MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer
Phase: PHASE3
Conditions: Breast Neoplasms
Sponsor: Eli Lilly and Company

 
 
 
 
 
 
Protocol I3Y-MC-JPBL (d) 
 
 
 
 
 
MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant 
with or without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, 
HER2 Negative Locally Advanced or Metastatic Breast Cancer 
 
 
 
 
 
NCT02107703 
 
 
 
 
 
Approval Date: 26-Apr-2016  

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1.
Protocol I3Y-MC-JPBL(d)
MONARCH 2:  A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Fulvestrant with or without 
Abemaciclib, a CDK4/6 Inhibitor, for Women with 
Hormone Receptor Positive, HER2 Negative Locally 
Advanced or Metastatic Breast Cancer
Confidential Information
The information contained in this protocol 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, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act Exemption 4.
LY2835219 (Abemaciclib)
This study is a global, multicenter, double-blind, placebo-controlled, Phase 3 trial for 
women with hormone receptor positive, HER2 negative locally advanced or metastatic 
breast cancer randomized to receive fulvestrant with or without abemaciclib.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly:  01 April 2014
Amendment (a) Approved by Lilly:  12 January 2015
Amendment (b) Approved by Lilly:  30 March 2015
Amendment (c) Approved by Lilly:  27 October 2015
Amendment (d) Electronically Signed and Approved by Lilly
on date provided below.
Approval Date: 26-Apr-2016 GMT

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2.
Synopsis
Study Rationale
Abemaciclib is an oral, selective, and potent small molecule cyclin-dependent kinases (CDKs) 4 
and 6 (CDK4 and CDK6) dual inhibitor with antitumor activity within multiple preclinical 
pharmacology models and an acceptable toxicity profile in nonclinical species.  Abemaciclib
mesylate has been shown to significantly inhibit tumor growth in multiple murine xenograft 
models for human cancer.  Published studies that evaluated in vitro growth inhibition with other 
CDK4 and CDK6 inhibitors across a diverse panel of 47 breast cell lines showed greater 
sensitivity to CDK4 and CDK6 inhibition in estrogen receptor positive (ER+) lines. Specifically, 
studies with abemaciclib indicate differential sensitivity to CDK4 and CDK6 inhibition based on 
histological and genetic characteristics.  Growth inhibition in vitro across a diverse panel of 
46 breast cancer cell lines, representing the known molecular subgroups of breast cancer, 
indicates that sensitivity to CDK4 and CDK6 inhibition is greater in ER+ breast cancers with 
luminal histology.
Importantly, abemaciclib has demonstrated evidence of clinical activity in a tumor-specific 
cohort of women with metastatic breast cancer (mBC).  In Study I3Y-MC-JPBA, 47 patients 
with a median of 7 prior systemic regimens received therapy with abemaciclib.  Among the 
36 patients with hormone receptor positive (HR+) mBC, the median progression-free survival
(PFS) was 8.8 months and there were 12 confirmed partial responses (PR) for an objective 
response rate of 33.3%.  In the same study, the combination of abemaciclib plus fulvestrant was 
also evaluated and demonstrated an acceptable safety profile in 19 women with HR+ mBC.  In 
addition, 4 confirmed partial responses were observed in these 19 patients. These results support 
further investigation of abemaciclib in combination with fulvestrant for women with HR+ locally 
advanced or metastatic breast cancer.
Study I3Y-MC-JPBL is a randomized, double-blind, placebo-controlled Phase 3 study of 
fulvestrant with or without abemaciclib for women with HR+, human epidermal growth factor 
receptor 2 negative (HER2-) locally advanced (not amenable to curative treatment by surgery) or 
metastatic breast cancer.

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Clinical Protocol Synopsis:  Study I3Y-MC-JPBL
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  MONARCH 2:  A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant 
with or without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative 
Locally Advanced or Metastatic Breast Cancer 
Number of Planned Patients:  630
Entered:  750
Enrolled:  630
Completed:  630
Phase of Development:  3
Length of Study:  Approximately 72 months
Planned first patient visit:  July 2014
Planned last patient visit:  August 2020
Planned interim analyses:  265 (approximately 70% of the planned) progression-free survival (PFS) events 
Objectives:  The primary objective of Study I3Y-MC-JPBL (JPBL) is to compare abemaciclib plus fulvestrant 
versus placebo plus fulvestrant with respect to PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
The secondary objectives of the study are to compare abemaciclib plus fulvestrant versus placebo plus fulvestrant 
with respect to each of the following:
•
overall survival (OS)

OS rate at 1, 2, and 3 years
•
objective response rate [complete response (CR) + partial response (PR)]
•
duration of response (DoR) [CR + PR]
•
disease control rate (DCR) [CR + PR + stable disease (SD)]
•
clinical benefit rate (CBR) [CR + PR + SD ≥6 months]
•
safety and tolerability
•
pain and symptom burden using the Brief Pain Inventory (BPI), the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
and the EORTC QLQ-BR23 (breast) questionnaires, and health status scores from the EuroQol
5-Dimension 5 Level (EQ-5D 5L)
•
pharmacokinetics (PK) of abemaciclib, its metabolites, and fulvestrant
The exploratory objectives are:
•
To explore potential biomarkers related to the retinoblastoma (Rb) pathway and/or the 
pathogenesis of breast cancer
•
To explore if change in tumor size is associated with PFS and OS
•
To explore time to progressive bone metastases by treatment arm

time to worsening of Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 
≥2

time to first skeletal-related event (SRE; defined as either pathological fracture, spinal cord
compression, radiation to the bone, or surgery to the bone)

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Study Design:  Study JPBL is a multicenter, randomized, double-blind, Phase 3 trial for women with HR+, HER2-
locally advanced or metastatic breast cancer.  Approximately 630 endocrine therapy pretreated (EP) patients will 
be randomized 2:1 between the 2 arms, and enrollment will be closed when approximately 450 EP patients have 
been enrolled at a starting dose of 150 mg every 12 hours (Q12H).  Patients will be randomized using the following 
stratification factors:  nature of disease (visceral metastases versus bone only metastases versus other) and
sensitivity to endocrine therapy (primary resistance versus secondary resistance).  The presence of visceral 
metastases refers to lung, liver, pleural, or peritoneal involvement at the time of randomization. Primary clinical 
resistance to endocrine therapy is defined as follows:  1) for endocrine therapy in the adjuvant setting, recurrence 
within the first 2 years of adjuvant endocrine therapy while on endocrine therapy or 2) for endocrine therapy in the 
locally advanced or metastatic setting, progression within first 6 months of initiating first-line endocrine therapy 
while on endocrine therapy.  Patients receiving prior endocrine therapy who do not meet the definition of primary 
clinical resistance will be considered to have secondary clinical resistance.
Diagnosis and Main Criteria for Inclusion and Exclusions: Patients are eligible to be included in the study if 
they meet following criteria:  1) have a diagnosis of HR+, HER2- breast cancer; 2) have inoperable locally 
advanced or metastatic disease and relapsed with radiologic evidence of progression; 3) have postmenopausal 
status due to either surgical/natural menopause or ovarian suppression with a gonadotropin-releasing hormone 
(GnRH) agonist such as goserelin; 4) have a negative serum pregnancy test at baseline (within 14 days prior to 
randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 
weeks following the last dose of abemaciclib if postmenopausal status is due to ovarian suppression with a GnRH 
agonist; 5) have either measurable disease or nonmeasurable bone only disease; 6) are female and >18 years of 
age; 7) have given written informed consent prior to any study-specific procedures; 8) have adequate organ 
function; 9) have a performance status ≤1 on the ECOG scale; 10) have discontinued previous therapies for cancer, 
for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving 
study drug, and recovered from the acute effects of therapy;11) are willing to participate for the duration of the 
study and to follow study procedures; and 12) are able to swallow capsules.
Patients will be excluded from the study if they meet any of the following criteria:  13) are currently receiving an 
investigational drug in a clinical trial or participating in any other type of medical research judged not to be 
scientifically or medically compatible with this study; 14) have visceral crisis, lymphangitic spread, or 
leptomeningeal carcinomatosis; 15) have a history of central nervous system metastasis; 16) have received prior 
treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, everolimus, or any 
CDK4/6 inhibitor; 17) have received treatment with a drug that has not received regulatory approval for any 
indication within 14 or 21 days prior to randomization of study drug for a nonmyelosuppressive or 
myelosuppressive agent, respectively; 18) have received recent (within 28 days prior to randomization) yellow 
fever vaccination; 19) have had major surgery within 14 days prior to randomization; 20) have a personal history 
within the last 12 months of any of the following conditions:  syncope of cardiovascular etiology, ventricular 
tachycardia, ventricular fibrillation, or sudden cardiac arrest; 21) have serious preexisting medical conditions that, 
in the judgment of the investigator, would preclude participation in this study; 22) have inflammatory breast cancer 
or a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in 
complete remission with no therapy for a minimum of 3 years; 23) have received an autologous or allogeneic stem-
cell transplant; 24) have active bacterial or fungal infection, or detectable viral infection; 25) are pregnant or 
breastfeeding; or 26) have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for 
example, denosumab) <7 days prior to randomization.
Test Product, Dosage, and Mode of Administration:
Abemaciclib will be supplied as capsules administered orally, 150 mg Q12H on Days 1 to 28 of a 28-day cycle,
plus fulvestrant will be administered 500 mg intramuscularly into the buttocks slowly (1 to 2 minutes per injection) 
as two 250-mg injections, one in each buttock, on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond.

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Planned Duration of Treatment:
Treatment period: until disease progression or other discontinuation criteria are fulfilled.
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death
Reference Therapy, Dose, and Mode of Administration:  Placebo will be supplied as capsules administered
orally Q12H on Days 1 to 28 of a 28-day cycle plus fulvestrant will be administered 500 mg intramuscularly into 
the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, one in each buttock, on Days 1 and 15 
of Cycle 1, then on Day 1 of Cycle 2 and beyond.
Criteria for Evaluation:
Efficacy:

PFS

OS 

OS at 1, 2, and 3 years

Objective Response Rate

DoR

DCR
Safety:

Adverse events
Health Outcomes:

BPI:  proportion of patients with “worst pain” increase of 2 points or more at any time on-therapy, 
compared to baseline 

EORTC QLQ-C30 and EORTC QLQ-BR23: Describe target tumor symptom changes 

EQ-5D 5L: Describe health status changes 
Pharmacokinetics:

Population PK parameters for abemaciclib and fulvestrant 

Plasma concentration levels of fulvestrant during Cycle 1/Cycle 2
Exploratory

Potential biomarkers related to the Rb pathway and/or the pathogenesis of breast cancer.

Time course of change in tumor size

Time from randomization to documentation of the first occurrence of any SRE

Time from randomization to documentation of the first occurrence of any PS of ≥2

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Statistical Methods:
Statistical:  The primary objective of this study is to compare abemaciclib plus fulvestrant versus placebo plus 
fulvestrant in terms of PFS for women with HR+, HER2- locally advanced or metastatic breast cancer.  An 
important secondary objective of this study is to compare the 2 arms with respect to OS.
A 2-look group sequential design on the primary endpoint of PFS will be utilized, with 1 interim analysis and 
1 final PFS analyses occurring at approximately 265  and 378 investigator-assessed PFS events in the EP stratum.  
A fixed alpha-spending method will be used to maintain the cumulative 1-sided Type I error rate of .025.  
Assuming a hazard ratio (HR) of 0.703, this design yields approximately 90% statistical power to detect superiority 
of the abemaciclib plus fulvestrant arm over placebo plus fulvestrant arm with the use of a 1-sided log-rank test 
and a cumulative type I error rate of 0.025.
OS is an important secondary endpoint for this study. OS will be tested only if the test of PFS is significant. The 
final OS analysis will be performed when approximately 441 OS events have been observed in the EP stratum.
Efficacy:
The PFS and OS analyses to test the superiority of abemaciclib to placebo in improving PFS and OS time will use 
the log-rank test stratified by stratification variables.  Additional analyses will be performed using the 
Kaplan-Meier method to estimate the PFS and OS curves and rates, and the Cox proportional hazard model will be 
used to estimate the PFS and OS HRs and corresponding 95% confidence interval.
Safety:
All safety summaries and analyses will be based on the Safety Population.  Patients will be grouped according to 
treatment received in Cycle 1.
Health Outcomes:
The maximum change from baseline score will be calculated and summarized for BPI “worst pain” and EORTC 
composite scores.  The number and reason for missing and incomplete questionnaires/assessments will be 
summarized for each instrument and study arm.
Pharmacokinetics:
PK parameters for abemaciclib in plasma (clearance, exposure, volume of distribution, and half-lives) and 
inter-individual PK variability will be computed using nonlinear mixed effect modeling implemented in 
NONMEM.  If warranted by the data, PK parameters for fulvestrant in plasma and inter-individual variability 
estimates will also be computed using nonlinear mixed effect modeling implemented in NONMEM.
Pharmacodynamics:
Pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) may be analyzed by means 
of NONMEM and connected to the population PK model for abemaciclib and/or fulvestrant in a 
PK/pharmacodynamic model.
Tailoring biomarkers:
Summary statistics will include means, medians, corresponding standard errors, quartiles, and ranges.  Biomarkers 
with discrete measures, such as genotype locus, will be summarized in frequency tables.  Correlative analyses may 
be performed to investigate associations between biomarkers and clinical endpoints.

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3.
Table of Contents
MONARCH 2:  A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Fulvestrant with or without 
Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or 
Metastatic Breast Cancer
Section
Page
1.
Protocol I3Y-MC-JPBL(d)  MONARCH 2:  A Randomized, Double-
Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or 
without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or Metastatic 
Breast Cancer......................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
5.1.
Rationale for Amendment (a).......................................................................................20
5.1.1.
Dose Rationale.....................................................................................................20
5.2.
Rationale for Amendment (b).......................................................................................21
5.3.
Rationale for Amendment (c).......................................................................................22
5.4.
Rationale for Amendment (d).......................................................................................22
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Study Population...............................................................................................................25
7.1.
Inclusion Criteria..........................................................................................................25
7.2.
Exclusion Criteria ........................................................................................................27
7.3.
Discontinuations ..........................................................................................................28
7.3.1.
Discontinuation of Patients...................................................................................28
7.3.2.
Discontinuation of Study Sites .............................................................................29
7.3.3.
Discontinuation of the Study................................................................................29
8.
Investigational Plan...........................................................................................................30
8.1.
Summary of Study Design............................................................................................30
8.1.1.
Study Completion and End of Trial......................................................................31
8.1.2.
Extension Period..................................................................................................32

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8.2.
Discussion of Design and Control ................................................................................33
9.
Treatment..........................................................................................................................34
9.1.
Treatments Administered .............................................................................................34
9.2.
Materials and Supplies .................................................................................................35
9.3.
Method of Assignment to Treatment ............................................................................35
9.4.
Selection and Timing of Doses.....................................................................................35
9.4.1.
Special Treatment Considerations ........................................................................37
9.4.1.1.
Dose Adjustments and Delays ........................................................................37
9.4.1.1.1.
Dose Adjustments.....................................................................................38
9.4.1.1.1.1.
Blinded Study Drug ............................................................................38
9.4.1.1.1.2.
Fulvestrant ..........................................................................................38
9.4.1.1.2.
Dose Suspension (within a cycle) and Cycle Delays..................................38
9.4.1.1.3.
Hematologic Toxicity ...............................................................................39
9.4.1.1.4.
Nonhematologic Toxicity..........................................................................39
9.4.1.1.4.1.
Diarrhea..............................................................................................39
9.5.
Blinding .......................................................................................................................40
9.5.1.
Unblinding at Interim Analyses............................................................................40
9.5.2.
Emergency Unblinding ........................................................................................40
9.5.3.
Inadvertent Unblinding ........................................................................................41
9.6.
Concomitant Therapy...................................................................................................41
9.6.1.
Surgery and/or Radiotherapy for Locally Advanced Breast 
Cancer..................................................................................................................41
9.6.2.
Radiotherapy........................................................................................................42
9.6.3.
Supportive Care ...................................................................................................42
9.6.4.
Growth Factors ....................................................................................................42
9.6.5.
Supportive Management for Diarrhea...................................................................42
9.6.6.
Bisphosphonates and RANK-L Targeted Agents..................................................43
9.6.7.
Ovarian Suppression with Gonadotropin-Releasing Hormone 
Agonists...............................................................................................................43
9.7.
Treatment Compliance .................................................................................................43
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................44
10.1. Efficacy Measures........................................................................................................44
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................44
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................45
10.1.3.
Primary Efficacy Measure....................................................................................45

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10.1.4.
Secondary Efficacy Measures...............................................................................46
10.1.5.
Exploratory Efficacy Measures ............................................................................47
10.2. Health Outcome/Quality of Life Measures ...................................................................47
10.2.1.
Patient-Reported Outcomes..................................................................................47
10.2.1.1.
Pain Intensity..................................................................................................48
10.2.1.2.
Health-Related Quality of Life........................................................................48
10.2.1.3.
Health Status ..................................................................................................49
10.2.2.
Resource Utilization.............................................................................................49
10.3. Safety Evaluations........................................................................................................49
10.3.1.
Adverse Events ....................................................................................................50
10.3.1.1.
Serious Adverse Events ..................................................................................51
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................53
10.3.2.
Other Safety Measures .........................................................................................53
10.3.2.1.
Electrocardiograms.........................................................................................53
10.3.3.
Safety Monitoring ................................................................................................53
10.3.4.
Complaint Handling.............................................................................................54
10.4. Sample Collection and Testing.....................................................................................54
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................54
10.4.2.
Samples for Tailoring Biomarkers........................................................................55
10.4.2.1.
Archived Tumor Tissue ..................................................................................55
10.4.2.2.
Blood Samples for Pharmacogenetic Evaluations............................................56
10.4.2.3.
Plasma Samples for Exploratory Biomarker Evaluations.................................56
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................56
10.5. Appropriateness of Measurements................................................................................57
11.
Data Quality Assurance.....................................................................................................58
11.1. Data Capture System....................................................................................................58
12.
Sample Size and Statistical Methods .................................................................................59
12.1. Determination of Sample Size ......................................................................................59
12.2. Statistical and Analytical Plans.....................................................................................60
12.2.1.
Analysis Populations............................................................................................60
12.2.2.
General Considerations ........................................................................................60
12.2.3.
Patient Disposition...............................................................................................60
12.2.4.
Patient Characteristics..........................................................................................61
12.2.5.
Concomitant Therapy...........................................................................................61
12.2.5.1.
Postdiscontinuation Therapy...........................................................................61
12.2.6.
Treatment Compliance .........................................................................................61
12.2.7.
Primary Outcome and Methodology.....................................................................62

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12.2.8.
Secondary Outcomes and Methodology ...............................................................63
12.2.8.1.
Overall Survival .............................................................................................63
12.2.8.2.
Objective Response Rate, DCR, CBR, and DoR.............................................63
12.2.8.3.
Other Secondary Endpoints ............................................................................64
12.2.9.
Sensitivity Analysis..............................................................................................64
12.2.10. Pharmacokinetic and Pharmacodynamic Analyses ...............................................64
12.2.11. Tailoring Biomarker Analyses..............................................................................64
12.2.12. Health Outcome/Quality of Life Analyses............................................................65
12.2.12.1. Pain Intensity..................................................................................................65
12.2.12.2. Pain Assessment.............................................................................................65
12.2.12.3. Health-Related Quality of Life........................................................................66
12.2.12.4. Utilization ......................................................................................................66
12.2.12.5. Health State Utility.........................................................................................66
12.2.12.6. Exploratory Analyses .....................................................................................66
12.2.13. Safety Analyses....................................................................................................67
12.2.14. Subgroup Analyses ..............................................................................................68
12.2.15. Interim Analyses..................................................................................................68
12.2.15.1. Safety Interim Analyses..................................................................................68
12.2.15.2. Efficacy Interim Analyses...............................................................................69
12.2.15.3. Pharmacokinetic/Pharmacodynamic Interim Analyses....................................69
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................70
13.1. Informed Consent.........................................................................................................70
13.2. Ethical Review.............................................................................................................70
13.3. Regulatory Considerations ...........................................................................................70
13.3.1.
Investigator Information.......................................................................................71
13.3.2.
Protocol Signatures ..............................................................................................71
13.3.3.
Final Report Signature .........................................................................................71
14.
References ........................................................................................................................72

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List of Tables
Table
Page
Table JPBL.9.1.
Treatment Regimens/Dosing Schedule ...................................................34
Table JPBL.9.2.
Toxicity Dose Adjustments and Delays of Blinded Study Drug for 
Study JPBL ............................................................................................37
Table JPBL.9.3.
Dose Adjustments for Blinded Study Drug .............................................38
Table JPBL.10.1.
Secondary Efficacy Endpoints................................................................46
Table JPBL.10.2.
Exploratory Efficacy Endpoints..............................................................47
Table JPBL.10.3.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........50
Table JPBL.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................62

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List of Figures
Figure
Page
Figure JPBL.8.1.
Illustration of study design......................................................................30
Figure JPBL.8.2.
Study period and extension period diagram.............................................32

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBL Study Schedule ...............................................................75
Attachment 2.
Protocol JPBL Clinical Laboratory Tests................................................82
Attachment 3.
Protocol JPBL Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................83
Attachment 4.
Protocol JPBL ECOG Performance Status..............................................84
Attachment 5.
Protocol JPBL RECIST Criteria 1.1........................................................85
Attachment 6.
Protocol JPBL Sampling Summary.........................................................92
Attachment 7.
Protocol JPBL Electrocardiogram and Pharmacokinetic Sampling 
Schedule.................................................................................................93
Attachment 8.
Protocol JPBL Inducers, Strong Inhibitors of CYP3A, or 
Substrates of CYPs with Narrow Therapeutic Range ..............................95
Attachment 9.
Protocol JPBL CTCAE 4.03 Diarrhea Definition....................................96
Attachment 10.
Protocol JPBL Amendment(d) Summary MONARCH 2:  A 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
Fulvestrant with or without Abemaciclib, a CDK4/6 Inhibitor, for 
Women with Hormone Receptor Positive, HER2 Negative Locally 
Advanced or Metastatic Breast Cancer ...................................................97

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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]).
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
blinding/masking
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BPI-sf
Brief Pain Inventory-short form
CDK4 and CDK6
cyclin-dependent kinases 4 and 6
collection database
A computer database where clinical trial data are entered and validated.
CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.

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CI
confidence interval
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DMC
data monitoring committee
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EN
endocrine therapy naïve
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
EORTC BR23
EORTC Breast subscale, 23 items
EP
endocrine therapy pretreated
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
EQ-5D 5L
EuroQol 5-Dimension 5 Level

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extension period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit may continue to receive study 
therapy until one of the criteria for discontinuation is met.
FSH
follicle-stimulating hormone
GCP
good clinical practice
GnRH
gonadotropin-releasing hormone
HER
human epidermal growth factor receptor
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IND
Investigational New Drug application
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial 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.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.

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LLT
Lower Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PR
partial response
PRO/ePRO
patient-reported outcome/electronic patient-reported outcome
PS
performance status
PT
Preferred Term
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
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.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SMD
Lilly Senior Management Designee

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SOC
System Organ Class
SRE
skeletal-related event
Study completion
This study will be considered complete following evaluation of additional overall 
survival data as determined by Lilly.  
SUSARs
suspected unexpected serious adverse reactions 
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limits of normal
US
United States
VAS
visual analog scale

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MONARCH 2:  A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Fulvestrant with or without 
Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or 
Metastatic Breast Cancer
5.
Introduction
Breast cancer is one of the most common cancers among women in the United States and Europe
and is the second leading cause of cancer death in women. Early stage disease is treatable, but
metastatic breast cancer (mBC) has a median overall survival (OS) of only 2 to 3 years (Cardoso 
et al. 2012). While women who have been diagnosed with hormone receptor positive (HR+) 
mBC are typically treated with endocrine therapy, de novo or acquired resistance to endocrine 
therapy is a common clinical problem in this population.  Clinical studies have demonstrated that 
cyclinD is overexpressed in more than 50% of breast cancers, the majority of which are also 
estrogen receptor positive (ER+). CyclinD interacts directly with cyclin-dependent kinases 4 and 
6 (CDK4 and CDK6) in an active protein complex.  Therefore, CDK4 and CDK6 represents a 
potentially important target to address the unmet need for patients with mBC, in particular those 
with HR+ disease.
Abemaciclib is a potent and selective small molecule inhibitor of CDK4 and CDK6.  In the 
Phase 1 Study I3Y-MC-JPBA (JPBA), abemaciclib has shown acceptable safety across 
five tumor-specific cohorts, with the most common treatment-emergent adverse events (TEAEs) 
possibly related to study drug including diarrhea, nausea, fatigue, vomiting, and neutropenia.
Importantly, abemaciclib has demonstrated evidence of clinical activity in a tumor-specific 
cohort of women mBC.  In Study I3Y-MC-JPBA, 47 patients with a median of 7 prior systemic 
regimens received therapy with abemaciclib.  Among the 36 patients with HR+ mBC, the median 
progression-free survival (PFS) was 8.8 months and there were 12 confirmed partial responses
(PR) for an objective response rate of 33.3%.  In the same study, the combination of abemaciclib
plus fulvestrant was also evaluated and demonstrated an acceptable safety profile in 19 women 
with HR+ mBC.  In addition, 4 confirmed partial responses were observed in these 19 patients.  
These results support further investigation of abemaciclib in combination with fulvestrant for 
women with HR+ locally advanced or metastatic breast cancer.
Study I3Y-MC-JPBL is a randomized, double-blind, placebo-controlled Phase 3 study of 
fulvestrant with or without abemaciclib for women with HR+, human epidermal growth factor 
receptor 2 negative (HER2-) locally advanced (not amenable to curative treatment by surgery) or 
metastatic breast cancer.
More information about the known and expected benefits and risks of abemaciclib may be found 
in the Investigator’s Brochure (IB).  Information on adverse events (AEs) expected to be related 
to the study drug may be found in Section 7 (Development Core Safety Information) of the IB.  
Information on serious adverse events (SAEs) expected in the study population independent of 

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drug exposure and that will be assessed by the sponsor in aggregate, periodically during the 
course of the study, may be found in Section 6 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of fulvestrant may be 
found in the following:  Patient Information Leaflet, Package Insert, or Summary of Product 
Characteristics.
5.1.
Rationale for Amendment (a)
This protocol was amended so that the initial dose of abemaciclib when administered in 
combination with fulvestrant could be lowered from 200 mg every 12 hours (Q12H) to 150 mg 
Q12H.
Additionally, existing patients who have already started on 200 mg of blinded study drug will be 
dose reduced to 150 mg Q12H.
Further modifications were performed for clarity:  1) blinded study drug in relevant places 
defined; 2) supportive management for diarrhea modified.  Minor typographical and formatting 
edits were made throughout the document for clarity and consistency.
5.1.1. Dose Rationale
The rationale for reducing and selecting the starting dose was based on the preliminary blinded 
safety review of Study JPBL and updated safety and pharmacokinetic/pharmacodynamic 
(PK/PD) data from patients treated with endocrine therapies in combination with abemaciclib in 
advanced or metastatic breast cancer enrolled in Studies JPBA and JPBH.
Pharmacokinetic data obtained in Study JPBA for abemaciclib from a total of 124 patients dosed 
repeatedly with abemaciclib at 150 and 200 mg Q12H indicate that the range of steady-state 
exposures achieved with 150 mg Q12H is comparable to 200 mg Q12H.  In addition, in Study 
JPBA the steady-state exposures achieved with a 50-mg unit dose, which is the lowest possible 
allowed dose in Study JPBL in the case of dose reduction when needed for AEs, are within the 
low end of the range of exposures achieved by the 150- and 200-mg dose levels.  Skin biopsies 
collected in Study JPBA predose and 4 hours postdose on Cycle 1 Day 15 show a decrease in the 
pRb and topoIIα expression with increasing plasma concentration.  Abemaciclib effectively 
inhibits CDK4/6, which results in cell cycle inhibition upstream of the G1 restriction point at 
both doses of 150 and 200 mg.
Tumor responses were observed in patients receiving both 150 mg and 200 mg abemaciclib 
monotherapy.  As of 29 August 2014, findings in the 47 patients with advanced or metastatic 
breast cancer who have been enrolled in Part D of Study JPBA resulted in 12 confirmed PRs 
(including 8 responses at 150 mg Q12H and 4 responses at 200 mg Q12H) among the 36 patients 
in Part D with HR+ mBC, based on investigators’ assessment of response using RECIST v1.1.  
The ORR for the 36 patients in Part D with HR+ mBC was 33.3%, the DCR was 80.6%, the 
CBR was 61.1%, and median PFS was 8.8 months.
In a subsequent cohort of 19 patients with HR+, advanced or metastatic breast cancer enrolled in 
Part G of Study JPBA and treated with fulvestrant plus 200mg abemaciclib Q12H, 17 patients 

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with abemaciclib dose reductions were observed.  In addition, 4 confirmed PRs were observed 
for an ORR was 21.1% (36.4% in the 11 patients with measureable disease), the DCR was 
78.9%, the CBR was 63.2%, and the median PFS was 10.2 months.
Preliminary safety data from Study JPBH demonstrate that the AE profile of abemaciclib 
administered in combination with nonsteroidal aromatase inhibitors (NSAIs) is consistent with 
abemaciclib monotherapy, as the most common TEAEs possibly related to study drug were 
diarrhea, nausea, fatigue, and neutrophil count decreased.  However, at the 200-mg dose, the 
incidence of treatment-emergent Grade 3 diarrhea was found to be greater when abemaciclib was 
administered in combination with an NSAI from a review of the preliminary safety data in Study 
JPBH, compared to abemaciclib administered alone in Part D of Study JPBA. Nevertheless, 
when the abemaciclib dose was reduced from 200 mg to 150 mg or lower for some patients in 
Study JPBH, either the severity of diarrhea decreased or the event resolved.
The rationale for the underlying change in the abemaciclib starting dose is, that although the 
Phase 1 Study JPBA demonstrated that the 200mg Q12H abemaciclib dose was tolerable when 
administered in combination with fulvestrant, a substantial number of patients required 
abemaciclib dose suspension and/or reduction during the first 2 treatment cycles.  As a 
consequence of this observation, a review of dosing and tolerability data from patients enrolled 
during the first 5 months of this study was carried out as part of a regular blinded safety review 
to assess if a similar number of patients required dose alterations in the present study.  During the 
review of blinded safety data from Study JPBL, any alteration in dosing of abemaciclib or 
placebo was presumed to have occurred on the abemaciclib arm.  The data review did reveal a 
high number of dose alterations for abemaciclib or placebo.  The cause of this was principally 
diarrhea occurring in the first treatment cycle.  Therefore the initial dose of blinded study drug 
administered in combination with fulvestrant will be reduced to 150 mg Q12H.
5.2.
Rationale for Amendment (b)
Study JPBL protocol was amended to update the sample size for endocrine therapy pretreated 
(EP) patients enrolled at the 150-mg Q12H dose and to update the analysis plan. The EP
population is defined as those patients with progression on adjuvant endocrine therapy or within 
12 months of completion of adjuvant endocrine therapy, or those patients who have progressed 
on or after first-line endocrine therapy for metastatic disease. In addition, amendment (b)
removes the inclusion of endocrine therapy naïve (EN) patients and specifies that the previously 
enrolled EN patients will not be included in the primary analysis.
Prior to amendment (b), this study enrolled 2 strata of patients according to prior endocrine 
therapy: EP patients and EN patients.  Following the dose change in amendment (a), the study 
has been modified to focus the study objectives on the EP strata.  Amendment (b) removes 
inclusion of EN patients. The intent-to-treat (ITT) population is limited to those patients 
identified as EP at study entry.  Importantly, prior to amendment (b), randomization was 
stratified by sensitivity to prior endocrine therapy: no prior therapy (EN) versus primary 
resistance (EP) versus secondary resistance (EP).  The narrowing of the ITT population excludes 

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only those patients previously randomized within a specific randomization stratum. As a result, 
the treatment balance is preserved within the revised ITT population and also remains balanced 
with respect to the other stratification factor (nature of disease).
The initial study protocol specified an enrollment of 450 EP patients. Amendment (a) changed 
the starting dose of blinded study drug from 200 mg Q12H to 150 mg Q12H.  In addition to 
describing the safety profile in the full EP safety population, safety analyses will be conducted in 
the subgroup of patients enrolled under amendment (a) with a starting dose of 150 mg Q12H.  In 
order to do this robustly, enrollment to the study will continue until 450 EP patients are enrolled 
at a starting dose of 150 mg Q12H. Including the approximately 180 EP patients enrolled at a 
starting dose of 200 mg Q12H prior to amendment (a), approximately 630 EP patients will be 
enrolled.
Further Amendment (b) modifications included:  1) moving secondary objectives pertaining to 
skeletal-related events (SREs) and changes in Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) to exploratory objectives due to the low anticipated event rates in this 
study; 2) clarifying the EP population to be enrolled (Inclusion Criterion [2]); 3) limiting the 
timing of initiation of bone-modifying agents by adding Exclusion Criterion [26]; and 
4) clarifying administration of fulvestrant during blinded study drug dose suspensions.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.3.
Rationale for Amendment (c)
Study JPBL protocol was amended to update the dosing guidance for cases of hematologic 
toxicity and diarrhea, and guidance on the use of blood cell growth factors.  Lilly conducted a 
review across several clinical trials of abemaciclib in breast cancer and concluded that there were 
some inconsistencies.  This amendment will harmonize the dosing guidance and clarify that 
blood cell growth factors are only to be used in a manner consistent with American Society of 
Clinical Oncology (ASCO) guidelines.
The following were also included in the amendment: 1) caution when coadministering with
substrate drugs of cytochrome P450s (CYPs) with narrow therapeutic margin and 2) an 
additional window of up to 3 days prior to Day 1 of each cycle is allowed for flexibility in 
obtaining central laboratory and imaging results.
Furthermore, the statistical analysis plan (SAP) was updated. Specifically, the interim analysis 
boundaries, timing of interim analyses, and overall survival analysis plan were modified.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.4.
Rationale for Amendment (d)
Recent Phase 3 study disclosures (Cristofanilli et al. 2016) indicate the combination of 
fulvestrant and an inhibitor of CDK4 and CDK6 may be highly efficacious. Consequently, an 

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earlier final analysis will be conducted, after 378 PFS events, rather than the initially planned 
441 events, which still maintains the power at approximately 90% for the target hazard ratio of 
0.70.  A total of 378 PFS events at the final analysis corresponds to a censoring rate of 
approximately 40%, which is consistent with that of other trials conducted in a similar setting 
(for example, Di Leo et al. 2010; Baselga et al. 2012; Yardley et al. 2013; Cristofanilli et al. 
2016).  A final analysis at 378 events precludes the need for a second interim analysis at 
353 events, thus JPBL Amendment (d) removes the second interim analysis, leaving a single 
interim analysis at 265 events.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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6.
Objectives
6.1.
Primary Objective
The primary objective of Study JPBL is to compare abemaciclib plus fulvestrant versus placebo 
plus fulvestrant with respect to PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
6.2.
Secondary Objectives
The secondary objectives of the study are to compare abemaciclib plus fulvestrant versus 
placebo plus fulvestrant with respect to each of the following:

overall survival (OS)

OS rate at 1, 2, and 3 years

objective response rate [complete response (CR) + partial response (PR)]

duration of response (DoR) [CR + PR]

disease control rate (DCR) [CR + PR + stable disease (SD)]

clinical benefit rate (CBR) [CR + PR + SD ≥6 months]

safety and tolerability

pain and symptom burden using the Brief Pain Inventory (BPI), the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30) and the EORTC QLQ-BR23 (breast) questionnaires, 
and health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L)

pharmacokinetics (PK) of abemaciclib, its metabolites, and fulvestrant
6.3.
Exploratory Objectives

To explore potential biomarkers related to the retinoblastoma (Rb) pathway and/or 
the pathogenesis of breast cancer

To explore if change in tumor size is associated with PFS and OS

To explore time to progressive bone metastases by treatment arm

To evaluate time to worsening of ECOG PS of ≥2

To evaluate time to first SRE (defined as either pathological fracture, spinal cord 
compression, radiation to the bone, or surgery to the bone)

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7.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.
Study participants should be instructed not to donate blood or blood products during the study or 
for 9 months following the last dose of fulvestrant or 2 weeks following the last dose of blinded 
study drug, whichever is longer.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have a diagnosis of HR+, HER2- breast cancer

to fulfill the requirement of HR+ disease, a breast cancer must express, by 
immunohistochemistry (IHC), at least 1 of the hormone receptors 
(estrogen receptor [ER] or progesterone receptor [PgR]) as defined in the 
relevant American Society of Clinical Oncology (ASCO) / College of 
American Pathologists (CAP) Guidelines (Hammond et al. 2010).

to fulfill the requirement of HER2- disease, a breast cancer must not 
demonstrate, at initial diagnosis or upon subsequent biopsy,
overexpression of HER2 by either IHC or in-situ hybridization as defined 
in the relevant ASCO / CAP Guidelines (Wolff et al. 2013).  Although not 
required as a protocol procedure, a patient with a new metastatic lesion 
should be considered for biopsy whenever possible to reassess HER2 
status prior to study entry if clinically indicated.
[2]
have locally advanced disease not amenable to curative treatment by surgery
or metastatic disease.  In addition, patients must fulfill 1 of the following 
criteria:

relapsed with radiologic evidence of progression while receiving neoadjuvant or 
adjuvant endocrine therapy, with no subsequent endocrine therapy received 
following progression

relapsed with radiologic evidence of progression within 1 year from completion 
of adjuvant endocrine therapy, with no subsequent endocrine therapy received 
following progression

relapsed with radiologic evidence of progression more than 1 year from 
completion of adjuvant endocrine therapy and then subsequently relapsed with 
radiologic evidence of progression after receiving treatment with either an 
antiestrogen or an aromatase inhibitor as first-line endocrine therapy for 
metastatic disease.  Patients may not have received more than 1 line of endocrine 
therapy or any prior chemotherapy for metastatic disease.

presented de novo with metastatic disease and then relapsed with radiologic 
evidence of progression after receiving treatment with either an antiestrogen or an 

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aromatase inhibitor as first-line endocrine therapy for metastatic disease.  Patients 
may not have received more than 1 line of endocrine therapy or any prior 
chemotherapy for metastatic disease.
[3]
have postmenopausal status due to either surgical/natural menopause or 
ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with 
a gonadotropin-releasing hormone (GnRH) agonist such as goserelin. 
Postmenopausal status due to surgical/natural menopause requires at least 1 of 
the following:

prior bilateral oophorectomy

age ≥60 years

age <60 years and amenorrheic for at least 12 months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression) and 
follicle-stimulating hormone (FSH) and estradiol levels in the 
postmenopausal range
[4]
have a negative serum pregnancy test at baseline (within 14 days prior to 
randomization) and agree to use medically approved precautions to prevent 
pregnancy during the study and for 12 weeks following the last dose of 
abemaciclib if postmenopausal status is due to ovarian suppression with a 
GnRH agonist
[5]
have either measurable disease or nonmeasurable bone only disease.  
Measurable and nonmeasurable disease are defined according to the Response 
Evaluation Criteria in Solid Tumors (RECIST Version 1.1 [v1.1], Eisenhauer 
et al. 2009; refer to Attachment 5).  Nonmeasurable bone only disease may 
include any of the following:  blastic bone lesions, lytic bone lesions without a 
measurable soft tissue component, or mixed lytic-blastic bone lesions without 
a measurable soft tissue component.
[6]
are female and >18 years of age
[7]
have given written informed consent prior to any study-specific procedures
[8]
have adequate organ function, including:

hematologic:  absolute neutrophil count 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator; however, initial study drug treatment must not begin earlier 
than the day after the erythrocyte transfusion.

hepatic:  bilirubin 1.5 times upper limit of normal (ULN) and alanine 
aminotransferase (ALT) ≤3.0 times ULN

renal:  serum creatinine 1.5 times ULN
[9]
have a performance status ≤1 on the ECOG scale

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[10] have discontinued previous therapies for cancer (including specifically,
aromatase inhibitors, anti-estrogens, chemotherapy, radiotherapy, and
immunotherapy) for at least 21 days for myelosuppressive agents or 14 days 
for nonmyelosuppressive agents prior to receiving study drug, and recovered 
from the acute effects of therapy (until the toxicity resolves to either baseline
or at least Grade 1) except for residual alopecia or peripheral neuropathy
[11] are willing to participate for the duration of the study and to follow study 
procedures
[12] are able to swallow capsules
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[13] are currently receiving an investigational drug in a clinical trial or 
participating in any other type of medical research judged not to be 
scientifically or medically compatible with this study.  If a patient is currently 
enrolled in a clinical trial involving non-approved use of a device, then 
agreement with the investigator and Lilly clinical research physician (CRP) is 
required to establish eligibility.
[14] have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis.  
Visceral crisis is not the mere presence of visceral metastases but implies 
severe organ dysfunction as assessed by symptoms and signs, laboratory 
studies, and rapid progression of the disease.
[15] have clinical evidence or history of central nervous system metastasis. 
Screening is not required for enrollment.
[16] have received prior treatment with chemotherapy (except for neoadjuvant/ 
adjuvant chemotherapy), fulvestrant, everolimus, or any CDK4 and CDK6 
inhibitor
[17] have received treatment with a drug that has not received regulatory approval
for any indication within 14 or 21 days prior to randomization of study drug 
for a nonmyelosuppressive or myelosuppressive agent, respectively
[18] have received recent (within 28 days prior to randomization) yellow fever 
vaccination
[19] have had major surgery within 14 days prior to randomization of study drug to 
allow for post-operative healing of the surgical wound and site(s).
[20] have a personal history within the last 12 months of any of the following 
conditions: syncope of cardiovascular etiology, ventricular tachycardia, 
ventricular fibrillation, or sudden cardiac arrest
[21] have serious preexisting medical conditions that, in the judgment of the
investigator, would preclude participation in this study (for example, history
of major surgical resection involving the stomach or small bowel)

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[22] have inflammatory breast cancer or a history of any other cancer (except 
nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in 
complete remission with no therapy for a minimum of 3 years
[23] have received an autologous or allogeneic stem-cell transplant
[24] have active bacterial or fungal infection, or detectable viral infection (for 
example, human immunodeficiency virus [HIV] or viral hepatitis). Screening 
is not required for enrollment.
[25] are pregnant or breastfeeding
[26] have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted 
agents (for example, denosumab) <7 days prior to randomization
7.3.
Discontinuations
7.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 
with or without study drug.  Inadvertently enrolled patients may be maintained in the study and 
on study drug when the Lilly CRP agrees with the investigator that it is medically appropriate for
that patient. The patient may not continue in the study with or without study drug if the Lilly
CRP does not agree with the investigator’s determination that it is medically appropriate for the 
patient to continue. The investigator must obtain documented approval from the Lilly CRP to 
allow the inadvertently enrolled patient to continue in the study with or without study drug.
In addition, patients will be discontinued from the study drug(s) and/or from the study in the 
following circumstances:

Progressive disease (PD) as defined by RECIST v1.1.

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

investigator decision
o
the investigator decides that the patient should be discontinued from the study or 
study drugs
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drugs occurs prior to introduction of the new agent

patient decision
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to be withdrawn from the study or study drug

sponsor decision

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o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP)
The reason and date for discontinuation will be collected for all patients.  All randomized 
patients who discontinue regardless of whether or not they received study drug will have 
procedures performed as shown in the Study Schedule (Attachment 1).
7.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.
7.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study I3Y-MC-JPBL (JPBL) is a multicenter, randomized, double-blind, Phase 3 trial for 
women with HR+, HER2- locally advanced or metastatic breast cancer.  Figure JPBL.8.1
illustrates the study design.
Abbreviations:  HR+ = hormone receptor positive; HER2- = human epidermal growth factor receptor 2 
negative; N = number; PD = progressive disease.
Figure JPBL.8.1.
Illustration of study design.
Approximately 630 EP patients will be randomized 2:1 between the 2 arms:

Experimental Arm A:  abemaciclib 150 mg orally Q12H on Days 1 to 28 of a 28-day 
cycle plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 
1 of Cycle 2 and beyond

Control (Placebo) Arm B:  Placebo orally Q12H on Days 1 to 28 of a 28-day cycle plus 
fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 
2 and beyond
Enrollment will close when approximately 450 EP patients have been randomized at a starting 
dose of 150 mg Q12H.  Patients will be randomized using the following stratification factors: 
nature of disease (visceral metastases versus bone only metastases versus other) and sensitivity 
to endocrine therapy (primary resistance versus secondary resistance).  The presence of visceral 
metastases refers to lung, liver, pleural, or peritoneal involvement at the time of randomization.
Primary clinical resistance to endocrine therapy is defined as follows:  1) for endocrine therapy
in the adjuvant setting, recurrence within the first 2 years of adjuvant endocrine therapy while on 
endocrine therapy or 2) for endocrine therapy in the locally advanced or metastatic setting, 
progression within first 6 months of initiating first-line endocrine therapy while on endocrine 
therapy.  Patients receiving prior endocrine therapy who do not meet the definition of primary 
clinical resistance will be considered to have secondary clinical resistance.

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Data base lock for the interim analysis for efficacy will occur when approximately
265 investigator-assessed PFS events have been observed. Database lock for the final analysis of 
the PFS endpoint will occur when approximately 378 investigator-assessed PFS events have 
been observed. All patients will be followed for progression and survival information until death 
or study completion, whichever occurs first.
Details on sample size and analysis in Sections 12.1 and 12.2.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form (ICF) is signed and ends at the first 
study treatment (or at discontinuation, if no treatment is given).

Study Period:  begins at the first study treatment and ends at study completion. The 
study period does not include the extension period.
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from study treatment.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.
Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment and lasts 
approximately 30 days.
Long-term follow-up begins the day after short-term follow-up is completed 
and continues until the patient’s death or overall study completion.

Extension Period:  begins after study completion and ends at the end of trial.  During the 
extension period, patients on study therapy who continue to experience clinical benefit 
may continue to receive study therapy until one of the criteria for discontinuation is met.  
The extension period includes extension period short-term follow-up.
o
Extension period short-term follow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment in the 
extension period and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the evaluation of final OS data (refer to Figure JPBL.8.2), as determined 
by Lilly.  Investigators will continue to follow the study schedule for all patients until notified by 
Lilly that study completion has occurred.  “End of trial” refers to the date of the last visit or last 
scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed extension period follow-up (Figure JPBL.8.2).

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Abbreviations:  OS = overall survival; PFS = progression-free survival.
Figure JPBL.8.2.
Study period and extension period diagram.
8.1.2. Extension Period
After study completion, all patients who are on study treatment and who are eligible for the 
extension period will be unblinded.  Patients receiving study treatment and experiencing ongoing 
clinical benefit may continue to receive study treatment in the extension period until one of the 
criteria for discontinuation is met (Section 7.3).  During the extension period, placebo will no 
longer be administered, and crossover will not be permitted.  Lilly will notify investigators when 
the extension period begins.
Patients who are in short-term follow-up when the extension period begins will continue in 
short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the extension period begins will be discontinued 
from long-term follow-up.
During the extension period, all AEs, SAEs, and study drug exposure will be reported on the 
eCRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (GPS) (see 
Section 10.3.1).  In the event that an SAE occurs, Lilly may request additional information (such 
as local laboratory results, concomitant medications, and hospitalizations) in order to evaluate 
the reported SAE.

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Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly
will not routinely collect the results of these assessments.
8.2.
Discussion of Design and Control
A randomized, controlled design is being used in this study.  Randomization minimizes 
systematic bias in the selection and assignment of patients to study therapy and provides 
justification for inferential statistical methods to be used on data from this study.  Using an 
appropriate concurrent control arm enables direct statistical estimation of benefits and harms due 
to study therapy and minimizes bias in the assessment and interpretation of observed treatment 
effects. Patients will be stratified for differences in factors thought to be associated with clinical 
outcomes to further reduce the potential for bias and improve the power of the analyses. 
Assessment of bias is further minimized by the use of a double blind and placebo control. See 
Section 9.3.
Investigational treatment administration in this study is double-blind; that is, patients, 
investigational sites, and the sponsor study team do not have immediate access to treatment 
assignments for any patients.  This design feature minimizes potential bias due to knowledge of 
patient’s treatment during evaluation of study endpoints, at the patient level or aggregated across 
patients.

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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Experimental Arm A:  Abemaciclib 150 mg orally Q12H on Days 1 to 28 of a 28-day 
cycle plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 
1 of Cycle 2 and beyond

Control (Placebo) Arm B:  Placebo orally Q12H on Days 1 to 28 of a 28-day cycle plus 
fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of 
Cycle 2 and beyond
Blinded study drug is defined as abemaciclib or placebo.  Study treatment is defined as blinded 
study drug and/or fulvestrant.
For both experimental and control arms, fulvestrant 500 mg should be administered 
intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, 
one in each buttock; however, for patients with moderate hepatic impairment (defined as 
Child-Pugh Class B), including any patient who develops moderate hepatic impairment during 
study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock 
slowly (1 to 2 minutes) as one 250-mg injection.
Table JPBL.9.1 shows the treatment regimens.
Table JPBL.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose Day
Experimental Arm A
Abemaciclib
Treatment/28-day cycle
150 mg PO Q12H on Days 1-28
Fulvestrant
Treatment/28-day cycle
500 mg IM on Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyond
Control (Placebo) Arm B
Placebo
Treatment/28-day cycle
PO Q12H on Days 1-28
Fulvestrant
Treatment/28-day cycle
500 mg IM on Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyond
Abbreviations:  IM = intramuscular; PO = orally; Q12H = once every 12 hours.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative

verifying that instructions are followed properly

maintaining accurate records for dispensing and collection of study drugs

returning all unused medication to Lilly or its designee at the end of the study

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Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
9.2.
Materials and Supplies
Abemaciclib or placebo (blinded study drug) will be supplied as capsules for oral administration.
Blinded study drug capsules should be stored at room temperature according to the product label, 
and not opened, crushed, or dissolved.  Investigators should instruct patients to store the capsules
in the original package and in a location inaccessible to children. Blinded study drug will be 
labeled according to the country’s regulatory requirements.
Depending on country requirements, fulvestrant will be supplied by the site or centrally sourced 
by Lilly as 250-mg prefilled syringes (250 mg/5 mL). Sites should confirm fulvestrant source to 
ensure adequate supply.  Fulvestrant should be stored according to the instructions on the 
product label and administered according to the instructions in the protocol. Where fulvestrant is
supplied by Lilly, it will be labeled according to the country’s regulatory requirements.
9.3.
Method of Assignment to Treatment
Upon obtaining informed consent, site personnel should access the interactive web response 
system (IWRS) which will assign a patient number. Patients who meet all criteria for enrollment 
will be randomly assigned to receive either abemaciclib plus fulvestrant or placebo plus 
fulvestrant.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using the IWRS.
Randomization will be stratified by the following: nature of disease (visceral metastases versus 
bone only metastases versus other) and sensitivity to endocrine therapy (primary resistance 
versus secondary resistance).
The IWRS will be used to assign abemaciclib/placebo and fulvestrant (where supplied). Site 
personnel will confirm that they have located the correct study medication packages by entering 
a confirmation number found on the packages into the IWRS.
The period between randomization to blinded study drug in IWRS and the first dose (Cycle 1 
Day 1) should not exceed 7 days.
9.4.
Selection and Timing of Doses
Blinded study drug will be taken orally every 12 (±2) hours on Days 1 through 28 of a 28-day 
cycle, for a total of 56 doses per cycle.  Patients should not consume food beginning 1 hour 
before and ending 1 hour after taking blinded study drug.  During all cycles, blinded study drug
should be taken at approximately the same times each day.  If a patient misses or vomits a dose, 
that dose should be omitted.

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Fulvestrant should be administered at the same time as (or up to 20 minutes after) the morning 
dose of blinded study drug, except when specified otherwise in the PK Sampling Schedule 
(Attachment 7).  Fulvestrant will be administered intramuscularly on Days 1 and 15 of Cycle 1, 
then on Day 1 of Cycle 2 and beyond.  For Cycle 3 and beyond, the interval between blinded 
study drug and fulvestrant may be adjusted based on the judgment of the investigator.  In the 
event of a dose suspension of blinded study drug due to toxicity immediately prior to the 
beginning of a cycle, the PK Sampling Schedule may require adjustment.  In these exceptional 
circumstances, the Sponsor should be notified.
A cycle is defined as the planned treatment interval of 28 days plus any subsequent delay prior to 
start of the next cycle.  A delay in the start of a cycle due to holidays, weekends, bad weather, or 
other unforeseen circumstances will be permitted up to 7 days and not counted as a protocol 
deviation). For each 28-day cycle, a total of 56 doses of blinded study drug will be dispensed.  
In exceptional cases, for planned delays (including but not limited to vacation or holidays), 
additional blinded study drug may be dispensed.
A patient may continue to receive study drug(s) until she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3.1).

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9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
Table JPBL.9.2.
Toxicity Dose Adjustments and Delays of Blinded Study Drug for 
Study JPBL
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 9.4.1.1.3
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Hematologic Toxicity
Section 9.4.1.1.3
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity
Section 9.4.1.1.3
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity: Patient 
requires administration of 
blood cell growth factors
Sections 9.4.1.1.3 and 9.6.4
Regardless of severity
(Growth factors use according to 
ASCO Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
led to the use of growth 
factor.
Nonhematologic Toxicity 
(except diarrhea)
Section 9.4.1.1.4
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Nonhematologic Toxicity
Section 9.4.1.1.4
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Requires hospitalization or Grade 3 
or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 
24 hours to at least Grade 1
Dose SHOULD be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial 
Grade 2 diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Abbreviation:  ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; SHOULD = not mandatory but highly recommended; 
MUST = mandatory.

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9.4.1.1.1. Dose Adjustments
9.4.1.1.1.1.
Blinded Study Drug
Blinded study drug dose adjustments are allowed both within a cycle and between cycles.  
Blinded study drug must be reduced as outlined in Table JPBL.9.3.
For patients requiring dose reduction(s), re-escalation to a prior dose level is permitted only after
consultation with the Lilly CRP.
Table JPBL.9.3.
Dose Adjustments for Blinded Study Drug
Dose Adjustment
Oral Dose
Frequency
0
150 mg
Q12H
1
100 mg
Q12H
2
50 mg
Q12H
Abbreviation:  Q12H = every 12 hours.
In the event that blinded study drug must be discontinued, a patient may continue to receive 
fulvestrant.
9.4.1.1.1.2.
Fulvestrant
Dose adjustment for fulvestrant will be determined by the investigator in accordance with the 
label.  For patients with moderate hepatic impairment (defined as Child-Pugh Class B), including 
any patient who develops moderate hepatic impairment during study treatment, fulvestrant 
250 mg should be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one 
250-mg injection.  In the event that fulvestrant must be discontinued, a patient may continue to 
receive blinded study drug.
9.4.1.1.2. Dose Suspension (within a cycle) and Cycle Delays
Both dose suspension (within a cycle) and cycle delay are allowed up to 14 days to allow 
sufficient time for recovery from toxicity possibly related to a study drug.  In the event of a dose 
suspension of blinded study drug during Cycle 1, fulvestrant may be administered as scheduled 
on Cycle 1 Day 15.    If a toxicity possibly related to blinded study drug occurs prior to initiating 
the next cycle, fulvestrant may be administered and blinded study drug suspended until recovery 
from the toxicity.  If fulvestrant is administered but blinded study drug is suspended, the date of 
fulvestrant administration shall constitute Day 1 of the next cycle.  Patients not recovering from 
toxicity within 14 days beyond the last day of the previous cycle should be considered for dose 
adjustment or discontinuation of the relevant study drug(s).  In exceptional circumstances, a 
delay >14 days is permitted upon agreement between the investigator and the Lilly CRP.
In the event of a cycle delay due to logistical reasons (for example, due to patient availability), 
the patient should continue on blinded study drug if the patient has adequate drug supply.  If a 
patient’s blinded study drug is interrupted as a result of not having sufficient drug supply, the 
cycle may be delayed up to 7 days (and not considered a protocol violation).  In exceptional 
circumstances, a delay >7 days is permitted upon agreement between the investigator and the 
Lilly CRP.

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The start of a cycle may be delayed, or a current cycle interrupted, to allow a patient with a 
locally advanced breast cancer rendered operable by study treatment to receive surgery 
radiotherapy.  For additional information, refer to Section 9.6.1.
9.4.1.1.3. Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of blinded study drug must be reduced by 
1 dose level as outlined in Table JPBL.9.3.
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of blinded study may be reduced by 1 dose 
level as outlined in Table JPBL.9.3. If the patient experiences a recurrent episode of Grade 3 
hematologic toxicity, then dosing must be suspended (until the toxicity resolves to at least 
Grade 2) and the dose of blinded study must be reduced by 1 dose level.
If a patient requires administration of blood cell growth factors, the dose of study drug must be
suspended for at least 48 hours after the last dose of blood cell growth factors was administered 
and until toxicity resolves to at least Grade 2, then must be reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
Before re-initiation of blinded study drug, hematologic toxicity must resolve to at least Grade 2.
9.4.1.1.4. Nonhematologic Toxicity
If a patient experiences ≥ Grade 3 nonhematologic toxicity, then dosing must be suspended (until 
the toxicity resolves to either baseline or Grade 1) and the dose of blinded study drug must be 
reduced by 1 dose level as outlined in Table JPBL.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 9.4.1.1.4.1) that does not resolve with maximal supportive measures within 
7 days to either baseline or Grade 1, then blinded study drug dosing may be suspended (until the 
toxicity resolves to either baseline or Grade 1) and the dose of blinded study drug may be 
reduced by 1 dose level as outlined in Table JPBL.9.3 at the discretion of the investigator.
Before re-initiation of blinded study, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or Grade 1.
9.4.1.1.4.1.
Diarrhea
A patient experiencing diarrhea requiring hospitalization (irrespective of grade, that is, requiring 
intravenous [IV] rehydration) or severe diarrhea (Grade 3 or 4; see Attachment 9) must have 
study treatment suspended (until the toxicity resolves to at least Grade 1) and must have the 
blinded study drug dose reduced by one dose level as outlined in Table JPBL.9.3.
If a patient experiences persistent or recurrent diarrhea that does not resolve with maximal 
supportive measures (refer to Section 9.6.5) within 24 hours to at least Grade 1, then study 
treatment should be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
blinded study drug may be reduced by one dose level as outlined in Table JPBL.9.3 at the 

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discretion of the investigator. If the same dose level was resumed and diarrhea recurs despite 
maximal supportive measures, the dose of blinded study drug must be reduced by 1 dose level as 
outlined in Table JPBL.9.3.
9.5.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.  Access to 
unblinded data/documents will be controlled by restricting access to the data/documents in 
Lilly’s data and statistical warehouse.  Any changes to this unblinding plan may be described in 
a protocol amendment, the SAP, and/or a separate unblinding plan document.
Efficacy information will not be shared with sites until the study is completed.  Upon overall 
study completion (see Section 8.1.1), investigators may unblind patients to study treatment 
assignment.
9.5.1. Unblinding at Interim Analyses
Interim analyses for safety and efficacy will be conducted, using unblinded data, under the 
guidance of an independent Data Monitoring Committee (DMC).  The DMC will consist of at 
least 3 members, including at least 1 clinician and 1 statistician.  The DMC will communicate 
any recommendations based on interim analysis to the Lilly Senior Management Designee 
(SMD). If necessary, the SMD may form an Internal Review Committee (IRC) to review and act 
upon the recommendations of the DMC.  See Section 12.2.15 for details on the conduct of 
interim analyses.
9.5.2. Emergency Unblinding
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment unless this could delay emergency treatment of the patient.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.
Emergency unblinding for AEs must be performed through the IWRS. This option may be used
ONLY if the patient’s acute well-being requires knowledge of the patient’s treatment
assignment, or if the patient discontinues treatment due to disease progression based upon 
RECIST Version 1.1 (see Attachment 5) and knowledge of the patient’s treatment assignment is 
deemed essential to the selection of the patient’s next treatment regimen.  In the case of disease 
progression, the investigator must consult with the Lilly CRP prior to unblinding.
All calls resulting in an unblinding event are recorded and reported by the IWRS. If the
investigator or patient becomes unblinded, that patient will undergo postdiscontinuation 
follow-up (Attachment 1).

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9.5.3. Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms.  If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 
for that patient to be discontinued from study therapy or excluded from any safety or efficacy 
analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRFs and should be recorded throughout the 
patient’s participation in the study.  Concomitant medications and supportive care therapies must 
also be documented at the time of discontinuation and at the 30-day short-term follow-up visit.
With the exceptions listed in the sections below, therapies for cancer (including specifically 
aromatase inhibitors, anti-estrogens other than fulvestrant, chemotherapy, and immunotherapy) 
will not be permitted while patients are on study treatment.  Use of megestrol acetate as an 
appetite stimulant is not permitted.
The results from human disposition (I3Y-MC-JPBD) and in vitro human recombinant CYP 
phenotyping studies indicate that abemaciclib is extensively metabolized primarily via CYP3A. 
Based on these findings, grapefruit juice as well as inducers (for example, phenytoin or 
carbamazepine) and strong inhibitors of CYP3A should be substituted or avoided if possible
(Attachment 8).
In addition, in vitro studies in cultured human hepatocytes indicate that abemaciclib and its 
major metabolites LSN2839567 and LSN3106726 downregulate mRNA of CYPs including 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A at clinically relevant 
concentrations.  The mechanism of downregulation and its clinical relevance are presently not 
understood.  Therefore, care should be taken when coadministering substrate drugs of the above 
CYPs with narrow therapeutic margin (Attachment 8).
9.6.1. Surgery and/or Radiotherapy for Locally Advanced Breast 
Cancer
A patient with locally advanced breast cancer may receive surgery radiotherapy if study 
treatment renders the tumor operable.  However, such a patient should not receive study 
treatment for the period beginning at least 7 days prior to surgery and continuing until at least 
14 days after completion of surgery radiotherapy to allow for tissue healing and recovery.  
There is no restriction on the duration of this period without study treatment and, after this period 

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ends, study treatment and protocol procedures (Attachment 1) should either resume based upon 
the most recent cycle completed prior to surgery radiotherapy or the patient should be 
discontinued from study treatment.  Importantly, a patient who receives surgery radiotherapy 
for locally advanced breast cancer is not considered noncompliant and does not incur a protocol 
deviation.
9.6.2. Radiotherapy
Except as described in Section 9.6.1, radiotherapy is not permitted without permanent 
discontinuation from study treatment.  Except for a patient with locally advanced breast cancer 
rendered operable by study treatment who subsequently undergoes surgery + radiotherapy, all 
other patients requiring radiotherapy should discontinue permanently from study treatment and 
have a tumor assessment of the lesion(s) before receiving radiotherapy.
9.6.3. Supportive Care
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care as judged by their treating physician.  If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported in the eCRFs.
9.6.4. Growth Factors
Growth factors should not be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).
Dosing of study drug must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered. Following the administration of growth factors, the dose of study drug must be 
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
9.6.5. Supportive Management for Diarrhea
At randomization, patients should receive instructions on the management of diarrhea.  In the 
event of diarrhea, supportive measures should be initiated as early as possible.  These include the 
following:

At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (e.g.,
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up.

Patients 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, blinded study drug should be suspended until diarrhea is resolved to at least
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
When blinded study drug recommences, dosing should be adjusted as outlined in 
Section 9.4.1.1.1.1 and Table JPBL.9.3.
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 IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte 
replacement.
9.6.6. Bisphosphonates and RANK-L Targeted Agents
Patients with bone metastases present on baseline imaging may be appropriately treated with 
bisphosphonates or RANK-L targeted agents (for example, denosumab), per respective approved 
labels. Initiation of treatment with bone-modifying agents must begin at least 7 days prior to 
randomization. Patients receiving bisphosphonates or RANK-L targeted agents should not 
switch treatments (for example, replace a bisphosphonate with denosumab) while on study 
treatment. However, exceptional cases without evidence of PD may be considered in 
consultation with the Lilly CRP.  These exceptional cases will not incur a protocol deviation.
9.6.7. Ovarian Suppression with Gonadotropin-Releasing Hormone 
Agonists
Patients who are postmenopausal due to ovarian suppression should continue GnRH agonist 
therapy during study treatment.
9.7.
Treatment Compliance
Treatment compliance information for study drugs will be collected through counts at each visit, 
and the number of capsules taken relative to the number expected to be taken will be summarized 
for each cycle.  The patient must take ≥75% of the planned doses for assigned study drug in a 
cycle to be deemed compliant.  Similarly, a patient may be considered noncompliant if she is 
judged by the investigator to have intentionally or repeatedly taken ≥125% of the planned doses 
of study drug in a cycle.
Importantly, a patient who receives surgery radiotherapy for locally advanced breast cancer is 
not considered noncompliant and does not incur a protocol deviation.  For additional 
information, refer to Section 9.6.1.
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP or clinical research scientist before any determination is made 
to discontinue the patient.

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10. Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Study procedures related to efficacy, safety, health outcome/quality of life measures, sample 
collection, and testing assessments and their timing are described in the sections below and 
shown in the Study Schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 28 days of randomization, baseline tumor measurements will be performed on each 
patient.  Computed tomography (CT), including spiral CT, scans and magnetic resonance 
imaging (MRI) are the preferred methods of measurement.  In addition, bone scintigraphy will be 
performed for all patients at baseline (within 28 days of randomization). However, prior bone 
scintigraphy (obtained as part of routine clinical care) within 45 days before Day 1 of Cycle 1 is 
also acceptable. For only those patients with bone lesions identified by bone scintigraphy at 
baseline, all such lesions will be evaluated at baseline by focused studies (X-ray, CT scan with 
bone windows, or MRI) to enable serial assessment. For patients with inoperable locally 
advanced breast cancer, MRI scan of the breast will be performed at baseline.  For patients with 
visible tumor (such as skin lesions), photography will be performed at baseline and each 
photographic image of the tumor should include a ruler.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast). A PET scan alone or as part of a PET-CT 
scan may be performed separately as part of routine clinical care but cannot be used to assess 
response according to RECIST v1.1.
The methods of assessment used at baseline must be used consistently for tumor assessment and 
will be repeated (with the exception of bone scintigraphy) between Day 1 and Day 7 of every 
second cycle beginning with Cycle 3 and continuing through Cycle 13 (inclusive), between 
Day 1 and Day 7 of every third cycle after Cycle 13, and within 14 days of clinical progression.  
For assessment of response only in patients with bone lesions identified by scintigraphy at 
baseline, the method of assessment used at baseline (X-ray, CT scan with bone windows, or 
MRI) will be repeated between Day 1 and Day 7 of every second cycle beginning with Cycle 3 
and continuing through Cycle 13, between Day 1 and Day 7 of every third cycle after Cycle 13,
and within 14 days of clinical progression.  Bone scintigraphy should be repeated for all patients
between Day 1 and Day 7 of every sixth cycle beginning with Cycle 7, when complete response 
is identified in target disease, or when progression in bone is suspected.  For patients with new 
lesions identified by post-baseline bone scintigraphy, targeted assessment by X-ray, CT scan 
with bone windows, or MRI will be performed to confirm findings as described in the 

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Study Schedule (Attachment 1).  To allow flexibility in tumor assessments, imaging conducted 
up to 3 days prior to Day1 of the predefined cycles (as early as Day 26 of the prior cycle) will 
not be considered a protocol deviation.
For patients continuing treatment after study completion, efficacy assessments (frequency and 
type of assessments) will be at the discretion of the investigator.
10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1).
For those patients who are randomized and never receive study treatment or those who
discontinue study treatment without objectively measured PD, the investigative sites will 
continue to monitor patients and periodically evaluate tumor response approximately every 
8 weeks for the first 12 months following randomization and thereafter approximately every 
12 weeks by the same method used at baseline and throughout the study until the patient has 
objective disease progression, or until the final analysis of PFS.  After the patient has objective 
disease progression, radiologic tests are no longer required and the patient will be followed up 
approximately every 12 weeks (14 days) until the patient’s death or overall study completion.
Lilly will continue to collect survival data on all patients but may reduce data collection for other 
efficacy data. Lilly will notify investigators when this reduced data collection can begin.
10.1.3. Primary Efficacy Measure
The primary efficacy measure is progression-free survival as defined by RECIST Version 1.1 
(Eisenhauer et al. 2009) provided in Attachment 5.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  An independent review of imaging scans will be performed by an
independent panel of radiologists.
The PFS time is measured from the date of randomization to the date of objective progression or 
the date of death due to any cause, whichever is earlier.
For those patients with nonmeasurable, bone only disease (refer to Inclusion Criterion [5]), 
objective progression will be established if at least 1 of the following criteria is met:

the appearance of 1 or more new lesions (in bone or outside of bone), or

unequivocal progression of existing bone lesions.
Pathologic fracture, new compression fracture, or complications of bone metastases will not be 
considered as evidence of disease progression, unless at least 1 of the above criteria is met.
For those patients with locally advanced disease for whom surgery is performed with no 
evidence of residual disease post-operatively, objective progression will be established if at least 
1 of the following criteria is met:

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
local recurrence, or

new development of metastatic disease.
For those patients with locally advanced disease for whom surgery is performed with evidence of 
residual disease post-operatively, new baseline measurements should be taken and RECIST 
applied.
If a patient is not known to have progressed or died at the time of analysis, PFS time will be 
censored at the last known progression-free assessment.  See Section 12.2.7 for detailed 
censoring rules.
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBL.10.1) will be collected at the times 
shown in the Study Schedule (Attachment 1).
Table JPBL.10.1.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall Survival (OS)
The time from the date of randomization to the date of death from any cause
Objective Response Rate
The proportion of patients with CR or PR according to RECIST v1.1
Disease Control Rate (DCR)
The proportion of patients with CR, PR, or SD according to RECIST v1.1
Duration of Response (DoR)
The time from the date of first evidence of a confirmed CR or PR to the date of 
objective progression or death from any cause, whichever is earlier
Clinical Benefit Rate (CBR)
The proportion of patients with CR, PR, or SD ≥ 6 months according to RECIST 
v1.1
Abbreviations:  CR = complete response; PR = partial response; RECIST = Response Evaluation Criteria in Solid 
Tumors; SD = stable disease.
Overall Survival (OS): OS duration is measured from the date of randomization of any study 
drug to the date of death from any cause.  For each patient who is not known to have died as of 
the data-inclusion cutoff date for a particular analysis, OS will be censored for that analysis at 
the date of last contact prior to the data inclusion cutoff date (contacts considered in the 
determination of last contact date include AE date, lesion assessment date, visit date, and last 
known alive date).
Objective Response Rate: The objective response rate is the percentage of patients with a best 
response of CR or PR.
Duration of Response (DoR):  The DoR time is defined only for responders (patients with a 
confirmed CR or PR).  It is measured from the date of first evidence of CR or PR to the date of 
objective progression or the date of death due to any cause, whichever is earlier.  For clarity, the 
start date should be determined by the initial assessment of CR or PR, not the date of 
confirmation of CR or PR.  If a responder is not known to have died or have objective 
progression as of the data inclusion cutoff date scores, duration of response will be censored at 
the last complete objective progression-free disease assessment date.

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Disease Control Rate (DCR): The DCR is the percentage of patients with a best response of 
CR, PR, or SD.
Clinical Benefit Rate (CBR): The CBR is the percentage of patients with a best response of CR 
or PR, or SD for at least 6 months.
10.1.5. Exploratory Efficacy Measures
Table JPBL.10.2.
Exploratory Efficacy Endpoints
Time to Progression of Bone 
Metastases
The time from the date of randomization to the date of earliest development of 
new bone metastases 
Time to Worsening ECOG PS
The time from the date of randomization to the date of first PS ≥2
Time to First Skeletal-Related 
Event (TTFSRE)
The time from the date of randomization to the date of first:
Spinal cord compression OR
Pathological fracture OR
Radiation to bone OR
Surgery to bone
Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Time to First Skeletal-Related Event (TTFSRE): Patients will be monitored for development 
of SREs at each cycle.  An SRE will be defined as any of the following: spinal cord 
compression, pathological fracture, radiation to bone, or surgery to bone. The anatomic location, 
days of hospitalization, relatedness to breast cancer, and procedure(s) used for treatment will be 
captured.  Bone survey will be monitored according to the Study Schedule (Attachment 1).
TTFSRE and a comparison of the frequency of SREs between treatments will be conducted at 
the end of the study. TTFRSE is defined as the time from randomization to documentation of the 
first postbaseline occurrence of any SRE. Patients not known to have had an SRE at the time of 
the analysis will be censored at the date of their last complete documented assessment for SRE.
SRE-specific information should be collected until patient death, loss to follow-up, or study 
completion.
Time to Worsening ECOG PS:  will be defined as the time from randomization to an ECOG 
PS evaluation of 2 or worse.  Patients with no evaluation of 2 or worse will have their time to 
deterioration of PS censored at the date of the last PS evaluation.
10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
The primary health outcomes research goal is to determine if abemaciclib combination therapy is 
able to palliate pain, as measured by the mBPI-sf (Cleeland 1991).  Additionally, the EORTC 
QLQ-C30 (Aaronson et al. 1993) will assess the broader impact of abemaciclib combination 
therapy on quality of life, the EORTC QLQ-BR23 (Sprangers et al. 1996) will collect 
disease-specific data, and the EQ-5D 5L (Janssen et al. 2008) health status assessment will allow 
for comparison with other tumor types and disease states.

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Patient-reported questionnaires should be completed by patients when a language translation is 
available in which the patient is fluent or literate.
At each time point identified in the Study Schedule (Attachment 1), a paper copy of the mBPI-sf, 
EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D 5L questionnaires should be administered 
to the patient prior to extensive interaction with site staff and study drug administration.
10.2.1.1. Pain Intensity
The mBPI-sf (Cleeland 1991) is an 11-item instrument used as a multiple-item measure of cancer 
pain intensity.  In addition to pain intensity (4 items), the mBPI-sf is designed for patients to 
record the presence of pain in general, pain relief, and pain interference with function (general 
activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, and 
enjoyment of life).
Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales 
anchored at 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can 
imagine or completely interferes).  The mBPI-sf recall period is 24 hours, and typical completion 
time for this instrument is less than 5 minutes. Focused analysis will be on “worst pain”.
Use of pain medication will be assessed in conjunction with the mBPI-sf assessment.  Data on 
each individual prescription and over-the-counter analgesic medication will be recorded on the 
Concomitant Medications eCRF.  The use of pain medications should be reviewed with the 
patient at each subsequent visit.  Any changes to analgesic use (new or stopped analgesics) will
be recorded on the eCRF.  Pain medication will be classified into medication categories, using 
the World Health Organization analgesic ladder.  A medication category will be assigned based 
on the maximum analgesic therapy administered for that cycle on a routine basis.
The BPI population will include all patients who completed at least 1 baseline followed by at 
least 1 BPI “worst pain” postbaseline assessment.
10.2.1.2. Health-Related Quality of Life
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC 
QLQ-C30 (Aaronson et al. 1993) is a reliable and validated tool that has supported quality-of-life 
claims in both Food and Drug Administration (FDA) and European Medicines Evaluation 
Agency (EMA) labels.  The EORTC QLQ-C30 self-reported general cancer instrument 
(Aaronson et al. 1993) consists of 30 items covered by 1 of 3 dimensions:

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact)
The EORTC QLQ-BR23 (Sprangers et al. 1996) consists of 23 items covered by the following 
scales:

functional (body image and sexuality)

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
symptom scales (arm, breast, and systemic therapy side effects)
The EORTC QLQ-C30 and EORTC QLQ BR23 questionnaires are administered per the 
Study Schedule (Attachment 1). The recall period is the past week, completion time is typically 
5 to 7 minutes, and both questionnaires will be scored as described by the EORTC scoring 
manual (Fayers et al. 2001).  The EORTC population will include all patients who completed at 
least 1 baseline followed by at least 1 EORTC postbaseline assessment.
10.2.1.3. Health Status
The EQ-5D 5L (Janssen et al. 2008) is a standardized instrument for use across diseases as a 
measure of self-reported health status.  Specifically, this questionnaire is included in this trial to 
evaluate health-state utilities associated with advanced breast cancer.  These utility measures are 
an important input for economic evaluations concerning the value of treatment interventions.
The EQ-5D 5L is designed to be used in conjunction with other patient-reported measures.  
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the Study Schedule (Attachment 1).  A visual analog scale (VAS) 
"thermometer" measures current health state.  
Administration is preferably scheduled after the BPI and the EORTC, and before extensive 
contact with study personnel or clinicians, which could result in biased patient response.  The 
recall period is “today.”  The EQ-5D 5L is designed for self-completion by respondents and is 
cognitively simple, taking only a few minutes to complete.
The EQ-5D 5L population will include all patients who completed at least 1 baseline followed by 
at least 1 EQ-5D 5L assessment after 1 dose of study drug.
10.2.2. Resource Utilization
Investigators will be asked to report the use of concomitant medications (in particular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 
radiation therapy, surgery, and hospitalization days.  Data on neurosurgical blocks will be 
recorded on the Concomitant Medication and/or surgery eCRF as appropriate.  This information 
should be collected during the study and at the 30-day follow-up visit.
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator.

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The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JPBL.10.3 presents a summary of AE and SAE reporting guidelines.  Table JPBL.10.3
also shows which database or system is used to store AE and SAE data.
Table JPBL.10.3.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study drug or drug delivery system
x
x
Extension period
All AEs
x
All SAEs
x
x
Extension period follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study therapy and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study drug or drug delivery system
that the investigator becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug or drug delivery system in humans, whether or not it is 
considered related to that drug or drug delivery system.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, and other procedures that result in a diagnosis should be reported to Lilly or its 
designee.
Cases of pregnancy that occur during maternal exposures to study drug should be reported.  Data 
on fetal outcome and breast-feeding are collected for regulatory reporting and drug safety 
evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.

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After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drugs via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug or procedure, the following terminologies are 
defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug/study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator will be responsible 
for selecting the appropriate system organ class and assessing severity grade based on the 
intensity of the event.
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA®).
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

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
considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If alerts are 
issued via telephone, they are to be immediately followed with official notification on study-
specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
When a condition related to the prefilled fulvestrant syringes necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent damage to 
a body structure, the serious outcome of “required intervention” will be assigned on the eCRF.
If an investigator becomes aware of an SAE occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure, a study 
drug, or prefilled fulvestrant syringes, the investigator should report the SAE to the sponsor, and 
the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.

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10.3.1.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 
related to the study drug or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
10.3.2. Other Safety Measures
10.3.2.1.
Electrocardiograms
For each patient, a local 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, if clinically indicated.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present for immediate patient management, should any clinically relevant findings 
be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, or syncope) and to determine if the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation.
10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as is appropriate, consult with the functionally independent GPS therapeutic area physician 
or clinical scientist, and review:

trends in safety data

laboratory analytes

adverse events

If a patient experiences elevated ALT 5 times ULN and elevated total bilirubin 2
times ULN, clinical and laboratory monitoring should be initiated by the investigator.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of 
specifically recommended clinical information and follow-up laboratory tests. See
Attachment 3.

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In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (an advisory group for this study formed to protect 
the integrity of data; refer to Section 12.2.15) can conduct additional analyses of the safety data.
For the purpose of this study, in which survival is a key efficacy endpoint, all deaths and SAE 
reports will be reviewed in a blinded manner by Lilly during the clinical trial.  These reports will 
be reviewed to assure completeness and accuracy but will not be unblinded to Lilly during the 
clinical trial.  If a death or other clinical AE is deemed serious, unexpected, and possibly related 
to study drug, only Lilly GPS representatives external to the study team will be unblinded for 
regulatory reporting and safety monitoring purposes.  These measures will preserve the integrity 
of the data collected during this trial and minimize any potential for bias while providing for 
appropriate safety monitoring.
10.3.4. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Complaints related to fulvestrant or the prefilled fulvestrant syringes should be reported directly 
to the manufacturer in accordance with the package insert.
Complaints related to blinded study drug should be reported directly to Lilly.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
Attachment 7 lists the schedule for PK sampling during the study.
10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Central hematology and chemistry labs may be drawn up to 3 days 
prior to Day 1 of each cycle.  Enrollment and treatment decisions may be based upon results of 

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tests performed locally.  If local laboratory tests are used for this purpose, then a duplicate 
specimen must be submitted to the central laboratory.  Discrepancies between local and central 
laboratory that may have an impact on eligibility or treatment decisions will not be considered 
protocol deviations.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Tailoring Biomarkers
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Samples for biomarker research to be collected from all patients in this study:

blood

tumor tissue
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.
These samples are described in the following sections.
10.4.2.1. Archived Tumor Tissue
For patients in the study, a small amount of preserved tumor tissue, previously taken to evaluate 
the patient’s disease, should be requested for biomarker research.  Formalin-fixed paraffin-
embedded tumor tissue should be in a whole block, partial block, or unstained slides.  Any whole 
block submitted will be returned to the site.  Any partial blocks or slides will either be returned 
or discarded within 15 years after last patient visit for the trial.
In tumor tissue samples, the CDK4/6 pathway components (for example, Rb) and markers 
relevant breast cancer pathogenesis may be evaluated to assess any potential correlation with 
response to abemaciclib.  Tumor samples may be analyzed to explore potential tumor gene
signature(s) associated with response or resistance to abemaciclib therapy. These studies may be 
analyzed at a laboratory designated by the sponsor and may include IHC of proteins, FISH for 
copy number amplifications, RNA gene-expression profiling, and/or genetic analyses of the 
tumor specimen DNA.  Such analyses may employ targeted or high-throughput sequencing 
approaches. For this purpose, the results of this analysis will be correlated with clinical efficacy 
data.

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10.4.2.2. Blood Samples for Pharmacogenetic Evaluations
Where local regulations and ERBs allow, a blood sample will be collected for pharmacogenetic 
analysis. Samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to abemaciclib.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.4.2.3. Plasma Samples for Exploratory Biomarker Evaluations
Plasma samples will be collected and analysis may be performed on biomarkers that may play a 
role in the abemaciclib mechanism of action (refer to Attachment 1).  The evaluation of these 
samples may involve analysis of DNA, RNA, and proteins (including any of these components 
derived from exosomes) to investigate their association with observed clinical outcomes to study 
drug. The samples will be coded with the patient number and stored for up to a maximum 
15 years.  Details for collecting, processing, and storing the samples are similar those provided in 
Section 10.4.2.2.
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics
At the visits and times specified in the Pharmacokinetic Sampling Schedule (Attachment 7), 
venous blood samples of approximately 4 mL each will be collected to determine the plasma 
concentrations of abemaciclib and its metabolites LSN2839567, LSN3106726, and 
LSN3106729, as well as plasma concentrations of fulvestrant.
Separate blood samples are not required for the parent, its metabolites, and fulvestrant. After 
obtaining plasma, samples will be aliquoted into 2 approximately equal portions by site 
personnel, one for the determination of plasma concentrations of abemaciclib and its metabolites 
and the other for the determination of plasma concentrations of fulvestrant.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  It is preferred that the 
blood samples be obtained from a peripheral location.  Blood samples will be allowed from 
central access devices, but a sample drawn from a central catheter of any type for PK must take 
precautions to prevent obtaining a dilute sample.  If multiple samples are obtained centrally, the 
PK sample should be the last specimen drawn to reduce the potential for a diluted or improperly 
drawn sample.  The actual date and time (24-hour clock time) of each sampling will be recorded.
A maximum of 5 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and Lilly.

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These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib plus its metabolites LSN2839567, LSN3106726, and 
LSN3106729 will be assayed using a validated liquid chromatography/tandem mass 
spectrometry (LC/MS/MS) method.  Plasma concentrations of fulvestrant will also be analyzed 
using a validated LC/MS/MS method. Bioanalytical samples collected to measure study drug
concentration and metabolism and/or protein binding, will be retained for a maximum of 1 year 
following last patient visit for the study. The PK samples will be stored at a facility designated 
by the sponsor.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between effective and ineffective 
agents.
Safety measurements by laboratory monitoring are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between agents with acceptable and 
unacceptable safety profiles.

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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this study is to compare abemaciclib plus fulvestrant versus placebo 
plus fulvestrant in terms of PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
This study will enroll 2 strata of patients according to prior endocrine therapy: endocrine 
therapy pretreated (EP) patients and endocrine therapy naïve (EN) patients.
The primary statistical analyses will be performed on patients in the EP stratum.
The initial study protocol specified an enrollment of 450 EP patients. Amendment (a) changed 
the starting dose of blinded study drug from 200 mg Q12H to 150 mg Q12H.  In addition to 
describing the safety profile in the full EP safety population, safety analyses will be conducted in 
the subgroup of patients enrolled under Amendment (a) with a starting dose of 150 mg Q12H.  In 
order to do this robustly, enrollment to the study will continue until 450 EP patients are enrolled 
at a starting dose of 150 mg Q12H. As of the implementation of Amendment (a), approximately 
180 EP patients had been enrolled at a starting dose of 200 mg Q12H.  Including these 180 
patients, the final size of the EP stratum will be approximately 450 + 180 = 630 patients. 
Patients will be randomized in a 2:1 ratio using the following stratification factors:  nature of 
disease (visceral metastases versus bone only metastases versus other) and sensitivity to 
endocrine therapy (primary resistance versus secondary resistance).
A 2-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and final PFS analyses (see Section 12.2.7 for details). The 
final PFS analysis will be performed after 378 PFS events have occurred in the EP stratum (that 
is, a 40% censoring rate).  Assuming a hazard ratio (HR) of 0.703, this sample size yields 
approximately 90% statistical power to detect superiority of the abemaciclib plus fulvestrant arm
over the placebo plus fulvestrant arm with the use of a 1-sided log-rank test and a type I error of 
0.025. If the true median PFS for the placebo plus fulvestrant arm is 6.5 months, then the HR of 
0.703 amounts to an approximately 2.75-month (42%) improvement in median PFS for the 
abemaciclib plus fulvestrant arm under an additional assumption of exponential survival 
distribution.
OS is an important secondary endpoint for this study. OS will be tested only if the test of PFS is 
significant. The final OS analysis will be conducted at 441 OS events in the EP stratum (see 
Section 12.2.8 for details).
Prior to Amendment (b), no more than 100 patients were to be enrolled into the EN stratum.  
Amendment (b) removes the inclusion of EN patients and specifies that the previously enrolled 
EN patients will not be included in the primary analysis.  It is anticipated that approximately 
50 patients will be enrolled into this stratum.

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12.2. Statistical and Analytical Plans
12.2.1. Analysis Populations
The ITT population will be comprised of all randomized patients randomized within the EP 
strata (either primary endocrine resistance or secondary endocrine resistance), per IWRS.
The safety population will include all randomized EP patients who receive at least one dose of 
any study drug.
Patients randomized within the ‘no prior endocrine therapy’ stratum comprise the EN population. 
Exploratory efficacy analyses will be performed on this population. The EN safety population 
will include all randomized EN patients who receive at least one dose of any study drug.
12.2.2. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Primary statistical analyses will be conducted on the ITT population, as defined in 
Section 12.2.1.  Analyses will be performed based on the treatment group to which patients were 
randomized (regardless of which treatment was received).
Safety analyses will be based on the Safety Population, as defined in Section 12.2.1.  Patients 
will be grouped according to treatment received in Cycle 1.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all 
confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the SAP.
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.3. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated, as 

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well as number and percentage of patients completing the study or discontinuing (overall and by 
reason for discontinuation).
All patients entered in the study will be accounted for in the summation. The number of patients 
who do not qualify for analysis, who die, or who discontinue before treatment begins will be 
specified.
A summary of all important protocol deviations will be provided.
12.2.4. Patient Characteristics
Patient characteristics will include a summary, by treatment arm, of the following:

patient demographics

baseline disease characteristics

preexisting conditions

historical illnesses

prior endocrine therapy

prior chemotherapy (including both cytotoxic and targeted agents)
Other patient characteristics will be summarized as deemed appropriate.
12.2.5. Concomitant Therapy
Concomitant medication will be summarized by treatment arm in a frequency table listing the
terms recorded on the eCRF.
12.2.5.1. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy) and by drug 
name.
12.2.6. Treatment Compliance
The number of dose omissions, reductions, and delays, cycles received, and dose intensity will 
be summarized for all treated patients per treatment arm.
Treatment compliance information for blinded study drug will be collected through capsule
counts at each tumor assessment visit. The estimate of percent compliance will be given by:
Percent Compliance =
Actual cumulative dose taken
Expected cumulative dose to be taken x 100
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed. The 
expected cumulative dose to be taken will be determined based on the assigned dose and taking 
into account any dose reductions or omissions.

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12.2.7. Primary Outcome and Methodology
The primary endpoint of this study is PFS. PFS time is measured from the date of randomization 
to the date of investigator-determined objective progression as defined by RECIST v1.1, or death 
from any cause. Patients who have neither progressed nor died will be censored at the day of 
their last radiographic tumor assessment (if available) or date of randomization if no post 
initiation (that is, postbaseline) radiographic assessment is available. The detailed censoring 
rules are described below (Table JPBL.12.1).
Table JPBL.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no 
death 
Date of Randomization
Censored
3
No documented progression and no 
death (with a post-baseline tumor 
assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) 
before documented progression or 
death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented 
progression 
Date of death 
Progressed
7
Documented progression or death 
after missing ≥2 consecutive post-
baseline tumor assessments
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
The PFS analysis to test the superiority of abemaciclib to placebo in improving PFS time will be 
performed on the ITT population (as defined in Section 12.2.1) and will use the log-rank test 
stratified by nature of disease (visceral metastases versus bone only metastases versus other) and 
sensitivity to endocrine therapy (primary resistance versus secondary resistance). In addition, the 
Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curves as well 
as PFS rates at every 3 months for each treatment group. These rates will be compared based on 
a normal approximation for the difference between the rates.
The 2-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and final analyses. There is 1 planned interim analysis and 
1 final analysis for PFS in this study. The interim analysis is planned to take place after 

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approximately 265 (approximately 70% of the planned) investigator-assessed PFS events have 
occurred. The cumulative 1-sided type I error rate of .025 will be maintained using the following
method. At the interim analysis, the nominal significance level will be .00001.  The remaining 
alpha will be spent at the final analysis. The resulting boundary p-value for the final analysis is 
dependent on the exact number of events observed at each analysis and can be calculated using 
the method of Slud and Wei (1982). If the analyses are performed at exactly 265 and 378 events,
then the boundary p-value at the final analysis will be .02499996).
The actual boundary for the final analysis will be calculated based on the actual number of 
events observed at the time of each analysis using software that implements the α-spending 
scheme noted above (for example, ADDPLAN 6.0, SAS 9.2, or similar software).
If statistical significance is not observed at the interim analysis, the final PFS analysis will be 
performed after 378 PFS events have been observed in the ITT population based on investigator 
assessment.  Once statistical significance is declared at the interim analysis or the final analysis, 
the study will be positive based on the primary endpoint of PFS, and testing of secondary 
endpoints will proceed as described in the SAP.
The interim PFS analyses will be performed by DMC.  The requirements for unblinding the 
sponsor at the interim analyses are found in Section 12.2.15.
The primary test of PFS will compare the 2 treatment groups using a log-rank test stratified by 
the randomization factors.
A stratified Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the HR and corresponding 95% CI with Wald’s test p-value after adjusting for the same 
randomization variables specified for the primary analysis. An additional unstratified Cox 
regression model will be employed to explore the effects of prognostic variables, such as of the 
stratification variables and intrinsic/extrinsic factors, on treatment response.
12.2.8. Secondary Outcomes and Methodology
The secondary objectives can be found in Section 6.2.
12.2.8.1. Overall Survival
OS is an important secondary endpoint for this study. To maintain the study-wise type I error 
rate, OS will be hierarchically tested; that is, OS will only be tested inferentially for significance 
only if the test of PFS is significant. Further details will be in the SAP.
12.2.8.2. Objective Response Rate, DCR, CBR, and DoR
The objective response rate, DCR, and CBR of each treatment arm will be calculated as defined 
in Section 10.1.4 using the ITT population. All rates will be compared between treatment arms 
based on a normal approximation for the difference between the rates.
The DoR time is defined only for responders (patients with a best response of CR or PR).  It is 
measured from the date of first evidence of CR or PR to the date of objective progression or the 
date of death due to any cause, whichever is earlier.  A Kaplan-Meier analysis of DoR will be 
performed to estimate the DoR curve for each arm.

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12.2.8.3. Other Secondary Endpoints
Safety analyses are described in Section 12.2.13, pharmacokinetic analyses are described in 
Section 12.2.10, and health outcome analyses are described in Section 12.2.12.
12.2.9. Sensitivity Analysis
Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to 
evaluate the robustness of the analysis. Of specific note, a PFS analysis with a subgroup of the 
ITT population whose starting dose was 150 mg will be performed as a sensitivity analysis.  
Details can be found in the SAP.
In addition, a PFS analysis based on independent central review data will be conducted by 
applying the censoring rules from Table JPBL.12.1. Details can be found in the Central Review
SAP.
An additional OS analysis will also be conducted based on the following definition using similar 
methods as stated in Section 12.2.8: time is defined as the time from the date of study
enrollment to the date of death due to disease. Survival time will be censored on the date the
patient was last known to be alive for patients who have no reported event. For patients that 
have died due to reasons not disease related, survival time will be censored at the date of death.
12.2.10.
Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetics analyses will be conducted on all patients who have received at least 1 dose of 
abemaciclib and have had samples collected (see PK sampling schedule in Attachment 7).
Mean population PK parameters for abemaciclib and its metabolites in plasma (clearance, 
exposure, volume of distribution, and half-lives) and inter-individual PK variability will be 
computed using nonlinear mixed effect modeling implemented in NONMEM.  The current PK 
model for abemaciclib, which has been developed using plasma concentration data available 
from the Phase 1 Study JPBA, will be updated using the plasma data collected in this study.  
Covariate effects (such as age, weight, sex, creatinine clearance, and plasma protein levels) on 
the PK parameters of abemaciclib in plasma will also be investigated.
If warranted by the data, mean population PK parameters for fulvestrant in plasma and 
inter-individual variability estimates will also be computed using nonlinear mixed effect 
modeling implemented in NONMEM.
Finally, pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) 
collected in this study may be analyzed by means of NONMEM and connected to the population 
PK model for abemaciclib and/or fulvestrant in a PK/pharmacodynamic model.
The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.11.
Tailoring Biomarker Analyses
The distributions of biomarkers with continuous measures, such as gene or protein expression, 
will be described.  Summary statistics will include means, medians, corresponding standard 

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errors, quartiles, and ranges.  Biomarkers with discrete measures, such as genotype locus, will be 
summarized in frequency tables.  Correlative analyses may be performed to investigate 
associations between biomarkers and clinical endpoints as deemed appropriate.
12.2.12.
Health Outcome/Quality of Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

mBPI-sf (modified Brief Pain Inventory, Short Form)

EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30)

EORTC QLQ-BR23 (The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Breast cancer)

EQ-5D 5L (EuroQol 5-Dimension 5 Level)
For each patient with data from baseline and at least 1 other visit, the maximum change from 
baseline score will be calculated and summarized for BPI “worst pain”, EORTC composite 
scores.  The reason and number of missing and incomplete questionnaires/assessments by visit 
will be summarized for each instrument and study arm.
Further analysis details will be described in the SAP.
12.2.12.1.
Pain Intensity
Individual pain items on the mBPI-sf (that is, worst, least, average, and current pain) will be 
described using descriptive statistics by treatment arm. A mixed effects model, repeated 
measures model may be applied to compare between treatment arms, which will be adjusted for 
other covariates.  Corresponding analyses will also be conducted for the mean of 7 pain 
interference with function items.  If a patient does not complete Questions 5a through 5g on the 
BPI-sf, the mean score for the 7 pain interference items will be calculated based on those 
answered questions when at least 4 out of 7 questions were completed (that is, 50% of the 
questions were answered).
12.2.12.2.
Pain Assessment
Pain analysis will be based on all randomized patients with at least 1 baseline BPI “worst pain” 
and one BPI “worst pain” score on Cycle 2 Day 1 or later.
The mBPI-sf will be administered at baseline prior to study drug dosing and the Cycle 1, Day 1 
score will be treated as a baseline observation and the Day 1 score of each subsequent cycle will 
be attributed to the previous cycle.  The mBPI-sf will be administered at treatment 
discontinuation and grouped with observations from the previous cycle.
Time to worsening in pain will be described using the method of Kaplan and Meier and will be 
made between 2 arms by a log-rank test.  “Worsening” will be defined as either a “worst pain” 
increase of >2 points postbaseline or an analgesic drug class increase of >1 level.  Worsening 
rate at Years 1, 2, and 3 will be estimated and compared between the 2 arms. Number of events 
due to each criterion will be described.

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12.2.12.3.
Health-Related Quality of Life
EORTC QLQ-C30 instrument data will be scored as described by Aaronson and colleagues 
(Aaronson et al. 1993).  If not already addressed in the EORTC scoring manual (Fayers et al. 
2001), descriptive statistics for each EORTC QLQ-C30 scale will be calculated and compared 
between arms.
EORTC QLQ-BR23 data will be scored as described by the EORTC scoring manual
(Fayers et al. 2001).
12.2.12.4.
Utilization
Utilization data will be summarized descriptively by category across arms (for example,
analgesic use, bisphosphonate use, transfusions, radiation, surgery, and hospitalization days), 
including a frequency table with tabular statistics. For categorical variables, frequency and the 
corresponding percentage will be derived and measures of central tendency and variability will 
be calculated for continuous variables by arm. Tests for differences in proportion between 
treatment groups and between response groups will be performed.
12.2.12.5.
Health State Utility
The EQ-5D 5L data will be scored as described in an article that is under review for publication 
(van Hout et al. 2012).  The index score is calculated from a set of item weights to derive a score 
of 0 to 1, with 1 representing the best health status. Geographic-specific weights will be used as 
appropriate and when available.  The VAS is scored from 0 (worst imaginable health state) 
through 100 (best imaginable health state) to represent the patient’s self-report for each day.  
EQ-5D 5L responses for each item will be summarized by frequency and corresponding 
percentages. Descriptive statistics for the index and VAS will be calculated. Psychometric 
analyses, including calculation of reliability coefficients (Cronbach’s alpha), will also be 
performed.  The index scores and VAS may be analyzed using a mixed effects analysis of 
variance model.  Of interest is a significant time-by-group interaction for each of the items,
addressing whether treatment group profiles are different over time (from randomization through 
the last assessment following discontinuation).
12.2.12.6.
Exploratory Analyses
Joint modeling may be explored to characterize the relationship between features of the 
longitudinal PRO trajectories (individual items or composite scores) and the event times.
Time from randomization to earliest development of new bone metastases may be analyzed and 
compared between arms.
Proportion of patients who experience a “worst pain” increase of ≥2 points at any post-baseline 
visit (on or after Day 1 Cycle 2) will be compared between treatment arms. Changes in analgesic 
and bone agent use will be collected and summarized by arms.
Time from randomization to documentation of the first occurrence of any SRE will be 
evaluated. Patients not known to have had an SRE at the time of the analysis will be censored at 
the date of their last complete documented assessment for SRE. A log-rank test will be used to 
evaluate the difference of time to first SRE between treatments. Impact of other factors,

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including whether a patient had at least 1 SRE prior to randomization as well as those factors 
used to stratify treatment randomization, will be explored.
Time from randomization to documentation of the first occurrence of any PS of ≥2 will be 
evaluated.  Log-rank test will be used to evaluate the difference of time to worsening in ECOG
PS between treatments.
12.2.13.
Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1.
Overall exposure to study drug, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments.
Adverse events will be reported using the MedDRA dictionary.  Investigators will report a 
verbatim AE term and a CTCAE v4.0 term and severity for all AEs.  For analysis purposes, the 
following process will be used:

The CTCAE v4 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) using the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify.’

If the reported CTCAE term is ‘Other – specify,’ the MedDRA LLT, PT, and SOC 
centrally mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as adverse events that begin prior to the first dose of study 
drug.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline. Comparisons of preexisting conditions to on-treatment 
events at the LLT level will be used in the treatment-emergent computation.
The following summaries will be produced by PT within SOC: preexisting conditions, SAEs, 
TEAEs, drug-related TEAEs, and procedure-related TEAEs.
The following summaries will be produced by PT within SOC and maximum CTCAE grade: 
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs, 
and drug-related nonlaboratory-based TEAEs.
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation.
Hospitalizations and transfusions during the study treatment period or during the 30-day
short-term follow-up period will be summarized by treatment group.

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12.2.14.
Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic
subgroup variables:

All baseline stratification factors

Starting dose (200 mg versus 150 mg)

Measurable disease at baseline (yes versus no)

Number of organs involved (1 versus 2 vs. 3+)

Age (<65 years versus ≥65 years)

Region (North America, Europe, Asia)

Race (Caucasian, Asian, and Other)

PgR status (positive versus negative)

Baseline ECOG PS (0 versus 1)
If a level of a factor consists of fewer than 5% of randomized patients, analysis within that level 
may be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.
Other subgroup analyses may be performed as deemed appropriate. If any safety analyses 
described in Section 12.2.13 identify important imbalances between arms, subgroup analyses of 
these endpoints may be performed.
12.2.15.
Interim Analyses
12.2.15.1.
Safety Interim Analyses
The DMC is responsible for providing external oversight of patient safety in Study JPBL 
independently of the Lilly study team and Lilly GPS.
During the study, safety interim analyses will be performed every 3 months.  The first safety 
interim analysis will be triggered by the 90th patient enrolling, with the data cutoff for this 
analysis occurring 1 month after the trigger.  The safety interim analyses will be conducted to 
evaluate the overall safety profile of abemaciclib when given in combination with fulvestrant.  
At the recommendation of the DMC, the frequency of safety interim analyses may be modified.
Interim safety analyses will include both EP and EN patients.
At each interim analysis, the DMC may recommend the trial continue without modifications, 
continue with specific modifications, or be stopped for safety concerns. There will be no 
prespecified rules for stopping the trial due to safety concerns.  The DMC members will review 
unblinded safety data at each interim analysis. If a significant safety signal is identified, the 
DMC may recommend a protocol amendment, termination of enrollment, and/or termination of 
study treatment.  The recommendations of the DMC will be communicated to the Lilly SMD
and, if necessary, an IRC.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the treatment group level, members of the DMC can conduct additional analyses of the safety

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data. Additionally, unblinding of a limited number of Lilly representatives external to the study 
team may be required for evaluation of selected SAEs for determination of regulatory reporting.
12.2.15.2.
Efficacy Interim Analyses
One efficacy interim analysis of PFS is planned, as described in Section 12.2.7.  Multiple interim 
analyses of OS are planned as described in the SAP.
The interim PFS analysis will be conducted to provide early efficacy information and could 
potentially result in early communication with regulatory agencies. The DMC should 
recommend unblinding the sponsor if the following are observed:

The analysis of investigator-assessed PFS is significant at the alpha level specified in 
Section 12.2.7, with the observed stratified hazard ratio for investigator-assessed PFS less 
than 0.56 and

Results of the analysis of the centrally reviewed PFS that support the results of the 
investigator-assessed PFS analysis.
If the analysis of PFS is positive based on these requirements, the DMC will be instructed to 
recommend to the SMD that the sponsor be unblinded. The SMD may convene an IRC to
review the DMC’s recommendation prior to sponsor unblinding.
OS will be analyzed as described is Section 12.2.8.  Results of OS analyses will not be 
communicated until a significant result is observed or the final PFS analysis is performed.
The sponsor has no intent to stop the study based on interim analysis of efficacy, and all patients 
will continue follow-up for PFS and OS until study close.  Patients randomized to the control 
group will not be permitted to cross over to the experimental group in case early efficacy is 
observed during interim review, as this will confound the assessment of OS. In addition, patients 
will remain blinded for the duration of the study unless the criteria in Section 9.5 are met.  If the 
DMC makes a recommendation counter to this, for example, the DMC recommends crossing all 
patients over to the experimental treatment, FDA will be consulted before any action is taken, as 
well as other regulatory agencies if deemed appropriate.
The unblinded analysis, including review of the efficacy along with the safety data, will be 
conducted by DMC. Study sites will receive information about interim results ONLY if they 
need to know for the safety of their patients.
Unblinding details are specified in the unblinding plan section of the SAP.
12.2.15.3.
Pharmacokinetic/Pharmacodynamic Interim Analyses
A limited number of preidentified individuals independent of the study team may receive access 
to unblinded data, as specified in the unblinding plan, prior to the interim or final database lock, 
in order to initiate the final population PK/pharmacodynamic model development processes for 
interim or final analyses.  Information that may unblind the study during the analyses will not be 
reported to study sites or blinded study team until the study has been unblinded.

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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study drug.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative site(s).  
All ICFs must be compliant with the ICH guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

the ICH GCP Guideline (E6)

applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will be assigned to a third-party organization.

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An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Lilly will select an investigator to serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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14. References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F.The European Organisation for Research and Treatment 
of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85:365-376.
Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J, Burger HU. Blinded 
independent central review of progression in cancer clinical trials: results from a meta-
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Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini L. Pienkowski T, 
Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. 
Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.
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Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, 
Kyriakides S, Lin N, Pagani O, Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El 
Saghir N, Ganz PA, Gelmon K, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, 
Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van't Veer L, Viale G, 
Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). 
Breast. 2012;21(3):242-252.
Cleeland CS. Pain assessment in cancer. In: Osoba D(ed). Effect of Cancer on Quality of Life, 
Chapter 21. CRC Press, Boca Raton FL, 1991.
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
Cristofnilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, 
Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theal KP, Jiang Y, Barlett CH, Koehler M, 
Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of 
hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on 
previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, 
phase 3 randomised controlled trial. Lancet. 2016:17(4);425-439.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, 
Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, 
Martin M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with 
fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast 
cancer. J Clin Onc. 2010;28(30):4594-4600. Erratum in: J Clin Oncol. 2011;29(16):2293.
Dodd LE, Korn EL, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-free 
survival. Biometrics. 2011;67(3):1092-1099.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.

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Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med. 2010;29(2):219-228.
Hammond MEH, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College 
of American Pathologists guideline recommendations for immunohistochemical testing of 
estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
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Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value in Health. 2008;11(2):274-284.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Publish date:  
29 May 2009.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5:649-655.
Slud E, Wei LJ. Theory and method: two-sample repeated significance tests based on the 
modified Wilcoxon statistic. J Amer Stat Assoc. 1982;77(380):862-868.
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Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
Recommendations for the Use of White Blood Cell Growth Factors: American Society of 
Clinical Oncology Clinical Practice Guideline Update. J Clin Onc 2015, 
http://jco.ascopubs.org/content/early/2015/07/08/JCO.2015.62.3488.full. Accessed 01 October 
2015.
Sprangers MAG, Groenvold M, Arraras JI, Franklin J, te Velde A, ,Muller M, Franzini L, 
Williams A, Henneke CJM, Hopwood P, Cull A, Aaronson NK. The European Organization 
for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol. 1996;14(10):2756-2768.
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012;15(5):708-715.
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC,  
Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
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Yardley DA, Ismail-Khan RR, Melichar B, Lichinistser M, Munster PN, Klein PM, 
Cruickshank S, Miller KD, Lee MJ, Trepel JB. Randomized phase II, double-blind, placebo-
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treatment with a nonsteroidal aromatase inhibitor. J Clin Onc. 2013;31(17):2128-2135.

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Attachment 1.Protocol JPBL Study Schedule

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Study Schedule, Protocol I3Y-MC-JPBL
Perform procedure as indicated.
Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2 – 3
4 and Beyond 
(if Applicable)
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2 – 3
4 and Beyond 
(if Applicable)
801
802 - 8XX
Approximate 
Duration (days)
28
28
28
28
30±5
Variable
Relative day 
within a cycle
≤28
≤14
1
15±3
1p
1p
Procedure 
Category
Procedure
Protocol 
Reference
Study Entry 
/Enrollment
Informed Consent Form 
signedq
Section 8.1
Xq
Inclusion/Exclusion 
evaluation
Section 7
X
Medical 
History
Medical History
X
Historical illnesses
Section 12.2.4
X
Habits assessment
Section 12.2.4
X
Physical 
Examination
Height 
Section 12.2.4
X
Weight
Section 12.2.4
X
X
X
X
X
X
Vital Signs (Temp, BP, 
HR, RR)
Section 12.2.4
X
X
X
X
X
X
ECOG performance 
status
Section 7.1
Attachment 4
X
X
X
X
X
X
Tumor 
Assessment
Tumor measurement 
(palpable or visible)
c
Section 10.1.1
X
c
X
c
X
c
X
c
X
c
Radiologic imaging 
according to RECISTb
Section 10.1.1
Attachment 5
Xb
Xb
Xb
Xb
Xb
Bone Scintigraphyi
Section 10.1.1
Attachment 5
Xi
Xi
Xi
Xi
X-ray or CT scan with 
bone windows or MRIj
Section 10.1.1
Attachment 5
Xj
Xj
Xj
Xj
Xj

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Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2 – 3
4 and Beyond 
(if Applicable)
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2 – 3
4 and Beyond 
(if Applicable)
801
802 - 8XX
Approximate 
Duration 
(days)
28
28
28
28
30±5
Variable
Relative day 
within a cycle
28
≤14
1
15±3
1p
1p
Procedure 
Category
Procedure
Protocol 
Reference
Survival Informationd
Section 10.1
X
d
X
d
Adverse Event Collection/CTCAE
Grading
f
Section 10.3
Xf
Xf
Xf
Xf
Xf
Xf
Concomitant Medications (with 
analgesics)
Section 9.6
X
X
X
X
X
Lab/
Diagnostic 
Tests
Central hematology
Attachment 2
X
Xr
Xr
Xr
Xr
Xr
Central serum chemistry
Attachment 2
X
Xr
Xr
Xr
Xr
Xr
Local FSH and  
estradiol levelsn
Attachment 2
Xn
Local serum  pregnancy 
test o
Attachment 2
Xo
Central pharmacokinetic 
(PK) samplingm
Attachment 7
Xm
Xm
Xm
Pharmacogenetic blood 
sample
Section 
10.4.2.2
X
Biomarker plasma 
sample
Section 
10.4.2.3
X
Local ECGe
Section 
10.3.2.1
Xe
Xe
Xe
Xe
Xe
Archived Tumor 
Sampleh
Section 
10.4.2.1
Xh

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Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2 – 3
4 and Beyond 
(if Applicable)
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2 – 3
4 and Beyond 
(if Applicable)
801
802 - 8XX
Approximate 
Duration (days)
28
28
28
28
30±5
Variable
Relative day 
within a cycle
28
14
1
15±3
1p
1p
Procedure 
Category
Procedure
Protocol 
Reference
Study Drug
Fulvestrant Therapy g
Section 9.1
Days 1 and 15 of Cycle 1, then Day 1 of 
Cycle 2 and beyondg
Abemaciclib or Placebo 
Therapyg
Section 9.1
Q12H on Days 1 through 28 of every 
cycleg
Health 
Outcomes
BPI, EORTC QLQ-
C30, EORTC BR23, 
EQ-5D 5Lk
Section 
12.2.12
Xk
Xk
Xk
Xk
Skeletal-Related Events 
assessmentl
Section 
12.2.12
Xl
Xl
Xl
Xl
Hospitalization
Section 
12.2.12.4
X
X
X
X
Transfusion
Section 
12.2.12.4
X
X
X
X
Abbreviations:  BL = baseline; Temp = Temperature; BP = Blood Pressure; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GnRH = gonadotropin-releasing hormone; HR = heart rate;
IV = intravenous; PK = pharmacokinetics; MRI = magnetic resonance imaging; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory 
rate; Q12H = every 12 hours; SAEs = serious adverse events; FSH = follicular stimulating hormone.
a
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures are performed once at the end of this period.  Long-term follow-up begins the day after short-term 
follow-up is completed and continues until the patient’s death or overall study completion; the associated study procedures are performed approximately 
every 12 weeks (14 days) for the duration of this period.

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Study Schedule, Protocol I3Y-MC-JPBL (continued)
b For patients with inoperable locally advanced breast cancer, MRI scan of the breast is performed locally at baseline (Day -28 to Day -1), between Day 1 and 
Day 7 of every second cycle beginning with Cycle 3 and continuing through Cycle 13, between Day 1 and Day 7 of every third cycle after Cycle 13, and 
within 14 days of clinical progression.  For all patients, CT or MRI scan of the chest, abdomen, and pelvis is performed locally at baseline (Day -28 to 
Day -1), between Day 1 and Day 7 of every second cycle beginning with Cycle 3 and continuing through Cycle 13, between Day 1 and Day 7 of every third 
cycle after Cycle 13, and within 14 days of clinical progression. To allow flexibility in tumor assessments, imaging conducted up to 3 days prior to Day 1of 
the predefined cycles (as early as Day 26 of the prior cycle) will not be considered a protocol deviation.  It is recommended that CT imaging of the abdomen 
and pelvis be performed with IV contrast whenever possible. If this is not feasible due to hypersensitivity or other conditions, then gadolinium-enhanced MRI 
is preferred. For patients with known serious allergic reactions to CT contrast material, a CT of the chest without contrast and gadolinium-enhanced MRI of 
the abdomen/pelvis are encouraged.  For patients who discontinue study treatment without objectively measured progressive disease (PD), continue to 
evaluate tumor response approximately every 8 weeks for the first 12 months following randomization and thereafter approximately every 12 weeks by the 
same method used at baseline and throughout the study until the patient has objective disease progression or until study completion. After the patient has 
objective disease progression, radiologic tests are no longer required and the patient will continue with post-discontinuation follow-up until the patient’s death 
or overall study completion.
c
Visible tumor (such as skin lesions) should be documented by photography and each photographic image of the tumor should include a ruler.  For patients 
who discontinue study treatment without objectively measured progressive disease (PD), continue to evaluate tumor response approximately every 8 weeks 
for the first 12 months following randomization and thereafter approximately every 12 weeks by the same method used at baseline and throughout the study 
until the patient has objective disease progression or until study completion. After the patient has objective disease progression, tumor assessments are no 
longer required and the patient will continue with post-discontinuation follow-up until the patient’s death or overall study completion.
d Survival information is collected at baseline and during both study treatment and postdiscontinuation follow-up. During Long-Term Follow-Up, survival 
information is collected approximately every 12 weeks for the duration of this period. Although preferable to collect during a clinic visit, survival 
information may be collected by contacting the patient or family directly (for example, via telephone).  Long-Term Follow-up data collection may include
anticancer therapies.
e
A local ECG (no replicates required) should be obtained at baseline (Day -14 to Day -1), 2 to 4 hours after the LY dose on Cycle 1 Day 1, upon arrival at site 
but prior to fulvestrant dose on Cycle 1 Day 15, 2 to 4 hours after the LY dose on Cycle 4 Day 1, and at the short-term follow-up visit.
f
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety System.  During Long-Term Follow-Up, only 
SAEs that are related to study drugs or protocol procedures will be collected. All adverse events possibly related to study drugs or protocol procedures should 
be followed until they resolve, are no longer considered to be possibly related, become stable or return to baseline, the patient starts a new therapy, the patient 
expires, or the patient becomes lost to follow-up.  The frequency of evaluation is determined according to the judgment of the investigator.
g Blinded study drug should be administered orally Q12H on Days 1 through 28 of each cycle; patients should not consume food beginning 1 hour before and 
ending 1 hour after taking blinded study drug. Fulvestrant 500 mg should be administered intramuscularly into the buttocks slowly (1 to 2 minutes per 
injection) as two 250-mg injections, one in each buttock; however, for patients with moderate hepatic impairment (defined as Child-Pugh Class B), including 
any patient who develops moderate hepatic impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock 
slowly (1 to 2 minutes) as one 250-mg injection.
h Formalin-fixed paraffin-embedded tumor tissue (either block or 15-20 unstained slides) should be requested at the time of randomization.  However, if this 
sample is not available for a patient, it will not constitute a protocol deviation.

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Study Schedule, Protocol I3Y-MC-JPBL (concluded)
i
Bone scintigraphy is performed locally at baseline (Day -28 to Day -1) for all patients. If available, prior bone scintigraphy (obtained as part of routine clinical 
care) within 45 days before Day 1 of Cycle 1 is also acceptable.  Bone scintigraphy should be repeated for all patients between Day 1 and Day 7 of every sixth 
cycle beginning with Cycle 7, when complete response is identified in target disease, or when progression in bone is suspected.  To allow flexibility in tumor 
assessments, imaging conducted up to 3 days prior to Day 1of the predefined cycles (as early as Day 26 of the prior cycle) will not be considered a protocol 
deviation.  Importantly, RECIST v1.1 emphasizes that bone scintigraphy is not adequate to measure bone lesions; however, bone scintigraphy can be used to 
confirm the presence or disappearance of bone lesions.  For patients who discontinue study treatment without objectively measured progressive disease (PD), 
continue to evaluate tumor response approximately every 6 months until the patient has objective disease progression or until study completion. After the 
patient has objective disease progression, bone scintigraphy is no longer required and the patient will continue with post-discontinuation follow-up until the 
patient’s death or overall study completion.
j
One or more of these studies [X-ray, CT scan with bone windows, or MRI] is performed locally at baseline (Day -28 to Day -1), between Day 1 and Day 7 of 
every second cycle beginning with Cycle 3 and continuing through Cycle 13, between Day 1 and Day 7 of every third cycle after Cycle 13, and within 
14 days of clinical progression only for patients with bone lesions identified by bone scintigraphy at baseline. To allow flexibility in tumor assessments, 
imaging conducted up to 3 days prior to Day 1of the predefined cycles (as early as Day 26 of the prior cycle) will not be considered a protocol deviation.  For 
patients with new lesions identified by post-baseline bone scintigraphy, targeted assessment by X-ray, CT scan with bone windows, or MRI will be performed 
to confirm findings.  For patients who discontinue study treatment without objectively measured progressive disease (PD), continue to evaluate tumor 
response approximately every 8 weeks for the first 12 months following randomization and thereafter approximately every 12 weeks by the same method used 
at baseline and throughout the study until the patient has objective disease progression or until study completion. After the patient has objective disease 
progression, radiologic tests are no longer required and the patient will continue with post-discontinuation follow-up until the patient’s death or overall study 
completion.
k mBPI-sf, EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D 5L should be administered at baseline (Day -14 to Day -1), Cycle 2 Day 1, and then on Day 1 
of every second cycle beginning with Cycle 3 and continuing through Cycle 13, on Day 1 of every third cycle after Cycle 13, and at Short-Term Follow-Up. 
Patients should complete these assessments before extensive interaction with site staff. 
l
Skeletal-Related Events include pathological fracture, spinal cord compression, radiation to bone, and surgery to bone.
m See Pharmacokinetic Sampling Schedule (Attachment 7).
n FSH and estradiol levels are required only for women age <60 years and amenorrheic for at least 12 months.
o A serum pregnancy test is required only for patients receiving ovarian suppression with a GnRH agonist.
p For Cycle 2 and beyond, the start of a cycle may be delayed up to 7 days for logistical reasons and up to 14 days to allow sufficient time for recovery from 
toxicity possibly related to a study drug.  Refer to Section 9.4.1.1.2.
q Informed Consent Form is signed within 28 days prior to randomization of study drug and prior to performance of any protocol-specific tests/procedures.
r
Central hematology and chemistry labs may be drawn up to 3 days prior to Day 1 of each cycle.

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Study Schedule for the extension period only, Protocol I3Y-MC-JPBL
Perform procedure as indicated.
Patients on Study Treatment
Extension Period Follow-Up
Cycle
X-Y
Follow-Upa
Visit
501-5XX
901
Duration (days)
28
30±5
Relative day within a cycle
1
15
Procedure Category
Procedure
Protocol Reference
Adverse Events Collection/CTCAE Gradingb
Section 10.3
X
X
Study Drug
Fulvestrant Therapyc
Section 8.1.2
Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyondc
Abemaciclib Therapyc
Section 8.1.2
Daily Q12Hc
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; PK = pharmacokinetics; Q12H = every 12 hours; SAEs = serious adverse events.
a
The extension period begins after study completion and ends at the end of trial.
b
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly safety system.
c
Abemaciclib should be administered Q12H on Days 1 through 28 of each cycle. Patients should not consume food beginning 1 hour before and ending hour 
after taking study drug.
Fulvestrant 500 mg should be administered intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, one in each 
buttock; however, for patients with moderate hepatic impairment (defined as Child-Pugh Class B), including any patient who develops moderate hepatic 
impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one 250-mg 
injection.

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Attachment 2.Protocol JPBL Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Chloride
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Total bilirubin
Mean cell hemoglobin concentration (MCHC)
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils (segmented + bands)
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Calcium
Platelets
Total Protein
Albumin
Serum Pregnancy Testb,c (only for patients receiving 
ovarian suppression with a GnRH agonist)
FSH levelb,c
Estradiol levelb,c
Abbreviations:  FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; RBC = red blood 
cells; WBC = white blood cells.
a
Lilly-designated laboratory.
b Local- or investigator-designated laboratory.
c
To be performed at baseline only in order to establish eligibility.  FSH and estradiol levels are required only for 
women age <60 years and amenorrheic for at least 12 months.

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Attachment 3.Protocol JPBL Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.Protocol JPBL ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities. Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair
5
Dead.
Source:  Oken et al. 1982.

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Attachment 5.Protocol JPBL RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions,
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.
Cystic lesions:

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
Simple cysts should not be considered as malignant lesions (neither 
measurable nor nonmeasurable)

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Non-nodal 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements.  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the case record form (CRF) in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as 1 liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.

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An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and 
follow-up should be guided by the tumor type under investigation and the anatomic location of 
the disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 

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lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD).
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of 1 or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).

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Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease.; PD = progressive disease; 
NE = inevaluable. 
Table 2 is to be used when patients have nonmeasurable disease only.

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Table 2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; PD = progressive disease; NE = inevaluable.
a
non-CR/non-PD is preferred over SD for nontarget disease. 
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur; assessment of 
nontargets is not required.
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from randomization.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.

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Attachment 6.Protocol JPBL Sampling Summary
This table summarizes the purpose for sampling, sample types, maximum volume per sample, 
maximum number of samples, and maximum total volume during the study.  The summary 
below provides estimates. More samples could be required in the case of retests, additional 
health monitoring (if needed), or for patients continuing treatment beyond the protocol-specified 
number of cycles in the study. Fewer samples may actually be taken (for example, patients who 
discontinue from the study).
Protocol I3Y-MC-JPBL Sampling Summarya
Purpose
Sample 
Type
Maximum 
Amount per 
Sample
Maximum 
Number 
Samples
Maximum Total 
Amount
Screening/Study qualification
(Hematology and Clinical Chemistry)
Blood
7 mL
1
7 mL
Safety/Health monitoring
(Hematology and Clinical Chemistry)
Blood
7 mL
11
77 mL
Pharmacokinetic sample
Blood
4 mL
6
24 mL
Pharmacogenetic blood sample
Blood
10 mL
1
10 mL
Biomarker plasma sample
Blood
6 mL
1
6 mL
Total blood volume
Blood
124 mL
Hepatic monitoringb
Blood
3 - 30 mL
-
-
a
Covers Cycles 1 through 9.
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated medical monitor.

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Attachment 7.Protocol JPBL Electrocardiogram and 
Pharmacokinetic Sampling Schedule
The schedule for PK sampling is summarized in the table below.  The date and exact time of 
collection for each venous blood sample should be documented on the laboratory requisition.
Pharmacokinetic Sampling Schedule
Cycle (C) and Day
(D)
ECG
PK Sample 
Number
Dosing of 
Abemaciclib or 
Placebo 
(Blinded Study 
Drug)
Dosing of 
Fulvestrant
Sampling Time for 
PK from Blooda
Baseline 
(Day -14 to Day -1)
X
Day of visit
C1D1
X
1
X
X
2 to 4 hrs after 
fulvestrant and blinded 
study drug dose
C1D15
X
2
Xb
X
Upon arrival at site but 
prior to fulvestrant 
dose (that is, at least 4 
hrs after taking 
blinded study drug
dose at home)
C1D15
3
3 ± 0.5 hrs after PK 
Sample Number 2
(that is, at least 7 ± 0.5 
hrs after taking 
blinded study drug
dose at home)
C2D1
4
X
X
Prior to fulvestrant and 
blinded study drug
dose 
C2D1
5
3 ± 0.5 hrs after 
blinded study drug
dose 
C3D1
6
X
X
Prior to fulvestrant and 
blinded study drug 
dose
C4D1
X
2 to 4 hrs after blinded 
study drug dose
30-Day Follow-Up
X
Day of visit

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Pharmacokinetic Sampling Schedule (concluded)
Abbreviations:  C = Cycle; D = Day; hr = hour; PK = pharmacokinetic.
a
Samples of approximately 4 mL of whole blood will be drawn. After obtaining plasma, site personnel will 
aliquot samples into 2 approximately equal portions, one for measurement of LY2835219 and its metabolites
concentrations and the other for measurement of fulvestrant concentrations. Only samples No. 1, 2, 4, and 6 will 
be used for measurement of fulvestrant.  In the event of a dose suspension of blinded study drug due to toxicity 
immediately prior to the beginning of a cycle, the PK Sampling Schedule may require adjustment.  In these 
exceptional circumstances, the Sponsor should be notified.
b On Cycle 1 Day 15 only, patient should take blinded study drug dose at home at least 4 hours before arrival at 
site.  The time of blinded study drug dose intake must be recorded that day.

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Attachment 8.Protocol JPBL Inducers, Strong Inhibitors of 
CYP3A, or Substrates of CYPs with Narrow Therapeutic 
Range
The information in this attachment is provided for guidance to investigators and does not 
preclude the use of these medications if clinically indicated.
Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 
7 days, if clinically indicated.
Strong inhibitors of CYP3A
All HIV protease inhibitors
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine

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Attachment 9.Protocol JPBL CTCAE 4.03 Diarrhea Definition
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 revised:  CTCAE 4.03-June 14, 2010:  Gastrointestinal disorders. 
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of <4 
stools per day over 
baseline; mild 
increase in ostomy 
output compared 
to baseline.
Increase of 4-6 
stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline
Increase >= 7 stools 
per day over baseline; 
incontinence; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self-
care ADL
Life-threatening 
consequences; urgent 
intervention 
indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements
Abbreviation:  ADL = Activities of Daily Living.

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Attachment 10.
Protocol JPBL Amendment(d) Summary
MONARCH 2:  A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Fulvestrant with or without 
Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or 
Metastatic Breast Cancer
Study I3Y-MC-JPBL, A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
Fulvestrant with or without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer, has been 
amended.  The new protocol is indicated by amendment (d) and will be used to conduct the study 
in place of any preceding version.
The overall changes made to this protocol are as follows:

Section 5.4 incorporated rationale for Amendment (d).  An earlier final analysis will be 
conducted as a result of recent efficacy findings of CDK4 and CDK6 inhibitors in 
combination with fulvestrant.

Synopsis and Sections 12.1, 12.2.7, and 12.2.15.2 updated planned interim and final analyses 
and PFS events.

Sections 12.2.9 and 12.2.15.2 modified details for the SAP.

Sections 9.4.1.1.3 and 9.4.1.1.4 modified text to align with Table JPBL.9.2.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2.  Synopsis
Length of Study:  Approximately 72 months
Planned first patient visit:  July 2014
Planned last patient visit:  August 2020
Planned interim analyses:  265 (approximately 60% 70% of the planned) progression-free survival (PFS) events and 
353 (approximately 80% of the planned) PFS events
Statistical Methods:
Statistical:  The primary objective of this study is to compare abemaciclib plus fulvestrant versus placebo plus 
fulvestrant in terms of PFS for women with HR+, HER2- locally advanced or metastatic breast cancer.  An 
important secondary objective of this study is to compare the 2 arms with respect to OS.
A 32-look group sequential design on the primary endpoint of PFS will be utilized, with 2 1 interim analyses
analysis and 1 final PFS analyses occurring at approximately 265, 353, and 441378 investigator-assessed PFS events 
in the EP stratum.  A fixed alpha-spending method will be used to maintain the cumulative 1-sided Type I error rate 
of .025.  Assuming a hazard ratio (HR) of 0.703, this design yields more than approximately 90% statistical power 
to detect superiority of the abemaciclib plus fulvestrant arm over placebo plus fulvestrant arm with the use of a 
1-sided log-rank test and a cumulative type I error rate of 0.025.
OS is an important secondary endpoint for this study. OS will be tested only if the test of PFS is significant. The 
final OS analysis will be performed when approximately 441 OS events have been observed in the EP stratum.
5.4.  Rationale for Amendment (d)
Recent Phase 3 study disclosures (Cristofanilli et al. 2016) indicate the combination of 
fulvestrant and an inhibitor of CDK4 and CDK6 may be highly efficacious.  Consequently, an 
earlier final analysis will be conducted, after 378 PFS events, rather than the initially planned 
441 events, which still maintains the power at approximately 90% for the target hazard ratio of 
0.70.  A total of 378 PFS events at the final analysis corresponds to a censoring rate of 
approximately 40%, which is consistent with that of other trials conducted in a similar setting 
(for example, Di Leo et al. 2010; Baselga et al. 2012; Yardley et al. 2013; Cristofanilli et al. 
2016).  A final analysis at 378 events precludes the need for a second interim analysis at 
353 events, thus JPBL Amendment (d) removes the second interim analysis, leaving a single 
interim analysis at 265 events.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
8.1.  Summary of Study Design
Data base lock for the interim analyses analysis for efficacy will occur when approximately 265
and 353 investigator-assessed PFS events have been observed.  Database lock for the final 
analysis of the PFS endpoint will occur when approximately 441 378 investigator-assessed PFS 
events have been observed.  All patients will be followed for progression and survival 
information until death or study completion, whichever occurs first.

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9.4.1.1.3.  Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of blinded study drug must be reduced by 
1 dose level as outlined in Table JPBL.9.3.
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of blinded study may be reduced by 1 dose 
level as outlined in Table JPBL.9.3. If the patient experiences a recurrent episode of Grade 3 
hematologic toxicity, then dosing must be suspended (until the toxicity resolves to at least 
Grade 2) and the dose of blinded study must be reduced by 1 dose level.
If a patient requires administration of blood cell growth factors, the dose of study drug must be 
suspended for at least 48 hours after the last dose of blood cell growth factors was administered 
and until toxicity resolves to at least Grade 2, then must be reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
Before re-initiation of blinded study drug, hematologic toxicity possibly related to blinded study 
drug must resolve to at least Grade 2.
9.4.1.1.4.  Nonhematologic Toxicity
If a patient experiences ≥ Grade 3 nonhematologic toxicity, then dosing must be suspended (until 
the toxicity resolves to either baseline or at least Grade 1) and the dose of blinded study drug
must be reduced by 1 dose level as outlined in Table JPBL.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 9.4.1.1.4.1) possibly related to blinded study drug that does not resolve with 
maximal supportive measures within 7 days to either baseline or Grade 1, then blinded study 
drug dosing may be suspended (until the toxicity resolves to either baseline or at least Grade 1) 
and the dose of blinded study drug may be reduced by 1 dose level as outlined in Table JPBL.9.3
at the discretion of the investigator.
Before re-initiation of blinded study, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or at least Grade 1.
12.1.  Determination of Sample Size
A 32-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and final PFS analyses (see Section 12.2.7 for details).  The 
final PFS analysis will be performed after 441 378 PFS events have occurred in the EP stratum 
(that is, a 30% 40% censoring rate).  Assuming a hazard ratio (HR) of 0.703, this sample size 
yields more than approximately 90% statistical power to detect superiority of the abemaciclib
plus fulvestrant arm over the placebo plus fulvestrant arm with the use of a 1-sided log-rank test 
and a type I error of 0.025. If the true median PFS for the placebo plus fulvestrant arm is 6.5
months, then the HR of 0.703 amounts to an approximately 2.75-month (42%) improvement in 

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median PFS for the abemaciclib plus fulvestrant arm under an additional assumption of 
exponential survival distribution.
12.2.7.  Primary Outcome and Methodology
The 32-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and final analyses.  There are 2 is 1 planned interim analyses
analysis and 1 final analysis for PFS in this study.  The interim analyses are analysis is planned 
to take place after approximately 265 (approximately 60% of the planned) investigator-assessed 
PFS events have occurred and approximately 353 (approximately 80% 70% of the planned) 
investigator-assessed PFS events have occurred.  The cumulative 1-sided type I error rate of .025 
will be maintained using the following method.  At each the interim analysis, the nominal 
significance level will be .00001.  The remaining alpha will be spent at the final analysis.  The 
resulting boundary p-value for the final analysis is dependent on the exact number of events 
observed at each analysis and can be calculated using the method of Slud and Wei (1982).  If the
3 analyses are performed at exactly 265, 353, and 441 378 events, then the boundary p-value at 
the final analysis will be .0249997 02499996).
The actual boundary for the final analysis will be calculated based on the actual number of 
events observed at the time of each analysis using software that implements the α-spending 
scheme noted above (for example, ADDPLAN 6.0, SAS 9.2, or similar software).
If statistical significance is not declared at the first interim PFS analysis, the second interim PFS 
analysis will be performed after 353 PFS events have been observed in the ITT population.  Note 
that the second interim analysis of PFS will only be performed if statistical significance is not 
declared at the first interim PFS analysis.  If statistical significance is not observed at either at the 
interim analysis, the final PFS analysis will be performed after 441 378 PFS events have been 
observed in the ITT population based on investigator assessment.  Once statistical significance is 
declared at either the interim analysis or the final analysis, the study will be positive based on the 
primary endpoint of PFS, and testing of secondary endpoints will proceed as described in the 
SAP.
12.2.9.  Sensitivity Analysis
In addition, a PFS analysis based on independent central review data will be conducted by 
applying the censoring rules from Table JPBL.12.1.  The analysis will be conducted on a 
randomly selected subset of patients to evaluate the presence of investigator bias with the 
intention of evaluating the reliability of the treatment effect based on investigator assessment.  
Dodd (Dodd et al. 2011), Pharmaceutical Research and Manufacturers Association (PhRMA) 
methodology (Amit et al. 2011), or similar methodology will be used to determine audit size and 
evaluate the results and determine whether independent review of the remaining patients is 
warranted.  Details can be found in the Central Review SAP.

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12.2.14.  Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic
subgroup variables:

All baseline stratification factors

Starting dose (200 mg versus 150 mg)

Measurable disease at baseline (yes versus no)

Number of organs involved (1 versus 2 vs. 3+)

Age (<65 years versus ≥65 years)

Region (North America, Europe, Asia, and Other)

Race (Caucasian, Asian, and Other)

PgR status (positive versus negative)

Baseline ECOG PS (0 versus 1)
12.2.15.2.  Efficacy Interim Analyses
Two One efficacy interim analyses analysis of PFS are is planned, as described in Section 12.2.7.  
Four Multiple interim analyses of OS are planned (at as described in the time of each of the 
2 interim PFS analyses, at the time of the final PFS analysis, and at the time when approximately 
75% of the OS events have been observed; subsequently, a final OS analysis is planned) SAP.
The interim PFS analyses analysis will be conducted to provide early efficacy information and 
could potentially result in early communication with regulatory agencies.  The DMC should 
recommend unblinding the sponsor if the following are observed:

The analysis of investigator-assessed PFS is significant at the alpha level specified in 
Section 12.2.7, with the observed stratified hazard ratio for investigator-assessed PFS less 
than 0.56 at the first interim analysis or less than 0.6 at the second interim analysis, and

Results of the analysis of the centrally reviewed PFS that support the results of the 
investigator-assessed PFS analysis.
14.  References
Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini L. Pienkowski T, 
Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. 
Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.
2012;366(2):109-119.
Cristofnilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, 
Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theal KP, Jiang Y, Barlett CH, Koehler M, 
Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of 
hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on 
previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, 
phase 3 randomised controlled trial. Lancet. 2016:17(4);425-439.

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Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, 
Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, 
Martin M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with 
fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast 
cancer. J Clin Onc. 2010;28(30):4594-4600. Erratum in: J Clin Oncol. 2011;29(16):2293.
Yardley DA, Ismail-Khan RR, Melichar B, Lichinistser M, Munster PN, Klein PM, 
Cruickshank S, Miller KD, Lee MJ, Trepel JB. Randomized phase II, double-blind, placebo-
controlled study of exemestane with or without entinostat in postmenopausal women with 
locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on 
treatment with a nonsteroidal aromatase inhibitor. J Clin Onc. 2013;31(17):2128-2135.

Leo Document ID = 3e38f8f6-6bff-4bde-b8e2-9cf546aa0fc7
Approver: 
Approval Date & Time: 26-Apr-2016 14:58:34 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-Apr-2016 19:05:42 GMT
Signature meaning: Approved