eMonarcHER: A Randomized, Double Blind, Placebo-Controlled Phase 3 Study of Abemaciclib Plus Standard Adjuvant Endocrine Therapy in Participants With High-Risk, Node-Positive, HR+, HER2+ Early Breast Cancer Who Have Completed Adjuvant HER2-Targeted Therapy
Phase: PHASE3
Conditions: Breast Neoplasms
Sponsor: Eli Lilly and Company

Protocol Addendum I3Y-MC-JPCW(d) 
eMonarcHER: A Randomized, Double Blind, Placebo-Controlled Phase 3 Study of 
Abemaciclib plus Standard Adjuvant Endocrine Therapy in Participants with High-Risk, 
Node-Positive, HR+, HER2+ Early Breast Cancer Who Have Completed Adjuvant HER2-
Targeted Therapy
NCT04752332 
Approval Date: 14-Feb-2022 

CONFIDENTIAL
Protocol I3Y-MC-JPCW(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:
eMonarcHER: A Randomized, Double Blind, Placebo-Controlled Phase 3 Study of Abemaciclib 
plus Standard Adjuvant Endocrine Therapy in Participants with High-Risk, Node-Positive, HR+, 
HER2+ Early Breast Cancer Who Have Completed Adjuvant HER2-Targeted Therapy
Protocol Number: I3Y-MC-JPCW
Amendment Number: d
Compound: Abemaciclib (LY2835219)
Study Phase: 3
Short Title:
eMonarcHER: A Phase 3 Study of Abemaciclib plus Standard Adjuvant Endocrine Therapy in 
Participants with High-Risk, Node-Positive, HR+, HER2+ Breast Cancer
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana, USA 46285
Regulatory Agency Identifier Number(s)
IND: 106100
EudraCT: 2020-004035-24
Approval Date: Protocol Amendment (d) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 14-Feb-2022 GMT

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Protocol I3Y-MC-JPCW(d)
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Medical Monitor Name and Contact Information will be provided separately.

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Protocol I3Y-MC-JPCW(d)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (c)
14-Dec-2021
Amendment (b)
20-May-2021
Amendment (a)
06-Apr-2021
Original Protocol
08-Dec-2020
Amendment [d]
This amendment is considered to be substantial.
Overall Rationale for the Amendment:
Amendment (d) is necessary to allow for unblinding of participants following the decision to 
permanently close enrollment and proceed towards early termination. This amendment will allow 
for participants and investigators to make informed decisions regarding continuation or 
discontinuation of participation. Additionally, this update reflects the new AE monitoring as
primary endpoint, removal of efficacy endpoints and other secondary/tertiary endpoints, the total 
number of patients enrolled, and that no new patients will be enrolled.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 2.3.1.1 Study 
Intervention; 2.3.2 Benefit Assessment; 
2.3.3 Overall Benefit: Risk Conclusion; 
4.1 Overall Design; 5 Study 
Population; 6.1 Study Intervention(s) 
Administered; 7.1 Discontinuation of 
Study Intervention; 7.2.1 
Discontinuation of Inadvertently 
Enrolled Participants; 7.2 Participant 
Discontinuation/Withdrawal from the 
Study; 7.2.2 Discontinuation after 
Amendment (d)
Added details that no new patients will 
be enrolled into the study and that all 
currently enrolled patients will be 
unblinded
See Overall Rationale for 
Amendment
1.3 Schedule of Activities; 1.3.2
Pharmacokinetic, Genetics, and 
Biomarker Sampling Schedule; 8.5 
Pharmacokinetics; 8.7 Genetics; 8.8 
Biomarkers
Removed PK and biomarker sample 
collection from study schedule; 
specified that no additional PK analyses 
will be performed; specified no 
additional blood samples for 
genetics/biomarker analyses will be 
collected
Alignment with decision to 
remove PK and biomarker 
collection from study
1.3.1 Continued Access Schedule of 
Activities
Added schedule to protocol
Added for participants 
currently on study

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Protocol I3Y-MC-JPCW(d)
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1.1 Synopsis; 3 Objectives and 
Endpoints; 3.1 Objectives and 
Endpoints for Amendment (d)
Added objectives for amendment (d)
See Overall Rationale for 
Amendment
4.4 End of Study Definition; 6.7.1 
Study Completion Definition
Updated end of study and study 
completion definitions
Alignment with study 
update
6.3 Measure to Minimize Bias: 
Randomization and Blinding; 6.3.1 
Unblinding at Interim Analyses; 6.3.2 
Emergency Unblinding; 6.3.3 
Inadvertent Unblinding; 6.3.4 
Amendment (d) Patient Unblinding
Aligned sections with decision to 
unblind all participants
See Overall Rationale for 
Amendment
6.4 Study Intervention Compliance
Specified that study will not evaluate 
compliance/PK assessments; specified 
participants will not complete a Patient 
Dosing Diary
Alignment with study 
updates
6.5 Concomitant Therapy
Specified that use of concomitant 
medications will not be collected as of 
amendment (d)
Alignment with study 
updates
6.6 Dose Modification; 6.6.1 Dose 
Suspension and Cycle Delay
Specified that dose modifications, 
suspensions, and delays of abemaciclib 
will be at the investigator’s discretion
Alignment with study 
updates
7.3 Lost to Follow up
Removed collection of survival status
No longer applicable to 
study
8.1.1 Imaging and Recurrence 
Assessment; 8.1.2 Appropriateness of 
Assessments
Specified that imaging decisions should 
continue per investigator’s discretion; 
specified no additional efficacy data will 
be collected
Alignment with study 
updates
8.2 Safety Assessments; 8.2.1 Clinical 
Safety Laboratory Assessments; 10.2 
Appendix 2: Clinical Laboratory Tests
Specified that clinical laboratory test 
selection/timing/frequency will be at the 
investigator’s discretion; central labs 
will not be collected
Alignment with study 
updates
8.2.2 Hepatic Safety Monitoring
Updated safety data capture instructions
Alignment with study 
updates
8.10 Health Economics; 8.10.1 Patient-
Reported Outcomes; 8.10.2 Electronic 
Participant Daily e-Dairy Assessment; 
8.10.3 Healthcare Resource Utilization
Specified that no additional PRO 
questionnaires or assessments will be 
collected 
Alignment with study 
updates

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Protocol I3Y-MC-JPCW(d)
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9.1 Statistical Hypotheses; 9.2 Sample 
Size Determination; 9.4.1 General 
Considerations; 9.4.2 Primary 
Endpoint(s); 9.4.3 Secondary Efficacy 
Endpoint(s); 9.4.4 Tertiary/Exploratory 
Efficacy Endpoint(s); 9.4.5 Safety 
Analyses; 9.4.6.3 Concomitant 
Therapy; 9.4.6.4 Treatment 
Compliance; 9.4.6.5 Extent of 
Exposure; 9.4.6.6. Post-Study 
intervention Therapy; 9.4.6.7 Subgroup 
Analyses; 9.4.6.8 Pharmacokinetic and 
Exposure-Response Analyses; 9.4.6.9 
Biomarker Analyses; 9.4.6.10 Health 
Economics Analyses; 9.5.1 Interim 
Analyses for Efficacy/Futility; 9.5.2 
Interim Analyses for Safety
Revised sections to state which analyses 
will not be performed
Alignment with study 
updates
10.1.6 Data Quality Assurance
Specified that eCOA data will not be 
collected, analyzed, or reported as of 
amendment (d)
Alignment with study 
updates
10.1.9 Publication Policy
Specified that the study results will not 
be published
Alignment with study 
updates
10.8 Appendix 8: Protocol JPCW 
Breast Cancer Recurrence and Other 
Cancer Events
Removed appendix
No longer applicable for 
study
Throughout the protocol
Minor editorial and formatting changes
Minor; therefore not 
detailed

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Protocol I3Y-MC-JPCW(d)
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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.
Continued Access Schedule of Activities....................................................................30
1.3.2.
Pharmacokinetic, Genetics, and Biomarker Sampling Schedule ..................................30
2.
Introduction..............................................................................................................31
2.1.
Study Rationale ..........................................................................................................31
2.2.
Background ................................................................................................................33
2.2.1.
Trastuzumab...............................................................................................................34
2.2.2.
Pertuzumab.................................................................................................................35
2.2.3.
Trastuzumab Emtansine (T-DM1) ..............................................................................35
2.2.4.
Neratinib ....................................................................................................................36
2.2.5.
Endocrine Therapy .....................................................................................................36
2.2.6.
Abemaciclib ...............................................................................................................37
2.3.
Benefit/Risk Assessment ............................................................................................37
2.3.1.
Risk Assessment.........................................................................................................38
2.3.2.
Benefit Assessment.....................................................................................................41
2.3.3.
Overall Benefit: Risk Conclusion................................................................................41
3.
Objectives and Endpoints.........................................................................................43
3.1.
Objectives and Endpoints as of Amendment (d)..........................................................44
4.
Study Design .............................................................................................................45
4.1.
Overall Design............................................................................................................45
4.2.
Scientific Rationale for Study Design .........................................................................45
4.3.
Justification for Dose..................................................................................................45
4.4.
End of Study Definition..............................................................................................46
5.
Study Population ......................................................................................................47
5.1.
Inclusion Criteria........................................................................................................47
5.2.
Exclusion Criteria.......................................................................................................52
5.3.
Lifestyle Considerations .............................................................................................54
5.4.
Screen Failures...........................................................................................................54
6.
Study Intervention....................................................................................................56
6.1.
Study Intervention(s) Administered ............................................................................56
6.2.
Preparation/Handling/Storage/Accountability.............................................................56
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................57
6.3.1.
Unblinding at Interim Analyses ..................................................................................57
6.3.2.
Emergency Unblinding...............................................................................................57
6.3.3.
Inadvertent Unblinding...............................................................................................57
6.3.4.
Amendment (d) Unblinding ........................................................................................58
6.4.
Study Intervention Compliance...................................................................................58
6.5.
Concomitant Therapy .................................................................................................58
6.5.1.
Supportive Care..........................................................................................................59

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6.5.2.
Supportive Management for Diarrhea in Participants Receiving 
Blinded Study Intervention .........................................................................................60
6.6.
Dose Modification......................................................................................................60
6.6.1.
Dose Suspension and Cycle Delay..............................................................................63
6.7.
Intervention after the End of the Study........................................................................63
6.7.1.
Study Completion Definition ......................................................................................63
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................64
7.1.
Discontinuation of Study Intervention ........................................................................64
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................64
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................64
7.2.2.
Discontinuation after Amendment (d).........................................................................65
7.3.
Lost to Follow up .......................................................................................................65
8.
Study Assessments and Procedures .........................................................................66
8.1.
Efficacy Assessments .................................................................................................66
8.1.1.
Imaging and Recurrence Assessment ..........................................................................66
8.1.2.
Appropriateness of Assessments.................................................................................66
8.2.
Safety Assessments ....................................................................................................66
8.2.1.
Clinical Safety Laboratory Assessments .....................................................................67
8.2.2.
Hepatic Safety Monitoring..........................................................................................68
8.2.3.
Venous Thromboembolic Events (VTEs)....................................................................69
8.2.4.
Serum Creatinine Increased ........................................................................................69
8.2.5.
Interstitial Lung Disease (ILD)/Pneumonitis...............................................................70
8.3.
Adverse Events and Serious Adverse Events ..............................................................70
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................70
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................71
8.3.3.
Follow-up of AEs and SAEs.......................................................................................71
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................71
8.3.5.
Pregnancy...................................................................................................................72
8.3.6.
Events or Outcomes....................................................................................................72
8.3.7.
Adverse Events of Special Interest..............................................................................72
8.3.8.
Product Complaints ....................................................................................................72
8.4.
Treatment of Overdose ...............................................................................................73
8.5.
Pharmacokinetics........................................................................................................73
8.6.
Pharmacodynamics.....................................................................................................74
8.7.
Genetics .....................................................................................................................74
8.8.
Biomarkers.................................................................................................................74
8.8.1.
Plasma and Serum Samples for Biomarker Research ..................................................74
8.8.2.
Tissue Samples for Biomarker Research.....................................................................74
8.8.3.
Whole-Blood Sample for Biomarker Research............................................................74
8.9.
Immunogenicity Assessments.....................................................................................74
8.10.
Health Economics.......................................................................................................74
8.10.1.
Patient-Reported Outcomes (PRO) .............................................................................74
8.10.2.
Electronic Participant Daily e-Diary Assessment ........................................................74
8.10.3.
Healthcare Resource Utilization..................................................................................74

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Protocol I3Y-MC-JPCW(d)
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9.
Statistical Considerations.........................................................................................75
9.1.
Statistical Hypotheses.................................................................................................75
9.2.
Sample Size Determination.........................................................................................75
9.3.
Populations for Analyses ............................................................................................75
9.4.
Statistical Analyses.....................................................................................................75
9.4.1.
General Considerations...............................................................................................75
9.4.2.
Primary Endpoint(s) ...................................................................................................75
9.4.3.
Secondary Efficacy Endpoint(s)..................................................................................76
9.4.5.
Safety Analyses ..........................................................................................................76
9.4.6.
Other Analyses ...........................................................................................................76
9.5.
Interim Analyses.........................................................................................................77
9.5.1.
Interim Analyses for Efficacy/Futility:........................................................................77
9.5.2.
Interim Analyses for Safety ........................................................................................77
9.6.
Data Monitoring Committee (DMC)...........................................................................77
10.
Supporting Documentation and Operational Considerations ................................78
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................78
10.1.1.
Regulatory and Ethical Considerations........................................................................78
10.1.2.
Financial Disclosure ...................................................................................................78
10.1.3.
Informed Consent Process ..........................................................................................79
10.1.4.
Data Protection...........................................................................................................79
10.1.5.
Dissemination of Clinical Study Data .........................................................................80
10.1.6.
Data Quality Assurance ..............................................................................................80
10.1.7.
Source Documents......................................................................................................82
10.1.8.
Study and Site Start and Closure.................................................................................82
10.1.9.
Publication Policy.......................................................................................................82
10.1.10. Investigator Information .............................................................................................83
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................84
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................86
10.3.1.
Definition of AE.........................................................................................................86
10.3.2.
Definition of SAE.......................................................................................................87
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................88
10.3.4.
Reporting of SAEs......................................................................................................90
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................91
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................94
10.6.
Appendix 6: Country-specific Requirements...............................................................96
10.6.1.
Discontinuation of Inadvertently Enrolled Participants in the 
United Kingdom.........................................................................................................96
10.6.2.
Removal of the Legally Authorized Representative, Legal 
Guardian, Parents, Designee, Surrogate, and Caregiver in 
Germany.....................................................................................................................96
CCI

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Protocol I3Y-MC-JPCW(d)
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10.7.
Appendix 7: Protocol JPCW Inducers and Strong Inhibitors 
of CYP3A...................................................................................................................97
10.8.
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.........................................................................................99
10.9.
Appendix 9: Abbreviations .......................................................................................102
10.10.
Appendix 10: Protocol Amendment History .............................................................108
11.
References...............................................................................................................124

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Protocol I3Y-MC-JPCW(d)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: eMonarcHER: A Randomized, Double Blind, Placebo-Controlled Phase 3 Study 
of Abemaciclib plus Standard Adjuvant Endocrine Therapy in Participants with High-Risk, 
Node-Positive, HR+, HER2+ Early Breast Cancer Who Have Completed Adjuvant 
HER2-Targeted Therapy.
Short Title: eMonarcHER: A Phase 3 Study of Abemaciclib plus Standard Adjuvant Endocrine 
Therapy in Participants with High-Risk, Node-Positive, HR+, HER2+ Breast Cancer.
Rationale:
Study I3Y-MC-JPCW (JPCW; eMonarcHER) is a Phase 3 study that will evaluate the potential
for abemaciclib, a potent inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 and 6), to enhance 
adjuvant endocrine therapy (ET) compared to standard adjuvant ET alone, in participants with 
node-positive, hormone receptor positive (HR+), human epidermal growth factor receptor-2 
positive (HER2+) early breast cancer who are at high risk of disease recurrence.
The currently approved standards of care offered to this patient population include a combination 
of systemic treatments with (neo)adjuvant cytotoxic chemotherapy, HER2-targeted therapy, ET, 
surgery, and radiotherapy, if clinically indicated. Despite advances in therapeutic options for 
early-stage breast cancer, a high-risk subpopulation receives suboptimum benefit and may 
demonstrate resistance to anti-estrogen therapy at the time of recurrence. This phenomenon 
could be explained as a consequence of cancer cell clones that survive through or evolve during 
standard endocrine and HER2-targeted therapies.
In HR+, HER2+ early breast cancer, the average time-to-disease recurrence is less than 3 years 
from the initiation of adjuvant HER2-targeted therapy (Chumsri et al. 2019). Once distant 
disease recurrence occurs, the disease is considered metastatic and incurable. There remains a 
large unmet need for patients with HR+, HER2+ breast cancer who are at high risk of recurrence, 
including those with node-positive disease. Therefore, improving on the absolute benefit 
observed with standard of care adjuvant ET is necessary for this high-risk subgroup.  
Nonclinical and clinical data support the activity of abemaciclib in HER2+ breast cancer. 
Study I3Y-MC-JPBZ (MonarcHER) provided a proof of concept for the activity of abemaciclib
in combination with HER2-targeted therapy, trastuzumab, and ET in HR+, HER2+ advanced
disease (Tolaney et al. 2020a). In addition, abemaciclib combined with ET has demonstrated
clinical efficacy in HR+, HER2-negative advanced breast cancer, including those who are 
endocrine resistant (Sledge et al. 2017; Sledge et al. 2019). In the adjuvant setting, a recent study
demonstrated that the addition of abemaciclib to ET improved invasive disease-free survival 
(IDFS) compared to standard of care endocrine monotherapy in patients with node-positive, 
HR+, HER2-negative early breast cancer at high risk of disease recurrence (monarchE)
(Johnston et al. 2020). 
We are proposing this Phase 3 adjuvant study in patients with high-risk, node-positive, HR+,
HER2+ early breast cancer. This proposed study builds on the benefit observed in monarchE in 
the HR+ early breast cancer patients, aiming to improve the absolute benefit of adjuvant ET by 

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Protocol I3Y-MC-JPCW(d)
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investigating the activity of abemaciclib in combination with ET as adjuvant treatment for HR+,
HER2+ patients who have completed standard HER2-targeted therapy in the adjuvant setting.
The development of novel therapeutic strategies is an important unmet medical need for patients 
with this disease, as current standard of care is suboptimal for these patients. Several factors have 
been identified in the literature that are associated with high risk of disease recurrence in this
group, such as presence of tumor involvement in the axillary lymph node at the time of 
diagnosis, larger primary breast tumors (≥5 cm), higher histologic grade, and residual disease
after neoadjuvant treatment (Lambertini et al. 2019; von Minckwitz et al. 2017; von Minckwitz 
et al. 2019).
For eMonarcHER, high risk has been defined by the following characteristics at the time of 
definitive surgery:

Participants who received neoadjuvant chemotherapy along with HER2-targeted 
treatment and

residual disease in at least 1 axillary lymph node or

a residual tumor measuring ≥5 cm, or

a residual tumor of any size that has direct extension to the chest wall and/or skin 
(ulceration or skin nodules).

Participants who had definitive surgery prior to systemic therapy, completed adjuvant 
chemotherapy along with HER2-targeted therapies (trastuzumab and pertuzumab), and

tumor involvement in ≥4 ipsilateral axillary lymph nodes, or

tumor involvement in 1 to 3 ipsilateral axillary lymph node(s) and

histological Grade 3, or

primary tumor size of ≥5 cm.
Objectives and Endpoints (prior to amendment [d])
Objectives
Endpoints
Primary

To compare the efficacy of abemaciclib plus 
physician’s choice ET versus placebo plus 
physician’s choice ET in the study population.

IDFS as defined by the STEEP System (Hudis 
et al. 2007)
Secondary

To compare the efficacy of abemaciclib plus 
ET versus placebo plus physician’s choice ET
in the study population.

OS

DRFS

Incidence of CNS metastases as the first site 
of disease recurrence

To assess the safety profile of abemaciclib 
plus physician’s choice ET versus placebo 
plus ET in the study population.

Safety, including but not limited to TEAEs 
SAEs, hospitalizations, clinical laboratory 
tests, vital signs, and physical examinations

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Objectives
Endpoints

To evaluate participant-reported symptoms, 
function and global health status/QOL 
(EORTC QLQ-C30).

To compare EORTC QLQ-C30 scales 
between treatment arms

To evaluate health status in the study 
population to inform decision modeling for 
health economic evaluation using the EQ-5D 
5L.

The EQ-5D 5L the index score and the 
single-item health status measure 

To evaluate the PK of abemaciclib.

Abemaciclib concentrations
Abbreviations: CNS = central nervous system; DRFS = distant relapse-free survival; EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer quality of life questionnaire Core 30; ET = endocrine 
therapy; IDFS = invasive disease-free survival; OS = overall survival; PK = pharmacokinetics; QOL = quality of 
life; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Objectives and Endpoints as of Amendment (d)
Objectives
Endpoints
To monitor the safety of abemaciclib plus 
physician’s choice ET in the study 
population. 
AEs and SAEs per CTCAE v5.0
Abbreviations: AEs = adverse events; CTCAE = Common Terminology Criteria for Adverse Events; ET = 
endocrine therapy; SAEs = serious adverse events
Overall Design
eMonarcHER is a Phase 3 multicenter, randomized, double-blinded, placebo-controlled trial in 
participants with high-risk, node-positive, HR+, HER2+ early breast cancer who have completed 
adjuvant HER2-targeted therapy.
Approximately 2450 participants will be enrolled in a 1:1 randomization. Participants will be 
assigned to blinded study drug (abemaciclib or placebo) plus ET. Study intervention will be 
given for up to 26 cycles (approximately 2 years, where a cycle = 28 days), or until evidence of 
disease recurrence or another discontinuation criterion is met, whichever occurs first. 
Endocrine therapy will be taken as prescribed during the on-study intervention period 
(approximately 2 years). After the on-study intervention period, standard adjuvant ET should 
continue for a duration of 3 to 8 additional years, for a total duration of up to 10 years, if deemed 
medically appropriate. 
Standard approved adjuvant ET is per physician’s choice (such as, tamoxifen or an aromatase 
inhibitor, with or without ovarian function suppression per standard practice). Adjuvant 
treatment with fulvestrant is not allowed at any time during the study. 

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As of amendment (d), no new patients will be enrolled, investigators and patients will be 
unblinded to treatment arm.
Disclosure Statement: This is a parallel treatment study with 2 arms that are blinded.
Changes Upon Approval of Amendment (d)
The study was determined to be no longer feasible due to slow accrual and changes in the
treatment landscape for HER2+ breast cancer that are anticipated to improve patient outcomes 
and diminish the unmet medical need; therefore, enrollment was terminated.
After approval of amendment (d), and according to local regulations, participants who are on 
study treatment will be unblinded and enter the Continued Access period and follow the 
Continued Access SoA (Section 1.3). If the investigator determines that continuation of 
abemaciclib may offer potential benefit to participants receiving study treatment, participants 
may continue to receive study treatment in the Continued Access period for a maximum of 26 
cycles until any of the criteria for discontinuation are met (Section 7.1). Investigators will 
perform standard procedures and tests for breast cancer surveillance and management. 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 unless they provide source documentation for 
an AE. Participants receiving placebo will be discontinued. 
The sole primary endpoint will be AE monitoring for participants who remain on abemaciclib.
Patients who discontinue therapy will have a short-term follow-up visit. Long-term follow-up
does not apply.
Number of Participants:
Approximately 2450 participants were planned to be randomized in the study; however, as of 
amendment (d), enrollment and randomization of new patients was stopped and unblinding of 
participants was allowed. Approximately 115 participants were randomized into the study.
Intervention Groups and Duration:
Arm
Arm A (experimental)
Arm B (control)
Intervention
Abemaciclib
ET
Placebo
ET
Dose
150 mg (3, 50-mg 
tablets
Standard adjuvant ET
of physician’s choice
3 placebo tablets
Standard adjuvant 
ET of physician’s 
choice
Schedule
BID
BID
Route
PO
PO
Abbreviations: BID = twice a day, at least approximately 6 hours apart; ET = endocrine therapy; PO = by mouth.
Data Monitoring Committee: 
As of amendment (d), there will be no data monitoring committee.

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Protocol I3Y-MC-JPCW(d)
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1.2.
Schema
* Upon approval of amendment (d), the study will no longer include long-term follow-up evaluation.
Abbreviations: ET = endocrine therapy; HR+ = hormone receptor-positive; HER2+ = human epidermal growth 
factor receptor-2 positive; R = randomization; T-DM1 = trastuzumab emtansine.
Note: Patients in both arms will receive 26 cycles of study intervention during the treatment period unless meeting a 
criterion for discontinuation.

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Protocol I3Y-MC-JPCW(d)
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1.3.
Schedule of Activities (SoA)
Upon approval of amendment (d), participants will follow the Continued Access SoA in 
Section 1.3.1.
Day 1 is the first dose of blinded study drug following randomization (abemaciclib or placebo), 
regardless of if the participant is receiving ET immediately prior to randomization. The first dose 
of blinded study drug and physician’s choice of ET should be initiated no later than 7 days 
following randomization. 
Clinic visits:
Clinic visits will occur more frequently early in the study intervention period. For the first 2
cycles, participants will return to the clinic every 2 weeks (14 ± 3 days); that is on Days 1 and 15 
of Cycles 1 and 2. For Cycles 3 and 4, clinic visits will occur on Day 1 of each cycle (±5 days). 
Beginning with Cycle 6, clinic visits occur on Day 1 (±5 days) of every third cycle (Cycles 6, 9,
and 12). Starting with Cycle 12, participants return to clinic on Day 1 (±5 days) of every sixth
cycle (Cycles 12, 18, and 24) and again at the completion of Cycle 26.  
Telephone visits:
Telephone visits will occur on Day 1 (±5 days) of Cycles 5, 7, 8, 10, 11, 14, 16, 20, 22 and 26.
Summary of Visit Type (in-clinic or phone visit) by Cycle 
Cycle
Visit type
Cycle
Visit type
Cycle
Visit type
Cycle
Visit type
Cycle
Visit type
C1a
Clinic
C2a
Clinic
C3
Clinic
C4
Clinic
C5
Phone
C6
Clinic
C7
Phone
C8
Phone
C9
Clinic
C10
Phone
C11
Phone
C12
Clinic
C13
None
C14
Phone
C15
None
C16
Phone
C17
None
C18
Clinic
C19
None
C20
Phone
C21
None
C22
Phone
C23
None
C24
Clinic
C25
None
C26b
Phone/clinic
V801
Clinic
V802
Clinic
V803-XX
Clinic preferred
Abbreviations: C = cycle; V = visit.
a C1 and C2 visits are every 2 weeks.
b C26 Day 1 is a phone visit; end of C26 is a clinic visit.
Detection of symptoms suspicious of disease recurrence is highly important. The investigator or 
another medically qualified individual is expected to conduct a comprehensive and systematic 
assessment of these symptoms during clinic and phone visits. Of note, the protocol does not 
prohibit more frequent monitoring by imaging, if judged necessary by the investigator for an 
individual patient. 

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
16
Short-term follow-up:
Participants discontinuing study intervention (either early discontinuation or at completion of 
26 cycles after initiation of abemaciclib) will return for an in-clinic visit (Visit 801). This visit 
will include physical examination, vital signs, Eastern Cooperative Oncology Group (ECOG) 
performance status, concomitant medication, adverse event collection, disease symptoms 
assessment, central chemistry, and hematology, and return of study drug.
The short-term follow-up visit takes place 30 days (±5 days) after 1 of the following time points, 
whichever occurs first:

after the completion of 26 cycles of the on-study intervention period.

after discontinuation criteria are met (Section 7.1) and decision is made for the participant 
to discontinue placebo as required at the time of unblinding or abemaciclib prior to the 
completion of the 26 cycles of the on-study intervention period.
Long-term follow-up:
Upon approval of amendment (d) the study will no longer include long-term follow-up
evaluation or data collection.   

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
17
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Informed consent
See 
instruction
s
ICF may be signed up to 3 months prior to 
C1D1.
ICF must be signed before any protocol-
specific procedures are performed
Inclusion/exclusio
n criteria
X
See Sections 5.1 and 5.2.
Medical history
X
Including assessment of preexisting 
conditions and historical illnesses, and habits 
(such as, tobacco and alcohol use).
Cancer treatment 
history
X
Record prior anticancer therapy.
Concomitant 
medication
X
X
X
At screening, record prior and concurrent 
medications.
Record all supportive care and concomitant 
medication continuously including over-
the-counter (including herbal and dietary 
supplements) at every visit through V801. 
Clinically 
directed physical 
examination
X
X
X
X
X
X
X
X
X
X
At each in-clinic visit. 

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
18
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Vital signs 
X
X
X
X
X
X
X
X
X
In-clinic visits only. Measure height 
(screening only), weight (D1 of each cycle 
and V801), and for each visit: temperature, 
blood pressure, pulse rate, pulse oximeter 
(SpO2), and respiration rate. 
If vital signs were collected within 3 days 
of D1, they do not need to be repeated at 
D1.
AE collection
X
X
X
See 
instructio
ns
Any AE, including SAEs are collected 
continuously at every in-clinic and phone 
visit and throughout the on-study
intervention period and short-term follow-
up. Only SAEs will be reported up to 5 
years during long-term follow-up period, 
regardless of causality to study intervention 
treatment.
CTCAE Version 5.0
ECOG PS
X
X
X
X
X
X
X
C1, C2, and all subsequent in-clinic visits 
during the on-study intervention period, 
and V801.
If performed 3 days prior to C1D1, may 
be used for C1D1 assessment.
ECG
X
Single, local during screening and when 
clinically indicated. 
Participant must be supine or near supine 
for approximately 5 to 10 minutes prior to 
collection and remain supine, but awake, 
during collection.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
19
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Hematology
X
X
X
X
X
X
X
X
X
See Appendix 2, Section 10.2.
Hematology labs required for visits held at 
the clinic.  
Hematology labs not required for phone 
visits; however, additional labs may be 
drawn as clinically indicated outside of in-
clinic scheduled visits.
Sample must be taken either within 14 days 
of C1D1 or on C1D1.
Clinical chemistry 
X
X
X
X
X
X
X
X
X
See Appendix 2, Section 10.2. 
Chemistry labs required for visits held at 
the clinic.  
Chemistry labs not required for phone 
visits; however, additional labs may be 
drawn as clinically indicated outside of in-
clinic scheduled visits.
If collected at baseline (≤14d from C1D1), 
then may be used in place of C1D1
collection.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
20
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Pregnancy test
X
X
See instructions
Applies only to women of childbearing 
potential.
Serum pregnancy test at screening, 
performed locally.
Urine or serum pregnancy test ≤24 hours of
C1D1, performed locally.
See Appendix 2, Section 10.2.
Note: During the on-study intervention 
period, local regulations and/or institutional 
guidelines may require additional testing.
Abdominal ± 
pelvic imaging 
(such as CT, 
PET/CT, MRI, 
ultrasound)
See 
instruction
s
See instructions
See instructions
During screening: Abdominal ± pelvic 
imaging MUST be performed prior to 
randomization. Abdominal ± pelvic 
imaging performed previously as part of 
routine care, any time in the process of or 
after diagnosing the patient with the 
current breast cancer diagnosis may be 
used as the baseline assessment. 
During treatment and follow-up: 
Abdominal ± pelvic imaging is to be 
performed ONLY if clinically indicated per 
the investigator’s judgment.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
21
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Bilateral imaging 
(such as, 
diagnostic 
mammogram or 
MRI of remaining 
breast tissue)
See 
instruction
s
See instructions
See instructions
During screening: Bilateral breast imaging 
of conserved and/or contralateral breast 
performed locally within 1 year prior to 
randomization MUST be obtained. Breast 
imaging performed as part of routine care 
within 1 year prior to randomization may 
be used as the baseline assessment. This is 
not required for patients who had bilateral 
mastectomy.
During treatment and follow-up: Repeat 
breast imaging either at yearly intervals or 
according to local standards as part of 
routine medical care. Patients who have 
had a mastectomy should be followed per 
local practice. 
Of note, international standard guidelines 
recommend breast imaging at yearly 
intervals. 
Ultrasound alone is not sufficient for 
bilateral imaging.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
22
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Chest imaging 
(such as, PET/CT, 
CT, or x-ray 
[should include 
lateral and PA 
views])
See 
instruction
s
See instructions
See instructions
During screening: Chest imaging MUST be 
performed prior to randomization. Imaging
performed previously as part of routine 
care, any time in the process of or after 
diagnosing the participant with the current 
breast cancer diagnosis, may be used as the 
baseline assessment. CT scan is permitted 
as an alternative if this is part of routine 
practice.
During treatment and follow-up: Chest 
imaging (chest x-ray with lateral and PA 
views or chest CT scan) is to be performed 
locally and ONLY if clinically indicated 
per the investigator’s judgment. If PET/CT 
is performed, additional imaging 
modalities are not required.  

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
23
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Bone nuclear 
imaging (such as, 
bone scan, PET 
scan, or PET/CT)
See 
instruction
s
See instructions
See instructions
Prior to randomization: Full body bone 
imaging per standard clinical practice 
MUST be performed prior to 
randomization to discard or confirm 
potential distant disease. Bone imaging 
performed previously as part of routine 
care, any time in the process of or after 
diagnosing the participant with the current 
breast cancer diagnosis, may be used as the 
baseline assessment.
Post randomization and follow-up: 
Performed locally and ONLY if clinically 
indicated per investigator’s judgment (for 
example, if participant is symptomatic for 
bone pain and/or if alkaline phosphatase is 
significantly elevated ≥3×ULN). If 
PET/CT is performed, additional imaging 
modalities are not required.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
24
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Disease 
recurrence 
assessment
X
X
X
X
X
X
X
X
At every indicated visit (in-clinic and 
phone) and as clinically indicated until 
distant disease recurrence or death, 
whatever occurs first. See Section 8.1 and 
Section 10.8. (Appendix 8).    
Assessment for changes in signs and 
symptoms suggestive of disease 
recurrence. 
Assessments will also be performed for 
participants who discontinue treatment 
without an IDFS event per STEEP system 
(Section 10.8.) or who are randomized and 
never received study intervention.
Participant PRO 
questionnaires on 
site-based 
electronic device:
EORTC QLQ-
C30, FACT-GP5, 
PRO-CTCAE 
selected items, 
and
EQ-5D 5L 
X
X
X
X
See instructions
See instructions
X
See 
instructio
ns
At in-clinic visits. Complete at the following 
timepoints prior to extensive contact with site 
personnel:
C1D1 (or ≤3 days prior to C1D1): Prior to 
starting blinded study drug
C1D15
Cycle 2 (D1, D15)
Cycles 3-26 on D1 of in-clinic visits (at 
Cycles 3, 4, 6, 9, 12, 18, 24); not collected 
at C26 Day 28.
Short-term follow-up
Long-term follow-up until end of Year 4 

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
25
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Participant PRO 
daily e-diary 
(participant 
subgroup)
See 
inst
ruc
tio
ns
X
X
X
X
See instructions
Screening: collect at least 1 day and up to 7 
days of daily data in the week prior to 
starting blinded study drug on C1D1
For Cycles 1, 2, and 3 only 
Subgroup of approximately 300 
participants will record daily e-diary 
information on the number of stools, 
diarrhea, use of loperamide, blinded study 
drug dosing, ET dosing, fatigue, arthralgia, 
and hot flashes.
Participant Paper 
Diary (blinded 
study drug)
See Instructions
Sites distribute the paper diary to 
participants on C1D1.
Participants record date and times of every 
dose of blinded study drug taken from 
C1D1 through C3D1.
Patients should bring paper diary to every 
visit for site review.
HCRU
X
X
See Instructions
See Instructions
X
X
Collected at in-clinic visits on Day 1 of 
cycles when PROs are collected. See 
Section 8.10.3.
Survival 
assessment
X
X
X

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
26
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Post-
discontinuation 
anticancer 
therapies
X
X
ET after study intervention discontinuation or 
other breast cancer treatment are collected 
until study completion, participant 
discontinuation from study, or death.
Administer 
abemaciclib/place
bo
X
X
C1D1 is defined as the date the first dose 
of blinded study treatment is taken by the 
patient.
See Section 6.1.
Administer ET 
FAX
X
X
Per standard of care as prescribed by 
physician. 
See Section 6.1.
Abemaciclib/plac
ebo drug 
accountability
X
X
X
X
X
Document tablets dispensed and returned at 
C1D1, C2D1, C3D1, and every in-clinic 
visit thereafter during the on-study 
intervention period.
See Section 6.3.4.
ET compliance 
X
X
X
X
See instructions
Recorded on C2D1, C3D1, and every 
subsequent visit (in-clinic and phone) 
during the on-study intervention period.
For each ET, record the number of doses 
missed since the previous visit.
For follow-up period, continue to 
document ET treatment (including 
switching of ET, and discontinuation and 
starting dates).
See Section 6.3.4.

CONFIDENTIAL
Protocol I3Y-MC-JPCW(d)
27
Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Sample 
collection
PK
See Section 1.3.2
Collected on C1D1, C2D1, and C3D1. See 
Section 1.3.2 for sample collection timing 
and procedure details.
See procedure row for Participant Paper 
Diary for tracking blinded study drug timing.
Whole blood for 
genetic/biomarker 
analysis
X
See Sections 1.3.2, 8.7, and 8.8. Whole-blood 
sample required.
Plasma for biomarkers
X
See 
instructi
ons
See 
instructio
ns
See 
instruct
ions
See Sections 8.8 and 1.3.2.  
Plasma collected D1 at Cycles 1, 3, 6, 12, 
C26 Day 28, V802, and Year 5 (first visit 
of Year 5). 
At C1D1, must be taken before first dose.  
V802 sample may be taken after V802 if 
missed at V802.
Year 5 sample for participants on study 
without IDFS event.
Serum for biomarkers
X
See Sections 8.8 and 1.3.2. 
Must be taken before first dose on C1D1.

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Screening, On-Study, and Post-Treatment Schedule of Activities (prior to amendment [d])
Screening
On-Study Intervention
Cycle = 28 days
Post-Treatment
(Day 
Relative 
to C1D1)
Cycle 1
Cycle 2
Cycles 3-12
Cycles 13-26
(even-numbered 
cycles only)
Cycle 26 
Short-
term 
follow-
upb
Long-
term 
follow-
upc
Instructions
(±3 
d)
(±3 d)
(±5 d)
(±10 d)
(±5 d)
(±5 d)
(±28 d)
2814
D1a
D15
D1
D15
D1
D1
D28
V801
V802-
8XX
Clinic visits: Cycles 1-4, 6, 9, 12, 18, 24, 26 
(Day 28), V801, V802. 
Phone visits: Cycles 5, 7, 8, 10, 11, 14, 16, 
20, 22, 26 (Day 1).
For V803-8XX, clinic visits are preferred, but 
phone visits are acceptable if unable to attend 
clinic visit. 
Procedure
Tumor tissue for 
biomarkers
X
See Sections 8.8 and 1.3.2.  
Confirm tissue availability prior to 
randomization.
Breast tissue preferred; lymph node tissue 
is acceptable.
For participants who received neoadjuvant 
therapy, both a pre- and a post-neoadjuvant 
treatment tissue sample should be sent to 
the central laboratory if available.
Recurrence tissue and 
plasma samples 
(biomarker)
Collect at time of local/regional and distant disease recurrence.

See Sections 8.8 and 1.3.2

Tissue sample mandatory for 
participants who undergo biopsy to 
confirm recurrence.

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Abbreviations: AE = adverse event; Blinded Study Intervention = abemaciclib/placebo; C = cycle; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; d = day; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; 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; ET = endocrine therapy; FACT-GP5 = Functional Assessment of Cancer Therapy- General item; HCRU = Health Care Resource 
Utilization; ICF = informed consent form; IDFS = invasive disease-free survival; MRI = magnetic resonance imaging; PA = posteroanterior; PET = positron 
emission tomography; PK = pharmacokinetics; PRO = patient-reported outcome; SAE = serious adverse event; ULN = upper limit of normal; V = visit.
a
C1D1 = date of first dose of blinded study drug.
b
The short-term follow-up visit takes place 30 days (±5 days) after the on-study intervention period discontinuation date.
c
The long-term follow-up period begins the day after the short-term follow-up visit, with visits occurring every 6 months (±28 days) until end of Year 5, then 
annually (±28 days) from Year 6 up to Year 10 or study completion, whichever occurs first.

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1.3.1.
Continued Access Schedule of Activities
Continued Access Schedule of Activities
Visit
Study 
Interventions
Short Term 
Follow-Up
Instructions
Cycle 1-26
V801
Administer study 
intervention
X
See Section 6.1 for administration 
details
Follow prescribing guidelines for 
routine monitoring
AE collection
X
X
Per CTCAE v5.0
Collect all AE and SAE regardless 
of causality
1.3.2.
Pharmacokinetic, Genetics, and Biomarker Sampling Schedule
Upon approval of amendment (d), PK and biomarker samples will longer be obtained, and this 
section is no longer applicable for participants on study.

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2.
Introduction
Study I3Y-MC-JPCW (JPCW; eMonarcHER) is a Phase 3 global, randomized, 
placebo-controlled trial in participants with high-risk, node-positive, hormone receptor positive 
(HR+), human epidermal growth factor receptor-2 positive (HER2+) early breast cancer who 
have completed standard adjuvant HER2-targeted therapy.
This proposed study will investigate whether the addition of abemaciclib, a potent inhibitor of 
cyclin-dependent kinase 4 and 6 (CDK4 and 6), to standard adjuvant endocrine therapy (ET) post 
completion of HER2-targeted therapy improves invasive disease-free survival (IDFS) in 
participants with node-positive, HR+, HER2+, breast cancer at high risk of recurrence by 
improving the absolute benefit from ET. 
2.1.
Study Rationale
Human epidermal growth factor receptor-2 is overexpressed in approximately 20% to 25% of 
breast carcinomas with approximately half of these being hormone receptor positive (HR+). 
Human epidermal growth factor receptor-2 positive breast cancer is associated with poor 
prognosis and high mortality rates. Although adjuvant HER2-targeted therapies have 
significantly improved outcomes in patients with early-stage HER2+ breast cancer, there is a 
subgroup of patients who will experience invasive disease recurrence either on or shortly after 
completion of optimal adjuvant HER2-targeted therapy, which could ultimately become 
incurable. Several clinicopathological factors are known to be associated with increased risk of 
recurrence: Presence of axillary lymph node involvement at diagnosis, large size of the primary 
invasive tumor (≥5 cm), higher histologic grade and pathological residual disease after 
neoadjuvant treatment (Lambertini et al. 2019; von Minckwitz et al. 2017; von Minckwitz et al.
2019). The reasons associated with early recurrences are not completely understood; however, 
this phenomenon could be explained because cancer cell clones may survive and evolve during 
standard endocrine and HER2-targeted therapies. In HER2+ breast cancer tumors, cyclin D1 and 
CDK4 are critical drivers in cell proliferation (Goel et al. 2016).
Abemaciclib is an oral, selective, and potent ATP-competitive inhibitor of CDK4 and CDK6. 
CDK4 and CDK6 complex with D-type cyclins to promote cell growth by facilitating the 
progression of cells from the G1 to the S-phase of the mammalian cell cycle (Ortega et al. 2002). 
This promotion of cell growth occurs primarily by counteracting the effects of the growth 
suppressor retinoblastoma (Rb) protein, whereby the reversal of Rb-mediated suppression is 
achieved by the phosphorylation of this protein by CDK4 and/or CDK6 (Ortega et al. 2002). 
Preclinical studies in breast cancer models with abemaciclib indicated that sensitivity to CDK4 
and CDK6 inhibition was greater in HR+ lines with luminal histology, including a subset of 
those that are estrogen receptor-positive (ER+), HER2+ (O’Brien et al. 2018). Work from Goel 
et al. suggests that CDK4 and CDK6 inhibitors can delay recurrence in a transgenic HER2+
breast cancer model. In mice models induced with HER2+ tumor formation, the onset of 
recurrent disease was significantly prolonged in abemaciclib-treated mice compared to the 
control group (median time to recurrence 108 days versus 135 days; hazard ratio=0.23; p=.035).
Their observations indicated that a small number of cyclin D1-expressing tumor cells survive 
HER2 withdrawal, and that targeting these cells with a CDK4 and CDK6 inhibitor can prolong 
the time to tumor recurrence. This suggests a role for CDK4 and CDK6 inhibitors as an adjuvant 

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therapy for breast cancer, treating microscopic residual disease with a view to preventing disease 
recurrence (Goel et al. 2016).
Abemaciclib has been approved for the treatment of patients with HR+, HER2-negative,
advanced or metastatic breast cancer. Indications include:

abemaciclib in combination with an aromatase inhibitor (AI) as initial endocrine-based 
therapy in post-menopausal women

abemaciclib in combination with fulvestrant in women with disease progression 
following endocrine therapy, or

abemaciclib as monotherapy in adults with disease progression following endocrine 
therapy and prior chemotherapy in the metastatic setting.
In a more recent Phase 3 study (monarchE), the efficacy of abemaciclib in combination with ET 
was compared to ET alone in patients with HR+, HER2-, node-positive, early breast cancer at 
high risk of recurrence. High risk was defined as: ≥4 positive axillary lymph nodes; 1-3 positive 
axillary lymph nodes with either histologic Grade 3 and/or tumor size ≥5 cm; or 1-3 positive 
axillary nodes with Ki-67 index ≥20% in pre-treated breast tissue as measured by a central 
laboratory. At a preplanned interim efficacy analysis, the combination resulted in a statistically 
significant and clinically meaningful improvement in IDFS (hazard ratio=0.75; confidence 
interval [CI]=95% [0.60 to 0.93]; p=.01) corresponding to a 25% reduction in the risk of 
developing invasive disease. Two-year IDFS rates were 92.2% in the abemaciclib arm vs 88.7% 
in the ET arm (Johnston et al. 2020).
The Phase 1 study, Study I3Y-MC-JPBA, demonstrated preliminary clinical activity for 
abemaciclib in patients with HER2+ mBC (Patnaik et al. 2016). In a subset of 11 patients with 
HR+, HER2+ mBC, an objective response rate of 36% (N=4, of which 3 were receiving 
concomitant ET) and a median progression-free survival (PFS) of 7.2 months. The Phase 2 study 
I3Y-MC-JPBO examined the impact of abemaciclib on brain metastases in patients with breast
or lung cancer and melanoma. In a subset of 27 patients with advanced HR+, HER2+ breast 
cancer, who received abemaciclib monotherapy (with no concomitant HER2-targeted therapy), a 
median extracranial progression-free survival (PFS) (per Response Evaluation Criteria in Solid 
Tumors [RECIST]) of 7.3 months (95% CI=3.3, 13.3) was reported (Tolaney et al. 2020b). In the 
Phase 2 study MonarcHER, in which patients with HR+, HER2+ mBC were enrolled, 
abemaciclib in combination with fulvestrant and trastuzumab showed a significant improvement 
in median PFS of 8.3 months vs 5.7 months in the standard of care group (chemotherapy and 
trastuzumab) with a hazard ratio=0.67 (95% CI=0.45, 1.00) and p=.051. The combination of 
abemaciclib, fulvestrant, and trastuzumab was also associated with improved overall response of 
36% (vs 16% standard of care) (Tolaney et al. 2020a).
Due to the high unmet need to develop new therapeutic options for patients with node-positive, 
HR+, HER2+, early breast cancer at high risk of recurrence, the scientific body of evidence 
supportive of the anticancer activity of abemaciclib in HER2+ disease, and the recent results of 
improved IDFS in high-risk, HR+, HER2-negative patients in the adjuvant setting, we propose to 
study abemaciclib in combination with ET after completion of adjuvant HER2-targeted therapies 
in high-risk participants. Optimizing standard adjuvant therapy by adding novel targeted 
therapies is warranted for patients with early breast cancer and at high risk of disease recurrence.

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For eMonarcHER, high risk has been defined by the following characteristics at the time of 
definitive surgery:

Participants who received neoadjuvant chemotherapy along with HER2-targeted treatment
and

residual disease in at least 1 axillary lymph node or

a residual tumor measuring ≥5 cm, or

a residual tumor of any size that has direct extension to the chest wall and/or skin 
(ulceration or skin nodules).

Participants who had definitive surgery prior to systemic therapy, completed adjuvant 
chemotherapy along with HER2-targeted therapies (trastuzumab and pertuzumab), and

tumor involvement in ≥4 ipsilateral axillary lymph nodes, or

tumor involvement in 1 to 3 ipsilateral axillary lymph node(s) and
histological Grade 3, or
primary tumor size of ≥5 cm.
2.2.
Background
Breast cancer is one of the most common cancers in women in the United States (US) and 
Europe and is the second leading cause of cancer death in women worldwide (Siegel et al. 2019). 
Approximately 1% of all breast cancers are diagnosed in men (Borgen et al. 1992; Senkus et al. 
2015). The HR+, HER2-negative breast cancer subtype is the most prevalent of breast cancer 
subtypes and accounts for approximately 70% of all breast cancers (Howlader et al. 2014). 
Overexpression of HER2 is predictive of treatment response and prognostic for disease 
recurrence and death and occurs in 20% to 25% of breast cancers, with at least half of these 
tumors being HR+ (Konecny et al. 2003; Ulas et al. 2015). Human epidermal growth factor 
receptor-2 overexpression is associated with an aggressive clinical phenotype that includes 
high-grade tumors, increased growth rates, early systemic metastasis, and decreased rates of 
disease-free and overall survival (OS) (Slamon et al. 1987; Iborra and Stickeler 2016). 
Approximately 90% of patients with breast cancer are diagnosed at an early stage of their disease 
(Howlader et al. 2016). Such patients do not possess evidence of overt distant tumor spread and,
therefore, may be treated with curative intent with surgical, radiotherapy, and systemic 
treatments (NCCN guidelines 2020). Depending on diagnosis, including histology, grade, tumor 
size, and lymph node involvement, treatment options may include neoadjuvant/adjuvant therapy 
with chemotherapy, ET, and HER2-targeted therapy (up to 1 year) (Goldhirsch et al. 2013;
NCCN 2020). Early recurrence within the first 2 years of adjuvant ET in HR+ breast cancer is 
known to represent primary endocrine resistance (Cardoso et al. 2018). For patients with HR+,
HER2+ early breast cancer treated with chemotherapy and trastuzumab therapies, the time to
recurrence (median 2.9 years) is longer compared to patients with HR-, HER2+ tumors (median 
1.9 years); however, a higher rate of relapse is noted between years 5 to 10 in patients with HR+,
HER2+ breast cancer with more lymph node involvement, particularly those with N3 disease 
(Chumsri et al. 2019). Patients with HR+ tumors are typically treated with about 5 to 10 years of 
ET (AIs with or without ovarian function suppression or tamoxifen as per physician’s choice) 
following surgery and/or completion of their cytotoxic chemotherapy according to international 
guidelines (Senkus et al. 2015; Cardoso et al. 2019). Women with early-stage HR+ breast cancer 
may initially respond to endocrine treatment; however, 15% to 20% of tumors are intrinsically 

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34
resistant to treatment, and another 30% to 40% acquire resistance to treatment over years,
leading to the development of metastases and death (Anurag et al. 2018; Cortés et al. 2020)
Features that may indicate a higher risk of distant disease relapse include: large primary tumor 
size, involvement and degree of involvement of axillary lymph nodes with tumor (regardless of 
HR status), high histologic grade of the primary tumor, HER2+ tumors, or lack of pathological 
complete response (pCR) after neoadjuvant therapy (Senkus et al. 2015; von Minckwitz et al. 
2019; Cortés et al. 2020). Specifically, patients with non-pCR after neoadjuvant chemotherapy
plus HER2-targeted therapy, and patients with lymph node involvement have been reported to 
have worse outcomes and higher recurrence rates (Chumsri et al. 2019; von Minckwitz et al. 
2019). For patients with HER2+ early breast cancer with lymph node involvement, the 
recurrence-free survival rate is approximately 73% compared to 89% for those with no lymph 
node involvement (Ulas et al. 2015). Despite the outstanding improvements in survival with the 
introduction of HER2-targeted agents, such as trastuzumab in the adjuvant setting, many 
patients, particularly those with high-risk disease, develop disease recurrence (approximately 
25% to 30%) and ultimately die from their cancer (De Laurentiis et al. 2005; Slamon et al. 2011; 
André et al. 2014; Perez et al. 2014; Slamon et al. 2016; Cameron et al. 2017).
Recently, 2 clinical studies evaluating adjuvant HER2-targeted therapies have shown benefit in 
improving IDFS in participants with HER2+ early breast cancer, including those with high-risk 
disease. In the APHINITY study, high-risk participants with 4 or more positive lymph nodes or 
≥5 cm tumors had a 3-year IDFS rate of 87.5%, each with adjuvant trastuzumab and pertuzumab 
combination (von Minckwitz et al. 2017). In the KATHERINE study, participants with 
node-positive residual disease post-neoadjuvant therapy who received trastuzumab emtansine 
(T-DM1) in the adjuvant setting had a 3-year IDFS rate of 83%. More specifically, participants 
with 2 and 3 positive regional lymph nodes at definitive surgery had 3-year IDFS rates of 81.1% 
and 52.0% respectively. Also notable, participants with residual tumors ≥5 cm or with direct 
extension into the chest wall and/or the skin had 3-year IDFS rates of 79.8% and 70% 
respectively. These data highlight a residual high-risk population who might benefit from 
additional therapies remains (von Minckwitz et al. 2019).
Beyond initial adjuvant HER2-targeted therapy, neratinib has recently been approved as 
extended adjuvant therapy after trastuzumab-based treatment. Neratinib showed a 2-year IDFS 
rate of 93.9% (95% CI=92.4, 95.2) in the neratinib group compared to 91.6% (90.0, 93.0) in the 
placebo group (Chan et al. 2016). However, neratinib use has not been reported as extended 
adjuvant treatment after trastuzumab combined with pertuzumab or TDM-1 regimens.
Importantly, despite improvements in IDFS for patients with high-risk early breast cancer, there 
remains an unmet medical need to provide new treatment options to further improve outcomes 
for HR+, HER2+ early breast cancer patients who have completed adjuvant HER2-targeted
therapy and have high-risk features.
2.2.1.
Trastuzumab
Based on 3 pivotal studies, 1 year of the monoclonal antibody trastuzumab-based therapy has 
become an established global standard of care in the adjuvant setting in patients with HER2+ 
early breast cancer. European Society for Medical Oncology (ESMO) clinical practice guidelines 
currently recommend 1 year as the standard (Cardoso et al. 2019). Trastuzumab binds to the 
extracellular domain intravenous (IV) of HER2, thereby inhibiting downstream cell signaling 

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that is implicated in cell proliferation, survival, motility, and adhesion (Ross et al. 2009). In the
preoperative setting, combination of trastuzumab with or without pertuzumab plus chemotherapy 
is recommended for patients with high-risk breast cancer. Post operatively, for patients with high 
risk for recurrence and/or non-pCR after neoadjuvant therapy, HER2-targeted therapy with 
trastuzumab is the standard adjuvant therapy for HER2+ breast cancer (von Minckwitz et al. 
2017; NCCN 2020). In the HERA trial, the relative reduction in risk of a disease-free event and 
death were 24% and 26%, respectively, with the addition of 1 year of adjuvant trastuzumab in 
women with HER2+ early breast cancer (Cameron et al. 2017). In patients with HER2+ disease, 
an overall 10-year disease-free survival of 69% following 1 year of trastuzumab was reported, 
and additionally in the HR+ cohort, the 10-year disease-free survival was 72% (Cameron et al. 
2017).
2.2.2.
Pertuzumab
Pertuzumab, a HER2/neu receptor antagonist, is a dimerized human monoclonal antibody that 
received approval for use in combination with trastuzumab in the neoadjuvant setting. In 2017, 
based on results of the APHINITY study (von Minckwitz et al. 2017), pertuzumab, combined 
with trastuzumab, received approval in the adjuvant treatment setting for patients with HER2+ 
early breast cancer at high risk of recurrence (pertuzumab package insert, 2013). High-risk 
patients included patients such as those with HR- or those with node-positive breast cancer. This
study demonstrated that the addition of pertuzumab to a trastuzumab-based regimen significantly 
improves IDFS rates. The 3-year IDFS rates were 94.1% versus 93.2% in the intent-to-treat 
(ITT) population (hazard ratio=0.81; 95% CI=0.66, 1.00; p=.045). The proportion of IDFS 
events for patients with node-positive disease was 9.2% (n=139) and 12.1% (n=181) in the 
pertuzumab and placebo arms, respectively (hazard ratio=0.77, 95% CI=0.62, 0.96). In the 
cohorts of participants with node-positive disease, the 3-year rates were 92% versus 90.2% 
(hazard ratio=0.77; 95% CI=0.62, 0.96; p=.02). Higher-risk participants with 4 or more positive-
nodes reported a 3-year IDFS of 87.5% versus 84.7% (hazard ratio=0.79; 95% CI=0.59, 1.05)
(von Minckwitz et al. 2017).
2.2.3.
Trastuzumab Emtansine (T-DM1)
In 2018, results from the KATHERINE study demonstrated that in participants who had residual
disease at surgery and after neoadjuvant chemotherapy plus anti-HER2-targeted therapy, 
14 cycles of T-DM1, an antibody drug conjugate of trastuzumab and the cytotoxic agent 
emtansine (DM1) resulted in a 50% lower risk of recurrence of invasive disease or death 
compared to adjuvant trastuzumab alone in patients with HER2+ early-stage breast cancer. The
estimated percentage of participants who were free of invasive disease at 3 years was 88.3% in 
the T-DM1 arm and 77.0% in the trastuzumab arm (hazard ratio for invasive disease or 
death=0.50; 95% CI=0.39, 0.64; p<.001) (von Minckwitz et al. 2019). Participants with 
node-positive residual disease remained at higher risk with a reported 3-year IDFS of 83% for 
T-DM1 versus 67.7% for trastuzumab (hazard ratio for invasive disease or death=0.52; 
95% CI=0.38, 0.71) (von Minckwitz et al. 2019). Trastuzumab emtansine in the adjuvant setting 
is currently approved for use in the US and Europe for patients with residual disease in the 
resected breast or axilla post-neoadjuvant therapy. 

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2.2.4.
Neratinib
ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor 
(TKI), significantly improves 2-year IDFS after (neo)adjuvant trastuzumab and chemotherapy 
(either sequentially or concomitantly) in women with HER2+ breast cancer (stratified hazard 
ratio=0.67; 95% CI=0.50, 0.91; p=.0091) compared to placebo. The 2-year IDFS rate was 93.9% 
(95% CI=92.4, 95.2) in the neratinib arm and 91.6% (95% CI=90.0, 93.0) in the placebo arm 
(Chan et al. 2016). In the subset analysis of IDFS, neratinib showed greater benefit to 
participants with HR+ breast cancer (hazard ratio=0.51; 95% CI=0.33, 0.77) (Chan et al. 2016). 
In the ExteNET trial, greater and more durable efficacy was observed in the subgroup with HR+ 
disease who initiated treatment within 1 year of completing trastuzumab. In this subgroup of 
patients, the absolute invasive disease-free survival (iDFS) benefit of neratinib versus placebo at 
5 years was 5.1%, and the absolute OS benefit at 8 years was 2.1% (Chan et al. 2020). Severe 
diarrhea was a limiting factor with 40% of participants who received neratinib experiencing 
Grade 3 events and less than 1% experiencing Grade 4 events. Diarrhea led to treatment 
discontinuation in 17% of participants after a median of 20 days (interquartile range 9-56) (Chan 
et al. 2016). There is no data to support the use of neratinib post pertuzumab or T-DM1, and it 
remains unknown if the benefit is maintained for patients who have previously received dual 
blockade with trastuzumab and pertuzumab.
2.2.5.
Endocrine Therapy
The majority of breast cancer diagnosis are known to be HR+. Endocrine therapy represents a 
key therapeutic strategy for patients with HR+ tumors and has been associated with significant 
clinical benefits. However, resistance to ET is a common clinical problem in this population 
which may lead to disease relapse and metastases. 
Neoadjuvant or adjuvant ET is indicated in all patients with detectable ER expression (defined as 
≥1% of invasive cancer cells), irrespective of the use of chemotherapy (NCCN 2020). The choice 
of endocrine agent (tamoxifen and/or one of the 3 selective AIs: Anastrozole, letrozole, or 
exemestane) is primarily determined by the patient’s menopausal status. All AIs have shown 
similar antitumor efficacy and toxicity profiles in randomized studies in the adjuvant and 
preoperative setting. Overall, international clinical guidelines (ESMO [Senkus et al. 2015], Saint 
Gallen International Expert Consensus [Coates et al. 2015]) and NCCN guidelines (2020) for 
postmenopausal patients, AI should be at least part of ET. In premenopausal patients, standard 
ET includes tamoxifen with or without ovarian suppression for 5 to 10 years, or an AI for 5 years 
with ovarian suppression in selected patients at high risk of disease recurrence (that is, pretreated 
with chemotherapy) based on the TEXT and SOFT studies (Francis et al. 2018). In 
postmenopausal patients, use of AIs (both nonsteroidal and steroidal) and tamoxifen either 
sequentially, as monotherapy, or extended therapy for a total duration of 5 to 10 years is a valid 
option (Francis et al. 2018). Men with breast cancer are treated with AI similarly to 
postmenopausal women, considering testicular suppression with a gonadotropin-releasing 
hormone (GnRH) analog (Zagouri et al. 2013).

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2.2.6.
Abemaciclib
Abemaciclib in combination with ET is approved globally for management of HR+, 
HER2-negative advanced breast cancer as initial therapy with an AI (MONARCH 3) (Goetz et 
al. 2017), or after disease progression on prior ET in combination with fulvestrant (MONARCH 
2) (Sledge et al. 2017; Sledge et al. 2019). Additionally, abemaciclib is approved by the US Food 
and Drug Administration (FDA) as monotherapy treatment for endocrine refractory disease in 
patients with HR+, HER2-negative advanced breast cancer (MONARCH 1) (Dickler et al. 2017). 
In the monarchE study, an open-label, randomized Phase 3 trial in participants with HR+, 
HER2-, node-positive, high-risk early breast cancer, the addition of abemaciclib to standard 
adjuvant ET resulted in a statistically significant improvement in IDFS. Participants with ≥4 
positive axillary lymph nodes; 1-3 positive axillary lymph nodes with either histologic Grade 3 
and/or tumor size ≥5 cm; or 1-3 positive axillary nodes with Ki-67 index ≥20% in pre-treated 
breast tissue as measured by a central laboratory were eligible to participate. The addition of 
abemaciclib resulted in a 25% reduction in the risk of developing an IDFS event relative to ET 
alone and an absolute improvement of 3.5% in 2-year IDFS rates (Johnston et al. 2020).
Abemaciclib has an acceptable safety profile in the respective patient populations studied in the 
two Phase 3 trials for advanced breast cancer (MONARCH 2 and MONARCH 3) in combination 
with ET, the Phase 2 study (MONARCH 1), a monotherapy study, and in a Phase 3 trial for early 
high-risk breast cancer (monarchE). The safety monitoring and corresponding dose adjustment 
guidelines used in these clinical studies effectively managed the toxicity profile of abemaciclib. 
The most frequently reported adverse events (AEs) include: diarrhea, neutropenia, fatigue, 
nausea, vomiting, abdominal pain, decreased appetite, and anemia. Additionally, other clinically 
relevant AEs are venous thromboembolic event (VTE, [including pulmonary embolism (PE) and 
deep vein thrombosis (DVT)]), alanine aminotransferase (ALT) increased, aspartate 
transaminase (AST) increased, and interstitial lung disease (ILD)/pneumonitis.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of abemaciclib may be found in the Investigator’s Brochure, Participant 
Information Leaflet, Package Insert, and/or Development Safety Update Report or Summary of 
Product Characteristics.
More detailed information about the known and expected benefits and risks of standard of care 
ETs, such as tamoxifen, anastrozole, letrozole, exemestane, and GnRH agonists, may be found in 
the respective Patient Information Leaflet, Package Insert, or Summary of Product 
Characteristics.

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2.3.1.
Risk Assessment
The risk assessment table below describes the risk assessment associated with abemaciclib. Since 
this study is a blinded study (abemaciclib plus ET versus placebo plus ET), it is unknown if all 
participants will experience any of these risks.
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention Abemaciclib
Grade ≥3 Diarrhea
In MONARCH 2 and MONARCH 
3 studies, diarrhea of any grade 
was observed in 81%-86% of 
abemaciclib-treated participants, 
and Grade ≥3 diarrhea was 
observed in 9%-13% of 
abemaciclib-treated participants.
In monarchE, diarrhea of any 
grade was observed in 83% of 
abemaciclib-treated participants, 
and Grade ≥3 diarrhea was 
observed in 8% of abemaciclib-
treated participants.
Grade ≥3 diarrhea is considered a 
key risk based on frequency of 
occurrence, severity, and potential
limited tolerability.
Investigators should evaluate prior 
history including 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 prior to 
participant inclusion into study.
Instruct participants to initiate 
anti-diarrheal therapy at first sign
of loose stools, increase oral fluid 
intake, and notify the investigator. 
Dose modifications and 
discontinuation of blinded study 
drug as per guidance provided in 
protocol table for management of 
diarrhea (See Section 6.6).
Grade ≥3 Neutropenia
Neutropenia of any grade occurred 
in 41%-46% of abemaciclib-
treated participants in 
MONARCH 2 and MONARCH 3 
studies. Grade ≥3 neutropenia 
occurred in 21%-27% of 
abemaciclib-treated participants. 
Median time to onset of 
neutropenia was 11-15 days.
Neutropenia of any grade occurred 
in 45% of abemaciclib-treated 
participants in monarchE. Grade 
≥3 neutropenia occurred in 19%.
Grade ≥3 neutropenia is 
considered a key risk based on 
frequency of occurrence, severity,
and the potential complication of 
serious and life-threatening/fatal 
infection.
Inclusion criterion of absolute 
neutrophil count (ANC)
1.5×109/L.
Laboratory monitoring of 
complete blood count every 
2 weeks for the first 2 months,
monthly for the next 2 months,
and as clinically indicated. 
Dose modifications and 
discontinuation of blinded study 
drug as per guidance provided in 
protocol table for management of 
hematological toxicity (see 
Section 6.6).

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39
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Interstitial Lung Disease 
(ILD)/Pneumonitis
Severe, life-threatening, or fatal 
ILD and/or pneumonitis can occur 
in participants treated with 
abemaciclib and other CDK4/6 
inhibitors. Across clinical trials 
(MONARCH 1, MONARCH 2, 
and MONARCH 3), 3.3% of 
abemaciclib-treated participants 
had ILD/pneumonitis of any 
grade, 0.6% had Grade 3 or 4, and 
0.4% had fatal outcomes.
In monarchE, 2.7% of 
abemaciclib-treated participants 
had ILD/pneumonitis of any 
grade, and 0.4% had Grade ≥3.
ILD/pneumonitis is included as a 
key risk based on severity of the 
condition, lack of predictability,
and association with significant
morbidity and mortality.
Investigator should assess for 
preexisting and active symptoms 
for ILD/pneumonitis and severe 
dyspnea at rest or requiring 
oxygen therapy prior to participant 
inclusion into study. Patients with 
such preexisting conditions or 
ongoing symptoms associated 
with ILD/pneumonitis are 
excluded from participation. 
Monitor for symptoms, such as 
hypoxia, cough, dyspnea, or 
radiologic changes (interstitial 
infiltrates) indicative of ILD. 
Dose modifications and 
discontinuation of blinded study 
drug as per guidance provided in 
protocol table for management of 
ILD/pneumonitis (Section 6.6).
Grade ≥3 ALT increased
In MONARCH 2 and MONARCH 
3 studies, Grade ≥3 increase in 
ALT was observed in 4% to 6% of 
abemaciclib-treated participants. 
In MONARCH 3, Grade ≥3 
increases in ALT (6% versus 2%) 
were reported in the abemaciclib 
and placebo arms, respectively. In 
MONARCH 2, Grade ≥3 
increases in ALT (4% versus 2%) 
were reported in the abemaciclib 
and placebo arms, respectively. 
In monarchE, Grade ≥3 increases
in ALT (2.5% vs 0.6%) were
reported in the abemaciclib vs ET 
alone arms, respectively.
ALT elevations (hepatic 
laboratory results) ≥5×ULN and 
≥10×ULN were reported with a 
higher incidence with the 
abemaciclib plus ET arm than 
with ET alone: MONARCH 3,
5.9% vs 1.9% and 1.24% vs 
0.63%, respectively; MONARCH 
2, 4.4% vs 0.9% and 2.3% vs 
0.9%, respectively.
Inclusion criterion of adequate 
hepatic function defined as total 
bilirubin ≤1.5×ULN and ALT and 
AST ≤3.0×ULN.
Laboratory monitoring of liver 
function tests (LFTs) every 
2 weeks for the first 2 months, 
monthly for the next 2 months, 
and as clinically indicated.
Dose modifications and 
discontinuation of blinded study 
drug as per guidance provided in 
protocol table for management of 
ALT increased (see Section 6.6).
Additional risk minimization
measure: Selected laboratory 
testing in the event of a 
treatment-emergent hepatic 
abnormality (Appendix 5, 
Section 10.5).

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40
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Median time to onset of Grade ≥3 
ALT elevation was 57 days in 
MONARCH 2 and 61 days in 
MONARCH 3. Median time to 
resolution of ALT elevation was 
14 days in both studies. Grade ≥3 
increased ALT is included as a 
key risk based on severity of the 
condition, potential association 
with hepatic synthetic dysfunction, 
and the requirement to discontinue 
abemaciclib in response to the 
event.
Venous Thromboembolic Events
(VTE)
In MONARCH 2 and 
MONARCH 3 studies, VTE was 
observed in 5% of participants 
treated with abemaciclib 
combined with ET (either AI or 
fulvestrant), and in 0.9% of 
participants treated with ET plus 
placebo.
In monarchE, VTE (all grades) 
was observed in 2.4% of 
participants treated with 
abemaciclib combined with ET
(either tamoxifen or AI).
VTE is included as a key risk 
based on severity of the 
conditions, lack of predictability,
and potentially significant clinical 
complications, including fatal 
outcomes.
Exclusion of participants with a 
history of VTE (for example, DVT 
of the leg or arm and/or 
pulmonary embolism) from study.
Monitor for symptoms and signs 
of DVT and pulmonary embolism
and treat as clinically indicated.
Suspend dose and treat as 
clinically indicated.
Blinded study drug may be 
resumed when participant is 
clinically stable (Section 6.6).
Abbreviations: AI = aromatase inhibitor; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CDK4/6 = cyclin-dependent kinases 4 and 6; DVT = deep vein thrombosis; NSAI = nonsteroidal aromatase
inhibitor; ULN = upper limit of normal.
2.3.1.1.
Study Intervention
This was initially a randomized, double-blinded, Phase 3 study of abemaciclib plus ET versus 
placebo plus ET in adult participants with high-risk, HR+, HER2+ early breast cancer who had 
completed standard adjuvant HER2-targeted therapy. Abemaciclib has an acceptable safety 
profile in the respective participant populations studied in the three Phase 3 trials (MONARCH 
2, MONARCH 3, and monarchE) in combination with ET and the Phase 2 monotherapy study 
(MONARCH 1). The safety monitoring and corresponding dose adjustment guidelines used in 
these clinical studies effectively managed the toxicity profile of abemaciclib. 

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41
The original design of the control arm was based on current standard medical practice, ethical 
standards, and the statistical analysis plan (SAP). Using an appropriate concurrent placebo-
control arm was intended to enable direct statistical estimation of benefits and harms due to 
study therapy and minimizes bias in the assessment and interpretation of observed treatment 
effects.
The rationale of using ET plus placebo as a control arm was because ET is currently the standard 
of care in this population and the use of a double-blind and placebo control minimizes the future 
assessment of bias.
After approval of amendment (d), and according to local regulations, participants who are on 
study treatment will be unblinded and enter the Continued Access period and follow the 
Continued Access SoA (Section 1.3). If the investigator determines that continuation of 
abemaciclib may offer potential benefit to participants receiving study treatment, participants 
may continue to receive study treatment in the Continued Access period for a maximum of 26 
cycles until any of the criteria for discontinuation are met (Section 7.1). Investigators will 
perform standard procedures and tests for breast cancer surveillance and management. 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 unless they provide source documentation for 
an AE. Participants receiving placebo will be discontinued. 
2.3.1.2.
Study Procedures
Venipuncture to obtain laboratory data is a common clinical practice with low risks of bleeding, 
vascular or soft tissue injury, and infection (Buowari 2013). Radiologic guidelines for detection 
of recurrent disease include commonly used imaging modalities. Risks include low levels of 
radiation exposure and allergic reactions to intravenous contrast (Sammet 2016; Garcia et al.
2017). The investigator will select the most appropriate imaging study for the participant, 
keeping in mind those potential risks.
2.3.2.
Benefit Assessment
Based on the efficacy and safety outcomes in three Phase 3 studies, 2 of which were in HR+, 
HER2-negative mBC, and 1 large study in HR+, HER2-negative early breast cancer, the use of 
abemaciclib in high-risk HR+, HER2+ early breast cancer was warranted to justify the study 
meet the unmet need in this patient population. Details are provided in Sections 2.1 and 2.2.
2.3.3.
Overall Benefit: Risk Conclusion
The key risks associated with abemaciclib and other approved CDK4 and CDK6 inhibitors are 
well known. Health care professionals involved in the care of cancer patients are familiar with 
the management of these risks. Additionally, the proposed language and guidance detailed in the 
protocol are considered sufficient for managing and mitigating the key risks.
The study was determined to be no longer feasible due to slow accrual and changes in the 
treatment landscape for HER2+ breast cancer that are anticipated to improve patient outcomes 
and diminish the unmet need; therefore, enrollment was terminated 03 February 2022. As of 

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Protocol I3Y-MC-JPCW(d)
42
amendment (d), investigators and participants will be unblinded so that they may make informed 
decisions regarding continued participation in the trial. 
Overall, given the current unmet medical need in the proposed study population and the well-
understood AE profile of abemaciclib and the required study procedures, participants 
randomized to abemaciclib who are deemed, by their investigator, to have potential benefit and 
who wish to continue the study will be allowed to remain on study. 

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Protocol I3Y-MC-JPCW(d)
43
3.
Objectives and Endpoints
Upon approval of amendment (d), the objectives and endpoints in Section 3.1 will be used in 
place of the objectives and endpoints in this section.
Objectives
Endpoints
Primary

To compare the efficacy of 
abemaciclib plus physician’s choice 
ET versus placebo plus physician’s 
choice ET in the study population.

IDFS as defined by the STEEP 
System (Hudis et al. 2007)
Secondary

To compare the efficacy of 
abemaciclib plus ET versus placebo 
plus physician’s choice ET in the 
study population.

OS

DRFS

Incidence of CNS metastases as the 
first site of disease recurrence

To assess the safety profile of 
abemaciclib plus physician’s choice 
ET versus placebo plus ET in the 
study population.

Safety, including but not limited to 
TEAEs, SAEs, hospitalizations, 
clinical laboratory tests, vital signs, 
and physical examinations

To evaluate participant-reported 
symptoms, function and global health 
status/QOL (EORTC QLQ-C30)

To compare EORTC QLQ-C30 scales
between treatment arms 

To evaluate health status in the study 
population to inform decision 
modeling for health economic 
evaluation using the EQ-5D 5L.

The EQ-5D 5L the index score and the 
single-item health status measure 

To evaluate the PK of abemaciclib. 

Abemaciclib concentrations
CCI

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44
Objectives
Endpoints
Abbreviations: AE = adverse event; CNS = central nervous system;
 
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; ET = endocrine therapy; 
IDFS = invasive disease-free survival; 
OS = overall survival; PK = pharmacokinetics; 
 SAE = serious adverse event;
TEAE = treatment-emergent adverse events.
a The 2 most common participant-felt symptoms from each monarchE treatment arm per Johnston et al. 2020.
3.1.
Objectives and Endpoints as of Amendment (d)
Objectives
Endpoints
To monitor the safety of abemaciclib plus 
physician’s choice ET in the study 
population. 
AEs and SAEs per CTCAE v5.0
Abbreviations: AEs = adverse events; CTCAE = Common Terminology Criteria for Adverse Events; ET = 
endocrine therapy; SAEs = serious adverse events
CCI
CCI
CCI
CCI

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Protocol I3Y-MC-JPCW(d)
45
4.
Study Design
4.1.
Overall Design
The eMonarcHER Study was initially a Phase 3 multicenter, randomized, double-blinded, 
placebo-controlled trial in participants with high risk, node-positive, HR+, HER2+ early breast 
cancer who had completed adjuvant HER2-targeted therapy. Approximately 2450 participants 
were planned to be enrolled in a 1:1 randomization with participants assigned to blinded study 
drug (either the abemaciclib or placebo treatment arm) plus ET. Blinded study drug was to have 
been given for up to 26 cycles, approximately 2 years, or until evidence of disease recurrence or 
another discontinuation criterion was met, whichever occurred first. 
Endocrine therapy was to have been taken as prescribed during the on-study intervention period 
(approximately 2 years). After the on-study intervention period, standard adjuvant ET was to 
have continued 3 to 8 additional years, for a total duration up to 10 years, if deemed medically 
appropriate. Standard approved adjuvant ET was per physician’s choice (such as tamoxifen or an 
AI, with or without ovarian function suppression per standard practice). Adjuvant treatment with 
fulvestrant was not allowed at any time during the study. 
However, the study was ultimately determined to be no longer feasible due to slow accrual and 
changes in the treatment landscape for HER2+ breast cancer that are anticipated to improve 
patient outcomes and diminish the unmet medical need; therefore, enrollment was terminated. 
After approval of amendment (d), and according to local regulations, participants who are on 
study treatment will be unblinded. If the investigator determines that continuation of 
abemaciclib may offer potential benefit to participants receiving study treatment, participants 
may continue to receive study treatment in the Continued Access period for a maximum of 26 
cycles until any of the criteria for discontinuation are met (Section 7.1). Participants receiving 
placebo will be discontinued. 
4.2.
Scientific Rationale for Study Design
See Section 2.1.
4.3.
Justification for Dose
Abemaciclib
In patients with HR+, HER2-negative mBC, abemaciclib is given orally at 150 mg twice daily in 
combination with nonsteroidal AIs (anastrozole or letrozole) or fulvestrant. This recommended 
starting dose is based on the pivotal Phase 3 studies, MONARCH 2 and MONARCH 3, in which 
the 150 mg twice daily dose exhibited acceptable safety and tolerability, and significant 
improvement in PFS. Dose adjustments (reductions and omissions) were permitted for 
tolerability.
In the pivotal Phase 3 study monarchE, participants with HR+, HER2-negative early breast 
cancer also received 150 mg twice daily abemaciclib, in combination with standard adjuvant ET.
This study demonstrated statistically significant improvement in IDFS and acceptable safety and 
tolerability. A minimum separation of 6 hours between doses was employed in monarchE to 

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Protocol I3Y-MC-JPCW(d)
46
allow maximal absorption between doses. As previously, dose adjustments (reductions and 
omissions) were permitted for tolerability.
Therefore, in eMonarcHER, abemaciclib will be administered orally at 150 mg twice daily (with 
at least approximately 6 hours between doses) in combination with ET with dose adjustments as 
needed for tolerability.
Standard Adjuvant Endocrine Therapy
In MONARCH 3 and Study I3Y-MC-JPBH it was established that abemaciclib does not affect 
the concentrations of anastrozole, letrozole, tamoxifen, or exemestane. Therefore, standard 
adjuvant ET will be administered per label or local guidelines at the recommended dose.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Continued Access SoA (Section 1.3.1) for the last 
participant in the trial globally.

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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Enrollment to the study stopped on 03 FEB 2022. As of amendment (d) all patients enrolled into 
the study will be unblinded.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Male or female participant must be ≥18 years of age inclusive, at the time of 
signing the informed consent (or of an acceptable age according to local 
regulations, whichever is older).
Type of Participant and Disease Characteristics
2. The participant has confirmed HR+, HER2-positive (HER2+), early invasive 
breast cancer without evidence of disease recurrence or distant metastases per 
STEEP criteria in Appendix 8 (Section 10.8).
a.
To fulfill the requirement for HR+ disease by local testing on primary 
disease specimen, tumor must be ER or progesterone receptor (PgR)
positive defined by immunohistochemistry (IHC) according to American 
Society of Clinical Oncology (ASCO)/College of American Pathologists 
(CAP) guidelines for hormone receptor testing (Hammond et al. 2010).
b. To fulfill the requirement of HER2+ disease by local testing on primary 
disease specimen, tumor must be HER2+ according to ASCO/CAP 
guidelines for HER2 testing (Wolff et al. 2018).
c.
Participants with bilateral breast cancer (confirmed pathologic diagnosis 
of invasive tumors in both breasts simultaneously or within 6 months of 
each other) or multi-focal disease can be eligible if all lesions tested are 
HR+, at least 1 lesion is HER2+, and adequate surgery has been 
performed in the affected breast(s) (see inclusion criterion [3]). The Lilly 
Clinical Research Physician or Clinical Research Scientist (CRP/CRS) 
must be consulted for all cases of bilateral breast cancer.
3. The participant must have undergone definitive surgery of the primary breast 
tumor(s).
a.
With the exceptions described below, the margins of the resected 
specimen must be histologically free of tumor (either invasive or ductal 
carcinoma in situ [DCIS]). If tumor was still present at the resected 
margin, the participant must have undergone re-excision or mastectomy. 
NOTE: participants with margins positive for LCIS are eligible without 
additional resection.

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48
b. Participants who, after mastectomy or wide local excision, had 
microscopic positive margins where the deep margin abutted the pectoralis 
fascia, may be eligible if they received chest wall radiation per local 
guidelines prior to study entry.
c.
Participants with positive anterior margins may be eligible if there was no 
residual gross disease and they received radiation therapy per local 
guidelines.
d. If surgical excision of supraclavicular or internal mammary nodes is not 
feasible, residual nodes should be irradiated per local guidelines.  
4. Participants must have high-risk disease as defined by one of the following 
criteria:
a.
Those who received neoadjuvant chemotherapy along with HER2-
targeted treatment must have
i.
residual disease in at least 1 axillary lymph node or 
ii.
a residual tumor ≥5 cm, or
iii.
a residual tumor of any size that has direct extension to the chest wall 
and/or skin (ulceration or skin nodules).
b. Those who had definitive surgery prior to systemic therapy and completed 
adjuvant chemotherapy along with HER2-targeted therapies (trastuzumab 
and pertuzumab) must have
i.
tumor involvement in ≥4 ipsilateral axillary lymph nodes, or 
ii.
tumor involvement in 1 to 3 ipsilateral axillary lymph node(s) and 
1. histological Grade 3, or
2. primary invasive tumor size of ≥5 cm on pathological
evaluation.
NOTE REGARDING TUMOR SIZE: Tumor measurement on pathological 
evaluation. If tumor size is needed to meet eligibility criteria, participants with 
multifocal/multicentric tumors may be eligible based on the sum of diameters of 
the individual lesions following discussion with the Lilly CRP/CRS.
NOTE REGARDING LYMPH NODE INVOLVEMENT: Microscopic tumor 
involvement is allowed if the tumor deposit measures a minimum of 0.2 mm.
Isolated tumor clusters less than 0.2 mm do not meet criteria. Ipsilateral internal 
mammary and supraclavicular lymph nodes are allowed, but do not count as
axillary lymph nodes.
NOTE ON HISTOLOGY GRADE: Defined by a combined score per the 
modified Bloom-Richardson grading system (Elston and Ellis 1991), also known 
as the Nottingham scale, or equivalent following discussion with the Lilly 
CRP/CRS.
5. Participants must be randomized within 20 months of primary breast cancer 
surgery.

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6. Participants have completed approximately 9 to 20 months of standard 
HER2-targeted therapy. The total duration of HER2-targeted therapy may include 
combination of neoadjuvant and adjuvant treatments. 
Eligible adjuvant HER2-targeted regimens include: 
a.
For patients treated with neoadjuvant chemotherapy and HER2-targeted
therapy, a minimum of 4 cycles of T-DM1 in the adjuvant setting.
NOTE: Participants may have received up to approximately 6 cycles of 
adjuvant trastuzumab prior to initiation of T-DM1. Additionally, 
participants may have switched to trastuzumab-based therapy 
(monotherapy or in combination with other HER2-targeted therapies) 
after 4 cycles of T-DM1.
b. For patients who had definitive surgery prior to systemic therapy, a 
minimum of 4 cycles of adjuvant pertuzumab with trastuzumab.
7. Participants must be randomized within 12 weeks of completion of adjuvant 
HER2-targeted therapy.
8. Participants may have received ET (such as tamoxifen or AI) concomitantly with 
their standard adjuvant HER2-targeted therapy as per physician’s choice and may 
have continued with up to 12 weeks single-agent ET after the completion of
HER2-targeted therapy prior to randomization.
NOTE: Use of GnRH analogues for ovarian suppression is not considered ET for 
the purposes of this criterion.  
9. Have received a minimum of 4 cycles of chemotherapy in either the neoadjuvant 
or adjuvant setting per standard of care. 
10. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (Oken et al. 1982).
11. The participant is able to swallow oral medications.
12. Have tumor tissue from breast (preferred) or lymph node for exploratory 
biomarker analysis available prior to randomization. 
NOTE: Sites should confirm the availability of tumor tissue for exploratory 
analysis (Section 8.8 and Section 1.3.2) with the pathological laboratory prior to 
randomization. The lack of tumor tissue in regions where regulations do not 
permit tissue collection does not constitute a protocol violation and participants 
may still participate.

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13. Participants must have discontinued previous treatments for cancer and recovered 
from the acute effects of therapy (i.e., Grade ≤1), except for residual alopecia or 
Grade ≤2 peripheral neuropathy. The washout period from prior treatment to 
randomization is shown below:
Previous Treatment
Length of Time Prior to Randomization
Cytotoxic therapies or targeted agents 
that are small molecule inhibitors
21 days or 5 half-lives, whichever is shorter from 
last dose received
Adjuvant HER2-targeted agents: 
pertuzumab, trastuzumab, or T-DM1
A washout period of at least >21 days is required 
between last dose of antibody treatment 
Exogenous reproductive hormone 
therapy for purposes other than early-
breast cancer (eBC) treatment (for 
example, birth control pills, hormone 
replacement therapy, or megestrol 
acetate). Note, this does NOT apply to 
ET (tamoxifen or AI) being 
administered as part of adjuvant 
therapy for eBC (see IC#8)
5 half-lives from last dose received
Radiotherapy
Adjuvant radiotherapy 
14 days
Major surgery
28 days
Minor surgery, excluding biopsy
days

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14. Have adequate organ function, as defined below: 
System
Laboratory Value
Hematologic
ANC
1.5×109/L
Platelets
100×109/L
Hemoglobin
g/dL
Note: Transfusions to increase a participant’s hemoglobin level or initiation of erythropoietin or 
G-CSF therapy to meet enrollment criteria are not allowed in the 14 days preceding the first 
dose of study intervention. If a participant receives transfusions, erythropoietin, or G-CSF 
therapy ≥14 days prior to the first dose, the hematologic criteria listed above must be met 
following the 14-day window and prior to the first dose of study therapy.
Hepatic
Total bilirubin
1.5×ULN
Participants with Gilbert’s syndrome 
with a total bilirubin ≤2.0 times ULN 
and direct bilirubin within normal limits 
are permitted.
ALT and AST
3× ULN 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal. 
Sex
15.
Male and/or female
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
a. Male participants:
Male participants are eligible to participate if they agree to refrain from donating sperm 
while taking blinded study drug. The use of contraception in male participants is not 
required. 
b. Female participants:
1. Women of childbearing potential (WOCBP) who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) 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 during study intervention period. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
2. Otherwise, WOCBP participating must agree to use one highly effective method (less 
than 1% failure rate) of contraception while taking blinded study drug and for 3 
weeks after the last dose of blinded study drug. 
Women of childbearing potential participating must test negative for pregnancy prior 
to initiation of treatment as indicated by a negative serum pregnancy test at the 
screening visit followed by a negative urine or serum pregnancy test within 24 hours 
prior to exposure.

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3. Women not of childbearing potential may participate and include those who are: 
A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as Mullerian agenesis; or 
B. post-menopausal – defined as either
i.
A woman at least 40 years of age with an intact uterus, not on hormone 
therapy, who has cessation of menses for at least 1 year without an 
alternative medical cause, AND a follicle-stimulating hormone ≥40 mIU/mL; 
or
ii.
A woman 55 or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
Informed Consent
16.
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1),
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
17.
Participant has breast cancer with any of the following features:

Disease recurrence or distant metastatic disease (including contralateral 
axillary lymph nodes)

Pathological complete response (pCR) from any prior early breast cancer 
treatments. Participants are required to have residual primary tumor and/or 
lymph node disease at the time of definitive surgery as indicated in 
inclusion criteria.

Inflammatory breast cancer. 
NOTE: Inflammatory carcinoma should not apply to a participant with 
neglected locally advanced breast cancer presenting late in the course 
of their disease (American Joint Committee on Cancer [AJCC] staging 
system for breast cancer 8th edition, Hortobagyi et al. 2017). The 
investigator should consult with the Lilly CRP/CRS regarding 
eligibility of participants with neglected inflammatoid disease.

Participants with a history of previous breast cancer, with the exception of 
ipsilateral DCIS treated by locoregional therapy alone ≥5 years ago. 
Participants with a history of contralateral DCIS treated by local regional 
therapy at any time may be eligible.  
18.
Participants with a history of any other cancer are excluded, unless in complete 
remission with no therapy for a minimum of 5 years from the date of 
randomization.  

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
For participants with a history of other non-breast cancers within 5 years 
from the date of randomization and considered to be very low risk of 
recurrence per investigator’s judgment (for example, papillary thyroid 
cancer treated with surgery), eligibility is to be discussed with the Lilly 
CRP/CRS. 

Participants with history of non-melanomatous skin cancer that was treated 
with curative intent, or appropriately treated carcinoma in situ (CIS) of 
cervix, bladder, colon are eligible.
19.
Females who are pregnant or lactating. 
20.
Participants with significant clinical cardiac abnormalities (e.g., clinical heart 
failure, unstable angina, or ejection fraction (EF) <35%) are excluded. This 
should be documented at the completion of adjuvant HER2 targeted therapy.
21.
The participant has 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], 
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, ulcerative colitis, or a preexisting chronic condition resulting in 
clinically significant diarrhea).
22.
Any participant with a history of VTE (for example, DVT of the leg or arm and/or 
PE) will be excluded. This includes a history of catheter-associated thromboses.
23.
Any participant that has known active systemic infections (for example, bacterial 
infection requiring IV antibiotics at time of initiating study intervention, fungal 
infection or detectable viral infection requiring systemic therapy) is not eligible. 
a.
Participants with uncontrolled human immunodeficiency virus (HIV)
infection or 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 hepatitis B virus 
(HBV) 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 hepatitis C virus (HCV) 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.
Prior/Concomitant Therapy
24.
The participant has previously received treatment with any CDK4 and 6 inhibitor. 

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25.
The participant has received prior adjuvant treatment with immunotherapy,
tucatinib, neratinib, any investigational HER2-directed therapy, or T-DXd
(DS8201) for treatment of breast cancer. Prior exposure with these agents during 
neoadjuvant treatment will be allowed.
26.
The participant has previously received ET (i.e., tamoxifen, raloxifene or AI) for 
breast cancer prevention (without diagnosis of breast cancer).
27.
The participant is receiving any additional chemotherapy, anticancer ET, or 
HER2-targeted therapy beyond standard of care at study enrollment. This includes
concurrent exogenous reproductive hormone therapy (for example, birth control 
pills, hormone replacement therapy, or megestrol acetate).  Note: Topical vaginal 
estrogen therapy is permitted if all other non-hormonal options are exhausted.
28.
Exclusion criterion [28] has been deleted.
29.
Participants with known or suspected hypersensitivity reactions or intolerance to 
abemaciclib or to any of the excipients (e.g., lactose) should not take abemaciclib 
unless deemed appropriate by the investigator.
Prior/Concurrent Clinical Study Experience
30.
Have participated, within the last 30 days; (3 months for studies conducted in the 
United Kingdom [UK]), in a clinical study involving an investigational product. If 
the previous investigational product has a long half-life, 5 half-lives or 30 days
(whichever is longer) and 3 months for studies conducted in the UK should have 
passed. Exceptions will be considered on a case-by-case basis by the sponsor 
CRP/CRS.
5.3.
Lifestyle Considerations
Participants should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to the effect on cytochrome P450 (CYP)3A4. Investigators are 
expected to review the appropriate product label for the standard endocrine therapy treatment 
that he/she has proposed for the participant.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. 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 demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number. Individuals 
may be re-screened up to one time. The interval between a screen failure and the start of re-
screening must be at least 2 weeks. When re-screening is performed, the individual must sign a 
new ICF. Repeating of laboratory tests during the screening period or repeating screening tests to 
comply with the protocol designated screening period does not constitute rescreening.

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Potential reasons for rescreening:

Participants who have become eligible to enroll in the study as the result of a protocol 
amendment.

Participants status has changed such that the eligibility criterion that caused the 
participant to screen fail would no longer cause the participant to screen fail again.

Participants 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, or child illness).
Participants who decide to discontinue study intervention after randomization may not be 
rescreened or resume study intervention.
As of 03 February 2022, no new patients will be screened. 

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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol during the on-study intervention period (up to 26 cycles).
6.1.
Study Intervention(s) Administered
Arm
Arm A (experimental)
Arm B (control)
Intervention
Abemaciclib
ET
Placebo
ET
Dose
150 mg (3, 50 mg tablets)
Standard 
adjuvant ET of 
physician’s 
choice
3 placebo tablets
Standard 
adjuvant ET of 
physician’s 
choice
Schedule
BID
BID
Route
PO
PO
Abbreviations: BID = twice a day, at least approximately 6 hours apart; ET = endocrine therapy; PO = by mouth; 
mg = milligrams.
Abemaciclib/Placebo:
Initially, assignment to either abemaciclib or placebo was blinded to investigators and 
participants. Abemaciclib/placebo, hereafter described as “blinded study drug” will be 
administered at a starting dose of 150 mg twice daily and it is provided as 50-mg tablets. 
Participants were to have received blinded study drug up to 26 cycles (approximately 2 years).
Blinded study drug was to have been taken twice daily (with at least approximately 6 hours
separating doses) at the same time each day with a glass of water. Participants were instructed to 
swallow tablets whole and not chew or crush.
As of amendment (d), investigators and participants will be unblinded. Participants receiving 
placebo will be discontinued. See Section 2.3.1.1.
Endocrine therapy:
Initially, the investigator’s choice of standard of care ET was planned for up to 26 cycles
(approximately 2 years) on study and then up to 10 years total duration, as medically indicated. 
The investigator was to refer to the product label for administration of standard of care ET of 
choice. A switch to another standard ET was allowed as per the investigator’s discretion (Section
10.8). Adjuvant treatment with fulvestrant was not allowed at any time during the study.
As of amendment (d), ET choice and duration remains at the discretion of the investigator.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention. Only authorized
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel.

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3. The investigator or authorized study personnel is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Initially, this was a randomized, double-blind, placebo-controlled study. Participants who meet 
all criteria for enrollment were randomly assigned to Arm A (abemaciclib plus ET) or Arm B 
(placebo plus ET). Approximately 2450 participants were anticipated to enroll and be 
randomized 1:1 between the 2 arms using the following stratification factors:

Prior neoadjuvant systemic therapy: yes vs no

Menopausal status:  premenopausal vs postmenopausal (including males)
(menopausal status to be determined by investigator and based upon the participant’s 
status at the time of diagnosis)

Region: North America/West Europe vs Asia vs Other
All randomized participants were centrally assigned to treatment arms using an Interactive Web 
Response System (IWRS). Study intervention was dispensed at the study visits summarized in 
the SoA (Section 1.3).
Following the approval date of amendment (d), and subject to local guidelines, participants and 
investigators will be unblinded. See Section 6.3.4. Efficacy will no longer be an endpoint.
6.3.1.
Unblinding at Interim Analyses
Beginning with amendment (d), no interim analyses are planned.
6.3.2.
Emergency Unblinding
Upon approval of amendment (d), and subject to local guidelines, participants and investigators 
will be unblinded (see Section 6.3.4) without designation as emergency unblinding; therefore,
considerations for emergency blinding are no longer applicable.  Unblinding as of amendment 
(d) does not require participant discontinuation from the trial, if the participant is receiving 
abemaciclib. If the participant is receiving placebo, they will discontinue from the trial after the 
final short-term follow-up visit is completed. 
6.3.3.
Inadvertent Unblinding
Upon approval of amendment (d), and subject to local guidelines, all participants and 
investigators will be unblinded (see Section 6.3.4) and therefore considerations for inadvertent 
blinding are no longer applicable.  Intentional unblinding after amendment (d) does not require 
participant discontinuation from the trial if the participant is receiving abemaciclib. If the 
participant is receiving placebo, they will discontinue from the trial after the final short term 
follow up visit is completed. 

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6.3.4.
Amendment (d) Unblinding
Upon approval of amendment (d), and subject to local regulations, participants will be unblinded. 
Unblinding will not necessitate protocol discontinuation if the participant is receiving 
abemaciclib. If the patient is receiving placebo, they will discontinue from the trial after the final 
short term follow up visit is completed. 
6.4.
Study Intervention Compliance
Initially, when participants self-administered study intervention(s) at home, compliance was
assessed as per the SoA (Section 1.3). Compliance for blinded study drug was assessed by 
counting dispensed and returned tablets and this was to be recorded in the source documents and 
case report form (CRF). Compliance for ET was assessed by direct questioning and recorded in 
the source documents and CRF.
A record of the number of blinded study drug tablets dispensed was maintained and reconciled 
with study intervention and compliance records. Intervention start and stop dates, including dates 
for intervention delays and/or dose reductions were to have been recorded in the CRF.
A participant must have taken ≥75% of the planned doses to be deemed compliant. Similarly, a
participant may have been 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.
From Cycle 1 Day 1 to Cycle 3 Day 1, participants also completed a paper Patient Dosing Diary 
to record the exact time and date of study drug doses, which was intended to be utilized in PK 
assessments. This paper diary was not intended to monitor compliance.
As of amendment (d), the study will not evaluate compliance.
6.5.
Concomitant Therapy
Initially, all concomitant medications were to have been recorded throughout the on-study 
intervention period and through short-term follow-up. However, as of amendment (d), use of 
concomitant medications will not be collected. 
In general, the list of prohibited medications that affected participant eligibility or participation
in the study were limited to ET for breast cancer prevention, concurrent exogenous reproductive 
hormone therapy, and recent experimental treatment in a clinical trial. Replacement hormonal 
therapy (e.g., thyroid or adrenocorticoid supplementation) were allowed. Exogenous 
reproductive hormone therapy (for example, birth control pills, hormone replacement therapy, or 
megestrol acetate) were not allowed; however, topical vaginal estrogen therapy was permitted if 
all other non-hormonal options were exhausted. Concurrent treatment with standard of care 
bone-modifying agents (such as bisphosphonates and denosumab) was permitted.
As of amendment (d), concomitant medications were not routinely documented for the Sponsor 
unless they were associated with an AE.  Concomitant medications decisions are at discretion of 
the investigator.
Modulators of CYP3A
Abemaciclib is extensively metabolized through oxidation by CYP3A. In clinical drug 
interaction studies, 

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59

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 7, Section 10.7). This includes grapefruit or 
grapefruit juice. In particular, avoid oral administration of the very strong CYP3A inhibitor, 
ketoconazole.
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce
the dose of abemaciclib by 50 mg at the start of CYP3A inhibitor treatment. That is, for patients 
receiving 150 mg twice daily, reduce the dose to 100 mg twice daily. For patients who have 
already had dose reduced to 100 mg twice daily for tolerability, reduce the dose further to 50 mg 
twice daily. Alternatively, the investigator may consider suspending abemaciclib for the duration 
of the CYP3A inhibitor medication. 
Upon discontinuation of the strong CYP3A inhibitor, the dose of abemaciclib may be re-
escalated to the dose that was used before starting the strong inhibitor after a sufficient washout 
period (3 to 5 half-lives of the strong inhibitor) at the discretion of the investigator.
Inducers of CYP3A should be substituted or avoided if possible (Appendix 7, Section 10.7). 
Transporter Substrates
At clinically relevant concentrations, abemaciclib inhibits the transporters P-glycoprotein, breast 
cancer resistance protein, organic cation transporter 2 (OCT2), multidrug and toxin extrusion 
protein 1 (MATE1), and MATE2-K. The observed serum creatinine increase in clinical studies 
with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, 
and MATE2-K. In vivo interactions of abemaciclib with narrow therapeutic index substrates of 
these transporters, such as digoxin and dabigatran, may occur.
6.5.1.
Supportive Care
The need for any radiotherapy for treatment of breast cancer will be cause for early 
discontinuation from the study treatment.
In addition, any disease recurrence or progression requiring other specific antitumor therapy will 
necessitate early discontinuation from the study treatment. Initially, appropriate documentation 
for all forms of premedications, supportive care, and concomitant medications were to be 
captured on the CRF.  As of amendment (d), documentation of premedication, supportive care, 
and concomitant medications will not be captured on the CRF unless necessary to support 
documentation of a SAE.
Participants should receive full supportive care. The use of granulocyte-colony stimulating factor 
is permitted based on ASCO (Smith et al. 2015) and ESMO (Crawford et al. 2009) guidelines.  
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013).

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6.5.2.
Supportive Management for Diarrhea in Participants Receiving Blinded Study 
Intervention
Participants should receive instructions on the management of diarrhea at the initiation of study 
treatment. In the event of diarrhea, supportive measures should be initiated as early as possible. 
These include the following:

At the first sign of loose stools, the participant should initiate anti-diarrheal therapy (e.g., 
loperamide) and notify the investigator for further instructions and appropriate follow-up.

Participants should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to at least Grade 1 
(per Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), blinded 
study intervention should be suspended until diarrhea is resolved to at least Grade 1.

When blinded study intervention recommences, dosing should be adjusted as outlined in 
Section 6.6.1. In severe cases of diarrhea, the measuring of neutrophil counts and body 
temperature and proactive management of diarrhea with antidiarrheal agents should be 
considered.
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones should be considered.
Participants with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid and electrolyte replacement as 
clinically indicated.
6.6.
Dose Modification
Initially, investigators were referred to the following tables for dose modifications for adverse 
reactions related to blinded study drug. If dose reduction was necessary, the dose was decreased 
by 50 mg at a time. Blinded study drug was discontinued for participants unable to tolerate 50 
mg twice a day, at least approximately 6 hours apart (BID).
As of amendment (d), dose modifications will be at the investigator’s discretion, though the
modifications below are encouraged.
Blinded Study Drug Dose Modification For Adverse Reactions
Dose Level
Blinded Study Drug Dose 
Recommended starting dose
150 mg BID
First dose reduction
100 mg BID
Second dose reduction
50 mg BID
Third dose reduction
Not applicable

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Abbreviation: BID = twice a day, at least approximately 6 hours apart.
Blinded Study Drug Dose Modification and Management – Hematologic Toxicities
Monitor complete blood counts prior to the start of blinded study drug therapy, every 2 weeks for the first 
2 cycles, and then according to the SoA and as clinically indicated.
CTCAE Grade
Blinded Study Drug Dose Modifications
Grade 1 or 2
No dose modification is required
Grade 3
Suspend dose until toxicity resolves to ≤Grade 2
Dose reduction is not required
Grade 3, recurrent, or Grade 4a
Suspend dose until toxicity resolves to ≤Grade 2
Resume at next lower dose
Participant requires administration of a 
blood cell growth factor
Suspend blinded study drug dose for at least 48 hours after the last 
dose of blood cell growth factor and until toxicity resolves to 
≤Grade 2
Resume blinded study drug at next lower dose unless the dose was 
already reduced for the toxicity that led to the use of the growth 
factor
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; SoA = schedule of activities.
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event). As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a participant who 
experiences a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode 
of same Grade 3 hematological toxicity, the investigator may consider resuming the participant on the same drug 
dose should the participant satisfy the following conditions:

The participant showed stable hematological counts (Grade ≤2) during that timeframe

In the absence of any infectious sign or risk factor

The participant is benefiting from study treatment
Blinded Study Drug Dose Modification and Management – Diarrhea
At the first sign of loose stools, start treatment with antidiarrheal agents, such as loperamide.
CTCAE Grade
Blinded Study Drug Dose Modifications
Grade 1
No dose modification is required.
Grade 2
If toxicity does not resolve within 24 hours to 
≤Grade 1, suspend dose until resolution. Dose reduction 
is not required
Grade 2 that persists or recurs after resuming the 
same dose despite maximal supportive measuresa
Suspend dose until toxicity resolves to ≤Grade 1.
Resume at next lower dose
Grade 3 or 4 or requires hospitalization
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).

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Blinded Study Drug Dose Modification and Management – Increased ALT/AST
Monitor ALT/AST prior to the start of blinded study drug therapy, every 2 weeks for the first 2 cycles, and then 
according to the SoA and as clinically indicated.
CTCAE Grade
Blinded Study Drug Dose Modifications
Grade 1 (>ULN-3.0×ULN)
Grade 2 (>3.0-5.0×ULN)
No dose modification is required
Persistent or recurrenta Grade 2 or Grade 3 
(>5.0-20.0×ULN)
Suspend dose until toxicity resolves to baseline or 
Grade 1
Resume at next lower dose
≥Grade 2 (≥3.0×ULN) with total bilirubin 
>2×ULN, in the absence of cholestasis
Discontinue blinded study drug
Grade 4 (>20.0×ULN)
Discontinue blinded study drug
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; SoA = schedule of activities; ULN = upper limit of normal.
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).
Blinded Study Drug Dose Modification and Management – Interstitial Lung 
Disease/Pneumonitis
CTCAE Grade
Blinded Study Drug Dose Modifications
Grade 1 or 2
No dose modification is required.
Grade 2 that persists or recurs despite maximal 
supportive measures and does not return to 
baseline or Grade 1 within 7 daysa
Suspend dose until toxicity resolves to baseline or 
Grade ≤1.  
Resume at next lower dose.
Grade 3 or 4
Discontinue blinded study drug.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events. 
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).
Blinded Study Drug Dose Modification and Management –Venous Thromboembolic 
Events)
CTCAE Grade
Blinded Study Drug Dose Modifications
Any Grade
Suspend dose and treat as clinically indicated. May 
resume blinded study drug when participant is 
clinically stable.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events. 

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Blinded Study Drug Dose Modification and Management – Nonhematologic Toxicities 
Excluding Diarrhea, ALT/AST Increased, and ILD/pneumonitis and VTE)
CTCAE Grade
Blinded Study Drug Dose Modifications
Grade 1 or 2
No dose modification is required
Persistent or recurrent Grade 2 toxicity that does 
not resolve with maximal supportive measures 
within 7 days to baseline or Grade 1a
Suspend dose until toxicity resolves to baseline or 
Grade 1
Resume at next lower dose
Grade 3 or 4
Abbreviations: ALT = alanine aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; 
ILD = interstitial lung disease; VTE = venous thromboembolic event.
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).
6.6.1.
Dose Suspension and Cycle Delay
As of amendment (d), both dose suspension and delays of abemaciclib and ET will be 
determined by the investigator.  If abemaciclib dose hold or suspension exceeds 28 days, 
consideration of discontinuation is encouraged.
For participants undergoing surgery, the following recommendations should be considered: 

Minor Surgeries:
o
Abemaciclib should be suspended before surgery at investigator’s discretion, and 
for at least 14 days after surgery.

Major Surgeries:
o
Abemaciclib should be suspended for at least 7 days before surgery, and for at 
least 21 days after surgery.
For both minor and major surgeries, investigators should treat as clinically indicated and closely 
monitor any signs of infection or healing complications. Consider monitoring neutrophils and 
platelets before surgery and before resuming blinded study drug. The scars should be aseptic and 
healing process be reasonable before resuming blinded study drug.
6.7.
Intervention after the End of the Study
The end of study definition is defined in Section 4.4. Investigators will continue to follow the 
SoA provided in Section 1.3 until notified by sponsor that end of study has occurred.
6.7.1.
Study Completion Definition
As of amendment (d), the study will be considered complete when the final participant 
discontinues from the study or completes 26 cycles of abemaciclib and a final short-term follow-
up visit or is declared lost to follow-up.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants will remain on treatment unless/until a discontinuation criterion is met, at which 
point study intervention is permanently discontinued. Participants will then enter the follow-up 
period with follow-up procedures performed as shown in the SoA section (Section 1.3).
Participants will be discontinued from study intervention in the following circumstances:

The participant becomes pregnant while receiving study intervention

The participant is significantly noncompliant with study procedures and/or treatment

Disease recurrence

Unacceptable toxicity

The participant, for any reason, requires treatment from another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. Discontinuation 
from study intervention will occur prior to introduction of the new agent

Enrollment 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

If the investigator decides that the participant should be discontinued from the study 

After the completion of 26 cycles (approximately 2 years) of abemaciclib 

Upon unblinding, the participant is determined to have been receiving placebo.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:

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
If possible, at the time of discontinuation, a short-term follow-up visit (V801) should be 
conducted according to the SoA.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
As of amendment (d), any participant determined to have been inadvertently enrolled will be 
discontinued from the study unless their continuation had previously been approved by the 

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Sponsor.  Safety follow-up is as outlined in Section 1.3 (SoA), Section 8.2 (Safety Assessments), 
and Section 8.3 (Adverse Events and Serious Adverse Events) of the protocol
For sites located in the UK, refer to Appendix 6 (Section 10.6) for country-specific 
discontinuation guidelines.
7.2.2.
Discontinuation after Amendment (d)
Upon approval of amendment (d), the participant or investigator may request discontinuation 
from the study. Participants randomized to the placebo arm will be discontinued from the study. 
Participants randomized to the abemaciclib arm may remain on the study if deemed appropriate 
by the investigator and the participant wishes to continue.
7.3.
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1
(Section 10.1).

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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
8.1.
Efficacy Assessments
8.1.1.
Imaging and Recurrence Assessment
All applicable imaging will be done locally. No central imaging assessments will be performed 
during the study. For details, see SoA (Section 1.3).
Following approval of amendment (d), imaging decisions for disease recurrence should continue
per the investigator’s judgment and according to routine standard practice.  Efficacy data will not 
be collected, and safety will be the primary endpoint.
8.1.2.
Appropriateness of Assessments
With the termination of enrollment and changes to primary endpoint, no additional efficacy data 
will be collected as of amendment (d). 
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3). For each 
participant, vital signs, laboratory tests, and other tests should be collected as shown in the SoA 
(Section 1.3). After approval of amendment (d), clinical laboratory test selection, timing and 
frequency are at the discretion of the investigator.
Results from any clinical laboratory test analyzed by a central laboratory (refer to Section 10.2, 
Appendix 2) will be provided to investigative sites by Lilly or its designee. Upon approval of 
amendment (d), central labs will not be collected. 
Given the nonclinical safety findings related to eye (cataract, retinal atrophy, corneal 
inflammation) and testes (benign adenomas and impairment of fertility), during each clinic or 
phone visit, participants will be monitored for signs and symptoms of visual impairment and 
testicular anatomical changes. Refer to Section 8.3 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.

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8.2.1.
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA for the timing and frequency.
o
Upon approval of amendment (d), clinical laboratory test selection, timing and 
frequency are at the discretion of the investigator.

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. Additionally, if local laboratory results are 
used to make a treatment decision, the results must be entered into the CRF. If there is an 
abnormal laboratory value or abnormal value for any other diagnostic or screening test 
(for example, blood pressure increased, neutrophils decreased, etc.) and it is known to be 
related to a 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.
o
Upon approval of amendment (d), central laboratory samples will not be 
collected.  

The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition.
o
Upon approval of amendment (d), clinical laboratory test selection, timing and 
frequency are at the discretion of the investigator.  Laboratory results associated 
with an AE must be retained as specified above.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or until the completion of Visit 801 should be repeated until the 
values return to normal or baseline, or are no longer considered clinically significant by 
the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2
(Section 10.2), must be conducted in accordance with the laboratory manual, 
standard collection requirements, and the SoA.

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
Upon approval of amendment (d), clinical laboratory assessment is at the 
discretion of the investigator,
o
If laboratory values from nonprotocol-specified laboratory assessments performed 
at an investigator-designated local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE or dose modification), then report the information as an AE.
8.2.2.
Hepatic Safety Monitoring
Close Hepatic Monitoring and Evaluation
Liver testing (Appendix 5, Section 10.5), including ALT, AST, alkaline phosphatase (ALP), total
bilirubin (TBL), direct bilirubin (D. Bil), gamma-glutamyltransferase (GGT), and creatine kinase 
(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 <1.5×ULN
ALT or AST ≥5×ULN or
ALT or AST ≥3×ULN concurrent with TBL ≥2×ULN
ALT or AST ≥1.5×ULN
ALT or AST ≥3× baseline or
ALT or AST ≥2× baseline concurrent with 
TBL ≥2×ULN
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests, should be initiated by the investigator in consultation 
with the Lilly-designated medical monitor. At a minimum, this evaluation should include 
physical examination and a thorough medical history, including symptoms, recent illnesses (for 
example, heart failure, systemic infection, hypotension, or seizures), history of concomitant 
medications (including over-the-counter, herbal and dietary supplements, history of alcohol 
drinking, and other substance abuse). In addition, the evaluation should include a blood test for 
PT-INR; serological tests for viral hepatitis A, B, C, E, autoimmune hepatitis; and an abdominal 
imaging study (for example, ultrasound or computed tomography [CT] scan). 
Based on the participant’s history and initial evaluation results, further testing should be 
considered, in consultation with the Lilly-designated medical monitor, 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 serum phosphatidylethanol. Based on the circumstances 
and the investigator’s assessment of the participant’s clinical condition, the investigator should 
consider referring the participant for a hepatologist or gastroenterologist consultation, magnetic 
resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), cardiac echocardiogram, and/or a liver biopsy.  
Additional Hepatic Safety Data Collection

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Prior to amendment (d), additional safety data should be collected via the CRF if 1 or more of 
the following conditions occur: 
In participants enrolled with baseline ALT or AST <1.5×ULN

Elevation of serum ALT or AST to ≥5×ULN on 2 or more consecutive blood 
tests

The combination of elevated ALT or AST ≥3×ULN and elevated 
TBL ≥2×ULN
In participants enrolled with baseline ALT or AST ≥1.5×ULN

Elevated ALT or AST ≥3× baseline on 2 or more consecutive tests

The combination of elevated ALT or AST ≥2× baseline and elevated 
TBL ≥2×ULN
Safety data capture in the CRF is not required after approval of amendment (d), however 
source documents related to AE should be retained.
In all study participants (including after approval of amendment (d))

Discontinuation from study intervention due to a hepatic event or abnormality of 
liver tests

Occurrence of a hepatic event considered to be an SAE
8.2.3.
Venous Thromboembolic Events (VTEs)
In the randomized Phase 3 studies in patients with advanced or mBC (MONARCH 2, 
MONARCH 3 studies) or early breast cancer (monarchE study) treated with abemaciclib in 
combination with ET, a greater number of patients experienced VTE events in the abemaciclib 
plus ET arm than in the placebo plus ET arm or ET alone arm. The majority of patients who 
experienced VTEs were treated with anticoagulants. In the monarchE study, there was a trend 
towards an increased incidence of VTEs (including PE) in patients receiving tamoxifen as first 
background ET as compared to AIs. In next the MONARCH 1 study, a greater number of 
patients experienced VTE events in the abemaciclib plus tamoxifen arm compared with the 
abemaciclib monotherapy arms. No events of VTE resulted in death or discontinuation of the 
study treatment, and most patients were treated with LMWH.
Venous thromboembolic events is an adverse drug reaction for abemaciclib. At this time, the 
mechanism underlying the association between abemaciclib and the occurrence of VTEs is not 
known. Venous thromboembolic events have been reported with other CDK4 and CDK6 
inhibitors and ET is known to be associated with the occurrence of VTEs. Participants should be 
monitored for signs and symptoms of DVT and PE and treated as medically appropriate.
8.2.4.
Serum Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting glomerular filtration rate (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 

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upon treatment discontinuation, and were not accompanied by changes in markers of renal 
function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate 
based on cystatin C.  
Dose adjustment (omission, reduction, or discontinuation) should not be based solely on 
interpretation of serum creatinine values because these may not reflect renal function. If 
deterioration of renal function is suspected per the investigator’s clinical assessment, a cystatin C 
measurement may be performed to confirm renal status. Dose alteration should follow the 
protocol guidance for non-hematological toxicities.
8.2.5.
Interstitial Lung Disease (ILD)/Pneumonitis
Interstitial lung disease/pneumonitis is an AESI for abemaciclib. Severe, life-threatening, or fatal 
ILD and/or pneumonitis can occur in participants treated with abemaciclib. 
Ask your participants to report any new or worsening pulmonary symptoms such as dyspnea, 
cough, and fever, and investigate and treat as per your local clinical practice (including 
corticosteroids as appropriate). If ILD/pneumonitis is suspected, investigations may include 
thoracic imaging, such as high-resolution CT, bronchoalveolar lavage, and biopsy as clinically 
indicated.
Refer to Section 6.6.1 for guidance on dose adjustments of blinded study drug for participants 
with ILD/pneumonitis. Discontinue blinded study drug in cases of Grades 3 or 4
ILD/pneumonitis.
Additional information is available in the Investigator’s Brochure.
8.3.
Adverse Events and Serious Adverse Events
The investigator will use CTCAE Version 5.0 (National Cancer Institute [NCI] 2018) to assign 
AE severity grades.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study intervention or study procedures
during the on-study intervention period (up to 26 cycles), or that caused the participant to 
discontinue the study intervention (see Section 6.7.1).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs will be collected from the signing of the ICF until completion of Visit 801 (completion 
of the 26 cycles of study intervention from first dose of blinded study drug or at time of study 
intervention discontinuation and during short-term follow-up).
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the AE CRF.
All SAES will be reported to the sponsor once the participant has signed the ICF and has 
received the first dose of study drug. If an SAE occurs after signing the ICF, but prior to 

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receiving blinded study drug, it needs to be reported ONLY if it is considered reasonably 
possibly related to study procedures. Reporting and collection of SAEs must continue for 
5 years, or until participation in the study has ended, regardless of causality, relatedness, or the 
arm to which the participant was initially randomized.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. Serious AEs, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study intervention.
Investigators are not obligated to actively seek SAEs after conclusion of the 5-year duration after 
start of study intervention. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE 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 8.3.7), 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.2.2). Further information on follow-up procedures is 
provided in Appendix 3, Section 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

An investigator who receives an investigator safety report describing a 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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8.3.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of study 
intervention. 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, including fetal status (presence or absence of 
anomalies) or indication for the procedure. If a participant becomes pregnant, she will be 
discontinued from study intervention. The decision to continue in study will be at the 
participant’s and physician’s discretion.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4, 
Section 10.4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Events or Outcomes
Events leading to the clinical outcome of death due to disease recurrence or other endpoints, 
either invasive disease recurrence, distant disease recurrence, or CNS disease recurrence that are 
part of the efficacy analyses for this study, will not be reported to the sponsor or its designee as 
SAEs unless the investigator believes the event may have been caused by the investigational 
product.
8.3.7. Adverse Events of Special Interest 
The following AEs are considered to be AESIs for abemaciclib:  

Neutropenia,

Infections,

Diarrhea,

Hepatic events, including increases in AST and ALT,

VTEs, and 

ILD/pneumonitis.  
8.3.8. Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
trial intervention. 
Sponsor collects product complaints on investigational products and drug delivery systems used 
in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.

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Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Appendix 3, Section 10.3 of the protocol.
8.3.8.1.
Time Period for Detecting Product Complaints

Product complaints that result in an AE will be detected, documented, and reported to the 
sponsor during all periods of the study in which the drug is used.

If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a drug
provided for the study, the investigator will promptly notify the sponsor.
8.3.8.2. Prompt Reporting of Product Complaints to Sponsor

Product complaints will be reported to the sponsor within 24 hours after the investigator 
becomes aware of the complaint.

The Product Complaint Form will be sent to the sponsor by email. If email is unavailable, 
then an alternative should be utilized.
8.3.8.3.
Follow-up of Product Complaints

Follow-up applies to all participants, including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product 
complaint.

New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and submitted to the sponsor.
8.4.
Treatment of Overdose
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
3. Obtain a sample for pharmacokinetics (PK) analysis as soon as possible after the
overdose has been identified, unless the medical monitor specifies otherwise. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Initially, pharmacokinetic (PK) samples were to be collected from approximately 20% of study 
participants at the visits and times specified in the SoA (Section 1.3.2) to determine the 
concentrations of abemaciclib and its active metabolites, LSN3106726 (M20) and LSN2839567 
(M2).

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PK samples will be retained for a maximum of 1 year following last subject visit for the study.
Upon approval of amendment (d), no additional PK collection is planned.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Upon approval of amendment (d), no additional blood samples for genetic analyses will be 
collected. 
8.8.
Biomarkers
Upon approval of amendment (d), no additional blood samples for biomarker analyses will be 
collected. 
8.8.1.
Plasma and Serum Samples for Biomarker Research
Upon approval of amendment (d), no additional plasma and serum samples for biomarker 
research will be collected. 
8.8.2.
Tissue Samples for Biomarker Research
Upon approval of amendment (d), no new participants will be enrolled therefore no additional 
tissue samples for biomarker research will be collected.
8.8.3.
Whole-Blood Sample for Biomarker Research
Upon approval of amendment (d), no additional whole blood samples for biomarker research will 
be collected. 
8.9.
Immunogenicity Assessments
Not applicable. 
8.10.
Health Economics
Upon approval of amendment (d), no health economic questionnaires will not be collected.
8.10.1.
Patient-Reported Outcomes (PRO)
Upon approval of amendment (d), no further PRO assessment will be collected.
8.10.2.
Electronic Participant Daily e-Diary Assessment
Upon approval of amendment (d), PRO assessment will not be collected, and the e-diary portal 
will be discontinued.
8.10.3.
Healthcare Resource Utilization
Upon approval of amendment (d), healthcare resource utilization assessments will not be 
collected.

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9.
Statistical Considerations
9.1.
Statistical Hypotheses
Treatment of participants with high-risk, node-positive, HR+, HER2+ breast cancer (who have 
completed adjuvant HER2-targeted therapy) with abemaciclib plus ET will provide a clinically 
meaningful increase in IDFS over treatment with placebo plus ET.
Upon approval of amendment (d) and permanent closure of the study to enrollment, the sponsor
will not evaluate the statistical hypothesis as originally planned.  
9.2.
Sample Size Determination
Approximately 2450 participants were originally planned to be randomized.  At time of closure 
of the study to enrollment, the total enrollment is anticipated to be approximately 115 patients.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Intent-to-Treat (ITT)
All randomized participants, regardless of whether they took any 
doses of study intervention, or if they took the correct treatment. 
Participants will be analyzed according to the treatment group as 
randomized and not by actual treatment received.
Safety
All randomized participants who received at least 1 dose of any 
study intervention. Participants will be analyzed according to the 
first dose of study intervention they actually received, regardless 
of the arm to which they were randomized.
Pharmacokinetic (PK) 
Analysis
All randomized participants who received at least 1 dose of study 
intervention and have baseline and at least 1 postbaseline 
evaluable PK sample. Pharmacokinetic sampling is planned to 
occur in 20% of study participants.
As of amendment (d), no further PK sampling is planned.
9.4.
Statistical Analyses
9.4.1. General Considerations
Upon approval of amendment (d) and permanent closure of the study to enrollment, the sponsor 
will not evaluate the statistical hypothesis as originally planned, thus Sections 9.4.2, 9.4.3 and 
9.4.4 are no longer applicable.
9.4.2.
Primary Endpoint(s)
Upon approval of amendment (d), the sponsor will not evaluate the statistical hypothesis as
originally planned, thus Section 9.4.2 is no longer applicable. 

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9.4.3.
Secondary Efficacy Endpoint(s)
Upon approval of amendment (d), the sponsor will not evaluate any secondary efficacy 
endpoints, including overall survival and distant relapse-free survival. 
 
9.4.5.
Safety Analyses
All participants in the safety analysis set in Section 9.3 will be evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA®) Version 23.1 (or higher) will be 
used when reporting AEs by MedDRA terms. The MedDRA Lower Level Term will be used in 
the treatment-emergent computation. Treatment-emergent AEs will be summarized by System 
Organ Class (SOC) and by decreasing frequency of Preferred Term within SOC.
Safety analyses will include summaries of the following:

treatment-emergent AEs, including severity and possible relationship to study 
intervention

treatment-emergent SAEs, including possible relationship to study intervention

adverse events leading to dose adjustments

discontinuations from study intervention due to AEs or death
9.4.6.
Other Analyses 
9.4.6.1.
Participant Disposition
A detailed description of participant disposition will be provided, including a summary of the 
number and percentage of participants entered into the study, enrolled in the study, and treated, 
as well as number and percentage of participants completing the study, as defined in the SAP, or 
discontinuing prior to study completion (overall and by reason for discontinuation). A summary 
of all important protocol deviations will be provided.
9.4.6.2.
Participant Characteristics
A summary of participant demographics, baseline disease characteristics, historical diagnoses, 
preexisting conditions, and prior therapies will be reported using descriptive statistics.
9.4.6.3.
Concomitant Therapy
As of amendment (d), concomitant therapy will not be collected or reported.
9.4.6.4.
Treatment Compliance
As of amendment (d), treatment compliance will not be collected or reported.
9.4.6.5.
Extent of Exposure
As of amendment (d), exposure data will not be collected or reported.
CCI

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9.4.6.6.
Post-Study intervention Therapy
As of amendment (d), post-study intervention therapy will not be collected or reported.
9.4.6.7.
Subgroup Analyses
As of amendment (d), subgroup analyses will not be reported.
9.4.6.8.
Pharmacokinetic and Exposure-Response Analyses
As of amendment (d), PK and exposure-response analyses will not be performed.  No additional 
PK specimens will be collected.
9.4.6.9.
Biomarker Analyses
As of amendment (d), biomarker analyses will not be performed or reported. No additional 
biomarker specimens will be collected.
9.4.6.10.
Health Economics Analyses
As of amendment (d), health economic analyses will not be performed or reported. No additional 
health economic data will be collected.
9.5.
Interim Analyses 
9.5.1.
Interim Analyses for Efficacy/Futility:
Upon approval of amendment (d) the sponsor will not evaluate the statistical hypothesis as 
originally planned thus there will be no interim efficacy/futility analyses.
9.5.2.
Interim Analyses for Safety
Upon approval of amendment (d) the study will no longer be blinded, and an unblinded DMC 
will not be utilized.  The Sponsor will conduct trial level safety reviews of unblinded safety data. 
9.6.
Data Monitoring Committee (DMC)
Upon approval of amendment (d), there will be no data monitoring committee.

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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 International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other 
relevant documents (e.g., 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.
○
Substantial amendments to the protocol will require regulatory authority 
approval before implementation.
●
The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
○
Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
●
Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement (CTA).
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 

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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 or his/her legally authorized 
representative and answer all questions regarding the study.
●
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.
●
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
●
Participants must be 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 or the participant’s 
legally authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
●
Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.
●
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security,
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.

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10.1.5.
Dissemination of Clinical Study Data
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. Data are available to request 6 months 
after the indication studied has been approved in the US and European Union and after primary 
publication acceptance, whichever is later. No expiration date of data requests is currently set 
once data are made available.
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. Data and 
documents, including the study protocol, SAP, clinical study report, 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.
10.1.6.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.
●
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.
●
Monitoring details describing strategy (e.g., 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).

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●
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 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 (EDC) system 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 (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.    
As of amendment (d), eCOA data will not be collected, analyzed, or reported. 
Data collected via the sponsor-provided data capture system 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. 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 electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system.

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10.1.7.
Source Documents
●
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.
●
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available.
●
Definition of what constitutes source data can be found in Section 10.1.6 (Data 
Quality Assurance).
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
The study or a study site will be discontinued if the sponsor or its designee judges it necessary 
for medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP. Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
●
Inadequate recruitment of participants by the investigator
●
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures
appropriate participant therapy and/or follow-up.
10.1.9.
Publication Policy
Results of this study will not be submitted for publication.

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10.1.10.
Investigator Information
Physicians with a specialty in oncology or surgery will participate as investigators in this clinical 
trial.

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10.2.
Appendix 2: Clinical Laboratory Tests
●
The tests detailed below will be performed by the laboratory indicated.
●
Local laboratory results are only required in the event that 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 
collected, it is important that the sample for central analysis is obtained at the 
same time. If there is an abnormal laboratory value or abnormal value for any 
other diagnostic or screening test (for example, blood pressure increased, 
neutrophils decreased, etc.) and it is known to be related to a 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.

Discrepancies between local and central laboratory results will not be considered protocol 
deviations when central labs are unavailable and local labs are used to make treatment 
decisions. 
●
In circumstances where the sponsor approves local laboratory testing in lieu of 
central testing (in the table below), the local laboratory must be qualified in 
accordance with applicable local regulations.
●
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.
●
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations and clinically 
significant findings should be reported in the CRF as an AE.

As of amendment (d), monitoring of participants who continue on study treatment will be 
at the discretion of investigator and should follow prescribing guidelines. Sponsor will 
not collect results of routine laboratory tests unless these are needed as source 
verification of an AE.
Investigators must document their review of the laboratory safety results.
Hematology – central laboratory

Leukocytes (WBC)

Neutrophils, absolute

Lymphocytes

Hemoglobin (HGB)

Hematocrit (HCT)

Platelets (PLT)
Chemistry –central laboratory
Serum concentrations of:

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
Alanine aminotransferase (ALT)

Alkaline phosphatase

Aspartate aminotransferase (AST)

Bilirubin, total

Blood urea nitrogen (BUN) or blood urea

Calcium

Chloride

Creatinine

Glucose

Potassium

Sodium

Total protein
Cystatin-C - central laboratory as clinically indicated
Hepatic Safety Monitoring – see Section 8.2.2 and Appendix 5 (Section 10.5)
Pregnancy test (for female participants of childbearing potential) – local laboratory

When a urine pregnancy test is performed, a minimum sensitivity of 25 IU/L or equivalent units of β-hCG
is required. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required. A serum pregnancy test is required at screening.
Abbreviations: RBC = red blood cell; WBC = white blood cell.
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be performed or 
auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the above parameters are 
calculated from measured values. Omission of calculated values will not be considered as a protocol violation.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of 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 which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

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
Medical or surgical procedure (e.g., endoscopy, appendectomy): The condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
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.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect

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Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.

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The investigator will use Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 (NCI 2018) to assign AE severity grades.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the 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.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to Sponsor or designee within 24 
hours of receipt of the information.

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10.3.4.
Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection 
tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SAE form.
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor 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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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Females are considered women not of childbearing potential if

they have a congenital anomaly such as Mullerian agenesis,

they are infertile due to surgical sterilization, or

they are post-menopausal.
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, tubal ligation.
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: Review of the participant’s 
medical records, medical examination, or medical history interview.
1. Postmenopausal female is defined as, women with:

12 months of amenorrhea for women >55, with no need for follicle-stimulating 
hormone (FSH)

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and no 
other medical condition such as anorexia nervosa and not taking medications during 
the amenorrhea (e.g., oral contraceptives, hormones, GnRH, anti-estrogens, selective 
ER modulators [SERMs], or chemotherapy that induced amenorrhea)

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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY
The choice of the most effective and appropriate contraception method is up to investigator´s 
judgment after discussion with the patient, taking into account age, pregnancy and other 
gyneco-obstetrical history, sexual activity, patients´ preference, acceptance of the 
contraception method, and potential adherence.
In patients with breast cancer, the use of estrogen-based hormonal contraception (includes the 
hormonal intrauterine devices [IUDs]) is contraindicated, and the effect of progestin-based 
hormonal contraception remains unclear.
The Clinical Trial Facilitation Group has defined highly effective/effective methods of 
contraception1.
Highly Effective Methods Allowed During the Study Include the Following:

IUD, only hormone-free

Bilateral tubal occlusion

Vasectomized partner2

Sexual abstinence3
Local regulation/guidelines are to be followed with regards to highly effective birth control 
method, if more restrictive.
1Clinical Trial Facilitation Group - Recommendations related to contraception and pregnancy testing in clinical 
trials. September 2014. Available at: http:hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CFTG_Contraception.pdf.Accessed May 02, 2016.
2 Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.
3 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
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.

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●
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 including fetal status (presence or absence of anomalies) and
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, including 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 
Section 8.3.5. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
●
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study intervention, follow the standard discontinuation process and continue 
directly to the follow-up phase. 

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10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 8.2.2
for guidance on appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly designated 
central laboratory except for Microbiology.

Local testing may be performed in addition to central testing when required for 
immediate participant management.

Upon approval of amendment (d), testing is at the discretion of the investigator and 
will be performed locally

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin 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)

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    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA d
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA d
    HSV (Type 1 and 2) DNA d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-
1) A tib d
Culture:
    Blood
    Urine
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio.
a
This is not required if anti-actin antibody is tested.
b
This is not required if ASMA is tested.
c
Assayed by investigator-designated local laboratory ONLY; no central testing available.
d
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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10.6.
Appendix 6: Country-specific Requirements
10.6.1.
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 and Serious Adverse Events), and Section 8.2 (Safety Assessments) of the protocol.
10.6.2.
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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10.7.
Appendix 7: Protocol JPCW 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

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Fosamprenavir and ritonavir
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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10.8.
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. 
Ethical review boards, regulatory bodies, and any other relevant local authorities, as required, will be 
notified as early as possible to communicate implementation of changes in study conduct due to 
exceptional circumstances. To protect the safety of study participants, urgent changes may be 
implemented before such communications are made, but all changes will be reported as soon as possible 
following implementation. If approval of ERBs, regulatory bodies, or both is required per local 
regulations, confirmation of this approval will be retained in the study records.
In the event written approval is granted by the sponsor for changes in study conduct, additional written 
guidance, if needed, will be provided by the sponsor.
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,”

dispensation of additional study intervention during an extended treatment period, 

alternate delivery of study intervention and ancillary supplies, and

provision of their personal or medical information required prior to implementation of these 
activities. 
Changes in Study Conduct During Exceptional circumstances
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.

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1.
Remote visits
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.
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 on the SoA may be 
performed at such visits.
Other alternative locations: Other procedures may be done at an alternate location in 
exceptional circumstances.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. Furthermore, 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.
2.
Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing with sponsor approval. 
However, central laboratory testing must be retained whenever possible for all visits where central 
laboratory testing is required. The local laboratory must be qualified in accordance with applicable 
local regulations. 
3.
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, and

arranging delivery of study supplies
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.

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4.
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken at 
screening visit(s) are valid for a maximum of 28 days as outlined in the study protocol. Informed 
consent can be signed up to 90 days prior to randomization; however, screening activities must be 
completed within 28 days prior to randomization. This screening period can be extended to 42 days 
under exceptional circumstances only. The following rules will be applied for active, nonrandomized 
participants who have signed informed consent and are undergoing screening procedures but whose 
participation in the study must be paused due to exceptional circumstances:

If the screening period lasts for more than 42 days due to exceptional circumstances: The 
participant must be discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. The screening procedures per the usual SoA 
should be followed, starting at screening visit(s) to ensure participant eligibility by Cycle 1 
Day 1. 
As of amendment (d), no new patients will be screened for study enrollment.
5.
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should follow the visit windows described in the 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 and approval 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.
As of amendment (d), the frequency of visits is at the discretion of the investigator.  See the 
Continued Access SoA (See Section 1.3.1)
Documentation
Changes to study conduct will be documented:

Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site 
study records.

Source documents 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
Term
Definition
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
BID
twice a day, at least approximately 6 hours apart
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.
BUN
blood urea nitrogen
CEC
Clinical Events Committee
CDK4 and 6
cyclin-dependent kinases 4 and 6
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CIS
carcinoma in situ
CK
creatinine kinase
Cmax
maximum serum/plasma concentration
Cmin
minimum serum/plasma concentration
CMV
cytomegalovirus
CNS
central nervous system

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complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF
case report form
CRP/CRS
Clinical Research Physician or Clinical Research Scientist: Individual responsible for 
the medical conduct of the study. Responsibilities of the CRP may be performed by a 
physician, CRS, global safety physician or other medical officer.
CT
computed tomography
CTA
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
D. Bil
direct bilirubin
DCIS
ductal carcinoma in situ
DFS
disease-free survival
DMC
data monitoring committee
DNA
deoxyribose nucleic acid
DRFS
distant relapse-free survival
DVT
deep vein thrombosis
EBV
Epstein-Barr virus
ECG
electrocardiogram
eBC
early breast cancer
eCOA
electronic Clinical Outcome Assessment
ECOG
Eastern Cooperative Oncology Group
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
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
ER
estrogen receptor

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ERB
ethical review board
ERCP
endoscopic retrograde cholangiopancreatography
ESMO
European Society for Medical Oncology
ET
endocrine therapy
F
frequency
FACT-GP5
Functional Assessment of Cancer Therapy-General item
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone 
GCP
good clinical practice
GGT
gamma-glutamyltransferase
GnRH
gonadotropin-releasing hormone
HCRU
Health Care Resource Utilization
HDV
hepatitis D virus
HER2
human epidermal growth factor receptor-2
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hormone receptor
HRQoL
health-related quality of life
I
interference
IB
Investigator’s Brochure
IBTR
ipsilateral breast tumor recurrence
ICF
informed consent form
ICH
International Council for Harmonisation
iDFS
the absolute invasive disease-free survival
IDFS
invasive disease-free survival
IEC
independent ethics committees

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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.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
institutional review boards
IRC
Internal Review Committee
ITT
intent-to-treat: The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IUD
intrauterine device
IV
intravenous
IWRS
interactive web-response system
LCIS
lobular carcinoma in situ
mBC
metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRCP
magnetic resonance cholangiopancreatography
MRI
magnetic resonance imaging
OS
overall survival
PA
posteroanterior
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
pCR
pathological complete response
PE
pulmonary embolism

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PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetics
PO
by mouth
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
PT
prothrombin time
QTc
corrected QT interval
Rb
retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
S
severity
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SMD
senior management designee
SoA
Schedule of Activities
TBL
total bilirubin
T-DM1
trastuzumab emtansine
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.
TKI
tyrosine kinase inhibitor
TTR
time to response
ULN
upper limit of normal
UK
United Kingdom
US
United States
VAS
visual analog scale

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VTE
venous thromboembolic event
WOCBP
Women of childbearing potential

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10.10.
Appendix 10: Protocol Amendment History
Amendment [c]
This amendment is considered to be nonsubstantial.
Overall Rationale for the Amendment:
The primary rationale for this amendment is to make the changes noted in the below bullets and 
as summarized in the table. Minor editorial changes are not included in the table.

Modified definition of high risk in those treated with neoadjuvant therapy to include at 
least 1 lymph node, or residual disease of ≥5 cm, or a residual tumor of any size that has 
direct extension to the chest wall and/or skin (ulceration or skin nodules).

For those treated with neoadjuvant chemotherapy, removed the requirement that TDM1 
be the first therapy in the adjuvant setting.

Extended the allowed time from definitive surgical resection to randomization to 20 
months
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Modified definition of high risk in 
participants who received neoadjuvant 
therapy and participants who had 
definitive surgery prior to systemic 
therapy
For clarity
1.3 Schedule of Activities 
(section text)
Updated the language describing 
when participants have in-clinic visits 
and telephone visits
For clarity
Added Summary of Visit Type by 
Cycle table

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1.3 Schedule of Activities 
(table)
Hematology row: Updated last bullet 
point to “Sample must be taken either 
within 14 days of C1D1 or on C1D1.”
For clarity
Bilateral imaging row: Added bullet 
point “Ultrasound alone is not 
sufficient for bilateral imaging.” 
Participant PRO daily e-diary row: 
Updated first bullet point to 
“Screening: collect at least 1 day and 
up to 7 days of daily data in the week 
prior to starting blinded study drug on 
C1D1.”
HCRU row: Added a cross-reference 
to Section 8.10.3
1.3.1. Pharmacokinetics, 
Genetics, and Biomarker 
Sampling Schedule
In Sampling Schedule for 
Genetics/Biomarkers table, added “if 
available” to comment for required 
archival tumor tissue (biomarker) row
For clarity
2.1 Study Rationale
Modified definition of high risk in 
participants who received neoadjuvant 
therapy and participants who had 
definitive surgery prior to systemic 
therapy
For clarity
2.2 Background
Added justification for changes to 
high-risk definition for those treated 
with neoadjuvant therapy
For clarity
5.1 Inclusion Criteria
Inclusion Criterion 2: Removed “in 
initial diagnostic tissue”
For clarity
Inclusion Criterion 3: Revised 
descriptions of definitive surgery of 
the primary breast tumor(s)
Inclusion Criterion 4: Revised 
definitions of high-risk disease criteria 
and note regarding tumor size. Added 
notes regarding lymph node 
involvement and histology grade 
Inclusion Criterion 5: Updated 18 
months to 20 months
To accommodate real-
world practice

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Inclusion Criterion 6: Revised 
duration of HER2-targeted therapy 
and eligible adjuvant HER2-targeted 
regimens
For clarity
Inclusion Criterion 15b1: Revised 
guidance for abstinence and refraining 
from sexual intercourse with males 
during study intervention period
5.2 Exclusion Criteria
Exclusion Criterion 17: Removed 
“Lymph node negative status”. Added 
“Participants are required to have 
residual primary tumor and/or lymph 
node disease at the time of definitive 
surgery as indicated in inclusion 
criteria.” 
For clarity
Exclusion Criterion 22: Added “This 
includes a history of catheter-
associated thromboses.” 
Exclusion Criterion 25: Added “T-
DXd” along with DS8201
For additional detail
Exclusion Criterion 27: Removed 
“therapy for their breast cancer”
For clarity
6.1 Study Intervention(s)
Administered
Abemaciclib/Placebo: Removed 
“open” from last sentence
For clarity; this is a 
reference to capsules 
instead of tablets
6.4 Study Intervention 
Compliance
Added compliance guidance and 
paper dosing diary instructions
For clarity
6.5.1 Supportive Care
Clarified reasons for early 
discontinuation from study treatment
For clarity
6.5.2 Supportive 
Management for Diarrhea 
in Participants Receiving 
Blinded Study Intervention
Added “at the initiation of study 
treatment” timing to when participants 
should receive instructions on the 
management of diarrhea
For clarity
6.6.1 Dose Suspension and 
Cycle Delay
Added instructions for dose 
adjustment based on lab results
For clarity
Revised section to clarify that Day 1 
of a cycle is when study drug is 
dispensed or contact is made with a 
patient for a phone visit

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7.1 Discontinuation of 
Study Intervention
Added a new bullet point to this list
from Section 7.2: “Enrollment 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
For clarity
7.1.1 QTc Stopping Criteria
Removed this section
This information is not 
needed
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Removed bullet points that are already 
included in Section 7.1
Updated reference to Visit 801 to 
clarify that a short-term follow-up 
visit (V801) should be conducted at 
the time of discontinuation
For clarity
8.2.1 Clinical Safety 
Laboratory Assessments
Updated CRF guidance: 
“Additionally, if local laboratory 
results are used to make a treatment
decision, the results must be entered 
into the CRF.”
For clarity
8.10.2 Electronic
Participant Daily e-Diary 
Assessment
Updated collection instructional text 
for clarity. Added “can include C1D1 
if prior to starting blinded study drug” 
to screening period guidance
For clarity
Updated instructions for the eight 
items collected. Removed “in the 
order below”
10.2 Appendix 2: Clinical 
Laboratory Tests
Updated guidance about discrepancies 
between local and central laboratory 
results
For clarity
Updated “Neutrophils, segmented” to 
“Neutrophils, absolute”. Removed 
“Monocytes,” “Eosinophils,” 
“Basophils,” and “Erythrocytes 
(RBC)”
Updated pregnancy test information to 
include “A serum pregnancy test is 
required at screening.”

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10.9 Appendix 9: 
Provisions for Changes in 
Study Conduct During 
Exceptional Circumstances
Updated Screening period guidance
For clarity
10.11 Appendix 11: 
Protocol Amendment 
History
Added amendment history from Study 
JPCW(b)
Current protocol 
version is Study 
JPCW(c)

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Amendment [b]
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The primary rationale for this amendment is to make the changes noted in the below bullets and 
as summarized in the table. Minor editorial changes are not included in the table.

Modified definition of high risk with regard to histologic grade, restricting it to 
participants with histologic Grade 3 disease.

Resolved conflict between Inclusion Criteria 8 and 13; participants will not have to 
discontinue standard of care endocrine therapy received during the adjuvant anti-HER2 
therapy for early breast cancer.

Provided a conditional clause regarding the timing of the planned interim analysis in 
Section 9.4.2 (Primary Endpoint[s]).
Section
Description of Change
Brief Rationale
1.1 Synopsis
Changes in word choice when describing HR+, HER2+ 
breast cancer risk and risk of recurrence.
For clarity
1.1 Synopsis
Added citations for risk of disease recurrence.
For clarity
1.1 Synopsis
In defining “high risk” for eMonarcHER, revised wording 
to “participants who undergo surgery prior to 
administration of systemic therapy must have the 
following high-risk features and have completed adjuvant 
treatment with chemotherapy and HER2-targeted 
therapies (trastuzumab and pertuzumab):….”
For clarity
1.1 Synopsis
In defining “high risk” for eMonarcHER, histological 
Grade 2 was deleted, leaving just Grade 3.
To address FDA request.
1.2 Schema
Added heading boxes to the study schema to better label 
Study Intervention and Follow-up periods.
For clarity
1.3 Schedule of Activities 
(section text)
Updated the language describing when participants have 
in-clinic visits – accounting for the new Cycle 4 in-clinic 
visit.
Cycle 4 will now have an in-clinic 
visit.
1.3 Schedule of Activities 
(section text)
Minor edits in word choice.
For clarity
1.3 Schedule of Activities 
(table)
Edited header label for Cycles 14-24 to “Cycles 13-26” 
and incorporated column Cycle 26 D1.
For efficiency and clarity
1.3 Schedule of Activities 
(table)
Removed tolerance days for Cycle 1 Day 1, and added 
footnote defining C1D1 as date of first dose of blinded 
study drug.
For clarity regarding C1D1

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1.3 Schedule of Activities 
(table)
In the header instructions, added Cycle 4 as a Clinic visit 
and removed Cycle 4 from Phone visits.
Added Cycle 4 as clinic visit in order 
to accommodate hematology and 
hepatic testing in Cycle 4.
1.3 Schedule of Activities 
(table)
ECOG PS: Updated instructions: assess at C1, C2, and all 
subsequent in-clinic visits; and added V801.
For clarity
1.3 Schedule of Activities 
(table)
ECG: Moved the “X” to just the “≤28 days” column.
For clarity
1.3 Schedule of Activities 
(table)
Hematology and Clinical Chemistry line items: Added a 
bullet point “If collected at baseline (≤14d from C1D1), 
then may be used in place of a C1D1 collection”.
Allow sample collected at baseline to 
be used in place of C1D1 collection.
1.3 Schedule of Activities 
(table)
Hematology and Clinical Chemistry line items: Removed 
“X” from Long-term follow-up.
Sample is not necessary during long-
term follow-up.
1.3 Schedule of Activities 
(table)
Pregnancy test: Added occurrence “X” to C1D1.
For clarity on C1D1. 
1.3 Schedule of Activities 
(table)
Participant PRO questionnaire: Updated line-item title 
and clarified instructions related to administration method 
and occurrence. Removed “X” from Long-term follow-
up.
For clarity
1.3 Schedule of Activities 
(table)
Participant PRO daily e-diary: Updated collection 
instructions.
For clarity
1.3 Schedule of Activities 
(table)
Participant Paper Diary: Updated instructions to remind 
sites to distribute diary on C1D1.
For clarity
1.3 Schedule of Activities 
(table)
Survival assessment: removed instructions.
Instructions are not necessary.
1.3 Schedule of Activities 
(table)
Administer abemaciclib/placebo: Deleted “See 
instructions” from C1D1 cell. This row was also shifted 
up in the SoA, above “Sample collection” procedure 
subheading.
For clarity - Perform as indicated by 
“X” spanning on-study period.
1.3 Schedule of Activities 
(table)
Administer ET: This row was shifted up in the SoA, 
above “Sample collection” procedure subheading.
For clarity
1.3 Schedule of Activities 
(table)
Abemaciclib/placebo drug accountability: Added line 
item. 
For clarity – as reminder
1.3 Schedule of Activities 
(table)
ET Compliance: Added line item.
For clarity – as reminder
1.3 Schedule of Activities 
(table)
PK: Sampling schedule instructions updated.
For clarity
1.3 Schedule of Activities 
(table)
Whole blood for genetic/biomarker analysis: Updated 
line-item title and instructions.
For clarity

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1.3 Schedule of Activities 
(table)
Serum for biomarkers: Added this line item.
New procedure item added for 
collecting serum sample for 
biomarkers. 
1.3 Schedule of Activities 
(table)
Tumor tissue for biomarkers: Moved the “X” to just the 
“≤28 days” column.
For clarity
1.3 Schedule of Activities 
(table)
Updated footnote “c” with specific frequency and 
duration.
For clarity – as reminder
1.3.1 Pharmacokinetic, 
Genetics, and Biomarker 
Sampling Schedule (text)
For subsection, Sampling Schedule for Pharmacokinetics,
updated the section methods content – making it more 
explicit.
For clarity
1.3.1 Pharmacokinetic, 
Genetics, and Biomarker 
Sampling Schedule 
PK Sampling Schedule table: Added superscript “f” to “2-
8 hours” of Cycle 1 Day 1 Sample Number 1, Cycle 2 
Day 1 Sample Number 2, and Cycle 3 Day 1, Sample 
Number 5.
Error correction
1.3.1 Pharmacokinetic, 
Genetics, and Biomarker 
Sampling Schedule 
Sampling Schedule for Genetics/Biomarkers: Added line 
item for collection of Serum (biomarker).
To align with needs in 
Genetics/Biomarker sections.
2.1 Study Rationale
Added citations Lambertini et al. 2019 and Ortega et al. 
2002.
To support grade as factor in risk of 
recurrence (Lambertini et al. 2019); 
and D-type cyclins in cell growth 
(Ortega et al. 2002).
2.1 Study Rationale
Updated text related to approved indications for 
abemaciclib. 
For clarity
2.1 Study Rationale
Updated definition of high risk used for entry to 
monarchE.
For clarity
2.1 Study Rationale
In defining “high risk” for eMonarcHER, revised wording 
to “participants who undergo surgery prior to 
administration of systemic therapy must have the 
following high-risk features and have completed adjuvant 
treatment with chemotherapy and HER2-targeted 
therapies (trastuzumab and pertuzumab):….”
For clarity
2.1 Study Rationale
For eMonarcHER, the definition of high risk was updated 
to delete histological Grade 2.
Per FDA request.
2.2 Background
Added citation for von Minckwitz et al. 2019.
Support of residual disease as a risk 
feature for distant relapse.
2.2.6 Abemaciclib
Deleted redundant block of background text regarding 
mechanism of action of abemaciclib.
For clarity
2.2.6 Abemaciclib
Updated definition of high risk used for entry to 
monarchE.
For clarity

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2.3.1 Risk Assessment
Grade ≥3 Diarrhea: In summary of data, added specific 
study names for clarity, and added data for monarchE.
In mitigation strategy, deleted monitoring of renal 
function and vital signs. 
For clarity and completeness
2.3.1 Risk Assessment
Grade ≥3 Neutropenia: In summary of data, added 
specific study names for clarity, made correction for 
Grade ≥3 neutropenia in Monarch 3 (21%) and Monarch 
2 (27%), and added data for monarchE.
In mitigation strategy, updated the lab monitoring timing.
For clarity, accuracy, and 
completeness. Addition of laboratory 
monitoring in Cycle 4.
2.3.1 Risk Assessment
Interstitial Lung Disease (ILD)/Pneumonitis: In summary 
of data, added data for monarchE, and deleted 
“potentially limited tolerability”.
For completeness and clarity
2.3.1 Risk Assessment
Grade ≥3 ALT increased: In summary of data, added 
specific study names for clarity, made a correction (4% to 
6%), and added data for monarchE. Clarified text in ALT 
elevations section. In median time to onset section, 
clarified text and made correction (Monarch 3: 61 days).
In mitigation strategy, updated the lab monitoring timing.
For clarity, completeness, and 
accuracy. Addition of laboratory 
monitoring in Cycle 4.
2.3.1 Risk Assessment
Venous Thromboembolic Events (VTE): In summary of 
data, added specific study names for clarity, and added 
data for monarchE. 
For clarity and completeness
4.3 Justification for Dose
Minor formatting change, and added “Therefore, standard 
adjuvant ET will be administered per label or local 
guidelines at the recommended dose.”
For clarity
5.1 Inclusion Criteria
Inclusion Criterion 2c: Refined eligibility criteria related 
to disease characteristics.
For consistency with standard of care 
and real-world practice.
5.1 Inclusion Criteria
Inclusion Criterion 4a: Replaced “trastuzumab-based” 
with “HER2-targeted” and deleted “trastuzumab 
monotherapy or in combination with other HER2-targeted 
therapies”.
For clarity
5.1 Inclusion Criteria
Inclusion Criterion 4bii1: Deleted histologic Grade 2 
from the high-risk eligibility criteria. Remains at 
histologic Grade 3.
Per FDA request
5.1 Inclusion Criteria
Inclusion Criterion 8: Edited wording to remove apparent 
conflict with Inclusion Criterion 13.
Per FDA request, for clarity

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Protocol I3Y-MC-JPCW(d)
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5.1 Inclusion Criteria
Inclusion Criterion 13: Added wording to remove conflict 
with Inclusion Criterion 8.
Per FDA request. Restriction on the 
use exogenous reproductive hormone 
therapy does NOT apply to ET 
(tamoxifen or AI) being administered 
as part of adjuvant therapy for early 
breast cancer.
5.1 Inclusion Criteria
Inclusion Criterion 15b2: Modified text, adding “or 
serum” to urine, as type of pregnancy test type that can be 
used within 24 hours prior to exposure.
To allow flexibility at site
5.2 Exclusion Criteria
Exclusion Criterion 21: Deleted “active symptoms” 
related to ILD/pneumonitis.
For clarity
5.3 Lifestyle Considerations
Correction: replaced “chemotherapy” with “endocrine 
therapy”.
Error correction
5.4 Screen Failures
Updated wording for interval between screen failure and 
rescreening.
For clarity
6.1 Study Intervention(s) 
Administered
Endocrine therapy: in the sentence, “A switch to another 
standard ET in allowed...” deleted “only in the absence of 
an IDFS event”.
For clarity
6.4 Study Intervention 
Compliance
Modified wording to align with the new 
abemaciclib/placebo drug accountability, and ET 
Schedule of Activities, rows in the Schedule of Activities.
For clarity
6.5 Concomitant Therapy
Clarified that concomitant medications should be 
recorded through the on-study intervention period and 
short-term follow-up period.
For clarity
6.6.1 Dose Suspension and 
Cycle Delay
Revised section to clarify text for dose suspensions before 
and after minor and major surgical procedures.
For clarity
7.1 Discontinuation of Study 
Intervention
Modified discontinuation of study intervention text to 
reduce redundancy.
Added cross reference to Section 1.3 (Schedule of 
Activities) to add clarity regarding procedures to be 
performed upon discontinuation from study intervention.
Removed paragraph (“In rare instances..”) to reduce 
redundancy.
Moved QTc paragraph down to new Section 7.1.1 to 
improve flow and clarity.
Deleted sentence “After discontinuation are met…” due 
to redundancy with prior content in the section.
Removed redundant text for 
improved flow and clarity.
7.1.1 QTc Stopping Criteria
Moved QTc text block from Section 7.1 to new 
subsection 7.1.1.
For improved flow

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Protocol I3Y-MC-JPCW(d)
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7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Added reference to Visit 801 to clarify data to be 
collected at the time of discontinuation and follow-up.
For clarity
8.2 Safety Assessments
Deleted “and functional” from the text describing 
monitoring for testicular changes.
To clarify what we are expecting to 
be monitored.
8.2.3 Venous 
Thromboembolic Events 
(VTEs)
Replaced study codes with study names.
For clarity
8.2.3 Venous 
Thromboembolic Events 
(VTEs)
Updated with sentence - “The majority of patients who 
experienced VTEs were treated with anticoagulants.”
For clarity
8.2.3 Venous 
Thromboembolic Events 
(VTEs)
Deleted block of text pertaining to adjudication of VTEs.
Based on experience with monarchE, 
adjudication of non-confirmed cases 
of VTE is no longer required since 
only a low number of events were 
adjudicated and it had no impact in 
the overall frequency of VTE 
identified.
8.2.5 Interstitial Lung 
Disease (ILD)/Pneumonitis
Remove block text citing ILD/pneumonitis safety data in 
MONARCH 1, MONARCH 2, and MONARCH 3.
These data are redundant with data 
presented in Section 2.3.1.
8.5 Pharmacokinetics
Minor edits for clarity related to sample collection.
For clarity
8.7 Genetics
All section content updated.
Updated to clarify intended genetic 
research in this study.
8.8 Biomarkers
All section content updated.
Updated to clarify intended 
biomarker research in this study.
8.10.1 Patient-Reported 
Outcomes (PRO)
Updated opening sentence to clarify that PROs will be 
collected in the order listed, and prior to extensive contact 
with site personnel.
For clarity
8.10.2 Electronic Participant 
Daily e-Diary Assessment
Updated collection instructional text for clarity.
For clarity
9.4.2 Primary Endpoint(s)
Provided a conditional clause regarding the timing of the 
planned interim analysis.
Change was made to address FDA 
request. Clarified timing and strategy 
of planned interim efficacy analysis 
relative to final IDFS analysis.
9.4.6.4 Treatment 
Compliance
Aligned text related to ET compliance with SoA.
For clarity
10.2 Appendix 2: Clinical 
Laboratory Tests
Added text to state that discrepancies between local and 
central laboratory results will not be considered protocol 
deviations.
For clarity
10.2 Appendix 2: Clinical 
Laboratory Tests
Added cross-reference to Section 8.2.2.(Hepatic Safety 
Monitoring) and Appendix 5 (Liver Safety).
For clarity and ease of use

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Protocol I3Y-MC-JPCW(d)
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10.4 Appendix 4: 
Contraceptive Guidance 
and Collection of Pregnancy 
Information
Updated definition of females considered not of child 
bearing potential.
To align definition in appendix with 
definition in Inclusion Criterion 15b3.
10.6.2 Appendix 6: Removal 
of the Legally Authorized 
Representative, Legal 
Guardian, Parents, 
Designee, Surrogate, and 
Caregiver in Germany
Added text for Germany, requiring the participant to 
complete the ICF, AE, and discontinuation/withdrawal
processes, and not a legally authorized representative, 
legal guardian, parent, designee, surrogate, or caregiver. 
Per request of German Ethics 
Committee.
10.7 Appendix 7: Protocol 
JPCW Inducers and Strong 
Inhibitors of CYP3A
Updated list of inducers and strong inhibitors.
To provide the current list of inducers 
and strong inhibitors.
10.8 Appendix 8: Protocol 
JPCW Breast Cancer 
Recurrence and Other 
Cancer Events
Edited bullet 2 to clarify breast cancer recurrence 
language.
For clarity
10.11 Protocol Amendment 
History
Added amendment history from Study JPCW(a).
Current protocol version is Study 
JPCW(b).
Abbreviations: ALT = alanine aminotransferase; C1 = Cycle 1; d = day; D1 = Day 1: ET = endocrine therapy; FDA 
= Food and Drug Administration; HR+ = hormone receptor-positive; HER2+ = human epidermal growth factor 
receptor-2 positive; IDFS = invasive disease-free survival; ILD = interstitial lung disease; PK = pharmacokinetic; 
PRO = patient-reported outcomes; QTc = QT interval corrected; V801 = visit 801; VTE = venous 
thromboembolic event.

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Protocol I3Y-MC-JPCW(d)
120
Amendment [a]
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Based on the grounds for non-acceptance (GNAs) resulting from the voluntary harmonization procedure 
(VHP) assessment and additional Lilly items, this amendment addresses

minor edit in Schema

changes to the Schedule of Activities

changes to the Inclusion and Exclusion Criteria

correction in Risk Assessment table

corrections to CYP3A guidance text

text moved to Discontinuation of Study Intervention

added text to Safety Assessments

changes in futility interim analyses text

removed select contraception text in Appendix 4

other changes and clarifications throughout the protocol
Section
Description of Change
Brief Rationale
1.2
Schema
Edited study schema - Changed neoadjuvant “trastuzumab” in bottom row to 
“HER2 targeted therapy”
To clarify 
neoadjuvant
1.3
Schedule of Activities 
(text section)
Moved block of text related to V801 to the Short-term follow-up section 
directly below original location.
Moved for clarity
1.3
Schedule of Activities 
(text section)
Moved discontinuation text in Short-term follow-up to Section 7.1 
(Discontinuation of Study Intervention).
Moved for clarity 
to Discontinuation 
section
1.3
Schedule of Activities 
(text section)
Minor edit in Long-term follow-up text – added the word “…including…” in 
the 2nd paragraph.
Added for clarity
1.3
Schedule of Activities 
(SoA)
Added a visit column for Cycle 26 Day 28 to improve clarity regarding which 
procedures to be completed.
Added as aid to 
investigators/sites 
1.3
Schedule of Activities
(SoA)
Added a footnote explaining the timing of Short-term follow-up.
Added for clarity
1.3
Schedule of Activities 
(SoA)
Added a footnote explaining the timing of Long-term follow-up.
Added for clarity

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Protocol I3Y-MC-JPCW(d)
121
1.3
Schedule of Activities 
(SoA)
Refined Cycle and Day headings for clarity.
Added for clarity
1.3
Schedule of Activities 
(SoA)
Edited instructions for Clinic visits and Phone visits.
To clarify type of 
visits needed for 
each cycle during 
study
1.3
Schedule of Activities 
(SoA)
Edited procedure for Pregnancy test, removing required test at V801, and 
editing instructions for clarity.
Clarity for 
procedure 
frequency and 
timing
1.3
Schedule of Activities 
(SoA)
Abdominal ± pelvic imaging – edited formatting - referred to instructions.
Added clarifying text in instructions for During treatment “and follow-up..”
Clarity for 
procedure
1.3
Schedule of Activities 
(SoA)
For Bilateral imaging - in Short-term follow-up (V801), removed “X” –
edited formatting - referred to instructions.  Added clarifying text in 
instructions for During treatment “and follow-up..”
Clarity for 
procedure
1.3
Schedule of Activities 
(SoA)
Chest imaging – edited formatting - referred to instructions.
Added language to clarify that imaging must be performed prior to 
randomization.
Added clarifying text in instructions for During treatment “and follow-up..”
Clarity for 
procedure
1.3
Schedule of Activities 
(SoA)
Bone nuclear imaging – edited formatting - referred to instructions.
Added clarifying text in instructions for During treatment “and follow-up..”
Clarity for 
procedure
1.3
Schedule of Activities 
(SoA)
Added procedure row for Participant Paper Diary for tracking date/time of 
abemaciclib/placebo doses taken.
As aid for 
investigators and 
sites
1.3
Schedule of Activities 
(SoA)
Minor add - note to PK procedure row cross-referencing to paper diary.
As aid for 
investigators and 
sites
1.3
Schedule of Activities 
(SoA)
For Plasma for biomarker item, clarified instructional note for consistency 
with biomarker sampling schedule in Section 1.3.1.
Clarity for 
procedure
2.3.1
Risk Assessment
Corrected text in first column, first row to Grade ≥3 Diarrhea.
Correction
GNA 8
5.1
Inclusion Criteria
Inclusion Criterion 2: Added STEEP criteria in text and cross reference to 
Appendix 8.
GNA 1
Added for clarity
5.1
Inclusion Criteria
Inclusion Criterion 4: added parenthetical explanation to “trastuzumab-based 
therapy” - (trastuzumab monotherapy or in combination with other 
HER2-targeted therapies).
Added for clarity
5.1
Inclusion Criteria
Inclusion Criterion 6: Edited language for required duration (approximately 9 
months to 1 year) of standard HER2-targeted therapy.
GNA 2
Added for clarity
5.1
Inclusion Criteria
Inclusion Criterion 6a and 6b: Added clarifying language for eligible adjuvant 
regimens.
GNA 2
Added for clarity

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Protocol I3Y-MC-JPCW(d)
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5.1
Inclusion Criteria
Inclusion Criterion 15:
Modified IC 15a for male participants, replaced “during the intervention 
period” with “while taking blinded study drug”; and added “The use of 
contraception in male participants is not required.”
Modified IC 15b-2 for female participants, to add 3 weeks to time 
requirement for using highly effective contraception following last dose of 
blinded study drug. Also deleted subpoints B and C.
GNA 10
Updated to align 
with current 
guidance
5.2
Exclusion Criteria
Exclusion Criterion 23: Added word “known”.
GNA 3
Added for clarity
5.2
Exclusion Criteria
Exclusion Criterion 23a: Added units “µL” to cell count (cells/µL).
Correction
5.2
Exclusion Criteria
Exclusion Criterion 28: Deleted.
Medical decision
6.5
Concomitant 
Therapy
Added sentence stating that concurrent treatment with standard of care bone-
modifying agents is permitted.
Added for clarity
6.5
Concomitant 
Therapy
Replaced “abemaciclib” with “blinded study drug”.
GNA 12
Correction
6.5
Concomitant 
Therapy
Transporter Substrates section: Added descriptive text “At clinically relevant 
concentrations…” at start of section text.
Added for clarity
7.1
Discontinuation of 
Study Intervention
Inserted discontinuation explanatory text that was moved from Section 1.3.
Added for clarity
8.1.1
Imaging and 
Recurrence 
Assessment
Changed section title to better reflect content.
Changed for clarity
8.2
Safety Assessments
Added content addressing monitoring participants for signs and symptoms of 
visual impairment and/or testicular anatomical and functional changes.
GNA 9
Added for clarity
8.5
Pharmacokinetics
Inserted minor text and corrected visit text for PK sampling.
Correction
9.5.1
Interim Analyses for 
Efficacy/Futility
Added content further detailing the process of the futility interim analyses.
GNA 16
Added for clarity
10.2
Appendix 2
Labs test removed for Cell morphology (RBC and WBC).
This lab test is not 
necessary
10.4
Appendix 4
Contraception Guidance: CONTRACEPTIVES ALLOWED DURING THE 
STUDY. Removed block of text:
“If the highly effective contraceptive methods are contraindicated or strictly 
declined by the patient…  …or sponge with spermicide (double-barrier 
method) is also considered an acceptable birth control method.”
Updated to align 
with current 
guidance
10.8
Appendix 8
Minor modification of text related to the definition of Distant Recurrence for 
clarity.
Added clarity

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Protocol I3Y-MC-JPCW(d)
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Throughout 
Document
Minor editorial and format changes.
Editorial
Abbreviations: HER2 = human epidermal growth factor receptor-2; PK = pharmacokinetics; RBC = red blood cell; 
STEEP = Standardized Definitions for Efficacy Endpoints; V = visit; WBC = white blood cell.

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