, alone or in combination with a CDK4/6 
inhibitor, with no treatment for advanced disease 
b. relapsed with evidence of progression >12 months from completion of 
(neo)adjuvant ET, with subsequent progression on or after only 1 line of therapy 
with an AI, alone or in combination with a CDK4/6 inhibitor. Patients may not 
have received any other prior therapy (other than the aforementioned: AI, alone or 
in combination with a CDK4/6 inhibitor) in the advanced/metastatic setting 
c. presented de novo with metastatic disease, with subsequent progression on or 
after only 1 line of therapy with an AI, alone or in combination with a CDK4/6 
inhibitor. Patients may not have received any other prior therapy (other than the 
aforementioned: AI, alone or in combination with a CDK4/6 inhibitor) in the 
advanced/metastatic setting. 
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Section 7.1. Participant Discontinuation/Withdrawal from Study Treatment 
Patients will be discontinued from study treatment in the following circumstances:  
 if the participant is significantly noncompliant with study procedures and/or 
treatment 
 disease progression Exceptions for continuing study treatment beyond 
confirmed radiographic progression may be made on a case-by-case basis for 
patients who are believed to be clinically benefiting from study treatment, 
and the investigator and the Sponsor agree that continuing study treatment is 
in the patient’s best interest, and 
 unacceptable toxicity. 
 
 
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10.10.4. 
Germany  
This addendum will address feedback from Germany regarding the request to amend the 
EMBER-3 protocol. The following table describes the changes being made to Protocol JZLC for 
participants in Germany: 
Protocol Section # and Name 
Description of Change 
1.3. Schedule of Activities 
Addition of pregnancy test at the short-term follow-up 
visit. 
Note: this was included in the global protocol with 
amendment (a). 
1.3. Schedule of Activities 
5.2. Exclusion Criteria 
Modified criterion 27 to require HIV screening test for 
enrollment and added procedure to Schedule of 
Activities. 
5.1. Inclusion Criteria 
Modified criteria 6 and 7 to specify that patients that 
receive fulvestrant should use highly effective methods 
of contraception for 2 years after the last dose. 
Note: this was included in the global protocol with 
amendment (a). 
5.1. Inclusion Criteria 
Modified criterion 11 to allow for an acceptable 
washout period for safety reasons. 
7.1. Participant Discontinuation/Withdrawal from 
Study Treatment 
8.3. Adverse Events, Serious Adverse Events, and 
Product Complaints 
10.1.3. Informed Consent Process 
Removed references to the participant’s “legally 
authorized representative”. 
10.7. Appendix 7: Contraceptive Guidance and 
Collection of Pregnancy Information 
Modified to specify that double barrier methods of 
contraception are not allowed. 
Note: this was included in the global protocol with 
amendment (a), (b). 
10.10.1. Discontinuation of Inadvertently Enrolled 
Patients in the United Kingdom 
Modified section to include Germany. 
10.16. Appendix 16: Provisions for Changes in Study 
Conduct during Exceptional Circumstances 
Modified to reflect submission of an addendum in 
Germany when implementing activities under 
exceptional circumstances. 
All additions have been identified by the use of underline, and deletions have been identified by 
strikethrough. 
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Section 1.3. Schedule of Activities (Germany) 
 
Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 
2–3 
4 and 
Beyond (if 
Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
 
Visit 
0 
1 
2 
3–4 
5 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c  
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Lab/Diagnostic 
Tests 
Pregnancy test 
X 
 
 
 
 
X 
 
Section 10.7 
Appendix 7 
 Local testing 
 For Screening: serum pregnancy 
test required for women of child-
bearing potential 
 For on Study: per local 
regulations and/or institutional 
guidelines  
HIV and viral 
hepatitis screening  
X 
 
 
 
 
 
 
 
 
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Section 5.1. Inclusion Criteria 
6. If female and postmenopausal status is due to ovarian suppression, participants must have 
a negative serum pregnancy test at baseline (within 14 days prior to enrollment) and 
agree to use highly effective, medically approved precautions to prevent pregnancy (see 
Section 10.7 Appendix 7) during the study and for 6 months (2 years for patients 
receiving fulvestrant) following the last dose of study treatment 
 
7. If male, must agree to use the following: 
a. hormone suppression (received monthly and initiated at least 28 days prior to 
Cycle 1 Day 1) with a gonadotropin-releasing hormone agonist such as goserelin 
or leuprolide 
b. highly effective methods of birth control and to not donate sperm during the study 
and for at least 6 months (2 years for patients receiving fulvestrant) following the 
last dose of study drug(s), or for the duration specified in country requirements, 
whichever is longer 
 
11. Have discontinued previous therapies for cancer prior to receiving study drug, and 
recovered from the acute effects of therapy to at least Grade 1, except for residual 
alopecia and peripheral neuropathy, with the following therapy washout periods required 
prior to receiving study drug:  
a. for myelosuppressive agents (for example, CDK4/6 inhibitors): at least 21 days  
b. for nonmyelosuppressive agents (for example, Endocrine Therapy): 7 days or 5 
half-lives, whichever is shorterlonger 
c. for investigational agents: 28 days or 5 half-lives, whichever is shorterlonger 
Section 5.2. Exclusion Criteria  
27. Have active bacterial or fungal infection, or detectable viral infection (for example, 
human immunodeficiency virus [HIV] or viral hepatitis). Screening is not required for 
enrollment 
Section 7.1. Participant Discontinuation/Withdrawal from Study Treatment 
Patients will be discontinued from study treatment in the following circumstances: 
 at any time at his or her own request  
 at the request of his or her designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
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Section 8.3. Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.6, Appendix 6: 
 Adverse events 
 Serious adverse events, and 
 Product complaints. 
These events will be reported by the participant (or, when appropriate, by a caregiver, or 
surrogate, or the participant’s legally authorized representative). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient and/or legal guardian is the preferred method to 
inquire about AE occurrences. 
Section 10.1.3. Informed Consent Process 
 The investigator or his or her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his or 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 (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file. Participants who are rescreened are required 
to sign a new ICF. 
Section 10.7. Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
If the highly effective contraceptive methods are contraindicated or strictly declined by the 
patient, or in the event of sexual activity of low frequency, a combination of male condom with 
cap, diaphragm, or sponge with spermicide (double-barrier methods) is also considered an 
acceptable birth control method. 
Due to the possible risk of human teratogenicity/fetotoxicity, double-barrier methods of 
contraception are not allowed. 
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Local regulation/guidelines are to be followed with regard to highly effective birth control 
method, if more restrictive. 
Section 10.10.1. Discontinuation of Inadvertently Enrolled Patients in the United Kingdom 
and Germany 
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 
8.3 (Adverse Events, Serious Adverse Events, and Product Complaints), and Section 8.2 (Safety 
Assessments) of the protocol. 
Section 10.16. Appendix 16: Provisions for Changes in Study Conduct during Exceptional 
Circumstances 
Implementing changes under exceptional circumstances  
In an exceptional circumstance, after receiving the sponsor’s written approval, 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. For Germany, a country level addendum must be 
submitted. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
 
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10.10.5. 
Italy  
This addendum will address feedback from Italy regarding the request to amend the EMBER-3 
protocol. The following table describes the changes being made to Protocol JZLC for 
participants in Italy: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of Activities 
Expanded AE collection to include 
any SAE regardless of relationship to 
study treatment and AEs possibly 
related to study treatment or study 
procedure during the long-term 
follow-up period. 
Note: the revision above was added 
to the global protocol in amendment 
(a). 
Included coagulation assessments on 
Day 1 of Cycle 1 and Cycle 2. 
To comply with feedback 
from the Italian 
Medicines Agency. 
Section 5.1 Inclusion 
Criteria 
Updated language in Criterion 5. 
To align the definition of 
postmenopausal state 
with the 2014 Clinical 
Trial Facilitation and 
Coordination Group 
recommendations related 
to contraception and 
pregnancy testing in 
clinical trials. 
All deletions have been identified by strikethrough; all additions have been identified by the use 
of underscore. 
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Section 1.3 Schedule of Activities (Italy) 
 
 
Study Period 
Baseline 
Study Treatment (Cycle =28 days) 
Post-discontinuation 
Follow-Up 
 
 
 
Cycle 
Screening 
1 
2–3 
4 and 
Beyond (if 
Applicable) 
Short-
Term 
Follow-
Upa 
Long-
Term 
Follow-
Upa 
 
 
 
Visit 
0 
1 
2 
3–4 
5 and 
Beyond (if 
Applicable) 
801 
802–8XX 
 
 
 
Relative Day 
within a Cycle 
≤28 
Day 1 
 
Day 15c 
(± 3) 
Day 1 
(± 3) 
Day 1 
(± 3) 
Day 30 
(± 7) 
(± 14) 
 
 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
Protocol 
Reference 
Instructions 
Adverse Event 
Collection/ 
CTCAE 
Grading 
 
X 
X 
 
X 
X 
X 
X 
Section 8.3  
 Collect continuously at every visit 
and throughout the study 
 CTCAE Version 5.0 
 For long-term follow-up: only all 
SAEs that are related to study drugs 
or protocol procedures regardless of 
relationship to study treatment and 
adverse events possibly related to 
study treatment or study procedure 
will be collected 
 All adverse events possibly related to 
study drugs or protocol procedures 
should be followed until they resolve, 
are no longer considered to be 
possibly related, become stable or 
return to baseline, the patient starts a 
new therapy, the patient expires, or 
the patient becomes lost to follow-up. 
The frequency of evaluation is 
determined according to the 
judgment of the investigator 
Lab/Diagnostic 
Tests 
Coagulation 
X 
X 
 
X 
 
 
 
Section 10.4 
Appendix 4 
 Perform at baseline, Cycle 2 Day 1 
(Visit 3), and as clinically indicated 
 Local testing  
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Section 5.1 Inclusion Criteria 
5. If female, have a postmenopausal status due either surgical/natural menopause or ovarian 
suppression (received monthly and initiated at least 28 days prior to Cycle 1 Day 1) with a 
gonadotropin-releasing hormone agonist such as goserelin or leuprolide. Postmenopausal 
due to surgical/natural menopause requires at least 1 of the following: 
a. prior bilateral oophorectomy 
b. age ≥60 years, amenorrheic for at least 12 months, in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression 
c. age <60 years, amenorrheic for at least 12 months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression), and FSH and estradiol levels in the 
postmenopausal range. 
 
 
 
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10.10.6. 
Spain  
This addendum will address feedback from Spain regarding the request to amend the EMBER-3 
protocol. The following table describes the change is being made to Protocol JZLC for 
participants in Spain: 
Protocol Section # and Name 
Description of Change 
5.2. Exclusion Criteria 
Updated criterion 15 to state the following, 
“Patients who have completed a prior 
exemestane treatment may not receive 
exemestane if they are randomized to the 
control arm”. 
 
All deletions have been identified by strikethrough; all additions have been identified by the use 
of underscore. 
Section 5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria applies: 
[15] Have received prior treatment with chemotherapy (except for neoadjuvant/adjuvant 
chemotherapy), fulvestrant, any investigational-ER-directed therapy (including SERDs 
and non-SERDs), any PI3K-, mTOR-, or AKT-inhibitor. Patients who have completed 
prior exemestane treatment may not receive exemestane if randomized to the control arm. 
 
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10.11. 
Appendix 11: 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 
St John’s wort 
 
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 
Thioridazine 
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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10.12. 
Appendix 12: 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 
Midostaurin 
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 
Eliglustat 
Ticagrelor 
Elvitegravir 
Tipranavir 
Entrectinib 
Tolvaptan 
Eplerenone 
Triazolam 
Everolimus 
Ulipristal 
Felodipine 
Ubrogepant 
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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10.13. 
Appendix 13: 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 of ≥5-
fold with strong index inhibitors of a given metabolic pathway in clinical drug–drug interaction studies. 
 
 
 
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10.14. 
Appendix 14: Inhibitors and inducers of UGT1A1  
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated. 
Dasabuvir 
Paritaprevir 
Faldaprevir 
Ritonavir 
Ombitasvir 
Telaprevir 
Source: University of Washington Drug Interactions Database accessed August 2020. 
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10.15. 
Appendix 15: 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 
In an exceptional circumstance, after receiving the sponsor’s written approval, 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 “Remote Visits,” 
 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. 
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Remote visits 
Types of remote visits 
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 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
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 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
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, visits 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 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
 
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10.16. 
Appendix 16: Abbreviations  
Term 
Definition 
Abuse 
Use of a study intervention for recreational purposes or to maintain an 
addiction or dependence. 
AE 
adverse event 
AI 
aromatase inhibitor 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance 
with Regulation (EC) No 726/2004 or in any Member State concerned in 
accordance with Directive 2001/83/EC, irrespective of changes to the 
labelling of the medicinal product, which is used as an investigational 
medicinal product. 
authorized AxMP 
Applicable to the EU only: a medicinal product authorized in accordance 
with Regulation (EC) No 726/2004, or in any Member State concerned in 
accordance with Directive 2001/83/EC, irrespective of changes to the 
labelling of the medicinal product, which is used as an auxiliary medicinal 
product. 
AxMP 
auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in 
the protocol, but not as an investigational medicinal product. Examples 
include rescue medication, challenge agents, agents to assess endpoints in 
the clinical trial, or background treatment. AxMP does not include 
investigational medicinal product (IMP) or concomitant medications. 
Concomitant medications are medications unrelated to the clinical trial and 
not relevant for the design of the clinical trial. 
BCRP 
Breast Cancer Resistance Protein 
BIRC 
Blinded Independent Review Committee 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CDK 
cyclin-dependent kinase 
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CFR 
Code of Federal Regulations 
CFS 
chemotherapy-free survival 
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. 
CR 
complete response 
CRF 
case report form 
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. 
CRS 
clinical research scientist 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicities 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCFR 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
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. 
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ER 
estrogen receptor 
ER+ 
estrogen receptor-positive 
ERα 
estrogen receptor α 
EDC 
electronic data capture system 
EEC 
endometrial endometrioid cancer 
ERB 
Ethical Review Board 
ET 
endocrine therapy 
FES 
F-fluoroestradiol 
FSH 
follicular stimulating hormone 
G 
grade 
GCP 
Good Clinical Practice 
GDPR 
EU General Data Protection Regulation 
HER2- 
human epidermal growth factor receptor 2 negative 
HR 
hormone receptor 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including 
as a placebo, in a clinical trial. 
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 that are relevant to the participant’s decision to 
participate. Informed consent is documented by means of a written, signed, 
and dated informed consent form. 
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INR 
international normalized ratio 
Interim analysis 
An interim analysis is an analysis of clinical study data, separated into 
treatment groups, that is conducted before the final reporting database is 
created/locked. 
Investigational 
product 
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 
IRC 
Internal Review Committee 
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. 
IWRS 
interactive web response system 
mBC 
metastatic breast cancer 
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medication error 
Errors in the prescribing, dispensing, or administration of a study 
intervention, regardless of whether or not the medication is administered 
to the participant or the error leads to an AE. Medication error generally 
involves a failure to uphold 1 or more of the 5 “rights” of medication 
use: the right participant, the right drug, the right dose, right route, at the 
right time. 
In addition to the core 5 rights, the following may also represent 
medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique 
inconsistent with the medication’s labeling, for example, Summary of 
Product Characteristics, IB, local label, protocol, or 
• shared use of cartridges or prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent 
with the prescribed dosing regimen, indication, or both, or is obtained 
without a prescription. 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
NCI 
National Cancer Institute 
NIMP 
Non-investigational Medicinal Product See AxMP. 
A medicinal product used for the needs of a clinical trial as described in 
the protocol, but not as an investigational medicinal product. Examples 
include rescue medication, challenge agents, agents to assess endpoints in 
the clinical trial, or background treatment. 
NRS 
numeric rating scale 
OS 
overall survival 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a 
clinical trial, either as recipient of an investigational medicinal product or 
as a control 
P-gp 
P-glycoprotein 1 
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PET 
positron emission tomography 
PI3K 
phosphoinositide 3-kinase 
PK/PD 
pharmacokinetics/pharmacodynamics 
P-gp 
p-glycoprotein 
PGR 
progesterone receptor 
PFS 
progression-free survival 
PO 
orally 
PR 
partial response 
PRO/ePRO 
Patient-reported outcomes/electronic patient-reported outcomes 
PS 
performance status 
PT 
prothrombin time 
QD 
once daily 
SAC 
statistical analysis center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
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.  
SD 
stable disease 
SERD 
selective estrogen receptor degrader 
SoA 
Schedule of Activities 
SOC 
standard of care 
STFU 
short-term follow-up 
SMD 
Senior Management Designee 
SRE 
skeletal-related event 
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SUSARs 
suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which 
is assessed by the sponsor and or study investigator as being unexpected, 
serious, and as having a reasonable possibility of a causal relationship with 
the study intervention. 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event: an untoward medical occurrence that 
emerges during a defined treatment period, having been absent 
pretreatment, or worsens relative to the pretreatment state, and does not 
necessarily have to have a causal relationship with this treatment. 
TTC 
time to chemotherapy 
UGT1A1 
UDP Glucuronosyltransferase Family 1 Member A1 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 
 
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10.17. 
Appendix 17: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [c] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to increase the sample size for PFS between Arm A 
and Arm B (for the first two primary endpoints). Changes are outlined in this table. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis 
Updated to match changes in the main 
protocol 
Update 
Section 1.2. Schema 
Removed the footnote addressing Arm B 
enrollment. 
Arm B is now wider, so the 
schema shows all study arms will 
close at the same time. 
 
 
Section 1.3. Schedule of 
Activities 
Clarified short-term and long-term 
follow-up visit day; clarified footnote “a” 
and included details of Cycle 2 Day 15 
under Foot note “c” 
Correction 
Added text to second instructional 
comment for Bone scintigraphy line item: 
“...start of a new anticancer therapy...”  
For consistency with radiologic 
imaging 
Section 2. Introduction 
Added Introduction/Rationale for 
Amendment (c) 
Addition 
Section 3. Objectives and 
Endpoints 
Added row under exploratory analysis: 
“To assess clinical efficacy parameters of 
Arm C compared to Arm B” for endpoints 
PFS and OS 
Updates to study design 
Section 4.1. Overall Design; 
Section 6.3. Measures to 
Minimize Bias: 
Randomization and Blinding 
Clarified language regarding 
randomization into Arm A, B, and C; 
updated language regarding analysis of 
PFS 
Updates to study design  
Section 5.1. Inclusion 
Criteria 
Criterion 3:  
Additional notes added to better 
understand criterion #3 in a global study 
without any changes in actual eligibility 
criterion. 
Criterion 5: removed “and FSH” from note 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.1. Imlunestrant 
Dose Adjustments for 
Treatment-Emergent, 
Related, and Clinically 
Significant Adverse Events 
Included AST/ALT >8 x ULN under 
toxicity profile and severity for 
hepatotoxicity 
Clarification 
Section 6.1. Study 
Intervention(s) Administered 
Edited fulvestrant paragraph, removing 
specific language for “1 to 2 minutes per 
injection,” and referenced approved label 
Added text to exemestane paragraph; 
referred to approved label 
Clarification 
Section 7.1. Participant 
Discontinuation/Withdrawal 
from Study Treatment 
Deleted sentence following bullet points 
stating that “discontinuation is expected to 
be uncommon” 
Not appropriate for this study 
Section 9.2. Sample Size 
Determination; Section 
9.4.3.1 Primary Analyses; 
Section 9.5.2. Efficacy 
Interim Analyses 
Increased the number of events/total 
sample size for the PFS between Arm A 
and Arm B 
Removed detailed enrollment assumptions 
in Section 9.2 and referenced the SAP 
Updates to study design (sample 
size), and clarification 
Section 9.4.3.1. Primary 
Analyses 
Included the word “PFS” 
Clarification 
Section 9.4.3.3. Other 
Secondary Analyses 
Removed language regarding measurable 
disease in the analysis of DoR 
Clarification 
Section 9.4.7.1. Exploratory 
Analyses 
Added “…unless otherwise stated”; added 
language regarding Arm C and Arm B 
comparison 
Clarification and updates to study 
design 
Section 9.5.2. Efficacy 
Interim Analyses 
Updated the table “Stopping Boundaries 
for Each Analysis between Arm A and 
Arm B in the ITT Population” 
Updates to study design (stopping 
boundaries) 
Throughout 
Minor editorial and formatting changes 
Minor, therefore, not detailed 
Amendment b: 17-Aug-2022 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the primary objective with ESR1-mutation 
detected population. Additional edits have been made to incorporate emerging data and to 
provide clarifications in response to site and regulatory feedback. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 3 Objectives 
and Endpoints 
Added new primary objective and 
endpoint for progression-free survival 
(PFS) in the ESR1-mutation detected 
population  
Updated to integrate evolving 
clinical data relevant to this trial 
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Section # and Name 
Description of Change 
Brief Rationale 
Added new secondary objective and 
endpoint for overall survival (OS) in the 
ESR1-mutation detected population 
Removed secondary endpoint for 
investigator-assessed PFS by ESR1 
mutation status in plasma/ctDNA 
Clarified the patient population (ITT or 
ESR1-mutation detected) for both 
objectives and endpoints  
1.3 Schedule of Activities 
Revised the instructions for the following 
procedures: 
 Radiologic imaging according to 
RECIST 
 Brain imaging 
 Bone scintigraphy 
 FSH and estradiol levels 
 Pregnancy test 
 Fasting lipid testing 
 Local ECG 
 PK sample 
 Biomarker plasma sample 
 PRO 
Added “see instructions” for PRO for the 
“Study Treatment” study period 
Removed “at the end of this period” from 
footnote “a” defining Short-term follow-up 
Revised footnote “b” to revise the intervals 
relative to Cycle 1 Day 1 to evaluate tumor 
response 
Revised footnote “c” regarding Cycle 1 
Day 15 
Revisions were made to these 
sections to provide clarity and 
make corrections. No new 
activities were added.  
1.3.1 Schedule of 
Assessments for Patient-
Reported Outcomes 
Revised the instructions to remove 
administration of the following patient-
reported outcomes during short-term 
follow-up: 
 EORTC QLQ-C30 
 EORTC IL 19 
Clarification 
2 Introduction 
Revised section to provide rationale for 
addition of PFS in the ESR1-mutation 
detected population 
Updated to reflect changes in 
objectives and endpoints 
1.1 Synopsis; 4.1 Overall 
Design  
Revised section based on changes made in 
Section 3 and Section 5 (inclusion criterion 
5) 
Updated to include emerging 
information 
5.1 Inclusion Criteria 
 
Criterion 3: Revised 3a-c criteria for 
locally advanced (not amenable to curative 
treatment by surgery) or metastatic disease  
Additional clarity and to maintain 
a patient population reflective of 
the standard of care 
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Section # and Name 
Description of Change 
Brief Rationale 
Criterion 5: Revised to allow the Sponsor 
to limit the number of participants enrolled 
onto this study who have NOT received a 
prior CDK4/6 inhibitor  
Edited to maintain a patient 
population reflective of the 
standard of care  
Criterion 7a: Addition of a note to include 
participants established on a less frequent 
GnRH agonist administration schedule 
Operational/editorial 
Criterion 10: Revised measured creatinine 
clearance and hemoglobin laboratory 
values 
Regulatory suggestion 
5.2 Exclusion Criteria 
Criterion 20: “Consent” replaced by 
“randomization” 
Operational/editorial 
Criterion 21: Changed the number of days 
prior to randomization for participants 
undergoing major surgery from 14 to 28 
days 
Regulatory suggestion 
Criterion 23i: Added “at several 
consecutive days of assessment” 
Operational/editorial 
Criterion 24: “Active symptoms” replaced 
by “pre-existing medical condition” 
Operational/editorial 
5.4 Screen Failures 
Removed “If the results of a repeated 
laboratory test meet the eligibility criteria, 
that laboratory test must be repeated to 
confirm eligibility” 
Clarification  
6.1 Study Intervention(s) 
Administered 
Updated instructions for imlunestrant 
administration 
Clarification 
6.6 Dose Modification 
Replaced the sub-heading “The sections 
below detail dose modification and delays 
of imlunestrant” with “General 
Considerations for Dose Delays” 
Clarification 
8.1.1 Efficacy Assessments 
at Baseline and during Study 
Treatment 
Revised the brain imaging instructions to 
align with changes in schedule of activities 
Clarification 
8.2.2.1 Hepatic Safety 
Monitoring 
Added “For patients that meet the criteria 
above, whenever possible and as clinically 
appropriate, continue monitoring after 
discontinuation of imlunestrant until 
values are back to baseline”. 
Operational 
8.8 Biomarkers 
Added patient’s consent to be obtained to 
undergo a fresh tumor biopsy prior to 
treatment if patients do not have adequate 
archival tumor tissue available 
Revised the eligibility criteria if archival 
tissue is not available and a fresh tumor 
biopsy cannot be performed 
Added “Personal identification 
information that can directly identify a 
Operational/editorial 
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Section # and Name 
Description of Change 
Brief Rationale 
patient will not be included with the 
sample”. 
9.1 Statistical Hypotheses 
Added hypotheses 2 for ESR1-mutation 
detected population 
Updated to reflect changes in 
objectives and endpoints and to 
incorporate emerging information 
1.1 Synopsis; 4.1 Overall 
Design; 9.2 Sample Size 
Determination 
Added the hypothesis for ESR1-mutation 
detected population  
Added the graphical approach that will be 
used to test the PFS hypotheses and the OS 
hypotheses  
Updated to reflect changes in 
objectives and endpoints and to 
incorporate emerging information 
4.1 Overall Design; 9.4.3.1 
Primary Analyses 
Added the analysis for ESR1-mutation 
detected population 
Clarified the patient population (ITT or 
ESR1-mutation detected)  
Updated to incorporate emerging 
information 
9.4.3.2 Key Secondary 
Analyses 
Added reference to SAP for the graphical 
approach for OS endpoints that will be 
tested hierarchically  
Added OS between Arm A and Arm B in 
the ESR1-mutation detected population 
Clarified the patient population (ITT or 
ESR1-mutation detected) 
Added reference to SAP for analysis of 
each OS endpoint that will be conducted in 
the same analysis populations for PFS  
Updated to incorporate emerging 
information 
9.4.3.3 Other Secondary 
Analyses 
Clarified the patient population (ITT or 
ESR1-mutation detected) 
Removed PFS (investigator-assessed) by 
ESR1 mutation status (in plasma/ctDNA) 
Clarification 
9.4.4 Patient-Reported 
Outcomes and Medical 
Resource Utilization 
Clarified the patient population (ITT or 
ESR1-mutation detected) for each 
comparison 
Clarification 
9.4.7.1 Exploratory Analyses 
Clarified the patient population (ITT or 
ESR1-mutation detected) for each 
comparison 
Clarification 
9.4.7.3 Biomarker Analyses 
Updated with baseline ESR1 mutation 
status (mutation detected versus mutation 
not detected) 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
9.5.2 Efficacy Interim 
Analyses 
Revised the investigator-assessed events 
for the two interim analyses planned for 
the primary endpoint of PFS between Arm 
A and Arm B in the ITT population 
Updated the hazard ratio to be 
recommended by the DMC to stop the trial 
for futility  
Updated the number of events in the ITT 
population  
Updated stratified log-rank test p-value 
Updated second interim analysis plan for 
the PFS between Arm A and Arm B in the 
ITT population 
Added interim analysis plan for PFS 
between Arm A and Arm B in the ESR1-
mutation detected population  
Revised stopping boundaries for each 
analysis between Arm A and Arm B in the 
ITT population based on the initial 
allocation of alpha 
Updated to reflect changes in 
objectives and endpoints and to 
incorporate emerging information 
10.3 Appendix 3: Protocol 
JZLC RECIST Criteria 1.1 
Revised the specifications by methods of 
measurement to include the timeline 
exception of obtaining baseline bone 
scintigraphy  
Operational clarification 
10.4 Appendix 4: Clinical 
Laboratory Tests 
Formatted table for clinical laboratory 
tests. 
Revised footnote c to include FSH and 
estradiol at screening for women <60 years 
of age  
Operational/editorial for additional 
clarity 
10.7 Appendix 7: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information 
Minor revisions made for women in the 
following categories to not be considered 
as woman of childbearing potential 
 Premenopausal female 
 Postmenopausal female 
Operational/editorial for additional 
clarity 
10.9 Appendix 9: Liver 
Safety: Suggested Actions 
and Follow-Up Assessments 
Formatted table for hepatic evaluation tests 
Editorial for additional clarity 
10.10 Appendix 10: Country-
specific Requirements 
Added appendix to include EU specific 
requirements for the following countries: 
 Belgium 
 Czech Republic 
 France 
 Germany 
 Italy, and 
 Spain 
Regulatory request 
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Section # and Name 
Description of Change 
Brief Rationale 
10.10.1 Discontinuation of 
Inadvertently Enrolled 
Patients in Germany 
Removed duplicate section to align with 
Germany appendix (Section 10.10.4) 
Editorial 
10.16 Appendix 16: 
Abbreviations 
Updated abbreviations 
Editorial 
11 References 
Updated citations 
Editorial  
Throughout 
Minor editorial and formatting changes 
Minor, therefore, not detailed 
 
Amendment a: 8-Oct-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to incorporate a new treatment arm into the study 
design. Additional edits have been made to incorporate emerging data and to provide 
clarifications in response to site and regulatory feedback. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Approval Page 
Removed page 
Medical monitor name and contact 
information will be provided in 
separate document 
Title Page; 1.1 Synopsis; 
1.2 Schema; 1.3 Schedule 
of Activities; 1.3.2 
Sampling Schedules for 
Pharmacokinetics; 4.1 
Overall Design; 6.1 Study 
Intervention(s) 
Administered; 
6.1.4 Arm C Imlunestrant + 
Abemaciclib: General Dosing 
Instructions; 6.6.4 Re- 
escalation Criteria; 8.4 
Treatment of Overdose; 8.5 
Pharmacokinetics; 9 
Statistical Considerations 
Added treatment arm 3, imlunestrant plus 
abemaciclib, to study design; language 
added throughout protocol to reflect 
addition of abemaciclib to study design 
and analyses 
New arm added to study design to 
incorporate abemaciclib + 
imlunestrant combination 
1.1 Synopsis; 3 Objectives 
and Endpoints 
Added new primary, secondary, and 
exploratory objectives 
New objectives added for Arm C 
1.3 Schedule of Activities 
Added additional visits / assessments for 
Arms A and C 
Added for abemaciclib safety 
monitoring 
1.3 Schedule of Activities 
Added clarification that patient diary is for 
patients randomized to Arms A or C 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Clarified long-term follow-up adverse 
event collection 
Clarification 
1.3 Schedule of Activities 
Added collection windows for hematology 
and clinical chemistry 
Added for flexibility 
1.3 Schedule of Activities; 
5.1 Inclusion criteria 
Added on study and follow-up FSH and 
estradiol procedures; updated ovarian 
function requirements in Inclusion #5 
Allowance of more flexible GnRH 
agonist administration 
1.3 Schedule of Activities 
Removed Visit 0 PRO assessment 
PROs will not be collected at Visit 0 
1.3.1 Schedule of 
Assessments for Patient- 
Reported Outcomes 
Revised Instructions 
Operational/editorial 
2 Introduction; 2.1 Study 
rationale; 2.2 Background 
Revised section to provide introduction to 
CDK4/6 inhibitors, rationale and 
background for abemaciclib combination, 
and remove information detailed in other 
documents 
Updated to reflect changes in study 
design and to remove information 
detailed in other documents 
2.3 Benefit/Risk Assessment 
Updated benefit/risk assessment to include 
more recent information and to include 
abemaciclib 
Updated to reflect changes in study 
design and to incorporate emerging 
information 
4.3 Justification for Dose 
Added justification for imlunestrant + 
abemaciclib combination dosing 
Added to provide 
rationale/justification for 
combination dosing 
5.1 Inclusion Criteria 
Criterion 3: Specified that prior treatment 
with CDK4/6 inhibitor is expected if 
treatment was approved and can be 
reimbursed 
Regulatory suggestion 
5.1 Inclusion Criteria 
Criteria 6 and 7: Added additional 
contraceptive requirements for patients 
receiving fulvestrant 
Inadvertent omission 
5.1 Inclusion Criteria 
Criterion 10: changed total bilirubin ≤3.0 
times ULN to ≤2.0 times ULN 
Modified for abemaciclib 
5.2 Exclusion Criteria 
Criterion 15: Specified that patients that 
have previously completed exemestane 
may not receive exemestane if randomized 
to the control arm 
Alignment with standard of care 
5.2 Exclusion Criteria 
Criterion 24: added examples of medical 
conditions precluding participation 
Modified for abemaciclib 
6.1 Study Intervention(s) 
Administered; 6.1.4 Arm C 
Imlunestrant + Abemaciclib: 
General Dosing Instructions 
Added dosing information for abemaciclib 
Added to reflect updated study 
design 
6.1.2 Arm A Imlunestrant: 
General Dosing Instructions 
Updated statement regarding effect of 
imlunestrant on coagulation 
Updated to include emerging 
information 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2.3 Arm C Preparation / 
Handling / Storage: 
Imlunestrant + Abemaciclib 
Added details for abemaciclib 
Added to reflect updated study 
design 
6.5 Concomitant Therapy 
Added instructions for documentation of 
concomitant therapy; added details for 
abemaciclib 
Documentation instructions added 
for clarification; abemaciclib 
details added to reflect updated 
study design 
6.5.1 Palliative Medicine 
and Supportive Care; 8.1.1 
Efficacy Assessments at 
Baseline and during Study 
Treatment 
Added instructions for patients with bone 
metastases present on baseline imaging 
Provide clarity of when RANK-L 
targeted agents may be initiated 
while on study 
6.5.2 Supportive 
Management for Diarrhea 
Updated supportive management 
instructions 
Alignment with abemaciclib 
guidance 
6.6 Dose Modification; 
6.6.1 Imlunestrant Dose 
Adjustments for Treatment- 
Emergent, Related, and 
Clinically Significant 
Adverse Events; 6.6.2 Dose 
Modifications for 
Endocrine Therapy of 
Investigator’s Choice; 6.6.3 
Dose Modifications for 
Abemaciclib 
Revised sections; added abemaciclib dose 
modification guidance 
Revised dose modification 
guidance for imlunestrant for 
readability and consistency with 
abemaciclib guidance; added 
abemaciclib guidance to align with 
updated study design 
6.7.1 Continued Access 
Removed unblinding language 
No blinding in study 
8.2.4 Guidance for 
Monitoring Renal 
Function; 
8.2.5 Guidance for 
Venous Thromboembolic 
Events; 
8.2.6 Guidance for 
Interstitial Lung 
Disease/Pneumonitis 
Added new safety sections 
Added sections for abemaciclib- 
related safety guidance 
8.3 Adverse Events, Serious 
Adverse Events, and Product 
Complaints 
Clarified that abnormal laboratory values 
should only be reported if they are 
clinically relevant 
Clarification 
8.8 Biomarkers 
Removed statement regarding additional 
samples for biomarker research; specified 
that archival blocks with be returned to the 
study site upon request 
Operational; clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
8.9.1 Patient-Reported 
Outcomes; 8.9.3 EORTC 
IL19: Physical Function; 
8.9.6 mBPI-sf; 8.9.7 Worst 
Pain NRS; 8.9.8 PRO- 
CTCAE 
Items 
for 
Diarrhea and Injection 
Site Pain and Swelling 
Updated descriptions of questionnaires and 
use on study 
Clarification/operational 
10.1.3 Informed Consent 
Process 
Specified investigator will explain a 
description of the investigational drug 
Clarification 
10.4 Appendix 4: Clinical 
Laboratory Tests 
Revised guidance for abnormal laboratory 
values; added statement for local chemistry 
results for enrollment decisions; removed 
urinalysis; added cystatin c; revised 
pregnancy/hormone testing 
Guidance revised for clarification; 
operational clarification; urinalysis 
removed due to not being part of 
study assessments, cystatin c added as 
part of abemaciclib renal monitoring; 
revised pregnancy/hormone testing to 
include pregnancy and 
postmenopausal status 
10.6. Appendix 6: Adverse 
Events: Definitions and 
Procedures for Recording, 
Removed statement for post-baseline 
CTCAE grading 
Grading will be performed per 
CTCAE version 5.0 for all items 
Evaluating, Follow-Up, and 
Reporting 
Appendix 7: Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Specified non-highly effective methods of 
contraception are not allowed 
Specification for safety 
10.9 Appendix 9: Liver 
Safety: Suggested Actions 
and Follow-Up 
Assessments 
Provided additional clarifications for 
hepatic evaluating testing 
Clarification 
10.10 Appendix 10: Country- 
specific Requirements 
Changed country-specific guidance from 
UK to Germany 
Regulatory request 
10.14 Appendix 14: 
Inhibitors of P-glycoprotein 
Removed appendix 
Appendix no longer applicable 
based on new data 
Throughout 
Changed LY3484356 to imlunestrant, 
where applicable 
Editorial 
Throughout 
Minor editorial and formatting changes 
Minor, therefore not detailed 
 
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11. 
References  
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