postMONARCH: A Randomized, Double Blind, Placebo-Controlled, Phase 3 Study to Compare the Efficacy of Abemaciclib Plus Fulvestrant to Placebo Plus Fulvestrant in Participants With HR+, HER2-, Advanced or Metastatic Breast Cancer Following Progression on a CDK4 & 6 Inhibitor and Endocrine Therapy
Phase: PHASE3
Conditions: Breast Neoplasm, Neoplasm Metastasis
Sponsor: Eli Lilly and Company

Protocol 13Y-MC-JPEF (d) 
postMONARCH: A Randomized, Double Blind, Placebo-Controlled, Phase 3 Study to Compare the Efficacy 
of Abemaciclib Plus Fulvestrant to Placebo Plus Fulvestrant in Participants With HR+, HER2-, 
Advanced or Metastatic Breast Cancer Following Progression on a CDK4 & 6 Inhibitor and Endocrine 
Therapy
NCT05169567
Approval Date: 04-Oct-2023

CONFIDENTIAL 
I3Y-MC-JPEF(d) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: postMONARCH: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study to Compare the Efficacy of Abemaciclib plus Fulvestrant to Placebo plus Fulvestrant in 
Participants with HR+, HER2-, Advanced or Metastatic Breast Cancer Following Progression on 
a CDK4 & 6 Inhibitor and Endocrine Therapy
Protocol Number: I3Y-MC-JPEF 
Amendment Number: d 
Compound: Abemaciclib (LY2835219) 
Brief Title: Abemaciclib plus Fulvestrant compared to Placebo plus Fulvestrant in HR+, HER2-, 
Advanced or Metastatic Breast Cancer previously treated with a CDK4/6 Inhibitor and 
Endocrine Therapy 
Study Phase: 3 
Acronym: postMONARCH 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Eli Lilly and Company, Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
IND: 106100 
EudraCT: 2021-002301-10 
EU Trial Number: 2023-506771-10-00 
Approval Date: Protocol Amendment (d) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-050468 
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I3Y-MC-JPEF(d) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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I3Y-MC-JPEF(d) 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment c 
17-Feb-2022 
Amendment b 
09-Dec-2021 
Amendment a 
02-Sep-2021 
Original Protocol 
13-Aug-2021 
Amendment (d)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to align with EU Clinical Trial Regulation (EU-CTR) 
requirements. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added 
 
EU Trial Number 
 
Study Population 
 
Last row for “Authorized as defined 
by EU Clinical Trial Regulation” in 
Study Intervention 
 
Ethical Considerations of 
Benefit/Risk 
For EU CTR compliance 
1.1. Synopsis 
4.1. Overall Design 
Added definition of visceral metastases: 
“visceral includes lung, liver, brain, 
pleural, and peritoneal involvement”  
For clarification 
1.3. Schedule of Activities 
(SoA) 
Updated the age of women from “<60 
years” to “<55 years” in FSH test for 
consistency with Inclusion Criteria and 
Appendix 4.  
For clarification 
1.3. Schedule of Activities  
8.3. Adverse Events, Serious 
Adverse Events, and Product 
Complaints 
8.3.1 Timing and Mechanism 
for Collecting Events     
10.3.1 Definition of AE 
Added statement about the reporting of 
AEs and SAEs, including death, caused 
by disease progression or otherwise due 
to study disease. 
For clarification 
5.1. Inclusion Criteria 
Updated the contraception language for 
WOCBP 
To comply with updated guidance 
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Section # and Name 
Description of Change 
Brief Rationale 
6. Study Intervention(s) and 
Concomitant Therapy 
Updated the definition of study 
intervention 
For EU CTR compliance 
6.1. Study Intervention(s) 
Administered 
 
Added last row for “Authorized as 
defined by EU Clinical Trial 
Regulation” 
 
Added a paragraph on “Packaging 
and labeling” 
9.3.1. General Considerations 
Added a paragraph on handling of 
missing, unused, and spurious 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 
10.1.4. Data Protection 
Updated the required language 
10.1.6. Dissemination of 
Clinical Study Data 
Updated the required language in 
“Reports” 
10.3.1. Definition of AE 
Added a bullet in “Events Meeting the 
AE Definition” 
10.3.6. Regulatory Reporting 
Requirements 
Updated the required language in “SAE 
Regulatory Reporting” 
10.4.1 Definitions  
Women not of child bearing potential 
row: 
 
updated the bullet for congenital 
anomaly 
 
added acceptable surgical 
sterilization methods 
Post-menopausal state row: 
 
changed FSH value from “>40” to 
“≥40” mIU/mL 
To comply with updated guidance 
10.4.2. Contraception Guidance 
 
Updated the language for WOCBP 
 
Updated the contraception language 
for WOCBP 
 
Added examples of highly effective 
contraception 
 
Added a note that male and female 
condoms should not be used in 
combination for effective 
contraception 
 
Deleted immunocontraceptives from 
ineffective forms of contraception 
10.5. Appendix 5: Liver Safety: 
Suggested Actions and Follow-
Up Assessments 
Deleted “segmented” from neutrophils 
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Section # and Name 
Description of Change 
Brief Rationale 
10.9. Appendix 9. 
Abbreviations and Definitions 
Added abbreviations and definitions 
For EU CTR compliance 
10.10. Appendix 10: Protocol 
Amendment History 
Inserted date, rationale, and summary of 
changes from amendment (c). 
To update document history 
Throughout the protocol 
Minor formatting and editorial changes 
For correction. Minor, therefore, 
not detailed 
 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
1.3.1. 
Schedule of Assessments for Patient-Reported Outcomes and 
HCRU .............................................................................................................................26 
1.3.2. 
PK Sampling Schedule ...................................................................................................27 
2. 
Introduction ...................................................................................................................28 
2.1. 
Study Rationale ...............................................................................................................28 
2.2. 
Background .....................................................................................................................29 
2.2.1. 
Treatment Options for HR+, HER2- Breast Cancer after Disease 
Progression or Recurrence on a CDK4 & 6 Inhibitor-Based 
Regimen ..........................................................................................................................29 
2.2.2. 
CDK4 & 6 Inhibition in HR+, HER2- Breast Cancer ....................................................30 
2.2.3. 
The Role of Endocrine Treatment in HR+, HER2- Breast Cancer .................................30 
2.3. 
Benefit/Risk Assessment ................................................................................................31 
2.3.1. 
Risk Assessment .............................................................................................................31 
2.3.2. 
Benefit Assessment .........................................................................................................32 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................32 
3. 
Objectives, Endpoints, and Estimands .......................................................................33 
4. 
Study Design ..................................................................................................................36 
4.1. 
Overall Design ................................................................................................................36 
4.2. 
Scientific Rationale for Study Design ............................................................................36 
4.3. 
Justification for Dose ......................................................................................................37 
4.3.1. 
Abemaciclib ....................................................................................................................37 
4.3.2. 
Fulvestrant.......................................................................................................................37 
4.4. 
End of Study Definition ..................................................................................................37 
5. 
Study Population ...........................................................................................................39 
5.1. 
Inclusion Criteria ............................................................................................................39 
5.2. 
Exclusion Criteria ...........................................................................................................42 
5.3. 
Lifestyle Considerations .................................................................................................43 
5.4. 
Screen Failures ................................................................................................................43 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................44 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................45 
6.1. 
Study Intervention(s) Administered................................................................................45 
6.1.1. 
Selection and Timing of Doses .......................................................................................45 
6.1.2. 
General Dosing Instructions ...........................................................................................46 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................46 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................46 
6.3.1. 
Emergency Unblinding ...................................................................................................48 
6.3.2. 
Inadvertent Unblinding ...................................................................................................48 
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6.4. 
6.4.1. 
6.4.2. 
6.5. 
6.5.1. 
6.5.2. 
6.6. 
6.7. 
6.8. 
6.8.1. 
6.8.2. 
6.8.3. 
6.8.4. 
6.8.5. 
7. 
7.1. 
7.2. 
7.3. 
8. 
8.1. 
8.1.1. 
8.1.2. 
8.1.3. 
8.2. 
8.2.1. 
8.2.2. 
8.2.3. 
8.2.4. 
8.2.5. 
8.2.6. 
8.3. 
8.3.1. 
8.3.2. 
8.3.3. 
8.3.4. 
8.4. 
8.5. 
8.6. 
8.7. 
8.7.1. 
8.7.2. 
8.7.3. 
8.8. 
Study Inte1vention Compliance ..................................................................................... .48 
Blinded Study Drng ....................................................................................................... .48 
Fulvestrant. ...................................................................................................................... 4 9 
Dose Modification .......................................................................................................... 49 
Blinded Study Drng ........................................................................................................ 49 
Fulvestrant. ...................................................................................................................... 52 
Continued Access to Study Inte1vention after the End of the 
Study ............................................................................................................................... 52 
Treatment of Overdose ................................................................................................... 53 
Concomitant Therapy ..................................................................................................... 53 
Palliative and Supp01tive Care ........................................................................................ 53 
Bisphosphonates and RANK-L Targeted Agents ........................................................... 54 
Supp01t ive Management for Diauhea ............................................................................ 54 
Concomitant Therapy ...................................................................................................... 54 
Medications and therapies not permitted ........................................................................ 55 
Discontinuation of Study Intervention and Participant 
Discon tin uatio n/With drawal. ....................................................................................... 56 
Discontinuation of Study lnteivention ............................................................................ 56 
Pa1ticipant Discontinuation/Withdrawal from the Study ................................................ 56 
Lost to Follow-Up ........................................................................................................... 56 
Study Assessments and Procedures ............................................................................. 58 
Efficacy Assessments ..................................................................................................... 58 
Efficacy Assessments at Baseline and during Study Treatment ..................................... 58 
Efficacy Assessments during Post-Discontinuation Follow-Up ..................................... 59 
Prima1y Efficacy Measure .............................................................................................. 59 
Safety Assessments ......................................................................................................... 59 
Clinical Safety Laboratory Tests .................................................................................... 59 
Pregnancy Testing ........................................................................................................... 60 
Hepatic Safety Monitoring .............................................................................................. 60 
Guidance for Monitoring Renal Function ....................................................................... 61 
Guidance for Venous Thromboembolic Events .............................................................. 62 
Guidance for Interstitial Lung Disease/Pneumonitis ...................................................... 62 
Adverse Events, Serious Adverse Events, and Product 
Complaints ...................................................................................................................... 62 
Timing and Mechanism for Collecting Events ............................................................... 64 
Pregnancy ........................................................................................................................ 67 
Events or Outcomes ........................................................................................................ 68 
Adverse Events of Special Interest ................................................................................. 68 
Phaimacokinetics ............................................................................................................ 68 
Pha1macodynamics ......................................................................................................... 69 
Genetics .......................................................................................................................... 69 
Biomarkers ...................................................................................................................... 70 
Samples for Biomarker Reseai·ch ..................................................... 71 
Tissue San1ples for Biomai·ker Research ........................................................................ 72 
Whole-Blood Sample for Biomarker Research .............................................................. 73 
Immunogenicity Assessments ......................................................................................... 73 
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8.9.7. 
9. 
9.1. 
9.1.1. 
9.2. 
9.3. 
9.3.1. 
9.3.2. 
9.3.3. 
9.3.4. 
9.3.5. 
9.4. 
9.4.1. 
9.4.2. 
9.5. 
10. 
10.1. 
10.1.1. 
10.1.2. 
10.1.3. 
10.1.4. 
10.1.5. 
10.1.6. 
10.1.7. 
10.1.8. 
10.1.9. 
10.1.10. 
10.1.11. 
10.1.12. 
10.2. 
10.3. 
10.3.1. 
10.3.2. 
Health Economics and Medical Resource Utilization .................................................... 73 
.................................................... 74 
.................................................... 74 
.................................................... 74 
.................................................... 74 
.................................................... 75 
.................................................... 75 
Health Care Resource Utilization ................................................................................... 76 
Statistical Considerations ............................................................................................. 77 
Statistical Hypotheses ..................................................................................................... 77 
Multiplicity Adjustment .................................................................................................. 77 
Analyses Sets .................................................................................................................. 77 
Statistical Analyses ......................................................................................................... 78 
General Considerations ................................................................................................... 78 
Prima1y Endpoint/Estimand Analysis ............................................................................. 79 
Secondaiy Endpoint( s) Analysis ..................................................................................... 80 
Safety Analyses ............................................................................................................... 81 
Other Analyses ................................................................................................................ 81 
Interim Analysis .............................................................................................................. 83 
Safety Interim Analyses .................................................................................................. 83 
Efficacy/Futility Interim Analyses .................................................................................. 83 
Sample Size Dete1mination ............................................................................................ 84 
Supporting Documentation and Operational Considerations .................................. 85 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................ 85 
Regulato1y and Ethical Considerations ........................................................................... 85 
Financial Disclosure ........................................................................................................ 86 
Info1med Consent Process .............................................................................................. 86 
Data Protection ................................................................................................................ 86 
Committees Stmcture ...................................................................................................... 87 
Dissemination of Clinical Study Data ............................................................................. 87 
Data Quality Assurance .................................................................................................. 88 
Source Documents .......................................................................................................... 89 
Study and Site Sta1t and Closure .................................................................................... 90 
Publication Policy ........................................................................................................... 90 
Investigator Inf mmation ................................................................................................. 90 
Sample Retention ............................................................................................................ 91 
Appendix 2: Clinical Laboratory Tests ........................................................................... 92 
Appendix 3: Adverse Events and Se1ious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Repoiting ........................................................................................................... 95 
Definition of AE ............................................................................................................. 95 
Definition of SAE ........................................................................................................... 96 
10.3.3. 
Definition of Product Complaints ................................................................................... 97 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ...................................................................................................................... 97 
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10.3.5. Reporting of SAEs ..........................................................................................................99 
10.3.6. Regulatory Reporting Requirements .............................................................................100 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ........................................................101 
10.4.1. Definitions.....................................................................................................................101 
10.4.2. Contraception Guidance................................................................................................102 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................104 
10.6. 
Appendix 6: Inducers and Strong Inhibitors of CYP3A ...............................................106 
10.7. 
Appendix 7: Country-Specific Requirements ...............................................................108 
10.7.1. Discontinuation of Inadvertently Enrolled Participants in the 
United Kingdom............................................................................................................108 
10.7.2. Removal of the Legally Authorized Representative, Legal 
Guardian, Parents, Designee, Surrogate, and Caregiver in 
Germany ........................................................................................................................108 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct during 
Exceptional Circumstances ...........................................................................................109 
10.9. 
Appendix 9: Abbreviations and Definitions .................................................................112 
10.10. 
Appendix 10: Protocol Amendment History ................................................................118 
11. 
References ....................................................................................................................124 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: postMONARCH: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study to Compare the Efficacy of Abemaciclib plus Fulvestrant to Placebo plus Fulvestrant in 
Participants with HR+, HER2-, Advanced or Metastatic Breast Cancer Following Progression on 
a CDK4 & 6 Inhibitor and Endocrine Therapy 
Brief Title: Abemaciclib plus Fulvestrant compared to Placebo plus Fulvestrant in HR+, HER2-, 
Advanced or Metastatic Breast Cancer previously treated with a CDK4/6 Inhibitor and 
Endocrine Therapy 
Regulatory Agency Identifier Numbers: 
IND: 106100 
EudraCT: 2021-002301-10 
EU Trial Number: 2023-506771-10-00 
Rationale: 
The incorporation of CDK4 & 6 inhibitors with endocrine therapy (ET) into first-line treatment 
of locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth 
factor receptor 2 negative (HER2-) breast cancer has dramatically improved outcomes (Finn et 
al. 2016; Tripathy et al. 2018; Johnston et al. 2019). However, these therapies are not curative, 
and nearly all MBC patients will experience disease progression. More recently, abemaciclib has 
shown significant improvement in invasive disease-free survival (IDFS) and distant relapse-free 
survival (DRFS) in the adjuvant setting (Johnston et al. 2020). As the use of CDK4 & 6 
inhibitors increases in earlier lines of therapy, the question of how to best treat patients following 
disease progression or relapse after CDK4 & 6-based therapy will become increasingly important 
to inform future practice. 
Following disease progression on a CDK4 & 6 inhibitor plus ET, there are a number of treatment 
options. However, most of these treatment options were tested before CDK4 & 6 inhibitors were 
available, with the exception of alpelisib in the BYLieve study (Rugo et al. 2021). Therefore, 
outcomes following treatment with a CDK4 & 6 inhibitor-containing therapy are not well 
understood, and there are no prospective Phase 3 studies to guide therapy for this population. 
Following CDK4 & 6 inhibitor-containing therapy, resistance mechanisms are multifactorial and 
could include resistance directed to the ET and/or CDK4 & 6 inhibitor component of the regimen 
(Alvarez-Fernandez and Malumbres 2020). Importantly, tumors that have developed class-
specific ET resistance (for example, ESR1 mutations in the setting of aromatase inhibitors) may 
have continued dependence on CDK4 & 6 pathway inhibition. Given the safety and tolerability 
of CDK4 & 6 inhibitors in combination with ET, there is growing interest in testing the 
continuation of CDK4 & 6 inhibition beyond progression while switching the ET backbone. 
Benefit from continuation of therapy beyond progression has been established in other disease 
states, such as in HER2+ MBC where HER2-directed therapy is continued while a new ET or 
cytotoxic chemotherapy regimen is initiated (von Minckwitz et al. 2011; Baselga et al. 2012b). 
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The ability to maintain disease control through multiple lines of endocrine-based therapies 
suggests persistent dependence on endocrine signaling after disease progression (Weatherman et 
al. 1999; Baselga et al. 2012a). Switching to an ET partner with a different mechanism provides 
continued endocrine signaling inhibition that can induce response or control disease progression, 
thus delaying the need for chemotherapy. Fulvestrant, a selective ER degrader (SERD), is one 
such option and is approved for use in the second-line setting. 
There is an unmet need to understand and improve outcomes in this setting through the 
evaluation of novel strategies in Phase 3 randomized trials. postMONARCH is a randomized, 
Phase-3 study of fulvestrant with or without abemaciclib in participants with HR+, HER2- 
advanced or metastatic breast cancer with disease progression on/after either adjuvant or first-
line treatment with a CDK4 & 6 inhibitor plus ET. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To compare the efficacy of fulvestrant with or 
without abemaciclib  
PFS as determined by investigator assessment 
using RECIST 1.1 
Secondary 
 
To further compare the efficacy of fulvestrant 
with or without abemaciclib 
 
OS 
 
PFS by BICR 
 
ORR 
 
CBR 
 
DCR 
 
DoR 
To further characterize the safety profile of 
abemaciclib in combination with fulvestrant  
Safety – including but not limited to TEAEs, 
SAEs, deaths, and clinical laboratory 
abnormalities  
To compare PRO measures of fulvestrant with or 
without abemaciclib  
 Time to worsening in worst pain via the mBPI- 
SF worst pain item 
 Time to deterioration in physical function via 
the EORTC IL-19 
To characterize the pharmacokinetics (PK) of 
abemaciclib in combination with fulvestrant 
Concentrations of abemaciclib  
Abbreviations: BICR = blinded independent central review; CBR = clinical benefit rate; DCR = disease control rate; 
DoR = duration of response; EORTC IL-19 = European Organisation for Research and Treatment of Cancer Item 
Library 19; mBPI-SF = modified Brief Pain Inventory-short form; ORR = objective response rate; OS = overall 
survival; PRO = patient-reported outcome; PFS = progression-free survival; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
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Overall Design 
postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled 
study in pa1t icipants with HR+, HER2- advanced or metastatic breast cancer. This study will 
emoll adults who experienced disease progression on a CDK4 & 6 inhibitor and an AI in the 
first-line setting or relapse on/after a CDK4 & 6 inhibitor with ET in the adjuvant setting. The 
intervention anns include: 
• 
Ann A: abemaciclib and fulvestrant (Investigational) 
• 
Alm B: placebo and fulvestrant (Control) 
Randomization will be 1: 1 and stratified by the following factors: 
• 
geography: 
• 
presence of visceral metastases: yes or no (visceral includes lung, liver, brain, pleural, 
and peritoneal involvement), and 
• 
duration on prior adjuvant/metastatic CDK4 & 6 inhibitor-based regimen (2 levels): 
The primary endpoint of PFS will be based upon investigator assessment. 
Duration of Treatment: 
Participants will be treated until disease progression or other discontinuation criteria are met. 
Study Population 
Pa1iicipants are eligible to be included in the study only if all the following criteria apply: 
• 
2::18 years of age ( or of an acceptable age according to local regulations, whichever is 
older) at the time of signing the info1med consent 
• 
have a diagnosis of HR+, HER2- breast cancer 
• 
have either advanced disease not amenable to curative surgical treatment or metastatic 
disease 
• 
have radiologic evidence of disease progression or recunence either 
o on treatment with a CDK4 & 6 inhibitor plus AI as initial therapy for advanced 
disease, or 
o on/after treatment with a CDK4 & 6 inhibitor plus ET administered as adjuvant 
therapy for early-stage breast cancer, and 
• 
have either measurable disease or non-measurable but evaluable disease as defined by 
RECIST Version 1.1. 
Number of Participants: 
Approximately 350 paiticipants will be randomly assigned to study intervention. 
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13 
Study Intervention: 
 
Arm A 
Arm B 
Treatment 
Abemaciclib 
Fulvestrant 
Placebo 
Fulvestrant 
Dose 
150 mg 
500 mg 
Matched to 
abemaciclib 
500 mg 
Route 
PO 
IM 
PO 
IM 
Schedule 
BID on Days 1-28 of 
each cycle 
C1D1 and C1D15, 
then on Day 1 of 
Cycle 2 and 
subsequent cycles 
BID on Days 1-28 of 
each cycle 
C1D1 and C1D15, 
then on Day 1 of 
Cycle 2 and 
subsequent cycles 
Authorized 
as defined 
by EU 
Clinical 
Trial 
Regulation 
Authorized and not 
used according to EU 
authorization 
 
Authorized and not 
used according to EU 
authorization 
 
Not authorized in EU 
Authorized and not 
used according to EU 
authorization 
 
Abbreviations: BID = twice daily; C = cycle; D = day; IM = intramuscular; mg = milligrams; PO = orally. 
Ethical Considerations of Benefit/Risk 
The potential risks of the abemaciclib plus fulvestrant combination are justified in consideration 
of the measures to minimize these risks and the anticipated benefit of improved disease control, 
as measured by improved PFS in participants with HR+, HER2- MBC, an incurable disease with 
a poor prognosis and limited non-cytotoxic therapeutic options. 
Data Monitoring Committee: Yes
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1.2. 
Schema 
Key Inclusion Criteria: 
• HR+, HER2- advanced or metastatic 
breast cancer 
• Men or pre-/post-menopausal women 
• Prior therapy: 
• Advanced setting: Disease 
progression on CDK4 & 6 inhibitor 
plus Al as initial therapy, OR 
• Adjuvant setting Disease recurrence 
on or after CDK4 & 6 inhibitor plus ET 
R 
1: 1 
N = 350 
A 
B 
Abemaciclib + Fulvestrant 
N = 175 
Placebo+ Fulvestrant 
N = 175 
• Geography: 
BY-MC-JPEF( d) 
Primary Endpoint: 
Investigator-assessed PFS 
Secondary Endpoints: 
OS, PFS by BICR, ORR, CBR. OCR, 
DoR, Safety, PRO, PK 
• Presence of visceral metastases: yes or no 
• Duration on rior CDK4 & 6 inhibitor-based re imen: 
Abbreviations: AI = aromatase inhibitor; BICR = blinded independent central review; CBR = clinical benefit rate; CDK = cyclin-dependent kinase; DCR = 
disease control rate; DoR = duration of response; ET = endocrine therapy; HER = human epidennal growth factor receptor; HR= hmmone receptor; N = number 
ofpait icipants; ORR= objective response rate; OS = overall survival; PFS = progression-free survival; PK = phatmacokinetics: PRO = patient-repo1t ed 
outcomes; R = randomization. 
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15 
1.3. 
Schedule of Activities (SoA)  
This section includes the following SoAs: 
 Screening, Treatment, and Post-Discontinuation Follow-Up SoA for all participants 
 Continued-Access SoA for participants on abemaciclib 
Overview 
The windows for the SoA and administration of first dose are based on calendar days. 
Study Period I – Screening & Baseline 
The screening period allows up to 28 days for confirmation of eligibility and completion of 
baseline assessments. 
Study Period II – Treatment 
During the on-study treatment period, participants will return to clinic every 2 weeks (14 ± 3 
days) for the first 2 cycles, and then monthly (28 ± 7 days) starting with Cycle 3 until start of 
short-term follow-up. The duration of this study period is not predefined as patients will remain 
on treatment until disease progression or discontinuation for any reason. 
Tumor Response 
Tumor response per RECIST 1.1 should be assessed approximately every 8 weeks for the first 12 
months (relative to Cycle 1 Day 1), and thereafter approximately every 12 weeks until the 
participant has objective disease progression, death, or study completion (following evaluation of 
final OS data). 
Study Period III – Short- and Long-Term Follow-Up 
Participants discontinuing study intervention will return for an in-clinic short-term follow-up 
visit (Visit 801). The short-term follow-up visit will take place 30 days (±7 days) after the 
decision is made to discontinue all study treatment. 
After the short-term follow-up visit, all participants will enter the long-term follow-up period 
(Visit 802-8XX). Long-term follow-up begins the day after the short-term follow-up visit is 
completed and continues until participant’s death, withdrawal from study, or study completion. 
Long-term follow-up visits should occur approximately every 2-3 months (Q60-90D) during 
long-term follow-up. The duration of this study period is not predefined as participants will 
remain in long-term follow-up until death, withdrawal from study, or study completion. 
Approved on 04 Oct 2023 GMT

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I3Y-MC-JPEF(d) 
16 
 
Screening, Treatment, and Post-Discontinuation Follow-Up SoA for All Participants 
 
Study Period 
Study Period I – Screeninga 
Study Period II – 
Treatment Period 
(Cycle = 28 Days) 
Study Period III 
– Post-
Discontinuation 
Follow-Up 
Period 
 
 
Cycle/Visit 
Baseline 
Cycles 1-2 
Cycle 
3-n 
Short-
Termb 
 
V801 
Long-
Termc 
 
V802-
V8XX 
Notes 
 
Relative Day within a Cycle 
≤28 
D1 
D15 
D1 
30 
Days 
(Q60-
90D) 
 For V802-V8XX, phone visits are acceptable 
 
Visit Interval Tolerance (Days) 
 
-3  
±3 
±7 
±7 
 
 -3 days for C1D1 
 ± 3 days for C1D15, C2D1, and C2D15 
 ± 7 days for C3D1-n 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
 
Study 
Entry/Enrollment 
Informed consent 
X 
 
 
 
 
 
 ICF must be signed before any protocol-
specific procedures are performed 
Inclusion and exclusion criteria 
X 
See note 
 
 
 
 
 Must be confirmed prior to randomization  
Demographics 
X 
 
 
 
 
 
  
Medical History 
Preexisting conditions and medical history, 
including relevant surgical history 
X 
 
 
 
 
 
 
Prior treatments for breast cancer 
X 
 
 
 
 
 
 Record cancer surgery, radiation, prior 
anticancer therapies 
Substance use (alcohol, tobacco use)  
X 
 
 
 
 
 
  
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
 
 Record all premedication, supportive care, 
and concomitant medication  
Adverse Event 
Collection/CTCAE 
Grading 
 
X 
X 
X 
X 
X 
X 
 CTCAE Version 5.0 
 AEs, including SAEs, are collected at every 
clinic visit, throughout the on-study 
intervention period and short-term follow-up, 
regardless of relationship to study 
intervention 
 AEs and SAEs, including death, caused by 
disease progression or otherwise due to study 
disease should not be reported unless the 
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I3Y-MC-JPEF(d) 
17 
 
Study Period 
Study Period I – Screeninga 
Study Period II – 
Treatment Period 
(Cycle = 28 Days) 
Study Period III 
– Post-
Discontinuation 
Follow-Up 
Period 
 
 
Cycle/Visit 
Baseline 
Cycles 1-2 
Cycle 
3-n 
Short-
Termb 
 
V801 
Long-
Termc 
 
V802-
V8XX 
Notes 
 
Relative Day within a Cycle 
≤28 
D1 
D15 
D1 
30 
Days 
(Q60-
90D) 
 For V802-V8XX, phone visits are acceptable 
 
Visit Interval Tolerance (Days) 
 
-3  
±3 
±7 
±7 
 
 -3 days for C1D1 
 ± 3 days for C1D15, C2D1, and C2D15 
 ± 7 days for C3D1-n 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
 
investigator deems them to be possibly 
related to study treatment. 
 For long-term follow-up: only SAEs that are 
related to study drugs or protocol procedures 
will be collected 
Survival 
Information 
 
  
  
  
  
X 
X 
  
Post-
Discontinuation 
Treatment 
 
  
  
  
  
X 
X 
  
Physical 
Evaluation 
Height 
X 
  
  
  
  
  
  
Weight 
X 
X 
X 
X 
X 
  
  
Vital signs 
X 
X 
X 
X 
X 
  
 Temperature, blood pressure, pulse rate, and 
respiration rate 
 If collected within 7 days of D1, they do not 
need to be repeated at D1 
Complete physical examination 
X 
X 
 
 
 
 
 Excludes pelvic and rectal exams 
 C1D1 only 
 If collected within 7 days of D1, does not 
need to be repeated 
Symptom-directed physical examination  
 
See note 
  
X 
X 
X 
  C2D1 and Day 1 of each cycle after C2 
ECOG PS status evaluation 
X 
X 
  
X 
X 
  
 
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CONFIDENTIAL 
Prncedure 
Cate 01-y 
Clinical Tumor 
Assessment 
Refer to Section 
8.1 
Tumor 
Assessment 
Refer to Section 
8.1 
Study Pe1iod 
Cycle/Visit 
Relative Day within a Cycle 
Visit Interval Tolernnce (Days) 
Procedure 
Study Pe1iod I - SCl'eeninga 
Baseline 
98 
18 
Study Period II -
Treatment Pe1i od 
(Cycle = 28 Days) 
Cycle 
Cycles 1-2 
3-n 
D1 
D15 
D1 
-3 
±3 
±7 
Approved on 04 Oct 2023 GMT 
Study Period III 
-Post-
Discontinuation 
Follow-Up 
Pe1iod 
Short-
Long-
Tumb Termc 
V801 
V802-
V8:XX 
30 
(Q60-
Days 
90D 
±7 
B Y-MC-JPEF( d) 
Notes 
• For V802-V8:XX, phone visits are acceptable 
• -3 days for CIDI 
• ± 3 days for ClDl5, C2D1, and C2Dl5 
• ± 7 da 
for C3D1-n 

CONFIDENTIAL 
Study Pe1iod 
Cycle/Visit 
Relative Day within a Cycle 
Visit Interval Tolernnce (Days) 
Prncedure 
Cate 01-y 
Tumor 
Assessment 
Refer to Section 
8.1 
Brain Imaging 
Refer to Section 
8.1 
Procedure 
Study Pe1iod I - SCl'eeninga 
Baseline 
98 
19 
Study Period II -
Treatment Pe1i od 
(Cycle = 28 Days) 
Cycle 
Cycles 1-2 
3-n 
D1 
D15 
D1 
-3 
±3 
±7 
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Study Period III 
-Post-
Discontinuation 
Follow-Up 
Pe1iod 
Short-
Long-
Tumb Termc 
V801 
V802-
V8:XX 
30 
(Q60-
Days 
90D 
±7 
B Y-MC-JPEF( d) 
Notes 
• For V802-V8:XX, phone visits are acceptable 
• -3 days for CIDI 
• ± 3 days for ClDl5, C2D1, and C2Dl5 
• ± 7 da 
for C3D1-n 

CONFIDENTIAL 
Prncedure 
Cate 01-y 
Tumor 
Assessment 
Refer to Section 
8.1 
Patient Dosing 
Diary (Paper) 
Lab/ diagnostic 
tests 
Study Pe1iod 
Cycle/Visit 
Relative Day within a Cycle 
Visit Interval Tolernnce (Days) 
Procedure 
12-lead ECG (Single, local) 
Study Pe1iod I - SCl'eeninga 
Baseline 
98 
X 
20 
Study Period II -
Treatment Pe1i od 
(Cycle = 28 Days) 
Cycle 
Cycles 1-2 
3-n 
D1 
D15 
D1 
-3 
±3 
±7 
See notes 
Approved on 04 Oct 2023 GMT 
Study Period III 
-Post-
Discontinuation 
Follow-Up 
Pe1iod 
Short-
Long-
Tumb Termc 
V801 
V802-
V8:XX 
30 
(Q60-
Days 
90D 
±7 
B Y-MC-JPEF( d) 
Notes 
• For V802-V8:XX, phone visits are acceptable 
• -3 days for CIDI 
• ± 3 days for ClDl5, C2Dl, and C2Dl5 
• ± 7 da 
for C3Dl -n 
• Dispense diary on D 1 of Cl and C2 
• Participants record date and times of every 
dose of blinded study drug taken from ClDl 
through C3DI 
• Collect and review diary from prior cycle on 
DI ofC2 and C3 
• See Section 1.3.2 for use with site PK dosing 
data en 

CONFIDENTIAL 
Study Pe1iod 
Cycle/Visit 
Relative Day within a Cycle 
Visit Interval Tolernnce (Days) 
Prncedure 
Cate 01 
Lab/Diagnostic 
Tests 
See Section 10.2, 
Appendix2 
Procedure 
Health Outcomes 
PROs and HCRU 
Study Pe1iod I - SCl'eeninga 
Baseline 
98 
21 
Study Period II -
Treatment Pe1i od 
(Cycle = 28 Days) 
Cycle 
Cycles 1-2 
3-n 
D1 
D15 
D1 
-3 
±3 
±7 
See Section 1.3.1 
Approved on 04 Oct 2023 GMT 
Study Period III 
-Post-
Discontinuation 
Follow-Up 
Pe1iod 
Short-
Long-
Tumb Termc 
V801 
V802-
V8:XX 
30 
(Q60-
Days 
90D 
±7 
B Y-MC-JPEF( d) 
Notes 
• For V802-V8:XX, phone visits are acceptable 
• -3 days for CIDI 
• ± 3 days for ClDl5, C2D1, and C2Dl5 
• ± 7 da 
for C3D1-n 

CONFIDENTIAL 
Study Pe1iod 
Cycle/Visit 
Relative Day within a Cycle 
Visit Interval Tolernnce (Days) 
Prncedure 
Cate 01 
Biomarlcer, 
Genetic, 
Pharmacokinetic, 
Tissue Collection 
Procedure 
Study Pe1iod I - SCl'eeninga 
Baseline 
98 
22 
Study Period II -
Treatment Pe1i od 
(Cycle = 28 Days) 
Cycle 
Cycles 1-2 
3-n 
D1 
D15 
D1 
-3 
±3 
±7 
Approved on 04 Oct 2023 GMT 
Study Period III 
-Post-
Discontinuation 
Follow-Up 
Pe1iod 
Short-
Long-
Tumb Termc 
V801 
V802-
V8:XX 
30 
(Q60-
Days 
90D 
±7 
B Y-MC-JPEF( d) 
Notes 
• For V802-V8:XX, phone visits are acceptable 
• -3 days for CIDI 
• ± 3 days for ClDl5, C2D1, and C2Dl5 
• ± 7 da 
for C3D1-n 

CONFIDENTIAL 
I3Y-MC-JPEF(d) 
23 
 
Study Period 
Study Period I – Screeninga 
Study Period II – 
Treatment Period 
(Cycle = 28 Days) 
Study Period III 
– Post-
Discontinuation 
Follow-Up 
Period 
 
 
Cycle/Visit 
Baseline 
Cycles 1-2 
Cycle 
3-n 
Short-
Termb 
 
V801 
Long-
Termc 
 
V802-
V8XX 
Notes 
 
Relative Day within a Cycle 
≤28 
D1 
D15 
D1 
30 
Days 
(Q60-
90D) 
 For V802-V8XX, phone visits are acceptable 
 
Visit Interval Tolerance (Days) 
 
-3  
±3 
±7 
±7 
 
 -3 days for C1D1 
 ± 3 days for C1D15, C2D1, and C2D15 
 ± 7 days for C3D1-n 
Procedure 
Category 
Procedure 
 
 
 
 
 
 
 
 
 
Dosing 
Study Drug 
Dosing 
 
See Section 6.1.2 
Dispense blinded study drug 
 
X  
  
 X 
  
  
 
Blinded study drug dosing 
 
See note 
 
 
 Orally BID on Days 1-28 of each cycle 
Fulvestrant dosing 
 
See notes 
 
 
 IM on C1D1 and C1D15, then on Day 1 of 
Cycle 2 and beyond 
 If participant misses the specified window 
around D1, administration should occur at 
earliest opportunity and not wait until 
following cycle to resume  
Observe participant administer oral study 
drug 
 
See notes 
 
 
 During PK cycles only – Cycles 1-3 
 Observation is to ensure proper timing of PK 
sampling 
 See Section 1.3.2 
Participant returns study drugs  
 
See note 
  
 Return at Day 1 of C2 and beyond and V801 
if applicable to assess compliance 
Abbreviations: AE = adverse event; BID = twice daily; C = Cycle; CRP/CRS = clinical research physician or clinical research scientist; CT = computed 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; FSH = follicle-stimulating hormone; HCRU = health care resource utilization; ICF = informed consent form; IM = intramuscular; 
MRI = magnetic resonance imaging; PK = pharmacokinetics; PRO = patient-reported outcomes; Q = every; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; SOC = standard of care; V = visit; WOCBP = women of child-bearing potential. 
a Screening procedures may be conducted over more than 1 day as long as all activities are completed within the allowable visit tolerance. 
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CONFIDENTIAL 
BY-MC-JPEF( d) 
b Short-term follow-up begins the day after the participant and the investigator agree that the participant will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures ai·e performed once at the end of this period. 
c Long-term follow-up begins the day after sh01t-term follow-up is completed and continues until the participant's death or overall study termination; the 
associated study procedures are performed every 60-90 days for the duration of tllis period. 
24 
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I3Y-MC-JPEF(d) 
25 
Continued-Access SoA (See also Section 6.6) 
Visita 
Study 
Intervention 
Continued-Access 
30-Day Follow-Up 
Instructions 
 
501-5XX 
901 
 
Duration (days) 
28 
30±5 
 
AE collection 
X 
X 
 Per CTCAE v5.0 
 Collect all AEs and SAEs regardless of causality during the 
continued-access and follow-up periods 
Administer study 
intervention 
X 
 
 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 continued-access period begins after study completion and ends at the end of trial. 
Approved on 04 Oct 2023 GMT

CONFIDENTIAL 
1.3.1. 
Schedule of Assessments for Patient-Reported Outcomes and HCRU 
Instrument 
\Vorst Pain 
Single Item 
mBPI-SF 
Scale 
PRO-CTCAE-
Dianhea 
EORTCQLQ-
C30b 
EORTC IL-19b 
EQ-5D-SL 
HCRU 
Completed at Home during All Cycles until Last 
Visit (SFU) 
Shol1-Term 
Follow-Up 
(30 days)• 
BY-MC-JPEF( d) 
Instructions 
• Participants complete using ePRO device 
• "Worst Pain Single Item" is-
as a single item and is 
also one of the 11 items in the mBPI-SF scale 
Abbreviations: C = cycle; CRF = case report fonn; D = day; EORTC IL-19 = European Organization for Research and Treatment of Cancer Item Libra1y 19; 
EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30; ePRO = electronic patient-
rep011ed outcomes; EQ-5D-5L = 5-level-EuroQol; HCRU = healthcare resource utilization; mBPI-SF = modified Brief Pain Invent01y-sh011 form; PROs = 
patient-reported outcomes; PRO-CTCAE = Patient-Repo1ted Outcomes - Common Terminology Criteria for Adverse Events; SFU = sho1t-tem1 follow-up. 
• Sho1t-te1m follow-up begins the day after the pa11icipant and the investigator agree that the participant will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures are perfonned once at the end of this period. 
26 
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I3Y-MC-JPEF(d) 
27 
1.3.2. 
PK Sampling Schedule  
Pharmacokinetics (PK) samples will be collected from all participants as specified below. 
Samples will be analyzed for concentrations of abemaciclib and its active metabolites, M2 and 
M20. 
The time and date of the PK sample draw should be recorded on the laboratory requisition form. 
Deviation from the specified sampling scheme is permitted when practical and logistical 
concerns arise. 
During the PK sampling period (Cycle 1 Day 1 to Cycle 3 Day 1), participants will complete a 
paper Patient Dosing Diary to record the time and date of blinded study drug doses. Dosing times 
should be entered into the eCRF for doses taken on 
 the morning of the planned PK collection and 
 the morning and evening doses taken the day before the planned PK collection (Cycle 2 
and beyond). 
Pharmacokinetic Sampling Schedule 
Sampling 
Day 
Sample 
Number 
Microsample PK 
Plasma PK 
Cycle 1 Day 1 
1 
Any time at least 1 h after the first 
blinded study drug dose
a 
Within ±10 minutes of microsample 
Cycle 2 Day 1 
2 
Predose
b,c 
None 
3 
Any time at least 4 h after the first 
daily blinded study drug dose
a,c,d 
None 
Cycle 3 Day 1 
4 
Predose
b 
Within ±10 minutes of microsample 
Abbreviations: h = hours; PK = pharmacokinetics. 
a The PK sample should be collected after the morning dose of blinded study drug. 
b  Participants should refrain from taking blinded study drug until arrival at the clinic. Blinded study drug 
administration may resume following the PK sample draw. 
c The sample may be collected by the participant or caregiver. 
d A minimum of 4 hours should separate PK samples on Cycle 2 Day 1. 
Approved on 04 Oct 2023 GMT

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I3Y-MC-JPEF(d) 
28 
2. 
Introduction  
This is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study for 
participants with HR+, HER2- MBC with disease progression on a CDK4 & 6 inhibitor and ET. 
The study will evaluate the benefits of continuing CDK4 & 6 inhibition while switching the class 
of ET partner to a SERD (fulvestrant). Specifically, the study will enroll adults with disease 
progression on a CDK4 & 6 inhibitor and an AI in the first-line metastatic setting or on/after a 
CDK4 & 6 inhibitor in combination with ET in the adjuvant setting. 
2.1. 
Study Rationale  
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). However, these therapies are not curative, and nearly all patients will experience disease 
progression. Additionally, CDK4 & 6 inhibitors are being tested in the adjuvant setting in 
patients with HR+, HER2-, high-risk, early breast cancer. The monarchE trial demonstrated 
significant and clinically meaningful improvement in IDFS and DRFS with the addition of 
abemaciclib to adjuvant ET (Johnston et al. 2020). 
Numerous options exist for the treatment of MBC following disease progression on a CDK4 & 6 
inhibitor; however, most of these therapies were tested in clinical trials before CDK4 & 6 
inhibitors became standard of care as first or later lines of MBC treatment. Therefore, outcomes 
for many of these therapies in patients who have received a prior CDK4 & 6 inhibitor are not 
well understood. 
Notably, there are no results from prospective Phase 3 studies to guide therapy for patients who 
develop disease progression during treatment with a CDK4 & 6 inhibitor and, although clinical 
guidelines offer various treatment options, there is no universally accepted standard of care for 
these patients. Thus, there is an unmet need to understand and improve outcomes through the 
evaluation of novel strategies in Phase 3 randomized trials. 
Underlying reasons for disease progression during treatment with a CDK4 & 6 inhibitor and ET 
are multifactorial but include primary or secondary resistance to the ET component of the 
regimen, which is commonly an aromatase inhibitor or tamoxifen. Tumors that develop 
endocrine resistance (e.g., through an ESR1 mutation, a common mechanism of acquired ET 
resistance) may have continued dependence on inhibition of the CDK4 & 6 pathway. Given the 
safety and tolerability of CDK4 & 6 inhibitors in combination with ET, there is growing interest 
in testing the continuation of CDK4 & 6 inhibition while switching the ET backbone to treat 
disease progression. Benefit from continuation of therapy beyond progression has been 
established in other disease states, such as in HER2+ MBC where HER2-directed therapy is 
continued while a new ET or cytotoxic chemotherapy regimen is initiated (von Minckwitz et al. 
2011; Baselga et al. 2012b). 
The ability to maintain disease control through multiple lines of endocrine-based therapies 
suggests persistent dependence on endocrine signaling after disease progression (Weatherman et 
al. 1999; Baselga et al. 2012a). Switching to an ET partner with a different mechanism of action 
provides continued endocrine signaling inhibition that can induce response or control disease 
Approved on 04 Oct 2023 GMT

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I3Y-MC-JPEF(d) 
29 
progression, thus delaying the need for chemotherapy. Fulvestrant is a SERD approved for use in 
the second-line setting and has proven efficacy. 
2.2. 
Background  
Globally, in 2020, breast cancer was the most common cancer diagnosed in females and the most 
common cause of cancer-related death among females (Sung et al. 2021). Most cases of MBC 
occur after locoregional and systemic treatments that were administered with curative intent. 
While CDK4 & 6 inhibition in combination with ET for initial treatment of HR+, HER2- MBC 
is effective and well tolerated, most patients ultimately develop progressive disease (Dickler et 
al. 2017; Gul et al. 2018; NCCN 2021). 
It is unclear if disease progression is the result of resistance to the ET, the CDK4 & 6 inhibitor, 
or both (McCartney et al. 2019). The ability to maintain disease control through multiple lines of 
endocrine-based therapies that have differing mechanisms of action suggests that some breast 
cancers retain a persistent dependence on endocrine signaling after disease progression 
(Weatherman et al. 1999; Baselga et al. 2012a). Additionally, tumors that have developed 
resistance to first-line ET and CDK4 & 6 inhibitor may have continued benefit from CDK4 & 6 
pathway inhibition when combined with an ET with a different mechanism of action. 
This trial will test abemaciclib plus fulvestrant compared to single-agent fulvestrant in 
participants with disease progression on a CDK4 & 6 inhibitor and ET. Fulvestrant is a SERD 
that is approved for use in the second-line setting for the treatment of HR+ MBC. Single-agent 
fulvestrant was selected as the control arm as the drug is commonly used as second-line therapy 
in patients with disease progression during first-line therapy of an AI in combination with a 
CDK4 & 6 inhibitor. Abemaciclib is a CDK4 & 6 inhibitor with proven benefit in PFS and OS in 
patients with MBC (Dickler et al. 2017; Spring et al. 2019; Sledge et al. 2020). Importantly, 
abemaciclib has demonstrated improved efficacy and OS when combined with fulvestrant 
compared to fulvestrant alone as second- or third-line therapy for treatment of HR+, HER2- 
MBC. 
In addition to the unmet clinical need, the rationale is supported by real-world, retrospective 
studies that have documented the off-label use of CDK4 & 6 inhibitor drugs in this population. 
These studies provide preliminary data suggesting clinical benefit when abemaciclib is 
administered following disease progression during treatment with a CDK4 & 6 inhibitor 
(Mariotti et al. 2020, Martin et al. 2021; Wander et al. 2021). 
2.2.1. 
Treatment Options for HR+, HER2- Breast Cancer after Disease Progression or 
Recurrence on a CDK4 & 6 Inhibitor-Based Regimen  
Importantly, there are no Phase 3 studies in this patient population to guide therapy. Given this 
lack of prospective evidence and an absence of standard care for relapsed MBC in the post-
CDK4 & 6 inhibitor setting, the 2020 ESMO and 2021 NCCN clinical guidelines support the use 
of various options including 
 ET alone: aromatase inhibitors (AIs), selective ER modulators (SERMs), or SERDs  
 ET in combination with PI3K pathway blockade, usually with everolimus or alpelisib (if 
an actionable PIK3CA mutation is detected) 
 cytotoxic chemotherapy, and 
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I3Y-MC-JPEF(d) 
30 
 clinical trial participation. 
Little direct data exist to define the best therapy for HR+ MBC after a CDK4 & 6 inhibitor. 
Moreover, while in some locations, everolimus and alpelisib in combination with second-line ET 
are approved (alpelisib specifically in patients with PIK3CA mutations), these data were 
generated exclusively in CDK4 & 6 inhibitor naive patients (Baselga et al. 2012a; André et al. 
2019), with the exception of alpelisib in the BYLieve study (Rugo et al. 2021). Thus, the efficacy 
of these agents post-CDK4 & 6 inhibitor treatment is unknown, and there is an unmet need to 
understand and improve outcomes through the evaluation of novel strategies in Phase 3 
randomized trials. Additionally, everolimus and alpelisib have substantial toxicities and not all 
patients are appropriate or willing to receive them. These factors collectively support the selected 
control arm of second-line fulvestrant monotherapy. 
2.2.2. 
CDK4 & 6 Inhibition in HR+, HER2- Breast Cancer  
The CDK4 & 6–retinoblastoma (Rb) axis plays a critical role in HR+, HER2- breast cancer. 
Mechanistically, the CDK4/6-cyclin D1 complex phosphorylates the Rb tumor suppressor 
protein leading to a loss of repression of E2F transcription factors, resulting in cell-cycle 
progression from G1 to S phase, and cancer proliferation. From a therapeutic standpoint, the goal 
of inhibiting CDK4 & 6 is to prevent cell-cycle progression, thus arresting tumor growth. 
Abemaciclib (Verzenio [LY2835219]) is an CDK4 & 6 inhibitor that is most active against 
cyclin D1/CDK4 in enzymatic assays, thereby preventing Rb phosphorylation, blocking 
progression from G1 into S phase of the cell cycle, and leading to suppression of tumor growth. 
Abemaciclib is approved for HR+, HER2- MBC based on improvements in PFS when added to 
anti-estrogen therapy (Spring et al. 2019). Abemaciclib is also approved as single-agent therapy 
for the treatment of HR+, HER2- MBC (Dickler et al. 2017). OS benefit has been confirmed for 
abemaciclib in combination with fulvestrant (Sledge et al. 2020) in ET-resistant MBC. 
Recently, results from 3 Phase 3 adjuvant studies of CDK4 & 6 inhibitors have been published, 
with abemaciclib being the only CDK4 & 6 inhibitor to show significant improvement in 
invasive disease-free survival (IDFS) and distant relapse free survival (DRFS) in the adjuvant 
setting in the monarchE study (Johnston et al. 2020; Loibl et al. 2021; Mayer et al. 2021). 
In HR+ breast cancer cell lines, sustained inhibition by abemaciclib prevents rebound of Rb 
phosphorylation and cell-cycle re-entry, resulting in senescence and apoptosis. In xenograft 
models, abemaciclib dosed daily without interruption at clinically relevant concentrations as a 
single agent or in combination with antiestrogens induced tumor response captured as a 
measurable reduction in tumor size. Abemaciclib is the only CDK4 & 6 inhibitor approved for 
continuous administration. 
2.2.3. 
The Role of Endocrine Treatment in HR+, HER2- Breast Cancer  
Over two-thirds of breast cancers express the estrogen receptor (ER), a key driver of breast 
cancer initiation and progression. Multiple means of ER signaling inhibition to exploit tumor 
dependency on estrogens are available. These include selective estrogen modulators (SERMs; 
tamoxifen), aromatase inhibitors (AIs; letrozole, anastrozole, and exemestane), and selective ER 
degraders (SERDs; fulvestrant). Patients with estrogen ER+ MBC often respond to ET alone or 
in combination with targeted agents, reducing tumor burden and symptoms with generally less 
Approved on 04 Oct 2023 GMT

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I3Y-MC-JPEF(d) 
31 
toxicity than chemotherapy, and thus form the backbone of initial MBC therapy (Cardoso et al. 
2020; NCCN 2021). 
While first-line ET is typically highly effective, especially in combination with CDK4 & 6 
inhibitors (Finn et al. 2016; Hortobagyi et al. 2016; Goetz et al. 2017), nearly all patients 
experience disease progression (Lei et al. 2019). Importantly, dependence on ER signaling can 
persist despite progression, as demonstrated by the ability to maintain disease control in some 
patients through multiple lines of endocrine-based therapies (Weatherman et al. 1999; Baselga et 
al. 2012a; Turner et al. 2015; Finn et al. 2016; André et al. 2019). 
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of abemaciclib may be found in the Investigator’s Brochure, Package 
Insert, or Summary of Product Characteristics. 
2.3.1. 
Risk Assessment  
Study Intervention 
This study aims to compare the efficacy and safety of abemaciclib plus fulvestrant (Arm A) 
versus placebo plus fulvestrant (Arm B). 
1. Arm A: abemaciclib plus fulvestrant 
The combination of abemaciclib 150 mg BID and fulvestrant is approved for use in HR+, HER2- 
MBC with a well-characterized efficacy and safety profile. In MONARCH 2 (Sledge et al. 
2017), this combination exhibited a manageable safety profile and resulted in clinically 
meaningful PFS and OS benefit compared to fulvestrant/placebo (Verzenio package insert, 2019; 
Verzenios SmPC, 2018). 
2. Arm B: placebo plus fulvestrant 
Fulvestrant as the control arm reflects an acceptable treatment option per ESMO and NCCN 
guidelines (Cardoso et al. 2020; NCCN 2021). 
Hematology, hepatic, and renal function tests are regularly monitored throughout the study with 
increased frequency in the early cycles when toxicity risks are highest. Increased susceptibility to 
infection will be monitored through regular hematology monitoring. These activities enable 
appropriate investigator oversight including the identification and management of AEs. 
Appropriate safety assessments, on-study monitoring, and AE management are detailed in 
Section 8.3 and Section 1.3 (SoA). 
Study Procedures 
A detailed schedule of study procedures and activities is presented in Section 1.3. 
Participants will undergo regularly scheduled blood draws by venipuncture, which is a common 
clinical practice with low risks of risk of complications such bleeding, vascular or soft tissue 
injury, and infection (Buowari 2013). 
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Participants will undergo regularly radiologic imaging. The investigator, in conjunction with 
guidance provided in Section 1.3, will select the most appropriate imaging study. Radiologic 
imaging is standard practice. Risks of imaging include low levels of radiation exposure and 
potential allergic reactions to intravenous contrast (Sammet 2016; Garcia et al. 2017). 
Tumor biopsy is requested if feasible, per investigator’s discretion. Common risks include injury 
of soft tissues, vascular tissues, and infections. According to the ASCO 2019 guidelines, this is 
considered low risk (Levit et al. 2019). 
2.3.2. Benefit Assessment  
All participants will receive a known active therapy for HR+, HER2- MBC, either abemaciclib 
or fulvestrant. Both abemaciclib and fulvestrant are approved as single agents for the treatment 
of MBC (abemaciclib and fulvestrant package inserts). Treatment with abemaciclib plus 
fulvestrant may result in improved clinical benefit compared to fulvestrant plus placebo. 
Based on known data, treatment with the combination of abemaciclib and fulvestrant is expected 
to be well tolerated and to delay disease progression. Prolonged disease control may also delay 
the need for cytotoxic chemotherapy. 
2.3.3. Overall Benefit Risk Conclusion  
The potential risks of the abemaciclib plus fulvestrant combination are justified in consideration 
of the measures to minimize these risks and the anticipated benefit of improved disease control, 
as measured by improved PFS in participants with HR+, HER2- MBC, an incurable disease with 
a poor prognosis and limited non-cytotoxic therapeutic options. 
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3. 
Objectives, Endpoints, and Estimands 
Ob· ectives 
End oints 
Primary 
To compare the efficacy of fulvestrant with or 
without abemaciclib 
Secondary 
To fiuther compare the efficacy of fulvestrant 
with or without abemaciclib 
To fiuther characterize the safety profile of 
abemaciclib in combination with fulvestrant 
To compare PRO measures of fulvestrant with or 
without abemaciclib 
To characterize the pharmacokinetics (PK) of 
abemaciclib in combination with fulvestrant 
To assess explorato1y clinical parameters of 
fulvestrant with and without abemaciclib 
PFS as determined by investigator assessment 
usin RECIST 1.1 
• 
OS 
• 
PFS byBICR 
• 
ORR 
• 
CBR 
• 
DCR 
• 
DoR 
Safety - including but not limited to TEAEs, 
SAEs, deaths, and clinical laborato1y 
abnormalities 
• Time to worsening in worst pain via the mBPI-
SF worst pain item 
• Time to deterioration in physical function via 
the EORTC IL-19 
Concentrations of abemaciclib 
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Ob"ectives 
To explore other PRO and HRQoL parameters 
of fulvestrnnt with and without abemaciclib 
To assess the relationship between biomarkers 
and clinical outcomes 
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• 
Outcomes such as clinical efficacy and safety, 
and/ or ex osme arameters 
Abbreviations: AE = adverse event; BICR = blinded independent central review; CBR = clinical benefit rate; 1111 
CTCAE = Common Tenninology Criteria for Adverse Events; DCR = disease 
control rate; DoR = duration of response; ECOG PS = Eastern Cooperative Oncology Group perfonnance status; 
EORTC IL-19 = Emopean Organisation 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 = EuroQOL 5 Dimension 5 Level; HRQoL = health-related quality of life; mBPI-SF = modified Brief 
Pain Inventory-sh011 fonn; ORR = objective response rate; OS = overall survival; PRO = patient-rep01t ed 
outcome; PFS = progression-free survival; 
RECIST = Response Evaluation 
Primary estimand 
The primary research question is: What is the difference in PFS time between Alm s A vs. B 
following progression/relapse on prior CDK4 & 6 inhibitor-based therapy in participants with 
advanced/metastatic HR+, HER2- breast cancer. 
The estimand for the primaiy objective is described by the following attributes: 
• 
Population: adult participants with advanced/metastatic HR+, HER2- breast cancer after 
progression/relapse on prior treatment with CDK4 & 6 inhibitor-based therapy, 
randomized to study intervention (primary analysis population). Further details can be 
found in Section 5. 
• 
Endpoint: investigator-assessed PFS in the primaiy analysis population, which is defined 
as the time from randomization until 
o 
first occunence of documented disease progression per RECIST 1.1, or 
o 
death from any cause in the absence of documented progressive disease. 
• 
Treatment condition: the randomized study intervention (Alm s A and B) will be 
administered until disease progression, unacceptable toxicity, or another protocol-defined 
reason for study intervention discontinuation (Section 7). Further details on study 
interventions, including interventions, concomitant therapy, and dose modification, can 
be found in Section 6. 
34 
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4. 
Study Design 
4.1. 
Overall Design 
postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled 
study in participants with HR+, HER2- advanced or metastatic breast cancer. This study will 
emoll adults who experienced disease progression on a CDK4 & 6 inhibitor and an AI in the 
first-line setting or relapse on/after CDK4 & 6 inhibitor with ET in the adjuvant setting. 
Approximately 350 pa1ticipants will be equally randomized between 2 treatment arms and will 
be treated until disease progression or other discontinuation criteria are met (Section 7). 
• 
Arm A: abemaciclib plus fulvestrant 
abemaciclib 150 mg orally BID on Days 1-28 of each cycle 
fulvestrant 500 mg IM on ClDl and ClD15, then on Day 1 of Cycle 2 and beyond 
• 
Arm B: placebo plus fulvestrant 
-
placebo BID on Days 1-28 of each cycle 
fulvestrant 500 mg IM on ClDl and ClD15, then on Day 1 of Cycle 2 and beyond 
• 
Participants will be randomized using the following stratification factors: 
• 
geography 
• 
presence of visceral metastases (Yes versus No; visceral includes lung, liver, brain, 
pleural, and peritoneal involvement) 
• 
duration on rior ad·uvant/metastatic CDK4 & 6 inhibitor-based re imen 2 levels : 
The primary efficacy measure is investigator-assessed PFS, defined as time from randomization 
to the first occmTence of documented disease progression per RECIST v 1.1, or death due to any 
cause in the absence of documented progressive disease. 
4.2. 
Scientific Rationale for Study Design 
Rationale for study design 
The overall rationale for the study design is described in Study Rationale (Section 2.1) and in the 
Statistical Considerations (Section 9) sections. Dose selection details can be found in Section 6.1. 
In this study, collection of demographic info1mation includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. This question can be answered only if the relevant data are collected. 
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4.3. 
Justification for Dose  
4.3.1. 
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 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; Verzenios SmPC, 2018). 
4.3.2. 
Fulvestrant  
In clinical studies of participants with breast cancer, no clinically relevant PK drug interactions 
were observed between abemaciclib and fulvestrant. Therefore, the recommended dose of 
fulvestrant in combination with abemaciclib is consistent with the approved monotherapy dose of 
fulvestrant. Accordingly, study participants in postMONARCH will receive fulvestrant 500 mg 
IM on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond according to the dosing 
information provided in the approved local label. 
4.4. 
End of Study Definition  
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 Continued-Access 
Period Diagram below) as determined by the Sponsor. Investigators will continue to follow the 
study schedule for all participants until notified by the Sponsor that study completion has occurred. 
“End of trial” refers to the date of the last visit or last scheduled procedure for the last participant. 
The end of trial occurs after study completion and after the last participant has discontinued study 
treatment and completed continued-access period follow-up (figure below). 
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38 
Study Period and Continued-Access Period Diagram
 
Abbreviations: IA = interim analysis; OS = overall survival; PFS = progression-free survival.
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Participants 
on study 
intervention 
----. 
Participant 
discontinues 
study 
intervention 
Short Term 
Follow Up 
----. 
Long Term 
Follow Up 
Participant on study intervention 
Study Period 
Efficacy IA at ~70% 
of planned events 
Primary PFS 
Analysis 
Long Term 
Follow Up 
i 
Short Term 
Follow Up 
Participant 
discontinues 
study 
intervention 
Participant 
on study 
intervention 
Final OS 
Analysis 
i 
Abbreviations: IA = interim analysis, PFS = progression free 
survival, OS = overall survival 
Participant 
on study 
intervention 
Participant 
discontinues 
study 
intervention 
Continued 
Access 
Period 
Follow Up 
Last visit or 
procedure for 
last participant 
i 
Study Completion 
Continued Access Period 
End ofTrial 

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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
“protocol waiver” or exemption, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. ≥18 years of age (or of an acceptable age according to local regulations, whichever is 
older) at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Have a diagnosis of HR+, HER2- breast cancer. To fulfill the requirement of 
a) HR+ disease: must express, by immunohistochemistry (IHC), at least 1 of 
the hormone receptors (estrogen receptor [ER] or progesterone receptor 
[PgR]) as defined in the relevant American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) Guidelines (Hammond 
et al. 2010). 
b) HER2- disease: must not demonstrate, at initial diagnosis or upon subsequent 
biopsy, overexpression of HER2 by either IHC or in-situ hybridization as defined 
in the relevant ASCO/CAP Guidelines (Wolff et al. 2018). 
3. Have either advanced disease not amenable to curative surgical treatment or metastatic 
disease. 
4. Have radiologic evidence of disease progression or recurrence either 
a) On treatment with a CDK4 & 6 inhibitor (palbociclib, ribociclib, or abemaciclib) 
plus AI as initial therapy for advanced disease, or 
b) On/after treatment with a CDK4 & 6 inhibitor (palbociclib, ribociclib, or 
abemaciclib) plus ET administered as adjuvant therapy for early-stage breast 
cancer. 
5. Have either measurable disease or non-measurable but evaluable disease. Measurable, 
non-measurable, and evaluable disease are defined according to the Response Evaluation 
Criteria in Solid Tumors (RECIST Version 1.1 [v1.1], Eisenhauer et al. 2009). 
6. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982). 
7. Must be deemed appropriate for treatment with ET. 
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8. Have discontinued previous treatments 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: 
Previous Treatment 
Length of Time Prior to First Dose of Study Drug 
CDK4 & 6 inhibitor 
7 days
Endocrine therapy 
 days or 5 half-lives, whichever is shorter
Radiotherapy 
 days 
Major surgery 
14 days
 
9. Have adequate organ function, as defined below: 
System 
Laboratory Value 
Hematologic 
  
ANC 
1.5×109/L 
Platelets 
100×109/L 
Hemoglobin 
8 g/dL 
Note: transfusions to increase a patient’s hemoglobin 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 
 
Participants with Gilbert’s syndrome with a total 
bilirubin ≤2.0×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. 
Sex and Contraceptive/Barrier Requirements 
Sex 
10. Males and females may participate. 
a. Male participants 
Must agree to use 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. Female participants 
Must have postmenopausal status due to 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 status due to surgical/natural menopause requires at least 1 of the 
following: 
a. prior bilateral oophorectomy 
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b. age ≥55 years and amenorrhoeic for at least 12 months or with a diagnosis of 
menopause 
c. age ≥40 and <55 years, amenorrhoeic for at least 12 months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH in the 
postmenopausal range (≥40 mIU/mL) 
Contraceptive/Barrier Requirements 
11. Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
a. Male participants 
No male contraception is required except in compliance with specific local government 
study requirements. Males are eligible to participate if they agree to refrain from donating 
sperm during the treatment period. Contraception requirements for male participants 
receiving fulvestrant should follow the approved local label. 
b. Female participants 
 Women of childbearing potential (WOCBP) must test negative for pregnancy prior to 
initiation of treatment with a negative serum pregnancy test at the screening visit, 
followed by a negative urine pregnancy test within 48 hours prior to first exposure to 
study drug, and 
 WOCBP should use highly effective contraception (less than 1% failure rate) to 
prevent pregnancy while receiving study treatment and for 3 weeks after the last dose 
of blinded study drug and for 2 years after the last dose of fulvestrant (or according to 
local approved fulvestrant label). 
Note: WOCBP who are completely abstinent or in a same-sex relationship as part of their 
preferred and usual lifestyle must agree to either remain abstinent or refrain from sexual 
intercourse with males.  
Please refer to Section 10.4 (Appendix 4) for definitions and additional guidance related to 
contraception. 
Informed Consent 
12. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
Other Inclusions 
13. Willing to participate for the duration of the study and to follow study procedures 
including use of Sponsor-provided electronic devices to collect patient reported outcomes 
14. Able to swallow capsules and tablets 
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5.2. 
Exclusion Criteria  
Participants are excluded if any of the following apply: 
Medical Conditions 
15. Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. 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. 
16. Have symptomatic or untreated central nervous system (CNS) metastasis. Participants 
with treated CNS metastases are eligible if 
a. they completed prior therapy (including radiation and/or surgery) ≥28 days prior 
to first dose of study treatment, and 
b. they have not received corticosteroids and/or anticonvulsants for at least 14 days 
prior to first dose of study treatment, and 
c. their disease is both asymptomatic and radiographically stable by repeat imaging 
for at least 28 days prior to consent (repeat imaging should be performed during 
study screening). 
17. Have a history within the last 12 months of any of the following conditions: syncope of 
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not 
limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
Exception: patients with controlled atrial fibrillation for >30 days prior to randomization 
are eligible. 
18. Have serious preexisting medical condition(s) 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], active symptoms 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 ulcerative colitis 
or a preexisting chronic condition resulting in clinically significant diarrhea). 
19. 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 
20. Have a known active systemic infection (for example, bacterial, fungal, or detectable 
viral infection requiring systemic therapy). 
a) Participants with uncontrolled human immunodeficiency virus (HIV) infection or an 
acquired immunodeficiency syndrome (AIDS) defining illness are not eligible. 
Participants with known HIV infection and CD4+ T-cell (CD4+) counts ≥350 
cells/µL are eligible. 
b) Participants with hepatitis B are not eligible unless viral load is below the level of 
quantification. 
c) Participants with known hepatitis C are not eligible unless they have completed 
curative anti-viral therapy and viral load is below the level of quantification. 
d) Screening for HIV, coronavirus disease 2019 (COVID-19), hepatitis B, or hepatitis C 
is not required. 
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Prior/Concomitant Therapy 
21. Have received any intervening line of systemic therapy between disease 
recurrence/progression and study screening. 
22. Have received more than 1 line of therapy for advanced or metastatic disease. 
23. Have received prior treatment with chemotherapy for MBC. 
24. Have received prior treatment with any CDK4 & 6 inhibitor-based regimen other than 
those specified. Prior treatment with a CDK4 & 6 inhibitor in more than 1 setting (e.g., 
adjuvant and then metastatic) is not permitted. 
25. Have received prior treatment with fulvestrant, any investigational ER-directed therapy 
(including SERDs and non-SERDs), any PI3K-, mTOR-, or AKT-inhibitor. 
26. Have known pathogenic germline mutations appropriate for a PARP inhibitor, in regions 
where these therapies are approved and available, per investigator’s discretion. 
27. Have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents 
(e.g. denosumab) <7 days prior to randomization. 
28. Are receiving concurrent exogenous reproductive hormone therapy (for example, birth 
control pills, hormone replacement therapy, or megestrol acetate). Appropriate washout 
period between last dose and randomization is up to the investigator’s medical judgment 
(for example, applying 7 days or 5 times the half-life elimination rule). Note: topical 
vaginal estrogen therapy is permitted if all other non-hormonal options are exhausted. 
29. Have received an autologous or allogeneic stem cell transplant. 
Prior/Concurrent Clinical Study Experience 
30. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
Other Exclusions 
31. Are pregnant or breastfeeding. 
32. Have known or suspected hypersensitivity reactions or intolerance to study drug or to any 
of the excipients (e.g., lactose), unless deemed appropriate by the investigator. 
5.3. 
Lifestyle Considerations  
Participants should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to their effect on cytochrome P450 (CYP)3A4. 
5.4. 
Screen Failures  
Screen failures are defined as patients who consent to participate but are not subsequently 
randomized to a study treatment due to inability to complete or meet the participation criteria 
(Sections 5.1 and 5.2) within the 28-day baseline screening period. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demographics, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
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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. Each time rescreening is performed, the patient must 
sign a new ICF and will be assigned a new identification number. All required tests (see SoA, 
Section 1.3) must be repeated for patients who are rescreened in a new 28-day baseline 
screening, unless approved by the Sponsor CRP/CRS. 
If initial laboratory screening result did not meet eligibility criteria, for example absolute 
neutrophil count (ANC) was too low, then the test can be repeated within the 28-day screening 
period to confirm eligibility without being considered a screening fail. 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. 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention of 
a Participant  
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any medicinal product(s) intended to be administered to or used 
by a study participant according to the study protocol.  
6.1. 
Study Intervention(s) Administered  
 
Arm A 
Arm B 
Treatment 
Abemaciclib 
Fulvestrant 
Placebo 
Fulvestrant 
Dose 
150 mg 
500 mg 
Matched to 
abemaciclib 
500 mg 
Route 
PO 
IM 
PO 
IM 
Schedule 
BID on Days 1-28 of 
each cycle 
C1D1 and C1D15, 
then on Day 1 of 
Cycle 2 and 
subsequent cycles 
BID on Days 1-28 of 
each cycle 
C1D1 and C1D15, 
then on Day 1 of 
Cycle 2 and 
subsequent cycles 
Authorized 
as defined 
by EU 
Clinical 
Trial 
Regulation 
Authorized and not 
used according to EU 
authorization 
Authorized and not 
used according to EU 
authorization 
Not authorized in EU 
Authorized and not 
used according to EU 
authorization 
Abbreviations: BID = twice daily; C = cycle; D = day; IM = intramuscular; mg = milligrams; PO = orally. 
 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Selection and Timing of Doses  
A cycle is defined as an interval of 28 days. The 28-day cycle length should be maintained 
throughout the treatment phase regardless of dose interruptions. Participants will begin dosing 
assigned treatment on C1D1. Every attempt should be made to maintain a 28-day +/- 7-day cycle 
for fulvestrant administration. When delays are required, doses should be resumed at earliest 
medically appropriate opportunity based on investigator judgment. Additional clinic visits may 
be required for administration. 
Treatment will continue until progression, unacceptable toxicity, or other discontinuation criteria 
are met (Section 7.1). 
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In addition to the perm itted protocol windows (see SoA, Section 1.3), a maximum of 7 days 
delay of a cycle start due to holiday, weekend, bad weather, or other unforeseen circumstances, 
but not due to AE, will be pe1mitted and not counted as a protocol deviation. In exceptional 
circumstances, a delay >7 days is permitted upon agreement between the investigator and the 
Sponsor CRP/CRS. Response assessments should remain on the original schedule (see SoA, 
Section 1.3). 
6.1.2. 
General Dosing Instructions 
Assignment to either abemaciclib (Am1 A) or placebo (Alm B) will be blinded to investigators and 
pa1ticipants. Blinded study drng will be administered at a sta1ting dose of 150 mg twice daily, and 
it is provided as 50 mg tablets. Blinded study drng should be taken twice daily (with at least 
approxinlately 6 horns separating doses) at the same tin1e each day with 6-8 ounces of water. 
Participants should be instrncted to swallow tablets whole and not chew or crnsh them. 
In rare circumstances, if an investigator clinically dete1mines and documents that it is in the best 
interest of the patient to sta1i at a dose of blinded study drng lower than 150 mg BID, the 
investigator may consult with the Sponsor CRP/CRS and request approval. If the initial reduced 
dose is tolerated, then subsequent dose escalation is encomaged and should be discussed with the 
Sponsor CRP/CRS for approval. 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only pa1ticipants emolled 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 (i.e., receipt, reconciliation, and 
final disposition records). 
4. Fmiher guidance and info1mation for the final disposition of unused study inte1ventions 
are provided in the Pharmacy Manual. 
Investigators should consult the study drng info1mation provided in the protocol, Investigator's 
Brochure, or label for the specific administration information (including warnings, precautions, 
contraindications, and adverse reactions). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomized at a ratio of 1: 1 to Alms A and B. Randomization will be 
stratified by the following 3 factors: 
• 
Geography (3 levels) 
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• 
Presence of visceral metastases (2 levels) 
o 
Yes, or 
o No 
• 
D 
. 
. 
.
. . 
Assignment to treatment groups will be detennined by a computer-generated random sequence 
using the IWRS. Upon obtaining informed consent, site personnel should access the IWRS, 
which will assign a patient number. Participants who meet all criteria for emollment will be 
randomly assigned to treatment. 
Arms A and B will be blinded to participants and investigators. 
The Sponsor will collect and store all tumor images throughout the study. An independent 
review of imaging measurements will be performed by an independent panel of radiologists. In 
addition, a secondary PFS analysis based on independent central review will be conducted. 
Participants randomized to the control group (Arm B) will not be permitted to cross over to the 
experimental group (Arm A). If a participant discontinues study treatment and knowledge of the 
participant's treatment assignment is deemed essential to the selection of the participant's next 
treatment regimen, the investigator may consult with the Sponsor CRP/CRS and request 
unblinding to guide further post-discontinuation therapies. There are no restrictions to post-
discontinuation therapy. 
Interim analyses for safety and efficacy/futility will be conducted under the guidance of an 
independent data monitoring committee (DMC). Refer to Section 10. 1.5 for additional details. 
For safety and efficacy/futility 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 actual treatment assignments. At the request 
of the Sponsor, the SAC may provide pooled summary reports to the Sponsor (for example, a 
summa1y of AEs across the study). These reports will not include treatment arms. 
Early access to PK Data 
To support timely exposure-response analyses, PK analyses will be conducted prior to the first 
efficacy interim analysis. Periodic transfers for review of data relevant to PK analyses, including 
dosing and bioanalytical results, will be performed. An early PK analysis will be performed 
when the majority of treated participants have completed their final PK sample collection visit, 
and prior to the first efficacy interim analysis. This early PK analysis will be performed by an 
independent team of PK analysts, and the results will not be shared with the study team until the 
trial is fully unblinded. Protocols will be in place to maintain the blind, including the use of 
• 
separate restricted data containers 
• 
aliased patient identifiers (IDs), and 
47 
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 datasets containing data required for population PK analysis only (specifically, no efficacy 
data). 
6.3.1. 
Emergency Unblinding  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Sponsor CRP/CRS prior to 
unblinding a participant’s treatment assignment unless this could delay emergency treatment of 
the participant. If a participant’s treatment assignment is unblinded, the Sponsor must be notified 
immediately. 
Emergency unblinding for AEs must be performed through the IWRS. This option may be used 
if the participant’s acute well-being requires knowledge of the participant’s treatment 
assignment. 
All calls resulting in an unblinding event are recorded and reported by the IWRS.  
If the investigator or participant becomes unblinded, that participant will be discontinued from 
study intervention and will undergo post-discontinuation follow-up. Long-term follow-up 
procedures will be followed until death, loss of follow-up, withdrawal of consent, or study 
completion. In cases in which there are ethical reasons for the participant to remain on the study 
intervention in the event of unblinding, the investigator must obtain specific approval from the 
Sponsor CRP/CRS for the participant to continue in the study. 
6.3.2. 
Inadvertent Unblinding  
Every effort will be made to blind both the participant and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a participant may occur. If an investigator, site 
personnel, or participant is inadvertently unblinded, the unblinding will not be sufficient cause 
for the participant to be discontinued from study intervention or excluded from study analyses. In 
cases in which there are ethical reasons for the participant to remain on the study intervention in 
the event of unblinding, the investigator must obtain specific approval from the Sponsor 
CRP/CRS for the participant to continue in the study. 
6.4. 
Study Intervention Compliance  
6.4.1. 
Blinded Study Drug  
The number of blinded study drug tablets dispensed to and returned by each participant must be 
maintained, reconciled, and recorded at each applicable clinic visit. Compliance will be assessed 
at each applicable clinic visit by direct questioning and counting of the returned tablets/capsules. 
These counts must be recorded in the source documents and CRF. 
From Cycle 1 Day 1 to Cycle 3 Day 1, participants will also complete a paper Patient Dosing 
Diary to record the exact time and date of study drug doses, which will be utilized in PK 
assessments. This paper diary is not intended to monitor compliance. 
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Start and stop dates, including dates for doses withheld, reductions, and/or re-escalations will be 
recorded in the CRF. 
A participant must take ≥75% of the planned doses to be deemed compliant. Similarly, 
participant may be considered noncompliant if he or she is judged by the investigator to have 
intentionally or repeatedly taken ≥125% of the planned doses of study drug in a cycle. 
6.4.2. 
Fulvestrant  
Fulvestrant will be administered under medical supervision by the investigator or designee. The 
investigative site will record the date, time, and dose in the source documents and CRF. The site 
will also record any dose adjustments and reason for adjustment. If the dose was not 
administered, the site will document the reason. 
6.5. 
Dose Modification  
In exceptional cases of planned delays (including but not limited to vacation or holidays), 
additional study drug may be dispensed. 
When treatment is delayed, if possible and appropriate, patients should resume within the same 
treatment cycle. If not possible, then every effort should be made to resume on the first day of 
the next scheduled cycle. In rare circumstances, if the participant has clinical benefit without 
disease progression and is recovering from toxicity, a delay of >28 days may be permitted. Such 
circumstances must be discussed with the Sponsor CRP/CRS. All dose modifications should be 
documented, including a clear rationale for the modification. 
Dose suspensions ≥28 days must be discussed with the Sponsor CRP/CRS. 
6.5.1. 
Blinded Study Drug  
Management of some adverse reactions may require dose interruption and/or dose reduction. 
When dose reduction is necessary, decrease the dose by 50 mg at a time. Discontinue blinded 
study drug for patients unable to tolerate 50 mg BID. If blinded study drug must be discontinued, 
a participant may continue to receive fulvestrant. 
Refer to the tables below for further details on dose modification and management. 
 Dose Reduction Guidelines 
Dose Adjustment 
Blinded Study Drug Dose  
Frequency 
Starting dose 
150 mg 
BID 
First dose reduction 
100 mg 
BID 
Second dose reduction 
50 mg 
BID 
Abbreviation: BID = twice a day. 
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6.5.1.1. 
Blinded Study Drug Dose Adjustments for Treatment-Emergent, Related* 
Adverse Events  
The table below provides guidance for the management of treatment-emergent, related (i.e., with 
reasonable causal relationship with blinded study drug) AEs. An investigator may use discretion 
and suspend or reduce doses without meeting one of the criteria below and this would not be 
considered a protocol deviation, though rationale should be documented. 
*Related means there is a reasonable causal relationship with blinded study drug. 
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 
Recurrent Grade 3, 
 or Grade 4 
Suspend until 
toxicity resolves to 
≤Grade 2 
Resume at next 
lower dose level 
Patient Requires Blood Cell Growth Factors 
 
Additional guidance for use of growth factors is in 
Section 6.8.1  
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, a 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 
or 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 6.8.3.  
Grade 1 
Not required 
Grade 2 that does 
not resolve to 
≤Grade 1 within 
24 hours  
Suspend until 
toxicity resolves to 
≤Grade 1 
Not required 
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Toxicity Type 
Severity 
Dose Suspension 
Dose Reduction 
Grade 2 that 
persists or recurs 
after resuming the 
same dose despite 
maximal supportive 
measures 
or Grade 3 or 4  
or Requires 
hospitalization 
Suspend until 
toxicity resolves to 
≤Grade 1 
Resume at next 
lower dose level 
ALT/AST Increased 
 
See Section 8.2.3 for additional guidance for 
hepatic monitoring and Section 8.2.3.1 for special 
hepatic safety data collection.  
Grade 1 or 2 
Not required 
Persistent or 
recurrent Grade 2,  
or Grade 3 
Suspend until 
toxicity resolves to 
baseline or Grade 1 
Resume at next 
lower dose level 
≥Grade 2 with total 
bilirubin >2×ULN, 
in the absence of 
cholestasis, 
or Grade 4 
Discontinue blinded study drug 
 
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 blinded study drug 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; 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 8 weeks (as measured from the stop date of the first event). As general guidance, for a 
participant who experiences a new episode of Grade 3 hematological toxicity more than 8 weeks from a previous 
episode of the same Grade 3 toxicity, the investigator may consider resuming the same dose if the participant 
satisfies the following conditions: 
 
stable hematological counts (Grade ≤2) during that time frame 
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 
absence of serious infections 
 
ongoing benefit 
6.5.1.2. 
Re-escalation Criteria for Blinded Study Drug  
If the blinded study drug dose is reduced for an 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 for ≥2 weeks, then the dose may be re-escalated to the prior dose 
level, at the discretion of the investigator and after consultation with the Sponsor CRP/CRS. Re-
escalation to the prior dose level will be permitted only once. After re-escalation, subsequent 
dose adjustments should be based on the dose that the patient is currently receiving. 
6.5.2. 
Fulvestrant  
Fulvestrant dose adjustments will be determined by the investigator in accordance with the 
approved product labels. Dose may be re-escalated at the discretion of the investigator and after 
consultation with the Sponsor CRP/CRS. 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. In the event that fulvestrant 
must be discontinued, a participant may continue to receive blinded study drug. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
After study completion (see Section 4.4), patients who are on study treatment and eligible for the 
continued-access period will be unblinded. 
Patients receiving study treatment and experiencing clinical benefit may continue to receive 
study treatment in the continued-access period until any of the criteria for discontinuation is met 
(Section 7). Placebo will no longer be administered. The continued-access period will apply only 
if at least 1 patient is receiving study intervention at study completion. 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. 
The continued-access period will begin after study completion and ends at the end of the study 
(Section 4.4). Continued-access follow-up will begin when the patient and the investigator agree 
to discontinue study treatment. Follow-up procedures will be performed as in the SoA (Section 
1.3). 
Patients 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 in long-term follow-up when the continued-access period begins will be discontinued 
from long-term follow-up. 
Investigators will perform standard procedures and tests. The choice and timing of the tests will 
be at the investigator’s discretion. The Sponsor will not routinely collect the results of these 
assessments. 
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6.7. 
Treatment of Overdose  
In case of overdose, use supportive therapy. There is no known antidote for abemaciclib 
overdose. 
In the event of an overdose, the investigator/treating physician should 
● 
contact the Medical Monitor immediately 
● 
evaluate the participant to determine, in consultation with the Sponsor CRP/CRS, 
whether study intervention should be interrupted or whether the dose should be 
reduced 
● 
closely monitor the participant for any AE/SAE and laboratory abnormalities 
● 
obtain a plasma sample for PK analysis following overdose if requested by the 
Medical Monitor (determined on a case-by-case basis), and 
● 
document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
6.8. 
Concomitant Therapy  
 Documentation of all premedications, supportive care, and concomitant medications must be 
captured at each visit in the eCRFs. Concomitant medications and supportive care therapies must 
also be documented at the time of discontinuation and at the 30-day short-term follow-up visit. 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine that the patient receives at enrollment, during the study, and after the 
last dose of study treatment at the short-term follow-up visit (see SoA, Section 1.3) must be 
recorded along with the 
 reason for use, and 
 dates of administration, including start and end dates. 
The Sponsor CRP/CRS should be contacted for any questions regarding concomitant or prior 
therapy. 
6.8.1. 
Palliative and Supportive Care  
Patients should receive supportive care to maximize quality of life as judged appropriated by the 
treating physician. If it is unclear whether a therapy should be regarded as supportive care, the 
investigator should consult the Sponsor CRP/CRS. Use of all supportive care therapy and 
concomitant medications should be captured in the eCRFs. 
Palliative radiation therapy is permitted for small areas of painful metastases that cannot be 
managed adequately using systemic or local analgesics after agreement of the Sponsor 
CRP/CRS. Such areas must not be a target lesion and must not 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. 
Use of granulocyte-colony stimulating factor, prophylactic antibiotics, erythropoietin, and blood 
product transfusions is allowed according to ASCO and ESMO guidelines (Rizzo et al. 2008; 
Crawford et al. 2009; Flowers et al. 2013; Smith et al. 2015)  
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6.8.2. 
Bisphosphonates and RANK-L Targeted Agents  
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, replacing bisphosphonate with denosumab, while on study treatment. 
However, exceptional cases without evidence of disease progression may be considered in 
consultation with the Sponsor CRP/CRS. These exceptional cases will not incur a protocol 
deviation. 
6.8.3. 
Supportive Management for Diarrhea  
It is important that all participants receive instructions for 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 begin antidiarrheal therapy (for 
example, loperamide) and communicate with site personnel for further instructions and 
follow-up. 
 Patients should also be encouraged to drink at least 64 ounces (approximately 2000 mL) 
fluids per day. 
 Site personnel should assess patient within 24 hours. 
 Follow dose-modification guidance for blinded study drug in Section 6.5.1.1, including 
dose suspension and/or reduction as appropriate. 
 For severe diarrhea, or diarrhea associated with 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. 
6.8.4. 
Concomitant Therapy  
The information in this section is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated. 
6.8.4.1. 
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 6, Section 10.6). This includes grapefruit or 
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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 blinded study drug 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 blinded study drug 
for the duration of the CYP3A inhibitor medication (see Section 6.5). 
Upon discontinuation of the strong CYP3A inhibitor, the dose of blinded study drug 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 blinded study drug dose 
requires review and approval from the Sponsor CRP/CRS. 
Inducers of CYP3A should be substituted or avoided if possible (Appendix 6, Section 10.6). 
Coadministration with a CYP3A inducer ≥28 days must be discussed with the Sponsor 
CRP/CRS. 
6.8.4.2. 
Transporter Substrates  
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. 
6.8.5. 
Medications and therapies not permitted  
With the exceptions listed in the sections below, therapies for cancer (including specifically 
aromatase inhibitors, anti-estrogens other than fulvestrant, chemotherapy, and immunotherapy) 
will not be permitted while patients are on study treatment. Use of megestrol acetate as an 
appetite stimulant is not permitted due to anti-estrogen effects. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will move into the post-discontinuation 
follow-up period. See the SoA for data to be collected and for any further evaluations that need 
to be completed. 
A participant should be permanently discontinued from study intervention if the participant or 
the participant’s designee requests to discontinue the study intervention 
In addition, participants will be discontinued from the study intervention in the following 
circumstances: 
 The participant becomes pregnant during the study. Refer to Section 8.3.2 for 
additional guidance. 
 The participant has evidence of progressive disease. 
 The participant experiences unacceptable toxicity. 
 The participant is significantly noncompliant with study procedures and/or treatment. 
 The investigator decides that the participant should be discontinued. 
 The participant, for any reason, requires treatment with another therapeutic agent with 
demonstrated efficacy for the study indication. Discontinuation from study 
intervention will occur prior to introduction of the new agent. 
 The participant enrolls in another clinical study judged not to be scientifically or 
medically compatible with this study. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study 
● at any time at his/her own request 
● at the request of his/her designee (for example, legal guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
When applicable, and if possible, an early discontinuation visit should be conducted. See SoA 
for data to be collected and any further evaluations that need to be completed. The participant 
will be permanently discontinued from all study interventions and the study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and that samples 
be not tested. The investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
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expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were unable to be followed. 
Within legal and ethical boundaries, study site personnel or an independent third party will 
attempt to collect the survival status for all randomized participants who are lost to follow-up, 
including those who do not receive study treatment. Public sources may be searched for survival 
status information. The survival status will be documented, and the participant will not be 
considered lost to follow-up if survival status is determined. 
Sponsor personnel will not be involved in any attempts to collect survival status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
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8. 
Study Assessments and Procedures  
● Study procedures and their timing are summarized in the SoA. 
● Immediate safety concerns should be discussed with the Sponsor 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. 
● All screening evaluations must be completed and reviewed to confirm that 
participants meet eligibility criteria. The investigator will maintain a screening log 
to record details and to confirm eligibility or reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments  
8.1.1. 
Efficacy Assessments at Baseline and during Study Treatment  
Imaging studies (CT, including spiral CT, or MRI scan of the chest, abdomen, and pelvis) will be 
performed locally per the SoA (Section 1.3). It is recommended that whenever possible, CT 
imaging of the abdomen and pelvis be performed with IV contrast. For patients with CT contrast 
hypersensitivity, a CT scan of the chest without contrast and gadolinium-enhanced MRI of the 
abdomen are encouraged. The CT portion of a PET-CT may be used for response assessment if 
the site can document that the CT is of identical quality to a diagnostic CT (with IV and oral 
contrast). A PET scan alone, or as part of a PET-CT, cannot be used to assess response according 
to RECIST v1.1. 
Bone scintigraphy will be performed at baseline and repeated per the SoA (Section 1.3). Bone 
scans should be repeated for suspicion of either a CR in target disease or bone progression. For 
patients with new lesions on post-baseline bone scintigraphy, targeted assessment by X-ray, CT 
scan with bone windows, or MRI should be performed to confirm findings. 
For patients with treated brain metastases, brain MRI with contrast is preferred; however, if 
contraindicated, then MRI without contrast or a CT with/without contrast is acceptable. Imaging 
should be performed at the RECIST response assessment intervals per the SoA (Section 1.3). 
For patients with RECIST non-measurable bone-only disease and lesions identified on baseline 
bone scintigraphy that are not visible on the chest, abdomen/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 per the SoA (Section 1.3). 
For patients with locoregionally recurrent breast cancer not amenable to curative treatment, 
breast MRI will be performed per the SoA (Section 1.3). 
For patients with visible tumor (such as skin lesions), photography will be performed. Each 
image of the tumor should include a ruler, patient identification, and the date. Photography 
should be performed per the SoA (Section 1.3). New skin lesions should be photographed. 
For patients in the continued-access period (after study completion), efficacy assessments 
(frequency and type) will be at the discretion of the investigator. 
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8.1.2. 
Efficacy Assessments during Post-Discontinuation Follow-Up  
Post-discontinuation follow-up is described in the SoA (Section 1.3). For randomized patients 
who never received study treatment or those who discontinued without objectively measured PD, 
the investigative sites will continue to monitor patients. Tumor response should be assessed 
approximately every 8 weeks for 12 months relative to Cycle 1 Day 1 and thereafter 
approximately every 12 weeks until the patient has objective disease progression, death, or study 
completion. In addition, anticancer therapies initiated after study treatment discontinuation will 
be collected during this follow-up period. 
After the patient experiences first objective disease progression, radiologic imaging and 
photographic images are no longer required. The patient will be followed approximately every 
12 weeks until the death or overall study completion. The Sponsor will continue to collect 
survival data on all patients but may reduce data collection for other efficacy data. Sponsor will 
notify investigators when reduced data collection can begin. 
8.1.3. 
Primary Efficacy Measure  
Response Evaluation Criteria in Solid Tumors v1.1 (Eisenhauer et al. 2009) will be applied for 
tumor response and progression. The method used at baseline must be consistent throughout the 
study. Local imaging (investigator assessment with site radiological reading) will be used. 
Sponsor, or its designee, will collect and store tumor assessment images to permit a blinded 
independent central review. Please see the Site Imaging Manual for guidelines on how imaging 
studies should be performed. 
For patients with non-measurable, bone-only disease (refer to Inclusion Criterion [5]), objective 
progression will be established if at least 1 of the following criteria is met: 
 the appearance of 1 or more new lesions (in or outside of bone), or 
 unequivocal progression of existing bone lesion(s). 
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 9.4.2 for definitions of the efficacy endpoints. 
8.2. 
Safety Assessments  
8.2.1. 
Clinical Safety Laboratory Tests  
 See Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency. 
 The investigator must review the laboratory results, document this review, and 
report any relevant changes as an AE. 
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 The laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. 
 Significant abnormal laboratory findings are those which are not associated with 
the underlying disease or are judged by the investigator to be more severe than 
expected for the participant’s condition. 
 Until the completion of V801 (inclusive of this visit), all abnormal laboratory 
tests considered significant should be repeated until the values return to normal, 
baseline, or are no longer considered clinically significant by the investigator or 
the Medical Monitor. 
○ If such values do not return to normal/baseline within a period of time, the 
etiology should be investigated, and the Sponsor notified. 
○ All required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA, standard collection requirements, and 
the laboratory manual. 
 If laboratory values from non-protocol specified assessments performed at a local 
laboratory require a change in participant management or are considered 
significant by the investigator (e.g., SAE or AE or dose modification), then this 
should be reported as an AE. 
8.2.2. 
Pregnancy Testing  
Perform pregnancy testing per the SoA (Section 1.3). 
8.2.3. 
Hepatic Safety Monitoring  
Close hepatic monitoring and evaluation 
Liver testing (Section 10.5, Appendix 5), including ALT, AST, ALP, TBL, D. Bil, GGT, and 
CK, should be repeated within 2 to 4 days to confirm the abnormality and to determine if it is 
increasing or decreasing, if one or more of these conditions occur: 
If a participant with baseline 
results of... 
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥5x ULN or 
ALT or AST ≥3x ULN concurrent with TBL ≥2x 
ULN 
ALT or AST ≥1.5x ULN 
ALT or AST ≥3x baseline or 
ALT or AST ≥2x baseline concurrent with TBL ≥2x 
ULN 
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, evaluation should include physical 
examination, a thorough medical history that includes symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), history of concomitant medications 
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(including over-the-counter, herbal, and dietary supplements), and history of alcohol drinking 
and/or 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 CRP/CRS, including tests for hepatitis D virus (HDV), 
cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, acetaminophen 
protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl 
glucuronide, and blood phosphatidylethanol. Based on the circumstances and the investigator’s 
assessment of the participant’s clinical condition, the investigator should consider referring the 
participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, and/or a liver biopsy. 
8.2.3.1. 
Additional Hepatic Safety Data Collection  
Additional safety data should be collected via the CRF if any of the following conditions occur: 
In participants enrolled with baseline ALT or AST <1.5x ULN 
 Elevation of serum ALT or AST to ≥5x ULN on 2 or more consecutive tests 
 The combination of elevated ALT or AST ≥3x ULN and elevated TBL ≥2x 
ULN 
In participants enrolled with baseline ALT or AST ≥1.5x ULN 
 Elevated ALT or AST ≥3x baseline on 2 or more consecutive tests 
 The combination of elevated ALT or AST ≥2x baseline and elevated TBL ≥2x 
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 an SAE 
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. 
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Blinded study drug dose adjustment should follow the protocol guidance for non-hematological 
toxicities in Section 6.5.1. 
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 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 6.5.1 for guidance on dose adjustments of 
blinded study drug 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 6.5.1 
for guidance on dose adjustments or discontinuation of blinded study drug for patients with 
ILD/pneumonitis. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Product complaints (PCs) 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
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After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.4) 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 
Appendix 3, Section 10.3. 
SAEs, including death, caused by disease progression or otherwise due to study disease should 
not be reported unless the investigator deems them to be possibly related to study treatment.
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8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Cycles/Visits Impacted 
Collection Start 
Collection Stop 
Timing for Reporting 
to Sponsor or Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
 
Adverse Event 
All AEs 
 Baseline (Pretreatment) 
 Cycle 1–Cycle XX (Treatment Period) 
 V801 (Short-Term Follow-Up Period) 
 V501–V5XX (Continued-Access Period) 
 V901 (Continued-Access Follow-Up Period) 
Signing of the ICF 
End of 30-day short-
term post-
discontinuation 
follow-up 
As soon as possible 
upon site awareness 
AE eCRF 
N/A 
 
Serious Adverse Event* 
SAE and SAE updates – prior 
to start of study intervention 
and deemed reasonably 
possibly related to study 
procedures 
Baseline (Pretreatment) 
Signing of the ICF 
Start of intervention 
Within 24 hours of 
awareness 
SAE eCRF 
SAE paper 
form 
All SAE and SAE updates – 
after start of study intervention 
 Cycle 1–Cycle XX (Treatment Period) 
 V801 (Short-Term Follow-Up Period) 
 V501–V5XX (Continued-Access Period) 
 V901 (Continued-Access Follow-Up Period) 
Start of intervention 
End of short-term 
follow-up 
Within 24 hours of 
awareness 
SAE eCRF 
SAE paper 
form 
All SAEs related to protocol 
procedures or study treatment 
and SAE updates 
V802–V8XX (Long-Term Follow-Up) 
Start of long-term 
follow-up 
After participant’s 
study participation 
has ended (that is, no 
longer receiving 
study treatment and 
no longer in follow-
up) 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
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Event 
Cycles/Visits Impacted 
Collection Start 
Collection Stop 
Timing for Reporting 
to Sponsor or Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
SAEs related to protocol 
procedures or study treatment – 
after participant’s study 
participation has ended and the 
investigator becomes aware 
N/A 
After participant’s 
study participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
 
Pregnancy 
Pregnancy in female 
participants and female partners 
of male participants 
 Cycle 1–Cycle XX (Treatment Period) 
 V801 (Short-Term Follow-Up Period) 
 V501–V5XX (Continued-Access Period) 
 V901 (Continued-Access Follow-Up Period) 
After the start of 
study intervention 
1 week after last dose 
(see Section 8.3.2 for 
pregnancy outcome 
follow-up guidance) 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
SAE paper 
form 
 
Product Complaints 
PC associated with an SAE or 
might have led to an SAE 
 Cycle 1–Cycle XX (Treatment Period) 
 V801 (Short-Term Follow-Up Period) 
 V501–V5XX (Continued-Access Period) 
 V901 (Continued-Access Follow-Up Period) 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
Product Complaint 
form 
N/A 
PC not associated with an SAE 
 Cycle 1–Cycle XX (Treatment Period) 
 V801 (Short-Term Follow-Up Period) 
 V501–V5XX (Continued-Access Period) 
 V901 (Continued-Access Follow-Up Period) 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC information 
N/A 
N/A 
N/A 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator 
N/A 
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Event 
Cycles/Visits Impacted 
Collection Start 
Collection Stop 
Timing for Reporting 
to Sponsor or Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
PC (if investigator becomes 
aware) 
N/A 
Participation in 
study has ended 
N/A 
Promptly 
Product Complaint 
form 
N/A 
Abbreviations: AE = adverse event; CRF = case report form; eCRF = electronic case report form; ICF = informed consent form; PC = product complaint; SAE = 
serious adverse event. 
*Serious adverse events (including death) caused by disease progression or otherwise due to study disease should not be reported unless the investigator deems 
them to be possibly related to study treatment or study participation.
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8.3.2. 
Pregnancy  
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 
intervention. 
● 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 gestational age, 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 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 gestational age, fetal 
status (presence or absence of anomalies), or indication for the procedure. 
● 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 8.3.1. 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. 
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● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
Prior to continuation of study intervention following pregnancy, the following must occur: 
● The Sponsor and the relevant IRB/IEC give written approval. 
● The participant gives signed informed consent. 
● The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.3. 
Events or Outcomes  
Not applicable. 
8.3.4. Adverse Events of Special Interest  
Adverse events of special interest for abemaciclib include 
 neutropenia 
 infections 
 diarrhea 
 hepatic events, including increases in AST/ALT 
 VTEs, and 
 ILD/pneumonitis. 
No AEs need to be adjudicated. 
Section 6.8.1 describes supportive care measures for each abemaciclib AESI. Sections 6.5.1.1 
and 6.5.1.2 present the dose-modification guidelines for abemaciclib AESIs. 
Contact the Sponsor CRP/CRS if questions arise concerning AESIs. 
8.4. 
Pharmacokinetics  
Pharmacokinetic samples will be collected from study participants at the visits and times 
specified in the SoA (Section 1.3.2). At all PK timepoints, a volumetric absorptive 
microsampling device will be used to collect a blood sample by capillary puncture. In addition, 
on Cycle 1 Day 1 and Cycle 3 Day 1, a PK sample will also be collected at approximately the 
same time (within [+/-] 10 minutes) as the blood microsample via venous puncture collection 
into a vacutainer. It is important to collect accurate information for the time and date of each PK 
sample on the lab requisition form. 
It is also important to collection accurate information for the time and date of doses of blinded 
study drug around the PK sampling collection times. Accordingly, during the PK sampling 
period (Cycle 1 Day 1 to Cycle 3 Day 1), participants will complete a paper Patient Dosing Diary 
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to record the time and date of blinded study drng doses, which will be utilized in PK 
assessments. The infmmation in this diary should be collected and reviewed on Day 1 of Cycle 2 
and Cycle 3 for each prior cycle and be documented in the eCRF. This paper diary is not 
intended to monitor compliance. 
Pha1macokinetic samples will be analyzed at a laboratory approved by the Sponsor and stored at 
a facility designated by the Sponsor. Concentrations of abemaciclib and its metabolites, M2 and 
M20, will be determined using validated liquid chromatography with tandem mass spectrometry 
methods. 
Pharmacokinetic samples may be retained for a maximum of 1 year following last subject visit 
for the study. 
A maximum of 3 samples may be collected at additional time points during the study if 
warnnted and agreed upon between both the investigator and Sponsor. Instrnctions 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 sample will be recorded. 
8.5. 
Pharmacodynamics 
Pha1macodynalnic parameters are not evaluated in this study. 
8.6. 
Genetics 
A ge1mline DNA sample that can be used for genetic research will originate from the whole-
blood sample collected in Section 8.7.3 for biomarker research. 
Regardless of the technology utilized, data generated will be used only for the specific 
genetic research scope described in this section, and within the limits of this protocol. 
Genetic research may lead to the identification of genetic incidental findings. Genetic incidental 
findings are variations present in germline DNA that are discovered unintentionally and that may 
nonetheless be of medical value or utility to the physician and the patient. The methods used in 
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this study to perfmm genetic research are not clinically validated to detect germ.line variants, and 
therefore, no clinical conclusions can be derived from them. As such, subject to local regulations, 
no incidental findings will be reported to the patients paiticipating in genetic research. 
Genetic samples will be coded with the participant number. These samples and any data 
generated can be linked back to the participant only by the study site personnel. Samples will be 
retained for a maximum of 7 years after the last pa1ticipant visit for the study, or for a shmter 
period if local regulations and/or ERBs/IRBs in1pose shmter time limits, at a facility selected by 
the Sponsor or its designee. This retention period enables use of new technologies, response to 
questions from regulatory agencies, and investigation ofvai·iable response that may not be 
observed until later in the development of study treatment becomes commercially available. 
Technologies are expected to improve during the 7-year storage period and, therefore, cannot be 
specifically named. Regardless of the technology utilized, data generated will be used only for 
the specific genetic reseai·ch scope described in this section, and within the limits of this 
protocol. 
8. 7. 
Bio markers 
This study will analyze biomai·kers relevant to study intervention, mechanism of action, the 
variable response to study drng(s) (including evaluation of AEs or differences in efficacy), cell 
cycle, immune function, or pathways associated with breast cancer. Samples collected will 
enable examination of these questions through the measurement of biomolecules, including 
DNA, RNA, proteins, lipids, and other circulating or cellular elements. Except for the cases 
detailed in Sections 8.7.1 (ctDNA sequencing without patient-matched germ.line subtraction) and 
8.7.2 (tumor DNA sequencing without patient-matched germ.line subtraction), biomarker 
analyses will not produce interpretable results on germ.line DNA and therefore will not lead to 
the identification of genetic incidental findings as described in Section 8.6. Biomarker analyses 
using DNA as a substrate will generate interpretable infmmation on tumor somatic vai·iants, 
tumor somatic copy number changes and tumor somatic reanangements. Biomarker analyses 
using RNA as substrate will avoid the identification of genetic variants and will focus on 
quantifying gene expression and repo1ting tumor somatic gene fusions and other tumor somatic 
reanangements. Biomai-ker analysis results may occur after the CSR is written and therefore a 
separate biomarker Data Analysis Plan will be developed. 
Biomarker samples will include 
Samples for 
biomarker research will be collected from all participants as specified in the SoA (Section 1.3), 
where local regulations allow. It is possible that biomarker data for paiticipants in the study have 
ah-eady been generated from samples that were collected and analyzed prior to emolling in this 
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trial. 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 .1 and 8. 7. 2. 
Additional analyses within the specific research scope described in this section may be 
conducted if it is hypothesized that this may help fmther understand the clinical data. Samples 
may be used to develop related research methods or to validate diagnostic tools or assays, but 
only within the specific research scope described in this protocol. The samples may be analyzed 
as pa11 of a multi-study assessment of non-genetic factors involved in the response to study 
intervention or study inte1ventions of this class, and/or to understand study disease or related 
conditions, within the scope described in this protocol. 
A maximum of 3 samples may be collected at additional time points during the study if 
wananted and agreed upon by the investigator and Sponsor. 
All samples will be coded with the pai1icipant number. These samples and any data generated 
can be linked back to the participant only by the study site personnel. Samples will be retained 
for a maximl1111 of 7 years after the last participant visit for the study, or for a sh011er period if 
local regulations and/or ERBs/IRBs impose sh011er time limits, at a facility selected by the 
Sponsor or its designee. This retention period enables use of new technologies, response to 
questions from regulatory agencies, and investigation of vai·iable response that may not be 
obse1ved until later in the development of study treatment or after study treatment becomes 
coI11111ercially available. Technologies ai·e expected to improve during the 7-year storage period, 
and therefore, cannot be specifically named. Regardless of the technology utilized, data 
generated will be used only for the specific biomarker research scope described in this section, 
and within the limits of this protocol. 
8.7.1. 
Samples for Biomarker Research 
samples for biomarker research will be collected from all pa11icipants as 
specified in the SoA (Section 1.3) where local regulations allow. 
subject will originate from DNA extracted from whole blood as described in Section 8.7.3. 
Review of gennline DNA sequencing results may be conducted, but only for data quality control 
purposes. At no point in this process will ge1m line DNA variants be analyzed and interpreted by 
the research personnel. As such, -
analysis with gennline DNA subtraction will not 
produce interpretable results on ge1m line DNA, is not considered genetic research, and therefore, 
will not lead to the identification of genetic incidental findings as described in Section 8.6. 
-
analysis may also be pe1fo1med without ge1m line DNA subtraction. In this case, it may 
be considered genetic research and the identification of genetic incidental findings is possible. 
Regardless of whether patient-matched ge1mline DNA subtraction is used or not during the 
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-
analysis, the methods used in this study for biomarker analyses are not clinically 
validated to detect germline variants, and therefore, no clinical conclusions can be derived from 
them. As such, no incidental findings will be reported to the patients participating in biomarker 
research, subject to local regulations. 
8.7.2. 
Tissue Samples for Biomarker Research 
Submission of an archival tumor specimen is required, if tissue is available, subject to local 
regulations. Fo1malin-fixed paraffin-embedded tissue, if available, should be provided as a block 
(prefened) or freshly cut unstained slides. Due diligence should be used to make sure that tumor 
sample (not a n01mal adjacent or a tumor margin sample) is provided. 
A biopsy at baseline, as well as at the time of disease progression, is requested, if clinically 
feasible, per investigator's discretion and subject to participant's consent. Biopsy of a 
progressing metastatic lesion is prefen ed whenever possible. Bone biopsies are not prefened but 
are acceptable. 
Pathology report accompanying tumor tissue will be requested. Pathology rep01is must be coded 
with the pariicipant number. Personal identifiers, including the participant's name and initials, 
must be removed from the institutional pathology repo1i prior to submission. Archival blocks 
will be sectioned. Sponsor has a right to retain a po1tion of the submitted tissue, and archival 
blocks may be returned to the study site, upon request. Tissue blocks from biopsies collected at 
baseline/disease progression may be returned to sites if there is available tissue left over, upon 
request. 
Various non-genetic biomarkers with potential prognostic or predictive value for the treatment of 
breast cancer with study treatment are cmTently under investigation and may be assessed in this 
study_ 
Tumor DNA analysis (whole exome or panel DNA sequencing) may be performed with patient-
matched germline DNA subtraction. Ge1mline DNA for each subject will originate from DNA 
extracted from whole blood as described in Section 8.7.3. Review of ge1mline DNA sequencing 
results may be conducted, but only for data quality control purposes. At no point in this process 
will germline DNA variants be analyzed and interpreted by the research personnel. As such, 
tumor DNA analysis with germline DNA subtraction will not produce interpretable results on 
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gennline DNA, is not considered genetic research, and therefore, will not lead to the 
identification of genetic incidental findings as described in Section 8.6. 
Tumor DNA analysis may also be perfmmed without geimline DNA subtraction. In this case, it 
may be considered genetic research and the identification of genetic incidental findings is 
possible. Regardless of whether patient-matched geimline DNA subtraction is used or not during 
the tumor DNA analysis, the methods used in this study for biomarker analyses are not clinically 
validated to detect ge1mline variants, and therefore, no clinical conclusions can be derived from 
them. As such, no incidental findings will be repoited to the patients participating in biomarker 
research, subject to local regulations. 
Tumor RNA sequencing analyses quantitate tissue mRNA expression levels, repoit gene fusions, 
splice variants, and other somatic reanangements, and do not detect gemtline variants. 
Therefore, these analyses are not considered genetic research and no genetic incidental findings 
as described in Section 8.6 will be identified. 
8.7.3. 
Whole-Blood Sample for Biomarker Research 
A whole-blood sample for biomarker research will be collected from all paiticipants as specified 
in the SoA (Section 1.3), where local regulations allow. 
This whole-blood DNA sample will be used to obtain geimline DNA that may also be utilized 
for genetic research as described in Section 8.6. 
8.8. 
Immunogenicity Assessments 
Not applicable. 
8.9. 
Health Economics and Medical Resource Utilization 
Patient-repoited questionnaires will be administered using a provisioned electronic patient-
repoited outcome (ePRO) device in countiies where the questionnaires have been translated into 
the native language and linguistically validated. Only patients that are literate in an available 
translation will complete the questionnaires. Questionnaires will be administered on the device in 
the order presented below. The device will use an alaim feature to reinind the 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 the event that a device does 
not work properly, the site will follow the Initigation plan specified in the eCOA operations 
manual for collecting this data. 
Patient-repo1ted outcomes (PRO) will be used to compare changes in cancer-related symptoms, 
physical function, adverse effect of dianhea, and other health-related quality of life (HRQoL) 
outcomes between treatment aims. Data from the EQ-5D-5L will be used to generate health 
utility data by treatment aim. See Section 1. 3 .1 for PRO So A. 
Patients will receive the ePRO device at ClDl. All baseline assessment PRO questionnaires will 
be adininistered electronically on ClDl prior to extensive interaction with site staff and study 
drng administration. "Worst pain" as a single item is an exception and not adininistered at ClDl 
baseline since it is also pait of the mBPI-SF scale. EORTC IL-19 is also an exception and not 
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administered at baseline due to overlapping questions with EORTC QLQ-C30. Subsequent 
assessments, apait from the SFU visit, will be completed at home according to the SoA (Section 
1.3.1) to minimize required activities during clinic visits. At the SFU visit, patients will complete 
the specified assessments on the patient's ePRO device on site; therefore, patients will be asked 
to bring their device with them this SFU visit. 
Estimated completion time is 5-8 minutes for the PRO items collected on a monthly schedule. 
8.9.1. 
Worst Pain NRS Item Extracted from the BPI-SF 
The patient-repmted mBPI-SF "Worst Pain Single Item" is a single-item, 11-point numeric 
rating scale (NRS) scale anchored at O and 10, with O representing "no pain" and 10 representing 
"pain as bad as you can imagine." This "Worst Pain Single Item" is also included in the mBPI-
SF 11-item scale described in Section 8.9.2, and patients will complete either the single item or 
the scale, but not both on the same day 
sites will not administer this instrument. The 
assessments for 
mBPI-SF "Worst Pain Single Item" will be collected during the study period as described in 
Section 1.3.1. 
8.9.2. 
Modified BPI-SF Scale 
The mBPI-SF (Cleeland 1991) is an 11-item instrument used as a multiple-item measure of pain 
intensity and its impact on daily function (i.e., pain interference). In addition to pain intensity (4 
items: "worst pain", "least pain", "average pain", "pain now"), the mBPI-SF is designed for 
patients to record pain interference with function (7 pain interference items: general activity, 
mood, ability to walk, ability to perfmm nmmal work, relations with others, sleep, and 
enjoyment of life). Responses for the mBPI-SF items ai·e captured through the use of 11-point 
NRS anchored at O (no pain or does not interfere) and range through 10 (pain as bad as you can 
imagine or completely interferes). 
8.9.3. 
PRO-CTCAE-Dianhea 
The PRO-CTCAE is a measurement system developed by the National Cancer Institute to collect 
symptomatic AE data from patients with cancer emolled in clinical tr-ials (Basch et al. 2014; 
Dueck et al. 2015). The PRO-CTCAE item libra1y (Version 1.0) includes 78 symptomatic AE 
and a total of 124 items; some AEs include multiple items (e.g., frequency (F), severity (S), 
interference (I), and presence/absence (P) [NCI 2017). These items were developed to assess 
symptomatic AEs from the patient perspective and complement the CTCAE data collected at the 
site level (Basch et al. 2014; Atkinson et al. 2016). 
A single question from the PRO-CTCAE item library was selected to characterize dianhea (F). I 
8.9.4. 
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 and available in over 80 different languages, 
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EORTC QLQ-C30 is a reliable and validated tool that has supported quality-of-life claims in 
both Food and Drng Administration and European Medicines Evaluation Agency labels. 
The full EORTC QLQ-C30 self-repmted general cancer instrument consists of 30 items covering 
3 dimensions regarding the patient's experience during the past week: 
• 
global health status/quality oflife (2 items) 
• 
functional scales - 15 total items addressing either physical (described in EORTC IL-19 
below), role (limited in daily activities, limited in hobbies or leisure), emotional (feel 
tense, wony, ini table, depressed), cognitive (concentrating, remembering), or social 
functioning (interference with family life, interference with social activities), and 
• 
symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diaIThea, or financial impact). 
Patients select one of four response options for each EORTC functional and symptom item: "Not 
at All", "A little", "Quite a bit" and "Ve1y much". EORTC global health status and quality of life 
items include seven numeric response options: 1 ("Very poor") up to 7 ("Excellent"). 
Beginning ClDl, patients will complete the EORTC QLQ-C30 assessment using the ePRO 
device 
8.9.5. 
EORTC IL-19 
The EORTC IL-19 consists of 5 items that are identical to the EORTC QLQ-C30 physical 
functioning scale (Items 1-5: trouble with "doing strenuous activities", "taking a long walk", 
"taking a shmt walk"; "need to stay in bed or chair most of the day", "need help eating, dressing, 
washing, using the toilet"). This assessment will be completed by patients at home on an ePRO 
device on an 
schedule as described in Section 1.3.1. To minimize patient burden, 
the 
8.9.6. 
EQ-5D-SL 
Health status will be assessed using the EQ-5D-5L (Pickard et al. 2007; Janssen et al. 2008; 
Herdman et al. 2011 ). These utility measures are an impmtant 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 health you can imagine) to O (worst 
health you can imagine). The EQ-5D-5L is designed for self-completion by respondents, is 
cognitively simple, takes only a few minutes to complete, with a recall peri od of "today," and 
will be completed by patient using an electronic device, 
according to described in 
Section 1.3.1. 
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8.9.7. 
Health Care Resource Utilization  
For all participants throughout the study, the investigator and study site personnel will collect 
data about health care resource utilization (HCRU) associated with medical encounters and 
analgesic use. 
The data collected in the CRF, starting at C1D1, up to and including SFU will 
 include the reasons and duration of hospitalizations and emergency room visits, and 
 include analgesic use. 
The Sponsor may use the collected data to conduct economic analyses. 
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9. 
Statistical Considerations 
Statistical analysis of this study will be the responsibility of the 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 statistical analysis plan (SAP) and the CSR. Additional explorat01y analyses of the data 
will be conducted as deemed appropriate. 
The SAP will be finalized prior to first visit when a pa1ticipant receives study drng or any other 
protocol inte1vention and will include a more technical and detailed description of the statistical 
analyses desclibed in this section. 
9.1. 
Statistical Hypotheses 
Primary Hypothesis (Arm A versus Arm B): Treatment of participants with 
advanced/metastatic HR+, HER2- breast cancer with abemaciclib in combination with 
fulvestrant after prior treatment with CDK4 & 6 inhibitor-based regimen will provide a clinically 
meaningful increase in PFS over treatment with fulvestrant in combination with placebo. 
9.1.1. 
Multiplicity Adjustment 
9.2. 
Analyses Sets 
The populations for analysis are defined as follows. 
Population 
Desc1iption 
Entered 
All paiticipants who sign the ICF 
All pa1ticipants randomly assigned to study treatment, regardless of whether they take any 
ITT 
doses of study treatment, or if they take the conect treatment. Paiticipants will be analyzed 
according to the treatment group to which they were assigned 
Safety 
All pa1ticipants randomly assigned to study treatment and who take at least 1 dose of study 
treatment. Paiticipants will be analyzed according to the study treatment they actually received 
PK 
All paiticipants who have received at least I dose of abemaciclib, have at least I evaluable PK 
sample, and have sufficient dosing information 
Abbreviations: ICF = infonned consent fmm; ITT = intention to treat; PK = pha1macokinetics. 
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9.3. 
Statistical Analyses 
9.3.1. General Considerations 
Pa1iicipants will be randomized using the following stratification factors: 
• 
Presence of visceral metastases (2 levels) 
o Yes, or 
o No 
• 
Duration on prior adjuvant/metastatic CDK4 & 6 inhibitor-based regimen (2 levels): 
Any modifications or clarifications to the data analysis methods will be described and justified in 
the SAP before unblinding. 
The primary analysis of the primaiy endpoint of PFS is event driven and will be perfo1med when 
the required number of PFS events has been observed (for interim and final analyses). See 
Sections 9.4.2 and 9.5. All secondaiy endpoints will be evaluated at this time. Additional 
updated analyses of efficacy and safety may be conducted at later times if deemed approp1iate by 
the Sponsor. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the SAP, where appropriate. Adjustments to the planned analyses 
will be described in the final CSR. 
9.3.1.1. 
Treatment Group Considerations 
9.3.1.1.1. Participant disposition 
A detailed description of pa1iicipant disposition will be provided, according to CONSORT 
publishing requirements, including a summary of the number and percentage of pa1iicipants 
entered into the study, emolled in the study, and treated, as well as number and percentage of 
pa1iicipants completing the study, as defined in the SAP, or discontinuing prior to study 
completion ( overall and by reason for discontinuation). A summa1y of all impo1iant protocol 
deviations will be provided. 
9.3.1.1.2. Participant characteristics 
Demographic data are collected and repmied to demonstrate that the study population represents 
the target participant population considered for regulatmy approval. 
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A summaiy of baseline participant and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics. 
Other paiticipant baseline characteristics will be summarized by treatment ann as deemed 
appropriate. 
9.3.1.1.3. Concomitant therapy 
A summaiy of prior and concomitant medications by treatment will be reported. 
9.3.1.1.4. Treatment compliance 
Study treatment compliance will be assessed as the proport ion of treatment that is actually taken 
relative to what is expected, after accounting for protocol-defined dose adjustments. For oral 
components of study treatment, study treatment taken will be derived from the difference 
between the total number of pills dispensed and returned over the course of the participant's 
treatment. 
9.3.1.1.5. Extent of exposure 
The duration on therapy, dose omissions, dose reductions, dose delays, and dose intensity for 
each drng will be summarized for all treated participants by treatment aim. 
9.3.1.1. 6. Post-discontinuation treatment therapy 
The numbers and percentages of participants receiving post-discontinuation anticancer therapies 
will be provided by type of therapy (surgery, radiotherapy, or systemic therapy), and by dtug 
class and/or name, overall, and by line of therapy. Post-study treatment therapy will be 
summarized by treatment arm. 
9.3.2. 
Primary Endpoint/Estimand Analysis 
The primary endpoint, PFS by investigator assessment, is defined as the time 
from randomization until the first occun ence of documented disease progression as determined 
by investigator assessment per RECIST 1.1, or death from any cause in the absence of 
documented progressive disease. Paiticipants known to be alive and without disease progression 
will be censored at the time of the last adequate tumor assessment (a detailed PFS 
event/censoring scheme will be provided in the SAP). PFS will be compared between treatment 
aim s using a stratified log-rank test, stratified by the randomization strata in the ITT 
population. The conesponding hazai·d ratio between treatment aim s will be estimated using a 
stratified Cox regression model (Cox 1972), stratified by randomization strata. PFS curves, 
median PFS, and PFS rates at various time points with 95% CI for each treatment aim will be 
estimated using the Kaplan-Meier method (Kaplan and Meier 1958). Sensitivity analyses for PFS 
will be described in the SAP. 
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9.3.3. 
Secondary Endpoint(s) Analysis  
9.3.3.1. 
Progression-Free Survival by Blinded Independent Central Review (PFS by 
BICR)  
A PFS analysis based on blinded independent central review data will be conducted. Details can 
be found in the Central Review SAP. 
9.3.3.2. 
Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit 
Rate (CBR)  
Objective response rate (ORR) is defined as the number of participants who achieve a best 
overall response (BOR) of complete response (CR) or partial response (PR) divided by the total 
number of participants randomized to the corresponding treatment arm. Confirmation of CR and 
PR is not required. 
Disease control rate (DCR) is defined as the number of participants who achieve a BOR of CR, 
PR, or SD divided by the total number of participants randomized to the corresponding treatment 
arm (ITT population). Confirmation of CR and PR is not required. 
Clinical benefit rate (CBR) is defined as the number of participants who achieved a BOR of CR 
or PR, or SD ≥6 months, divided by the total number of participants randomized to the 
corresponding treatment arm (ITT population). Confirmation of CR and PR is not required. 
For each of these rates, point estimates and 95% confidence intervals (using the normal 
approximation to the binomial) will be calculated by treatment arm. Stratified tests comparing 
these rates between treatment arms will be conducted using the Cochran-Mantel-Haenszel test 
adjusting for the randomization strata. 
9.3.3.3. 
Duration of Response (DoR)  
Duration of response (DoR) is defined as the time from the date that measurement criteria for CR 
or PR (whichever is first recorded) are first met until the first date that disease is recurrent or 
documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from 
any cause in the absence of documented disease progression or recurrence. 
9.3.3.4. 
Overall Survival (OS)  
Overall survival (OS) is an important secondary endpoint for this study and 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 data analysis, OS data will be censored on the last date the patient is known to be alive. 
Further details concerning OS analyses can be found in the SAP. 
9.3.3.5. 
Health Outcomes  
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 worsening of worst pain will be summarized for each arm by the 
Kaplan-Meier method and will be compared between the 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 
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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. 
HCRU frequency counts of hospitalizations, emergency room visits, and analgesic use will be 
summarized descriptively for each arm. 
Full censoring rules for these endpoints will be described in the SAP. Further analysis details 
will be described in the SAP. 
9.3.4. 
Safety Analyses  
All participants in the safety analysis set in Section 9.3 will be evaluated for safety and toxicity.  
The most current version of the Medical Dictionary for Regulatory Activities (MedDRA®) will 
be used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term (LLT) will 
be used in the treatment-emergent computation.  Treatment-emergent adverse events will be 
summarized by System Organ Class (SOC) and by decreasing frequency of Preferred Term (PT) 
within SOC.   
Safety analyses will include summaries of the following:  
 
adverse events, including severity and possible relationship to study drug  
 
serious adverse events, including possible relationship to study drug  
 
adverse events leading to dose adjustments  
 
discontinuations from study treatment due to adverse events or death  
 
treatment-emergent abnormal changes in laboratory values   
 
treatment-emergent abnormal changes in vital signs and ECGs 
 The number of participants with any dose adjustment will be presented for entire treatment 
period as well as for each cycle. The number of participants with dose reductions, dose delays, or 
dose omissions will also be summarized, as will the reasons for dose adjustments. 
Preexisting conditions are defined as AEs that are either ongoing or end on or after informed 
consent. 
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation. 
9.3.5. 
Other Analyses  
A prespecified list of subgroups will be identified in the SAP. The treatment effect within each 
subgroup will be summarized. Other subgroup analyses not specified in the SAP may be 
performed as deemed appropriate. These subgroups will be based on important characteristics, 
for example, prognostic significance. 
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9.3.5.1. 
Exploratory Analyses 
9.3.5.2. 
Pha1·macokinetic and Exposure-Response Analyses 
Pha1macokinetic analyses will be conducted on all patients who have received 
• 
at least 1 dose of abemaciclib 
• 
at least 1 evaluable PK sample, and 
• 
sufficient dosing inf 01mation. 
Observed concentration data for each analyte will be graphically assessed and may also be 
summarized by time and/or dose. 
Population PK modeling approaches may also be used to compute mean PK parameters (for 
example, clearance, exposme, volume of distiibution) and interindividual PK variability. 
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9.4. 
Interim Analysis 
Only the DMC is authorized to evaluate unblinded interim efficacy/futility and safety analyses. 
Study sites will receive information about interim results only if they need to know for the safety 
of their participants. 
Unblinding details are specified in a separate blinding and unblinding plan document. 
9.4.1. 
Safety Interim Analyses 
The DMC will monitor the overall safety of the study. 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 emollment, and/or termination of study 
treatment. The recommendations of the DMC will be communicated to the Sponsor senior 
management designee (SMD). 
In the event that blinded safety monitoring by the study team 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 regulato1y reporting. 
There will be no prespecified mies for stopping the trial due to safety concerns. 
The DMC will meet and review the overall data approximately every 6 months thereafter while 
patients remain in the on-study intervention periods. At the recommendation of the DMC, the 
frequency of safety interim analyses may be modified. See Section 10.1.5 for further details. 
9.4.2. 
Efficacy/Futility Interim Analyses 
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HR 
Critical One-Sided 
Cumulative 
Cumulative Power 
Number 
Info1·mation 
Analysis 
boundary 
P-value Boundary 
Type I Errm· 
under Assumed 
of Events 
Fraction 
for Futility 
for Efficacy 
Rate 
HR of 0.7 
Inte1im 
• • - - -
PFS 
Final 
-
- - -
PFS 
Abbreviations: HR = hazard ratio; PFS = progression-free sw-vival. 
9.5. 
Sample Size Determination 
The study will randomize approximately 3 50 participants in 1: 1 randomization ratio, with 
approximately 175 pa1ticipants per treatment aim . 
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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 Good Clinical Practice (GCP) Guidelines 
○ 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. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
○ 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. 
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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. 
10.1.3. 
Informed Consent Process  
● The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions 
regarding the study. 
● Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the Sponsor 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. 
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● 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. 
 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. 
Committees Structure  
10.1.5.1. Data Monitoring Committee  
Interim analyses for safety and efficacy will be conducted, using unblinded data, under the 
guidance of an independent DMC. The DMC will consist of at least 3 members, including a 
chair, a physician, and a statistician. The DMC will communicate any recommendations based 
on interim analysis to the Sponsor. If necessary, the Sponsor may form an IRC to review and act 
upon the recommendations of the DMC. Details will be specified in a separate DMC charter. 
10.1.5.2. Early Safety Data Review  
● Participant safety will be continuously monitored by the external data monitoring committee, 
which includes safety signal detection at any time during the study. 
 In the event that blinded safety monitoring by the study team 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 
Sponsor’s representatives external to the study team may be required for evaluation of 
selected SAEs for determination of regulatory reporting. 
10.1.6. 
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 
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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, SAP, CSR, blank or annotated CRFs 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. 
10.1.7. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the Sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. This might include laboratory tests, 
medical records, and clinical notes. 
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
● Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These pre-
defined parameters will be monitored during the study, and important excursions 
from the QTLs and remedial actions taken will be summarized in the CSR. 
● 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 
(e.g., contract research organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
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● 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 (CTA) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
● In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by Sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the Sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, electronic Clinical Outcome Assessment (eCOA) data (participant-focused 
outcome instrument) will be directly recorded by the participant into an instrument (for example, 
handheld smart phone or tablet). 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 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. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports 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. 
10.1.8. 
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. 
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● Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study or Site Termination 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected, and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
For study termination: 
● 
Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the Sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the Sponsor, 
will participate as investigators in this clinical trial. 
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Sample Retention 
Sample retention 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 abemaciclib. 
Sample Type 
Custodian 
Retention Period after Last Patient Visit* 
ng-te1m storage samples Sponsor or Designee 
Sponsor or Designee 
haimacokinetics 
Sponsor or Designee 
Sponsor or Designee 
*Retention periods may differ locally. See Appendix 7, Section 10. 7 for country-specific differences from the above. 
The Sponsor has a right to retain a po1tion of submitted biopsy tissue. Archival blocks may be 
returned to the study site, upon request. Tissue blocks from biopsies collected at baseline/disease 
progression may be returned to sites if there is available tissue left over, upon request. 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
● The tests detailed in the table below will be performed by the central laboratory or 
by the local laboratory as indicated. 
● Local laboratory results are only required if the central laboratory results are not 
available in time for inclusion/exclusion determination, study intervention 
administration, and/or response evaluation. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time. 
o Discrepancies between local and central laboratory results that may impact 
eligibility or treatment decisions will not be considered protocol deviations. 
o If the local laboratory results are used to make either a study intervention 
decision or response evaluation, the local results must be recorded. 
o If there is an abnormal laboratory value or abnormal value for any other 
diagnostic or screening test (for example, increased blood pressure, 
neutrophils decreased, etc.) and it is known to be related to an existing 
diagnosis (for example, hypertension, neutropenia, etc.) this should be 
reported in the CRF as an AE. Do not enter the test abnormality; enter the 
disease, diagnosis, or categorical term. 
● In circumstances where the Sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations. 
● Protocol-specific requirements for participant inclusion and exclusion are detailed 
in Section 5. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Investigators must document their review of the laboratory safety results. 
 
 
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Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Sponsor-designated laboratory 
 
Hemoglobin 
Hematocrit 
Leukocytes (WBC)  
Neutrophils – absolute  
Lymphocytes – absolute 
Platelets 
  
  
Clinical Chemistry 
Assayed by Sponsor-designated laboratory 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) or blood urea 
Creatinine  
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
 
 
Coagulation 
 
Prothrombin time, INR (PT-INR) 
Evaluated by local laboratory 
 
 
Hormones (Female) 
  
Serum pregnancy test 
Evaluated by local laboratory 
Urine pregnancy test  
Evaluated by local laboratory 
Follicle-stimulating hormone (FSH)  
Evaluated by local laboratory 
Performed as needed to confirm postmenopausal status 
 
 
Other Testing 
 
Cystatin C 
Assayed by Sponsor-designated laboratory 
Obtained as clinically indicated 
 
 
Abemaciclib Pharmacokinetic Samples 
LSN3106726 (M20) 
Assayed by Sponsor-designated laboratory. 
 
Results will not be provided to the investigative sites 
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Clinical Laboratory Tests 
Comments 
LSN2839567 (M2) 
Genetics & Biomarker Samples 
Additional Hepatic Monitoring 
See Section 10.5, Appendix 5. 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related to 
progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 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.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
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 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. 
 Events, including death, caused by disease progression or otherwise due to study disease 
should not be reported unless the investigator deems them to be possibly related to study 
treatment. 
 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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
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 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.  
 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention. When the ability to use the study intervention safely 
is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic design 
elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
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practice. AE/SAE information is reported on the appropriate (e)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 (e)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 Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 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. The investigator will use clinical judgment to 
determine the relationship/ 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to Sponsor or designee. 
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 The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any post-mortem 
findings, including histopathology.  
10.3.5. 
Reporting of SAEs  
SAE Reporting via 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 SAE paper form (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 an SAE paper form (see next section) or 
to the Medical Monitor/SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in the SAE form. 
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the Medical Monitor or the SAE coordinator. 
 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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10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 Prompt notification by the investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
● The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will evaluate the reported SAEs, including confirmation 
of relatedness and assessment of expectedness. 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, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., 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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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of child 
bearing potential 
Females are considered a woman of child bearing potential if 
 
they have had at least one cycle of menses, or 
 
they have Tanner 4 breast development 
Any amount of spotting should be considered menarche. If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging. 
Women not of 
child bearing 
potential 
Females are considered women not of child bearing potential if 
 
they have a congenital anomaly such as Mullerian agenesis resulting in 
confirmed infertility,  
 
they are infertile due to surgical sterilization, or  
 
they are post-menopausal. 
Acceptable surgical sterilization methods are hysterectomy, bilateral salpingo-
oophorectomy, bilateral salpingectomy, or bilateral oophorectomy 
Post-menopausal 
state 
The post-menopausal state is defined as: 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with 
or without hysterectomy, confirmed by operative note; or  
2. A woman at least 40 years of age and up to 55 years old with an intact uterus, 
not on hormone therapy*, who has had cessation of menses for at least 12 
consecutive months without an alternative medical cause, AND With a follicle-
stimulating hormone ≥40 mIU/mL; or  
3. A woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea, or  
4. A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy  
*Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormone replacement therapy (HRT)s, gonadotropin-releasing 
hormone, anti-estrogens, selective estrogen receptor modulators (SERMs), or 
chemotherapy that could induce transient amenorrhea. 
 
 
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10.4.2. 
Contraception Guidance  
Please see guidance for specific patient populations below: 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle 
Must…  
Must not…  
agree to either remain abstinent, or stay in a same-
sex relationship without sexual relationships with 
males, and not plan a pregnancy during the study 
 
use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 
declare abstinence just for the duration of 
a trial or 
 
use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle 
Topic 
Explanation 
Pregnancy testing 
Negative serum result at screening followed by a 
negative urine result within 48 hours prior to first 
treatment exposure 
Note: subsequent pregnancy testing is compound 
specific 
Contraception 
Should use highly effective contraception (less 
than 1% failure rate) to prevent pregnancy while 
receiving study treatment and for 3 weeks after 
the last dose of blinded study drug and for 2 years 
after the last dose of fulvestrant (or according to 
local approved fulvestrant label) 
 
Examples of different forms of contraception: 
Methods 
Examples 
Highly effective contraception  
 
fallopian tube sterilization methods other 
than bilateral salpingectomy (laparoscopic 
bipolar electrocoagulation, plastic ring 
application on the uterine tubes, fallopian 
tube ligation, hysteroscopic sterilization). 
Note: Bilateral salpingectomy is 
indicative of permanent sterilization. 
Please refer to WNOCBP definition 
above.  
 
total abstinence 
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 
vasectomy, if only sexual partner 
 
fallopian tube implants, if confirmed by 
hysterosalpingogram 
 
intrauterine devices (only hormone free) 
 
Effective contraception  
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide. 
Note: Male and female condoms should not be 
used in combination. 
Ineffective forms of contraception 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
Hepatic Evaluation Testing 
See Section 10.2, Appendix 2 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs – red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs – white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
    HBV DNA b 
Anti-actin antibody c 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA b 
    EBV DNA b 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
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    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNA b 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA b 
    HSV (Type 1 and 2) DNA b 
Microbiology d 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
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10.6. 
Appendix 6: Inducers and Strong Inhibitors of CYP3A  
 
Strong Inducers of CYP3A 
Aminoglutethimide 
Apalutamide 
Carbamazepine 
Enzalutamide 
Fosphenytoin (see also phenytoin) 
Ivosidenib 
Lumacaftor 
Mitotane 
Phenobarbital/phenobarbitone 
Phenytoin 
Rifabutin 
Rifampicin (rifampin) 
Rifapentine 
St John’s wort 
 
Moderate Inducers of CYP3A 
Bosentan 
Cenobamate 
Dabrafenib 
Danshen (Salvia miltiorrhiza) 
Efavirenz 
Elagolix 
Encorafenib 
Etravirine 
Genistein 
Lopinavir (alone) 
Lorlatinib 
Modafinil 
Nafcillin (intravenous) 
Pentobarbital 
Primidone 
Thioridazine 
Tipranavir and ritonavir 
Tocilizumab (atlizumab) 
 
Strong Inhibitors of CYP3A 
Atazanavir and cobicistat 
Boceprevir 
Ceritinib 
Clarithromycin 
Cobicistat (see atazanavir and cobicistat) 
Conivaptan 
Danoprevir and ritonavir 
Elvitegravir and ritonavir 
Fosamprenavir and ritonavir 
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Grapefruit juice 
Idelalisib 
Indinavir and ritonavir  
Itraconazole 
Josamycin 
Ketoconazole 
Lonafarnib 
Lopinavir and ritonavir 
Mifepristone 
Nefazodone 
Nelfinavir 
Posaconazole 
Ribociclib 
Ritonavir 
Saquinavir and ritonavir 
Telithromycin 
Tipranavir and ritonavir 
Tucatinib 
Viekira Pak, Viekira XR (paritaprevir and ritonavir and ombitasvir and/or dasabuvir) 
Voriconazole 
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10.7. 
Appendix 7: Country-Specific Requirements  
10.7.1. 
Discontinuation of Inadvertently Enrolled Participants in the United Kingdom  
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 intervention 
and safety follow-up should be performed as outlined in Section 1.3 (SoA), Section 8.3 (Adverse 
Events, Serious Adverse Events, and Product Complaints), and Section 8.2 (Safety Assessments) 
of the protocol. 
10.7.2. 
Removal of the Legally Authorized Representative, Legal Guardian, Parents, 
Designee, Surrogate, and Caregiver in Germany  
The informed consent process (Section 10.1.3), reporting of adverse events (Section 8.3), and 
request to discontinue/withdraw from the study (Section 7.2) must be completed by the study 
participant; it is not permitted in Germany for these activities to be conducted by the 
participant’s parents, designee, caregiver, surrogate, or legally authorized representative. 
 
 
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10.8. 
Appendix 8: 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 Ethical Review Boards, 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 requirements 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 Good Clinical 
Practice, 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. 
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The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of Remote Visits 
Telemedicine: 
Telephone or technology-assisted virtual visits, or both, are acceptable to complete appropriate 
assessments. 
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other than the 
study site when participants cannot travel to the site due to an exceptional circumstance if written 
approval is provided by the Sponsor. Procedures performed at such visits may include, but are 
not limited to, concomitant medications, collection of blood samples, physical assessments, 
administration of PROs if validated for these types of visits, administration of study intervention, 
and collection of health information. 
Other alternative locations: 
Other procedures may be done at an alternate location in exceptional circumstances. 
Data Capture 
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 adverse events (AEs), serious adverse events (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. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for tests outlined in the Clinical Laboratory Tests appendix 
(Appendix 2, Section 10.2). The local laboratory must be qualified in accordance with applicable 
local regulations. 
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 actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf 
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 arranging delivery of study supplies, and 
 working with the Sponsor to determine how study intervention that is typically 
administered on site will be administered to the participant; for example, during a 
mobile healthcare visit or at an alternate location, such as an infusion center. 
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. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, this additional requirements must be met: 
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
Screening period guidance 
The screening procedures per the usual SoA should be followed 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. 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. 
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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10.9. 
Appendix 9: Abbreviations and Definitions  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
aromatase inhibitor 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASCO/CAP 
American Society of Clinical Oncology/College of American Pathologists 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
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 
BID 
twice a day, at least approximately 6 hours apart 
BOR 
best overall response 
BPI-SF 
Brief Pain Inventory-short form 
blinding 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the Sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or Sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
CDK4 & 6 
cyclin-dependent kinases 4 and 6 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatinine kinase 
CMV 
cytomegalovirus 
CONSORT 
Consolidated Standards of Reporting Trials 
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CNS 
Companion diagnostic 
complaint 
compliance 
CR 
CRF/eCRF 
CRP/CRS 
CSR 
CT 
1111 
CTA 
CTCAE 
CYP 
D. Bil 
Device deficiencies 
DMC 
DNA 
DRFS 
eCOA 
ECOGPS 
ECG 
em·oll 
enter 
BY-MC-JPEF( d) 
central nervous system 
An in vitro diagnostic device (assay or test) that provides infotmation that is essential 
for the safe and effective use of a con-esponding therapeutic product 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
perfonnance of a dmg or dmg delivery system. 
Adherence to all study-related, good clinical practice {GCP), and applicable regulatmy 
requirements. 
complete response 
case repo1t fonn/electronic case repmt fonn 
clinical research physician or clinical research scientist: Individual responsible for the 
medical conduct of the study. Responsibilities of the CRP may be pe1fo1med by a 
physician, clinical research scientist, global safety physician, or otl1er medical officer. 
clinical study repmt 
computed tomography 
Clinical Trial Agreement 
Common Ten-ninology Criteria for Adverse Events 
cytochrome P450 
direct bilimbin 
Equivalent to product complaint 
data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the Sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition oftl1e committee is dependent upon the scientific skills and 
knowledge required for monitoring the pa1ticular study. 
deoxyribonucleic acid 
distant relapse free survival 
electronic Clinical Outcome Assessment 
Eastern Cooperative Oncology Group perfo1mance status 
electrocardiogram 
The act of assigning a paiticipant to a treatment. Pa1ticipants who are enrolled in the 
study ai·e those who have been assigned to a treatment. 
Pa1ticipai1ts entered into a study are those who sign the informed consent form directly 
or tltrough their legally acceptable representatives. 
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EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality-of-Life 
Questionnaire Core 30 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQOL 5 Dimension 5 Level 
ER 
estrogen receptor 
ERB 
ethical review board 
ERCP 
endoscopic retrograde cholangiopancreatography 
ESMO 
European Society for Medical Oncology 
Estimand 
Describes the quantity (population parameter) to be estimated to characterize a causal 
treatment effect to address a specific study objective 
ET 
endocrine therapy 
FSH 
follicle-stimulating hormone  
GCP 
good clinical practice 
GDPR 
EU General Data Protection Regulation 
GGT 
gamma-glutamyltransferase 
HCRU 
Health Care Resource Utilization 
HDV 
hepatitis D virus 
HR+ 
hormone receptor positive 
HER2- 
human epidermal growth factor receptor-2 negative 
HER2 
human epidermal growth factor receptor-2 
HIV 
human immunodeficiency virus 
HR 
hormone receptor 
HRQoL 
health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDFS 
invasive disease-free survival 
IEC 
independent ethics committees 
IHC 
immunohistochemistry 
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ILD 
interstitial lung disease 
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. 
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 boards 
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 assigned 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 
mBPI-SF 
modified Brief Pain Inventory - short form 
MedDRA 
Medical Dictionary for Regulatory Activities 
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medication eno1· 
misuse 
MRCP 
MRI 
NRS 
OS 
participant 
PC 
PFS -
PK/PD 
PR 
PRO 
PET-CT 
RECIST 
SAC 
SAE 
SAP 
BY-MC-JPEF( d) 
Effors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
e1rnr leads to an AE. Medication e1rnr generally involves a failure to uphold 1 or more 
of the 5 "rights" of medication use: the 1ight pa1t icipant, the right drng, the 1ight dose, 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication e1rnrs: 
• dose 01nission 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 f01m or administration technique inconsistent with the 
medication's labeling, for example, Smmna1y of Product Characteristics, IB, local label, 
protocol, or 
• shared use of ca1t1i dges, prefilled pens, or both. 
Use of a study inte1vention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a presc1iption 
magnetic resonance cholangiopancreatography 
magnetic resonance imaging 
numeric rating scale 
overall smvival 
Equivalent to CDISC term "subject": an individual who pa1ticipates in a clinical tiial, 
either as recipient of an investigational medicinal product or as a conti·ol 
Throughout this protocol, the te1m "pa1ticipant" is used to indicate an individual who 
pa1ticipates in a clinical ti·ial, either as a recipient of an investigational inte1vention or as 
a conti·ol. This usage reflects preferences indicated by patient advocates to more 
accurately reflect the role of people who take pait in clinical ti·ials 
product complaint 
progression-free smvival 
phannacokinetic( s )/pha1macodyna1nic( s) 
partial response 
patient-rep01ted outcomes 
Positi·on emission tomography-computed tomography 
Response Evaluation Cliteria in Solid Tumors 
Statistical Analysis Centi·e 
serious adverse event 
statistical analysis plan 
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screen 
The act of determining if an individual meets the minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study.  
SD 
standard deviation 
SERD 
select estrogen receptor degrader 
SFU 
short-term follow-up 
SMD 
senior management designee 
SoA 
Schedule of Activities 
SRE 
skeletal-related event 
SUSAR 
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. 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
V 
visit 
VTE 
venous thromboembolic event 
WOCBP 
women of child-bearing potential 
 
 
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10.10. 
Appendix 10: 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]: (17-Feb 2022)  
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The main rationale for the current amendment is to incorporate feedback from the FDA. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1.2 Re-
escalation Criteria for 
Blinded Study Drug 
Updated text to indicate that re-
escalation to the prior dose will 
be permitted only once for the 
blinded study drug 
FDA feedback 
Section 6.8.2 
Bisphosphonates and 
RANK-L Targeted Agents 
Added text regarding 
concomitant therapy with 
bisphosphonates and RANK-L 
targeted agents 
For clarity 
Section 9.4.2 
Efficacy/Futility Interim 
Analyses 
Added futility stopping rule and 
detailed the process of the futility 
interim analysis 
FDA feedback 
Section 10.4. Appendix 4: 
Contraceptive and Barrier 
Guidance 
Updated examples of highly 
effective contraception 
For clarity 
Throughout the protocol 
Minor editorial and formatting 
changes 
Correction 
 
 
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Amendment [b]: (09-Dec-2021) 
Overall Rationale for the Amendment: 
The main rationale for the current amendment is to incorporate feedback from the Voluntary 
Harmonisation Procedure Clinical Trial Application. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Added clarification regarding the 
duration of study period. 
Voluntary 
Harmonisation 
Procedure Clinical Trial 
Application (VHP CTA) 
feedback 
Added coagulation tests at baseline 
and as clinically indicated for liver 
toxicity. 
Removed 14-day visit interval 
tolerance at study period III. 
Clarification regarding 
study periods 
Updated text to clarify the time points 
at which the participant should return 
study drugs. 
Clarification 
Section 5.1 Inclusion 
Criteria 
Updated Inclusion Criterion 11b 
related to contraception duration for 
women of childbearing potential 
(WOBCP) using fulvestrant. 
VHP CTA feedback 
Added clarification regarding 
WOBCP who are completely 
abstinent or in same-sex relationships. 
Clarification 
Section 5.2 Exclusion 
Criteria 
Added numbering that was missing 
for Criterion 19. 
Correction 
Section 6.1.2 General 
Dosing Instructions 
Clarified that the participant can be 
started at a lower dose if determined 
by the investigator. 
Clarification 
Section 6.3.1 Emergency 
Unblinding 
Added a description of unblinding of 
study medication in emergency 
situations. 
VHP CTA feedback 
Section 6.3.2 Inadvertent 
Unblinding 
Added text regarding inadvertent 
unblinding. 
Section 6.6 Continued 
Access to Study 
Intervention after the End 
of the Study 
Added clarification about continued 
access to study treatment and that 
placebo will no longer be 
administered during the continued 
access period. 
VHP CTA feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.7.2 Tissue 
Samples for Biomarker 
Research  
Updated text to clarify that biopsies 
are requested only if clinically 
feasible. 
VHP CTA feedback 
Section 9.3.2 Primary 
Endpoint/Estimand 
Analysis 
Added text that primary endpoint 
analyses will be done in the ITT 
population. 
VHP CTA feedback 
Section 9.3.3.4 Overall 
Survival (OS) 
Updated definition of overall survival. Clarification 
Section 9.4.2 Efficacy 
Interim Analyses 
Updated the text for efficacy interim 
analysis. 
VHP CTA feedback 
Added clarification that the trial will 
not stop early to conclude efficacy 
based on the interim analysis of 
efficacy. 
Section 10.1.6 
Dissemination of Clinical 
Study Data 
Added clarification that trial results 
will be posted in EudraCT.  
VHP CTA feedback 
Appendix 2 Clinical 
Laboratory Tests 
Added PT and INR as coagulation 
tests. 
VHP CTA feedback 
Throughout the Protocol 
Minor formatting and editorial 
changes. 
Correction 
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Amendment [a]: (02-Sep-2021) 
This amendment occurred before the protocol was submitted to any EU member state. 
Overall Rationale for the Amendment: 
The overall rationale for the current amendment is to add the biomarker exploratory objective 
and endpoint that were inadvertently omitted from the original protocol. Additional changes 
were made and are summarized in the below table; minor typographical or formatting edits are 
not presented.  
Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
(main table) 
Line item for Adverse Event 
Collection/CTCAE Grading – Removed 
note cross-referencing to Section 10.3 
(Appendix 3). 
For clarity 
1.3. Schedule of Activities 
(main table) 
Line item for Radiologic imaging 
according to RECIST 1.1 – Added 
“Required for all participants” 
For clarity 
1.3. Schedule of Activities 
(main table) 
Line item for Bone scintigraphy – Added 
“Required for all participants” 
For clarity 
1.3. Schedule of Activities 
(main table) 
Line item for Patient Dosing Diary 
(paper) – Removed “See comments” 
from cell and then shaded entire cell 
across Study Period I. 
Error correction 
and formatting 
1.3. Schedule of Activities 
(main table) 
Line item for Patient Dosing Diary 
(paper) – Removed shading from cell 
across Study Period II. 
Formatting 
1.3. Schedule of Activities 
(main table) 
Line item for Archival tumor tissue – 
Edited note indicating that archival tumor 
tissue is optional (deleted “Optional”). 
Archival tumor tissue is now required, if 
available. 
For clarity 
1.3. Schedule of Activities 
(main table) 
Line item for Tumor biopsy/biopsies – 
deleted “Optional” from procedure title.  
Added note stating biopsy/biopsies are 
requested if feasible, per investigator’s 
discretion, and cross-reference to 
protocol section. 
For clarity 
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Section # and Name 
1.3. Schedule of Activities 
(main table) 
Description of Change 
1.3. Continued-Access SoA 
Line item for AE collection-Deleted 
note cross-referencing to Section 10.3 
(Appendix 3) 
2.2.2. CDK4 & 6 Inhibition 
in HR+, HER2- Breast 
Cancer 
Reworded text at the end of the second 
paragraph - deleting "second- or third-
line therapy" and adding "ET-resistant 
MBC". 
BY-MC-JPEF( d) 
Brief Rationale 
For cla1·ity 
For clarity 
For clarity 
2.3.1. Risk Assessment 
In the Study Procedures, the fom1h 
For clari ty 
paragraph has been edited to indicate the 
tumor biopsy is requested if feasible, per 
investigator's discretion. 
3. Objectives, Endpoints, and Added biomarker exploratory objective 
Estimands 
and endpoint. 
5 .4. Screen Failures 
6.5.1.1. Blinded Study Drng 
Dose Adjustments for 
Treatment-Emergent, 
Related* Adverse Events 
6.5.2. Fulvestrant 
8.7.2. Tissue Samples for 
Biomarker Research 
8.7.2. Tissue Samples for 
Biomarker Research 
Reworded rescreening text in second and 
third paragraphs. 
For the ALT/AST Increased line item in 
the dose adjustments table, ULN format 
has been replaced with CTCAE grades. 
Added text stating that fulvestrant dose 
may be re-escalated at the discretion of 
the investigator and after consultation 
with the Sponsor CRP/CRS. 
Added text in the first paragraph 
indicating that archival tumor specimen 
is "required, if tissue is available, subject 
to local regulations". 
Added text in the second paragraph "A 
biopsy at baseline, as well as at the time 
of disease progression, is requested, if 
feasible, per investigator's discretion." 
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Enor cmTection -
this content was 
omitted from 
original protocol. 
For clarity 
For clarity and 
consistency 
For clarity 
For clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.12. Sample Retention 
Text directly below the table has been 
edited to state that archival blocks “may” 
be returned to the study site, “upon 
request”. 
Also deleted text stating “Slides and 
tissue samples collected on study will not 
be returned” and replaced it with “Tissue 
blocks from biopsies collected at 
baseline/disease progression may be 
returned to sites if there is available 
tissue left over, upon request.”    
For consistency 
and clarity 
10.2. Appendix 2: Clinical 
Laboratory Tests 
In Genetics & Biomarker Samples 
section of table – deleted “optional” from 
line item now reads “Tumor tissue from 
biopsy/biopsies”. 
For clarity 
10.3.4. Recording and 
Follow-Up of AE and/or 
SAE and Product Complaints  
Assessment of Intensity: Deleted text 
stating that post-baseline grading of all 
laboratory values should be done per 
normal reference limit references, 
regardless of whether the assessment is 
normal or abnormal at baseline. 
For consistency 
with CTCAE v5.0 
 
 
 
 
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11. 
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