A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI (Anastrozole or Letrozole) Plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or Plus Placebo, and to Compare Fulvestrant Plus Abemaciclib or Plus Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Eli Lilly and Company

 
Protocol I3Y-CR-JPBQ(e) 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI 
Anastrozole or Letrozole) plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus Placebo, and 
to Compare Fulvestrant plus Abemaciclib or plus Placebo in Postmenopausal Women with 
Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast 
Cancer 
 
NCT02763566 
 
Approval Date: 14-May-2019 
 
 

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1.
Protocol I3Y-CR-JPBQ(e)
A Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Study to Compare NSAI (Anastrozole or Letrozole) plus
Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus Placebo,
and to Compare Fulvestrant plus Abemaciclib or plus 
Placebo in Postmenopausal Women with Hormone 
Receptor-Positive, HER2-Negative Locoregionally 
Recurrent 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.
Abemaciclib (LY2835219)
This is a randomized, double-Blind, placebo-controlled, phase 3 study to compare NSAI 
plus abemaciclib, a CDK4 and CDK6 Inhibitor, or plus placebo, and to compare fulvestrant 
plus abemaciclib or plus placebo in postmenopausal women with hormone receptor-
positive, HER2-negative locoregionally recurrent or metastatic breast cancer
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on: 28 Jan 2016
Amendment (a) Approved by Lilly: 05 December 2016
Amendment (b) Electronically Signed and Approved by Lilly: 21 March 2017
Amendment (c) Electronically Signed and Approved by Lilly: 16 June 2017
Amendment (d) Electronically Signed and Approved by Lilly: 7 May 2018
Amendment (e) Electronically Signed and Approved by Lilly
on approval date provided below
Approval Date: 14-May-2019 GMT

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2.
Synopsis
Study Rationale
Abemaciclib is an oral, selective, and potent small molecule cyclin-dependent kinase 4 and 6 
(hereafter 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.  Studies with abemaciclib across breast cancer cell lines 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 estrogen receptor-positive (ER+) breast cancers with luminal 
histology.
In the Phase 1 Study I3Y-MC-JPBA (JPBA), abemaciclib has shown clinically manageable 
safety across 6 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 with metastatic breast cancer (mBC). In Study 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 (PRs), 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 PRs were observed in these 19 patients. These results support further 
investigation of abemaciclib in combination with fulvestrant for women with HR+ 
locoregionally recurrent or metastatic breast cancer.
In another ongoing Phase 1b study, Study I3Y-MC-JPBH (JPBH), safety and tolerability of 
abemaciclib in combination with endocrine therapies (including anastrozole and letrozole) are 
also being evaluated in patients with HR+, human epidermal growth factor receptor 2-negative
(HER2-) mBC. 
To further confirm the safety and efficacy of abemaciclib in combination with current standard 
endocrine therapies (either nonsteroidal aromatase inhibitors [NSAIs] or fulvestrant) in HR+, 
HER2- breast cancer, 2 randomized, double-blind, placebo-controlled, Phase 3 studies,  Studies 
I3Y-MC-JPBM and I3Y-MC-JPBL, are being conducted globally. Along with these 2 studies, 
this randomized, double-blind, placebo-controlled Phase 3 study, Study I3Y-CR-JPBQ (JPBQ)
will evaluate the safety and efficacy of abemaciclib in combination with both endocrine therapies 
in mainly east Asian patients with HR+, HER2- locoregionally recurrent or metastatic breast 
cancer and postmenopausal status.  

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Clinical Protocol Synopsis:  Study I3Y-CR-JPBQ
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI (Anastrozole 
or Letrozole) plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus Placebo, and to Compare Fulvestrant plus 
Abemaciclib or plus Placebo in Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative 
Locoregionally Recurrent or Metastatic Breast Cancer
Number of Planned Patients:
Entered: 500
Enrolled/Randomized: 450
Completed: 450
Phase of Development:  3
Length of Study:  approximately 38 months
Planned first patient visit:  October 2016
Planned last patient visit:  July 2019
Planned interim analysis:  An interim analysis is planned with 119 PFS events in the abemaciclib plus NSAI or 
placebo plus NSAI arms. The interim analysis of abemaciclib plus fulvestrant arm or placebo plus fulvestrant arm
will also be conducted once the above mentioned interim is positive.   
Objectives:  The primary objective of this study is to compare treatment with abemaciclib plus NSAI (anastrozole 
or letrozole) therapy versus placebo plus NSAI therapy with respect to PFS in postmenopausal women with HR+, 
HER2- locoregionally recurrent or metastatic breast cancer.
The key secondary objective of this study is to compare treatment with abemaciclib plus fulvestrant therapy versus 
placebo plus fulvestrant therapy with respect to PFS in postmenopausal women with HR+, HER2- locoregionally 
recurrent or metastatic breast cancer.
Other secondary objectives of this study are to compare the combination treatment of abemaciclib and NSAI 
therapy versus placebo plus NSAI therapy, and to compare the combination treatment of abemaciclib and 
fulvestrant therapy versus placebo plus fulvestrant therapy with respect to the following:
•
overall survival (OS)
•
OS rate at 1 and 2 years
•
objective response rate (complete response [CR] + 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
•
change in symptom burden using the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
•
pharmacokinetics (PK) of abemaciclib, its metabolites, NSAI, and fulvestrant.
The exploratory objectives of this study are:
•
to compare the combination treatment of abemaciclib and NSAI therapy versus placebo plus NSAI 
therapy, and to compare the combination treatment of abemaciclib and fulvestrant therapy versus placebo 
plus fulvestrant therapy with respect to change in pain burden using the modified Brief Pain Inventory
short form (mBPI-sf)
•
to explore potential biomarkers related to the mechanism of action of abemaciclib, NSAI, fulvestrant, the 
cell cycle, and/or the pathogenesis of breast cancer, and to correlate potential biomarkers to clinical 
outcomes
•
to explore if change in tumor size is associated with PFS and OS.

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Study Design:  Study JPBQ is a multicenter, randomized, double-blind, Phase 3 trial evaluating treatment of 
abemaciclib with NSAI (Cohort A)/fulvestrant (Cohort B) or placebo with NSAI/fulvestrant in postmenopausal
women with HR+, HER2- locoregionally recurrent or metastatic breast cancer.
The study will consist of 2 patient cohorts:
▪Cohort A will include approximately 300 patients with HR+, HER2- locoregionally recurrent or metastatic breast 
cancer meeting Inclusion Criterion 2a (see below). 
▪Cohort B will additionally include approximately 150 patients with HR+, HER2- locoregionally recurrent or 
metastatic breast cancer meeting Inclusion Criterion 2b (see below). The initiation of enrollment for patients in 
Cohort B will be triggered later according to Eli Lilly and Company (Lilly) global strategy.   
After confirmation of eligibility, patients in each cohort will be randomly assigned on a 2:1 basis to receive 
abemaciclib with NSAI (Cohort A)/fulvestrant (Cohort B) or placebo with NSAI (Cohort A)/fulvestrant (Cohort
B). 
Patients in Cohort A will be randomized using the following stratification factors:  nature of disease (visceral 
metastases vs. non-visceral metastases) and prior (neo)adjuvant endocrine therapy (prior therapy with disease-free 
interval > 12 months from completion of treatment vs. prior therapy with disease-free interval ≤12 months from 
completion of treatment vs. no prior therapy). Patients in Cohort B will be randomized using the following 
stratification factors:  nature of disease (visceral metastases vs. non-visceral metastases) and sensitivity to 
endocrine therapy (primary resistance vs. secondary resistance). 
Diagnosis and Main Criteria for Inclusion and Exclusions:  
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; 2) meet either Inclusion Criterion (2a) or (2b). Patients meeting Inclusion Criterion 2a 
will be enrolled in Cohort A and patients meeting Inclusion Criterion 2b will be enrolled in Cohort B. 2a) have 
locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic 
disease. In addition, patients must fulfill 1 of the following criteria: relapsed with radiologic evidence of 
progression more than 1 year from completion of/or with no adjuvant endocrine therapy and have received no prior 
endocrine therapy for locoregionally recurrent or metastatic disease; OR relapsed with radiologic evidence of 
progression less than 1 year from completion of or while receiving adjuvant endocrine therapy (except for letrozole 
or anastrozole) and have received no prior endocrine therapy for locoregionally recurrent or metastatic disease; OR
presented de novo mBC and not received any prior endocrine therapy; 2b) have locoregionally recurrent disease 
not amenable to resection or radiation therapy with curative intent or metastatic disease.  In addition, patients must 
fulfill 1 of the following criteria: relapsed with radiologic evidence of progression while receiving neoadjuvant or 
adjuvant letrozole or anastrozole, with no subsequent endocrine therapy received following progression OR
relapsed with radiologic evidence of progression within 1 year from completion of adjuvantletrozole or 
anastrozole, with no subsequent endocrine therapy received following progression OR 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) OR presented de novo with 
metastatic disease and then relapsed 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); 3) have postmenopausal status; 4) have measurable 
disease or nonmeasurable bone-only disease; 5) have a performance status (PS) of ≤1 on the Eastern Cooperative 
Oncology Group (ECOG) scale; 6) have adequate organ function; 7) are female and >18 years of age; 8) have 
discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 
weeks prior to randomization and recovered from the acute effects of therapy except for residual alopecia or 
peripheral neuropathy; 9) have given written informed consent prior to any study-specific procedures; 10) are able 
to swallow capsules; and 11) are reliable, willing to be available for the duration of the study, and willing to follow 
study procedures. 

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Patients will be excluded from the study if they meet any of the following criteria:  12) have visceral crisis, 
lymphangitic spread, or leptomeningeal carcinomatosis; 13) have inflammatory breast cancer; 14) have clinical 
evidence or a history of central nervous system (CNS) metastasis; 15) are currently receiving or have previously 
received chemotherapy for locoregionally recurrent or metastatic breast cancer; 16) have received prior treatment 
with everolimus or fulvestrant (for Cohort B only); 17) have received prior treatment with any CDK4 and CDK6
inhibitor; 18) have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents <7 days prior 
to randomization; 19) are currently enrolled in a clinical trial involving an investigational product (IP) or non-
approved use of a drug or device (other than the IP/device used in this study), or concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically compatible with this study; 20) have received 
treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of 
randomization for a nonmyelosuppressive or myelosuppressive agent, respectively; 21) have had major surgery 
within 14 days prior to randomization to allow for post-operative healing of the surgical wound and site(s); 22) 
have received recent live attenuated vaccines such as yellow fever vaccine; 23) have serious preexisting medical 
conditions that, in the judgment of the investigator, would preclude participation in this study; 24) 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; 25) have a history of any other cancer, 
unless in complete remission with no therapy for a minimum of 3 years; 26) have received an autologous or 
allogeneic stem-cell transplant; and 27) have clinical evidence of active bacterial or fungal infection or active viral 
infection that, in the judgment of the investigator, would preclude participation in this study
Test Product, Dosage, and Mode of Administration:  Abemaciclib or placebo will be supplied as capsules 
administered orally, 150 mg every 12 hours (Q12H) on Days 1 to 28 of a 28-day cycle. For patients in Cohort A, 
either 1 mg anastrozole or 2.5 mg letrozole will be administered orally every 24 hours (Q24H) on Day 1 to 28 of a 
28-day cycle. For patients in Cohort B, 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.
Planned Duration of Treatment:  
Treatment period:  until disease progression or other discontinuation criteria are fulfilled.
Short-term follow-up (postdiscontinuation):  30 days (7 days)
Long-term follow-up (postdiscontinuation):  until death  
Criteria for Evaluation:  
Efficacy:  
•
PFS 
•
OS
•
OS rate at 1 and 2 years
•
Objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1)
•
DoR (RECIST v1.1)
•
DCR (RECIST v1.1)
•
CBR (RECIST v1.1)
Safety:  Adverse events using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 and Medical Dictionary for Regulatory Activities (MedDRA)
Health Outcomes:  
•
EORTC QLQ-C30: describe target tumor symptom changes
•
mBPI-SF:  proportion of patients with “worst pain” increase of 2 points or more at any time on-therapy, 
compared to baseline 
Bioanalytical:  Plasma concentrations of abemaciclib and its major metabolites will be determined using a 
validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method.  Plasma concentrations of 
anastrozole, letrozole, and fulvestrant will also be determined using a validated LC-MS/MS method.
Pharmacokinetics/ Pharmacodynamics:  Population PK and/or pharmacodynamic parameters for abemaciclib and 
abemaciclib metabolites, letrozole, anastrozole, or fulvestrant.

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Exploratory:
•
to compare the combination treatment of abemaciclib and NSAI therapy versus placebo plus NSAI 
therapy, and to compare the combination treatment of abemaciclib and fulvestrant therapy versus placebo 
plus fulvestrant therapy with respect to change in pain burden using the mBPI-sf
•
to explore potential biomarkers related to the mechanism of action of abemaciclib, NSAI, fulvestrant, the 
cell cycle, and/or the pathogenesis of breast cancer, and to correlate potential biomarkers to clinical 
outcomes
•
to explore if change in tumor size is associated with PFS and OS.
Statistical Methods:  
Statistical:  The primary objective of this study is to compare treatment with abemaciclib plus NSAI therapy versus 
placebo plus NSAI therapy with respect to PFS in postmenopausal women with HR+, HER2- locoregionally 
recurrent or metastatic breast cancer. A key secondary objective of this study is to evaluate abemaciclib plus 
fulvestrant versus placebo plus fulvestrant in terms of PFS for women with HR+, HER2- locoregionally recurrent
or metastatic breast cancer.
The study will enroll approximately 450 patients in total, with 300 patients in Cohort A and 150 patients in Cohort
B. The initiation of enrollment for patients in Cohort B will be triggered later according to Lilly global strategy.
The primary PFS analysis will be performed after approximately 170 PFS events in Cohort A have occurred (ie, a 
43% censoring rate).  Assuming a hazard ratio of 0.626, this sample size yields at least 81.4% statistical power to 
detect superiority of the abemaciclib plus NSAI arm over the placebo plus NSAI arm with the use of a 1-sided log-
rank test and a type I error of 0.025.  
An interim analysis will be conducted on Cohort A when 119 PFS events have been observed. If positive, an 
interim of Cohort B will also be conducted on the same cutoff. If patients in Cohort A continue being followed for 
PFS until final analysis, the final analysis of Cohort B will be conducted at the same time of Cohort A final 
analysis. If Cohort A stops early at interim due to efficacy, the final analysis of Cohort B may be conducted after 
approximately 105 PFS events have been observed in Cohort B.
Efficacy:
For both Cohort A and Cohort B, the PFS analyses to test the superiority of abemaciclib to placebo in improving 
PFS 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 hazard ratios 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:
Change from baseline in symptom burden will be analyzed descriptively.  Treatment arms in each cohort will be 
compared using a repeated measures model, where appropriate.
Pharmacokinetics/ Pharmacodynamics:
Pharmacokinetic parameters (clearance, area under the plasma concentration versus time curve [AUC], volume of 
distribution, and half-lives) and inter-individual PK variability for abemaciclib in plasma and pharmacodynamic 
data (such as neutrophil, lymphocytes, or platelet counts in blood) will be computed using nonlinear mixed effect 
modeling implemented in NONMEM. 

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3.
Table of Contents
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study to Compare NSAI (Anastrozole or Letrozole) plus 
Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus Placebo, 
and to Compare Fulvestrant plus Abemaciclib or plus 
Placebo in Postmenopausal Women with Hormone Receptor-
Positive, HER2-Negative Locoregionally Recurrent or 
Metastatic Breast Cancer
Section
Page
1.
Protocol I3Y-CR-JPBQ(e) A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study to Compare NSAI (Anastrozole or 
Letrozole) plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus 
Placebo, and to Compare Fulvestrant plus Abemaciclib or plus 
Placebo in Postmenopausal Women with Hormone Receptor-
Positive, HER2-Negative Locoregionally Recurrent or Metastatic 
Breast Cancer......................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................20
6.
Objectives.........................................................................................................................23
6.1.
Primary Objective ........................................................................................................23
6.2.
Secondary Objectives...................................................................................................23
6.3.
Exploratory Objectives.................................................................................................23
7.
Study Population...............................................................................................................24
7.1.
Inclusion Criteria..........................................................................................................24
7.2.
Exclusion Criteria ........................................................................................................27
7.3.
Discontinuation............................................................................................................28
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................28
7.3.2.
Discontinuation of Study Drug(s).........................................................................28
7.3.3.
Discontinuation from the Study............................................................................29
7.3.4.
Patients Who Are Lost to Follow-Up....................................................................29
7.3.5.
Discontinuation of Study Sites .............................................................................29
7.3.6.
Discontinuation of the Study................................................................................30
8.
Investigational Plan...........................................................................................................31
8.1.
Summary of Study Design............................................................................................31

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8.1.1.
Study Completion and End of Trial......................................................................33
8.1.2.
Continued Access Period......................................................................................34
8.2.
Discussion of Design and Control ................................................................................35
9.
Treatment..........................................................................................................................36
9.1.
Treatments Administered .............................................................................................36
9.2.
Materials and Supplies .................................................................................................38
9.3.
Method of Assignment to Treatment ............................................................................38
9.4.
Selection and Timing of Doses.....................................................................................39
9.4.1.
Special Treatment Considerations ........................................................................39
9.4.1.1.
Dose Adjustments and Delays ........................................................................39
9.4.1.1.1.
Dose Adjustments.....................................................................................41
9.4.1.1.1.1.
Blinded Study Drug ............................................................................41
9.4.1.1.1.2.
NSAI/Fulvestrant................................................................................42
9.4.1.1.2.
Dose Suspension (within a Cycle) and Cycle Delay ..................................42
9.4.1.1.3.
Hematologic Toxicity ...............................................................................43
9.4.1.1.4.
Nonhematologic Toxicity..........................................................................43
9.4.1.1.4.1.
Diarrhea..............................................................................................44
9.4.1.1.4.2.
Hepatic Toxicity .................................................................................44
9.5.
Blinding .......................................................................................................................44
9.5.1.
Unblinding at Interim Analyses............................................................................45
9.5.2.
Emergency Unblinding ........................................................................................45
9.5.3.
Inadvertent Unblinding ........................................................................................45
9.6.
Concomitant Therapy...................................................................................................45
9.6.1.
Surgery and/or Radiotherapy for Locoregionally Recurrent 
Breast Cancer.......................................................................................................46
9.6.2.
Radiotherapy........................................................................................................46
9.6.3.
Supportive Care ...................................................................................................46
9.6.4.
Growth Factor......................................................................................................47
9.6.5.
Supportive Management for Diarrhea...................................................................47
9.6.6.
Bisphosphonates and RANK-L Targeted Agents..................................................47
9.7.
Treatment Compliance .................................................................................................48
9.7.1.
Patient Diaries......................................................................................................48
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................49
10.1. Efficacy Measures........................................................................................................49
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................49

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10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................50
10.1.3.
Primary Efficacy Measure....................................................................................50
10.1.4.
Secondary Efficacy Measures...............................................................................51
10.1.5.
Exploratory Measures ..........................................................................................52
10.2. Health Outcome/Quality of Life Measures ...................................................................53
10.2.1.
Patient-Reported Outcomes..................................................................................53
10.2.1.1.
Health-Related Quality of Life........................................................................53
10.2.1.2.
Pain Intensity..................................................................................................54
10.2.2.
Resource Utilization.............................................................................................54
10.3. Safety Evaluations........................................................................................................54
10.3.1.
Adverse Events ....................................................................................................55
10.3.1.1.
Serious Adverse Events ..................................................................................56
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................57
10.3.2.
Other Safety Measures .........................................................................................58
10.3.2.1.
Electrocardiograms.........................................................................................58
10.3.3.
Safety Monitoring ................................................................................................58
10.3.3.1.
Special Hepatic Safety Data Collection...........................................................58
10.3.3.2.
Renal Function ...............................................................................................59
10.3.3.3.
Venous Thromboembolic Events....................................................................59
10.3.4.
Complaint Handling.............................................................................................59
10.4. Sample Collection and Testing.....................................................................................60
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................60
10.4.2.
Samples for Biomarkers .......................................................................................60
10.4.2.1.
Whole Blood Sample for Pharmacogenetic Evaluations..................................61
10.4.2.2.
Plasma Samples for Exploratory Biomarker Evaluations.................................61
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................61
10.5. Appropriateness of Measurements................................................................................62
11.
Data Quality Assurance.....................................................................................................63
11.1. Data Capture System....................................................................................................63
12.
Sample Size and Statistical Methods .................................................................................64
12.1. Determination of Sample Size ......................................................................................64
12.2. Statistical and Analytical Plans.....................................................................................65
12.2.1.
General Considerations ........................................................................................65
12.2.2.
Patient Disposition...............................................................................................65
12.2.3.
Patient Characteristics..........................................................................................66
12.2.4.
Concomitant Therapy...........................................................................................66

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12.2.4.1.
Postdiscontinuation Therapy...........................................................................66
12.2.5.
Treatment Compliance .........................................................................................66
12.2.6.
Primary Outcome and Methodology.....................................................................67
12.2.7.
Secondary Outcomes and Methodology ...............................................................68
12.2.7.1.
Progression-Free Survival in Cohort B............................................................68
12.2.7.2.
Overall Survival .............................................................................................69
12.2.7.3.
Objective Response Rate, Disease Control Rate, Clinical 
Benefit Rate, and Duration of Response..........................................................69
12.2.8.
Sensitivity Analysis..............................................................................................69
12.2.9.
Pharmacokinetic and Pharmacodynamic Analyses ...............................................69
12.2.10. Biomarker Analyses.............................................................................................70
12.2.11. Health Outcome/Quality-of-Life Analyses ...........................................................70
12.2.11.1. Health-Related Quality of Life........................................................................70
12.2.11.2. Pain Intensity..................................................................................................70
12.2.11.3. Resource Utilization .......................................................................................71
12.2.12. Safety Analyses....................................................................................................71
12.2.13. Subgroup Analyses ..............................................................................................72
12.2.14. Interim Analysis and Other Planned Analyses......................................................72
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................74
13.1. Informed Consent.........................................................................................................74
13.2. Ethical Review.............................................................................................................74
13.3. Regulatory Considerations ...........................................................................................74
13.3.1.
Investigator Information.......................................................................................75
13.3.2.
Protocol Signatures ..............................................................................................75
13.3.3.
Final Report Signature .........................................................................................75
14.
References ........................................................................................................................76

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List of Tables
Table
Page
Table JPBQ.9.1.
Treatment Regimens/Dosing Schedule ...................................................37
Table JPBQ.9.2.
Toxicity Dose Adjustments and Delays of Blinded Study Drug for 
Study JPBQ............................................................................................40
Table JPBQ.9.3.
Dose Adjustments for Abemaciclib ........................................................41
Table JPBQ.10.1.
Other Secondary Efficacy Endpoints ......................................................52
Table JPBQ.10.2.
Exploratory Measures.............................................................................52
Table JPBQ.10.3.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........55
Table JPBQ.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................67
Table JPBQ.12.2.
Properties of Design for Progression-Free Survival.................................68

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List of Figures
Figure
Page
Figure JPBQ.8.1.
Illustration of study design......................................................................31
Figure JPBQ.8.2.
Study period and continued access diagram. ...........................................34

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List of Attachments
Attachment
Page
Protocol JPBQ Study Schedule...............................................................78
Attachment 1.
Protocol JPBQ Clinical Laboratory Tests................................................85
Attachment 2.
Protocol JPBQ Hepatic Monitoring Tests for Treatment-Emergent 
Attachment 3.
Abnormality ...........................................................................................86
Protocol JPBQ ECOG Performance Status .............................................87
Attachment 4.
Protocol JPBQ RECIST Criteria 1.1 .......................................................88
Attachment 5.
Protocol JPBQ Sampling Summary ........................................................95
Attachment 6.
Protocol JPBQ Pharmacokinetic
Attachment 7.
Sampling Schedule .................................................................................96
Protocol JPBQ Inducers of CYP3A, Strong Inhibitors of CYP3A, 
Attachment 8.
or Substrates of CYPs with Narrow Therapeutic Range ..........................97
Protocol JPBQ CTCAE 4.03 Diarrhea Definition ...................................99
Attachment 9.
Protocol JPBQ Amendment (e) Summary A Randomized, Double-
Attachment 10.
Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI 
(Anastrozole or Letrozole) plus Abemaciclib, a CDK4 and CDK6 
Inhibitor, or plus Placebo, and to Compare Fulvestrant plus 
Abemaciclib or plus Placebo in Postmenopausal Women with 
Hormone Receptor-Positive, HER2-Negative Locoregionally 
Recurrent or Metastatic Breast Cancer..................................................101

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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
ANC
absolute neutrophil count
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 ERBs). 
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
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, 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.
CAP
College of American Pathologists
CBR
clinical benefit rate
CDK4 and CDK6
cyclin-dependent kinases 4 and 6
CI
confidence interval
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.

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complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, GCP requirements, and the applicable 
regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit and no undue risks may continue to 
receive study therapy until one of the criteria for discontinuation is met. 
CR
complete response
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.
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTS
change in tumor size
A measure of tumor dynamics from which tumor response is derived.  Tumor size is the 
sum of tumor measurements across all target tumors at a given evaluation (RECIST 
criteria).
CYP
cytochrome P450
DCR
disease control rate
DFI
disease free interval (DFI) is defined as the period of time between the completion of 
adjuvant endocrine therapy and disease recurrence for those patients who received 
adjuvant endocrine therapy
DMC
Data Monitoring Committee
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
ethylenediamine tetraacetic acid

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end of trial
The end of trial occurs after study completion and after the last patient has discontinued 
study treatment and completed any applicable continued access follow-up.
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
European Organization for Research and Treatment of Cancer
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
ER
estrogen receptor
ER+
estrogen receptor-positive
ERB
ethical 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.
FSH
follicle-stimulating hormone
GCP
good clinical practice
HER2
human epidermal growth factor receptor 2
HER2-
human epidermal growth factor receptor 2-negative
HIV
human immunodeficiency virus
HR
hormone receptor
HR+
hormone receptor-positive
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
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.

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investigational 
product (IP)
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.
IRC
Internal Review Committee
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a 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.
IV
intravenous
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/tandem mass spectrometry
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.
LLT
Lower Level Term
mBC
metastatic breast cancer
mBPI-sf
modified Brief Pain Inventory short form
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid 
NCI
National Cancer Institute
NSAI
nonsteroidal aromatase inhibitor
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

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PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
Preferred Term
Q12H
every 12 hours
Q24H
every 24 hours
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis
RANK-L
RANK ligand
Rb
retinoblastoma
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
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SMD
Senior Management Designee
SOC
System Organ Class
study completion
This study will be considered complete, following the last required PFS event from 
Cohort A or Cohort B, whichever is longer, as determined by Lilly, when all of the 
required short-term follow-up assessment is completed.
SUSAR
suspected unexpected serious adverse reaction

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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.
TPO
third-party organization
ULN
upper limit of normal
VTE
venous thromboembolic event

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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study to Compare NSAI (Anastrozole or Letrozole) plus 
Abemaciclib, a CDK4 and CDK6 Inhibitor, or plus Placebo, 
and to Compare Fulvestrant plus Abemaciclib or plus 
Placebo in Postmenopausal Women with Hormone Receptor-
Positive, HER2-Negative Locoregionally Recurrent or 
Metastatic Breast Cancer
5.
Introduction
Breast cancer is one of the most common cancers in women.  In 2012, there were approximately 
1.7 million new cases of breast cancer worldwide; since 2008, the worldwide incidence of breast 
cancer has increased by more than 20% and mortality has increased by 14% (Bray et al. 2013; 
Ferlay et al. [WWW]). While early-stage disease is treatable, patients with metastatic breast 
cancer (mBC) have a median overall survival (OS) of only 2 to 3 years (Cardoso et al. 
2012). The treatment for women diagnosed with hormone receptor-positive (HR+) mBC 
includes endocrine therapy.  In postmenopausal women, aromatase inhibitors (including 
anastrozole and letrozole) are recommended for the initial treatment of mBC, if not used in the 
adjuvant setting or if discontinued for at least 12 months (Cardoso et al. 2012). However, 
de novo or acquired resistance to adjuvant endocrine therapy and mBC remains an important 
clinical challenge.
Cyclin D1 interacts with cyclin-dependent kinases 4 and 6 (hereafter CDK4 and CDK6) in an 
active protein complex that promotes cell proliferation (Velasco-Velazquez et al. 2011).  Many 
HR+ breast cancers demonstrate an intact retinoblastoma (Rb) tumor suppressive function;
however, overexpression of cyclin D1 protein by oncogenic signaling occurs in approximately 
30% to 50% of cancers.  Cyclin D1 is regarded as the most frequently overexpressed gene in 
primary breast cancer, with amplification of the encoding gene, CCND1, occurring in 
approximately 15% of breast cancers (Casimiro et al. 2014).  Therefore, CDK4 and CDK6
represent a potential therapeutic target for HR+ breast cancer. Consequently, further evaluation 
of CDK4 and CDK6 inhibitors to improve clinical outcomes for women with HR+ breast cancer 
is warranted.
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002). Cyclin-dependent kinase 
4 and CDK6 participate in a complex with the D-type cyclins to initiate progression through the 
G1 restriction point. The CDK4 and CDK6 – cyclin D1 complex regulates the G1 restriction 
point through phosphorylation and inactivation of the Rb tumor suppressor protein, thereby 
promoting S phase entry. Alterations in this pathway occur frequently in human cancers and 
involve:  1) loss of functional cyclin-dependent kinase inhibitors through deletion or epigenetic 
silencing; 2) activating mutations and/or overexpression of CDK4 and CDK6 or the D-type 
cyclins; and 3) loss of functional Rb through mutation or deletion. Except for tumors with 
functional loss of Rb, which functions downstream of the CDK4 and CDK6 – cyclin D1 

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complex, most cancers are potentially sensitive to pharmacologic inhibition of CDK4 and 
CDK6. From a therapeutic standpoint, the goal of inhibiting CDK4 and CDK6 with a small 
molecule is to prevent cell cycle progression through the G1 restriction point, thus arresting 
tumor growth.
Abemaciclib represents a selective and potent small molecule inhibitor of CDK4 and CDK6 with 
acceptable physical characteristics, pharmacokinetic (PK) properties, and safety profile in 
nonclinical species. There may be important opportunities to tailor therapy with abemaciclib for 
patients with breast cancer. 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.  In accordance 
with the known biology of CDK4 and CDK6, the results also indicate that many of these 
sensitive cell lines are also characterized as having amplification of CCND1, which is the gene 
that encodes cyclin D1.  These results are consistent with previous studies that demonstrate that 
effective induction of G1 cell cycle arrest by abemaciclib is dependent upon the presence of Rb.  
Findings from the Phase 1 Study I3Y-MC-JPBA (JPBA) indicate that the abemaciclib single-
agent maximum tolerated dose of 200 mg administered orally every 12 hours (Q12H)
demonstrates an acceptable safety profile.  Abemaciclib has demonstrated evidence of clinical 
activity in women with mBC at doses of both 150 mg and 200 mg Q12H.  Additionally, 
preliminary analysis of PK data from Study JPBA for abemaciclib as a single agent at 150 mg 
and 200 mg Q12H indicates that the range of steady-state exposures is comparable for the 2 
doses.  In Study JPBA, 47 patients with a median of 7 prior systemic regimens received therapy 
with abemaciclib.  In the mBC cohort, the most common treatment-emergent adverse events 
(TEAEs) possibly related to study drug included diarrhea, nausea, fatigue, neutropenia, and 
vomiting.  Among 36 patients with HR+ mBC receiving abemaciclib, the median progression-
free survival (PFS) was 8.8 months and there were 12 confirmed partial responses (PRs), 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 PRs were observed in these 19 patients.  Safety and 
tolerability of abemaciclib in combination with endocrine therapies (including anastrozole and 
letrozole) are being further evaluated in patients with HR+, human epidermal growth factor 
receptor 2-negative (HER2-) mBC, in the ongoing Phase 1b Study I3Y-MC-JPBH (JPBH).  
To further confirm the safety and efficacy of abemaciclib in combination with current standard 
endocrine therapies (either nonsteroidal aromatase inhibitors [NSAIs] or fulvestrant) in HR+, 
HER2- breast cancer, 2 randomized, double-blind, placebo-controlled, Phase 3 studies, Studies
I3Y-MC-JPBM and I3Y-MC-JPBL, are being conducted globally. Along with these 2 studies, 
this randomized, double-blind, placebo-controlled Phase 3 study, Study I3Y-CR-JPBQ (JPBQ),
will evaluate the safety and efficacy of abemaciclib in combination with both endocrine therapies 
in mainly east Asian patients with HR+, HER2- locoregionally recurrent or metastatic breast 
cancer and postmenopausal status.  

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More information about the known and expected benefits and risks and reasonably anticipated 
adverse events (AEs) of abemaciclib may be found in the Investigator’s Brochure (IB).  
Information on 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 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 abemaciclib may 
be found in the following:  Patient Information Leaflet, Package Insert, and Summary of Product 
Characteristics.

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6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to compare treatment with abemaciclib plus NSAI
(anastrozole or letrozole) therapy versus placebo plus NSAI therapy with respect to PFS in 
postmenopausal women with HR+, HER2- locoregionally recurrent or metastatic breast cancer.
6.2.
Secondary Objectives
The key secondary objective of this study is to compare treatment with abemaciclib plus 
fulvestrant therapy versus placebo plus fulvestrant therapy with respect to PFS for 
postmenopausal women with HR+, HER2- locoregionally recurrent or metastatic breast cancer.
Other secondary objectives of this study are to compare the combination treatment of 
abemaciclib and NSAI therapy versus placebo plus NSAI therapy, and to compare the 
combination treatment of abemaciclib and fulvestrant therapy versus placebo plus fulvestrant 
therapy with respect to the following:

OS

OS rate at 1 and 2 years

objective response rate (complete response [CR] + 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

change in symptom burden from baseline using the European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 

PK of abemaciclib, its metabolites, NSAI, and fulvestrant.
6.3.
Exploratory Objectives
The exploratory objectives of this study are:

to compare the combination treatment of abemaciclib and NSAI therapy versus placebo 
plus NSAI therapy, and to compare the combination treatment of abemaciclib and 
fulvestrant therapy versus placebo plus fulvestrant therapy with respect to change in pain 
burden using the modified Brief Pain Inventory short form (mBPI-sf).

to explore potential biomarkers related to the mechanism of action of abemaciclib, NSAI, 
fulvestrant, the cell cycle, and/or the pathogenesis of breast cancer, and to correlate 
potential biomarkers to clinical outcomes.

to explore if change in tumor size (CTS) is associated with PFS and OS.

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7.
Study Population
The study includes 2 cohorts. Patients meeting Inclusion Criterion 2a (Section 7.1) will be 
enrolled in Cohort A and patients meeting Inclusion Criterion 2b (Section 7.1) will be enrolled in 
Cohort B.
Re-screening of individuals who do not meet the criteria for participation in this study is not 
permitted.  
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.  Although not required as a 
protocol procedure, metastatic disease should be considered for biopsy 
whenever possible to reassess hormone receptor (HR) and human epidermal 
growth factor receptor 2 (HER2) status if clinically indicated.
•
To fulfill the requirement for HR+ disease, a breast cancer must express, 
by immunohistochemistry (IHC), at least 1 of the HRs (estrogen receptor 
[ER], 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).  
[2] meet either Inclusion Criterion (2a) or Inclusion Criterion (2b). Patients 
meeting Inclusion Criterion 2a will be enrolled in Cohort A and patients 
meeting Inclusion Criterion 2b will be enrolled in Cohort B.
(2a) have locoregionally recurrent disease not amenable to resection or 
radiation therapy with curative intent or metastatic disease

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•
relapsed with radiologic evidence of progression more than 1 year 
from completion of/or with no adjuvant endocrine therapy and have 
received no prior endocrine therapy for locoregionally recurrent or 
metastatic disease (Note: prior adjuvant endocrine therapy for 
localized disease may have included, but is not limited to, anti-
estrogens or aromatase inhibitors. In addition, a patient may be 
enrolled if she has received ≤2 weeks of NSAI in this disease setting 
immediately preceding screening and agrees to discontinue NSAI until 
study treatment initiation.)
OR
•
relapsed with radiologic evidence of progression less than 1 year from 
completion of or while receiving adjuvant endocrine therapy (except 
for letrozole or anastrozole) and have received no prior endocrine 
therapy for locoregionally recurrent or metastatic disease.
•
OR
•
presented de novo mBC and not received any prior endocrine therapy.
(2b) have locoregionally recurrent disease not amenable to resection or 
radiation therapy with curative intent or metastatic disease
•
relapsed with radiologic evidence of progression while receiving 
neoadjuvant or adjuvant letrozole or anastrozole, with no subsequent 
endocrine therapy received following progression
OR
•
relapsed with radiologic evidence of progression within 1 year from 
completion of adjuvant letrozole or anastrozole, with no subsequent 
endocrine therapy received following progression
OR
•
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
OR

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•
presented de novo with metastatic disease and then 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.
[3] have postmenopausal status defined as meeting 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 1 of the following, as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 (Eisenhauer et al. 2009; see Attachment 5):

Measurable disease

Nonmeasurable bone-only disease.  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. 
[5]
have a performance status (PS) of ≤1 on the Eastern Cooperative Oncology 
(ECOG) scale (see Attachment 4)
[6]
have adequate organ function, including:

hematologic:  absolute neutrophil count (ANC) 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:  Total bilirubin 1.5 times the upper limit of normal (ULN) and 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
3.0 times ULN (or ALT and AST 5 times ULN if liver metastases are 
present).  

renal:  serum creatinine 1.5 times ULN.
[7]
are female and >18 years of age
[8]
have discontinued previous localized radiotherapy for palliative purposes or 
for lytic lesions at risk of fracture at least 2 weeks prior to randomization 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

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[9]
have given written informed consent prior to any study-specific procedures
[10] are able to swallow capsules
[11] are reliable, willing to be available for the duration of the study, and willing to 
follow study procedures.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[12] 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
[13] have inflammatory breast cancer
[14] have clinical evidence or a history of central nervous system (CNS)
metastasis.  Screening test is not required for enrollment.
[15] are currently receiving or have previously received chemotherapy for 
locoregionally recurrent or metastatic breast cancer.  (Note:  Patients may be 
enrolled if they received prior [neo]adjuvant chemotherapy for localized 
disease.)
[16] have received prior treatment with everolimus or fulvestrant (for Cohort B 
only)
[17] have received prior treatment with any CDK4 and CDK6 inhibitor (or 
participated in any CDK4 and CDK6 inhibitor clinical trial for which 
treatment assignment is still blinded)
[18] have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted 
agents <7 days prior to randomization
[19] are currently enrolled in a clinical trial involving an investigational product 
(IP) or non-approved use of a drug or device (other than the IP/device used in 
this study), or concurrently enrolled 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 Eli Lilly and Company 
(Lilly) clinical research physician (CRP) is required to establish eligibility.
[20]  have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of randomization for a 
nonmyelosuppressive or myelosuppressive agent, respectively
[21] have had major surgery within 14 days prior to randomization to allow for 
post-operative healing of the surgical wound and site(s)
[22] have received recent (within 28 days prior to randomization) live attenuated 
vaccines such as yellow fever vaccine.

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[23] have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study (eg, history of major 
surgical resection involving the stomach or small bowel, or preexisting 
Crohn’s disease or ulcerative colitis)
[24] 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 
[25] have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years
[26] have received an autologous or allogeneic stem-cell transplant.
[27] have clinical evidence of active bacterial or fungal infection or active viral 
infection that, in the judgment of the investigator, would preclude 
participation in this study (eg, human immunodeficiency virus [HIV] or viral 
hepatitis).  Screening test is not required for enrollment.
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All randomized patients who discontinue, regardless of whether or not they received study 
treatment, will have procedures performed as shown in the Study Schedule (Attachment 1). 
Patients who are discontinued from the study drug early will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled 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 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.
7.3.2. Discontinuation of Study Drug(s)
Patients will be discontinued from the study drugs in the following circumstances:

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
progressive disease (PD) as defined by RECIST v1.1  

the investigator decides that the patient should be discontinued from study drugs

the patient or the patient’s designee (eg, parents or legal guardian) requests that the 
patient be withdrawn from study drugs

the patient is significantly noncompliant with study procedures and/or treatment

unacceptable toxicity

the patient has had 2 dose reductions and experiences an AE that would cause a third 
dose reduction

the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication, discontinuation 
from study drugs occurs prior to introduction of the new agent

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study
If patients discontinue NSAIs/fulvestrant but continue to receive blinded study drug, this will not 
be considered as discontinuation of study drug.
7.3.3. Discontinuation from the Study 
Patients will be discontinued from the study in the following circumstances:

the investigator decides that the patient should be discontinued from the study

the patient or the patient’s designee (eg, parents or legal guardian) requests that the 
patient be withdrawn from the study

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)
7.3.4. Patients Who Are Lost to Follow-Up
A patient will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow.
Site personnel, or an independent third party, will attempt to collect the vital status (ie, alive or 
dead) for all randomized patients who are lost to follow up, including randomized patients who 
do not receive study treatment, within legal and ethical boundaries.  Site personnel, or an 
independent third party, may search public sources for vital status information.  If the patient's 
vital status is determined, the vital status will be documented and the patient will not be 
considered lost to follow up.
Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5. 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 discontinuation of study site participation necessary for medical, 

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safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study 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 JPBQ is a multicenter, randomized, double-blind, Phase 3 trial for women with HR+, 
HER2- locoregionally recurrent or metastatic breast cancer.  
Figure JPBQ.8.1 illustrates the study design.
Abbreviations:  HER2- = human epidermal growth factor receptor 2-negative; HR+ = 
hormone receptor-positive; mBC = metastatic breast cancer; N = number of planned
patients; NSAI = nonsteroidal aromatase inhibitor; R = randomization 
a
The initiation of enrollment for patients in Cohort B was triggered later 
according to Lilly global strategy.  
Figure JPBQ.8.1.
Illustration of study design.
The study will consist of 2 patient cohorts:
▪Cohort A will include approximately 300 patients with HR+, HER2- locoregionally recurrent
or metastatic breast cancer who meet Inclusion Criterion 2a (Section 7.1).
▪Cohort B will additionally include approximately 150 patients with HR+, HER2-
locoregionally recurrent or metastatic breast cancer who meet Inclusion Criterion 2b (Section 
7.1). The initiation of enrollment for patients in Cohort B was triggered later according to Lilly 
global strategy.
Patients in each cohort will be randomized 2:1 between the experimental and control arms:

Arm A1: Abemaciclib 150 mg orally Q12H on Days 1 to 28 plus either anastrozole 1 mg 
or letrozole 2.5 mg orally Q24H of a 28-day cycle

Arm A2: Placebo orally Q12H on Days 1 to 28 plus either anastrozole 1 mg or letrozole 
2.5 mg orally Q24H of a 28-day cycle

Arm B1:  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

Arm B2:  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

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Patients in Cohort A will be randomized using the following stratification factors:  nature of 
disease (visceral metastases vs. non-visceral metastases) and prior (neo)adjuvant endocrine 
therapy (prior therapy with disease-free interval > 12 months from completion of treatment vs. 
prior therapy with disease-free interval ≤12 months from completion of treatment vs. no prior 
endocrine therapy).  The presence of visceral metastases refers to lung, liver, pleural, peritoneal, 
or adrenal gland involvement at the time of randomization.  
Patients in Cohort B will be randomized using the following stratification factors:  nature of 
disease (visceral metastases vs. non-visceral metastases) and sensitivity to endocrine therapy 
(primary resistance vs. secondary resistance). The presence of visceral metastases refers to lung, 
liver, pleural, or peritoneal, or adrenal gland 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 locoregionally recurrent 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.
The primary analysis of the PFS endpoint will occur after approximately 170 PFS events have 
been observed in Cohort A. An interim analysis will be conducted after approximately 119 PFS 
events are observed to provide early efficacy information and allow for potential early 
communication with regulatory agencies. (see Section 12.2.6 for details).
The interim analysis of Cohort B will follow the timeline of Cohort A, which will occur only if 
the interim of Cohort A turns out to be positive. If patients in Cohort A continue being followed
for PFS until final analysis, the final analysis of Cohort B will be conducted at the same time of 
Cohort A final analysis. If Cohort A stops early at interim due to efficacy, the final analysis of 
Cohort B may be conducted after approximately 105 PFS events have been observed in Cohort 
B. (see Section 12.2.14 for details).
For each cohort, all patients will be followed for progression and survival information until death 
or study completion, whichever occurs first.
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 dose (or at discontinuation, if no treatment is given).  This may be up to 
28 days prior to the first study treatment dose.

Study Period:  begins at the first study treatment and ends at study completion.  The 
study period does not include the continued access 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 
drug.  The date of this agreement is to be reported on the electronic case report 
form (eCRF) as the Date of Discontinuation from study drug.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study drug.

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Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue study drug and lasts 
approximately 30 days (7 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, whichever 
comes first.

Continued Access Period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on study treatment who continue to 
experience clinical benefit may continue to receive study treatment until one of the 
criteria for discontinuation is met.  
o
The continued access period includes continued access period short-term follow-
up.
o
Continued access short-term follow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue treatment in the 
continued access period and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
This study will be considered complete following the last required PFS event from Cohort A
(Figure JPBQ.8.2), as determined by Lilly. In case Cohort A stops early at interim due to 
efficacy and Cohort B continues thereafter, Cohort B will be considered complete following the 
final analysis of PFS in Cohort B. Investigators will continue to follow the study schedule for all 
patients until notified by Lilly that study completion has occurred.  
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.

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Figure JPBQ.8.2.
Study period and continued access diagram.
8.1.2. Continued Access Period
After study completion, all patients who are on study treatment and who are eligible for 
continued access will be unblinded. Patients receiving study treatment and experiencing ongoing 
clinical benefit and no undue risks may continue to receive study treatment in the continued 
access period until one of the criteria for discontinuation is met (see Section 7.3).  Lilly will 
notify investigators when the continued access period begins.  
Long-term follow-up does not apply in the continued access period.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.  
During the continued access period, all AEs, SAEs, and study drug exposure will be reported on 
the case report form (CRF).  Serious adverse events will also be reported to Lilly Global Patient 
Safety (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 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 investigational 
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.
The 4-arm design of this study will allow 2 investigations in 1 specific population (ie, HR+, 
HER2- locoregionally recurrent or metastatic breast cancer). Patients in different cohorts will
receive 2 standard endocrine therapies with or without abemaciclib, based on prior treatments 
and associated outcome, respectively. Furthermore, this design allows descriptive comparison of
safety between different combinations or potential pooled analysis within the same setting by 
eliminating cross-trial confounders and following a consistent data collection plan.

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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Arm A1:  Abemaciclib 150 mg orally Q12H plus either anastrozole 1 mg or letrozole 
2.5 mg orally Q24H on Days 1 to 28 of a 28-day cycle.

Arm A2:  Placebo orally Q12H plus either anastrozole 1 mg or letrozole 2.5 mg orally 
Q24H on Days 1 to 28 of a 28-day cycle.

Arm B1:  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

Arm B2:  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 NSAI/fulvestrant.
The specific NSAI (anastrozole or letrozole) administered to patients in Cohort A is determined 
by the investigator.  Patients should remain on the same NSAI throughout the study.  In 
exceptional cases, in the absence of evidence of PD, the investigator may discuss a change in 
NSAI with the Lilly CRP.  Nonsteroidal aromatase inhibitor is a co-administered standard-of-
care treatment.  The investigator should refer to the NSAI label (ie, Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics).  
Fulvestrant 500 mg should be administered intramuscularly into the buttocks of patients in 
Cohort B 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.  Fulvestrant is a co-administered standard-of-care treatment.  
The investigator should refer to the fulvestrant label (ie, Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics).  
Table JPBQ.9.1 shows the treatment regimens.

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Table JPBQ.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose Day 
Arm A1
Abemaciclib
Treatment/28-day cycle
150 mg PO Q12H on Days 1-28
Anastrozole
or
Letrozole
Treatment/28-day cycle
1 mg PO Q24H on Days 1-28a
or
2.5 mg PO Q24H on Days 1-28a
Arm A2b
Placebo
Treatment/28-day cycle
PO Q12H on Days 1-28
Anastrozole
or
Letrozole
Treatment/28-day cycle
1 mg PO Q24H on Days 1-28a
or
2.5 mg PO Q24H on Days 1-28a
Arm B1
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 beyondc
Arm B2 d
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 beyondc
Abbreviations:  IM = intramuscular; NSAI = nonsteroidal aromatase inhibitor; Q12H = once every 12 hours; Q24H 
= once every 24 hours; PK = pharmacokinetic; PO = orally.
a
For PK purposes, NSAI should be administered at the same time (or up to 20 minutes after) the first dose of 
blinded study drug through Cycle 4, Day 1.  Subsequently, the interval between administration of blinded study 
drug and NSAI may be adjusted based on the judgment of the investigator.
b   For patients in Arm A2 who crossover to Arm A1, the Arm A1 treatment schedule should be followed.
c   For PK purposes, fulvestrant should be administered at the same time as (or up to 20 minutes after) the first dose 
of blinded study drug, except when specified otherwise in the PK Sampling Schedule (Attachment 7) through 
Cycle 4 Day 1. Subsequently, the interval between administration of blinded study drug and fulvestrant may be 
adjusted based on the judgment of the investigator.
d   For patients in Arm B2 who crossover to Arm B1, the Arm B1 treatment schedule should be followed.
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 of study drugs dispensing and collection, and

returning all unused medication to Lilly or its designee at the end of the study.
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.

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Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug or drug delivery system 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 according to the product label, and not opened, 
crushed, or dissolved.  Blinded study drug will be labeled according to the country’s regulatory 
requirements.
Where required, letrozole, anastrozole, and fulvestrant will be supplied by Lilly and labeled 
according to country regulatory requirements.  All drugs should be stored according to the 
product label and will be provided as anastrozole 1-mg and letrozole 2.5-mg tablets or 
fulvestrant 250-mg prefilled syringes (250 mg/5 mL). 
Investigators should instruct patients to store the blinded study drug and NSAI in the original 
package provided and in a location inaccessible to children. 
Fulvestrant should be stored according to the instructions on the product label and administered 
according to the instructions in the protocol.
9.3.
Method of Assignment to Treatment
Upon obtaining informed consent, site personnel should access the interactive web response 
system (IWRS).  Patients who meet all criteria for enrollment will be randomly assigned to 
receive either abemaciclib plus NSAI/fulvestrant or placebo plus NSAI/fulvestrant.  Assignment 
to treatment groups will be determined by a computer-generated random sequence using the 
IWRS. Sites will be prompted to enter the specific NSAI at time of randomization for patients in 
Cohort A.
Randomization will be stratified by the following in Cohort A:  nature of disease (visceral 
metastases vs. non-visceral metastases), and prior (neo)adjuvant endocrine therapy (prior therapy 
with disease-free interval > 12 months from completion of treatment vs. prior therapy with 
disease-free interval ≤12 months from completion of treatment vs. no prior therapy).
Randomization will be stratified by the following in Cohort B:  nature of disease (visceral 
metastases vs. non-visceral metastases) and sensitivity to endocrine therapy (primary resistance 
vs. secondary resistance).
The IWRS will be used to assign abemaciclib or placebo and distribute NSAI/fulvestrant
supplied by Lilly (except distribution of NSAI in China).  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 and the first dose (Cycle 1, Day 1) 
should not exceed 7 days. 

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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.  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.
Anastrozole or letrozole will be administered orally every 24 hours (±2) on Days 1 through 28 of 
a 28-day cycle for a total of 28 doses per cycle.  For PK purposes, anastrozole or letrozole should 
be administered at the same time as (or up to 20 minutes after) the first dose of blinded study 
drug through Cycle 4, Day 1.  Subsequently, the interval between administration of blinded study 
drug and anastrozole or letrozole may be adjusted based on the judgment of the investigator.  If a 
patient misses or vomits an anastrozole or letrozole dose, that dose should be omitted.  
Fulvestrant will be administered intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of 
Cycle 2 and beyond. For PK purposes, fulvestrant should be administered at the same time as 
(or up to 20 minutes after) the first dose of blinded study drug, except when specified otherwise 
in the PK Sampling Schedule (Attachment 7) through Cycle 4, Day 1. Subsequently, the interval 
between administration of 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 at 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 an 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).  
A patient may continue to receive study treatment until she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3).
9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
Toxicity dose adjustments and delays of blinded study drug for this study are summarized in
Table JPBQ.9.2.

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Table JPBQ.9.2.
Toxicity Dose Adjustments and Delays of Blinded Study Drug for
Study JPBQ
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 at investigator’s
discretion.
Hematologic Toxicity
Section 9.4.1.1.3
Recurrent Grade 3 within 8 
weeks
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: If 
patient requires
administration of blood
cell growth factors 
Sections 9.4.1.1.3 and 
9.6.4
Regardless of severity
(Use growth factors 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 
Toxicityb
(except diarrhea and ALT 
increased) 
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 MUST be suspended until
toxicity resolves to either
baseline or Grade 1.
Dose MUST be reduced by 
1 dose level.
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
Grade 2 that does not resolve
within 24 hours to at least 
Grade 1
Dose MUST be suspended until
toxicity resolves to at least
Grade 1.
Dose reduction is NOT 
required.
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, 
or any Grade of diarrhea that 
requires hospitalization
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
Grade 3 or 4
Dose MUST be suspended until
toxicity resolves to at least
Grade 1.
Dose MUST be reduced by 
1 dose level.
ALT Increased 
(Sections 9.4.1.1.4.2. and 
10.3.3.1)
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN), or
Grade 3 (>5,0-20.0×ULN)c
Dose MUST be suspended until 
toxicity resolves to baseline or 
Grade 1.
Dose MUST be reduced by 
1 dose level.

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ALT Increased 
(Sections 9.4.1.1.4.2 and 
10.3.3.1)
Grade 4 (>20.0×ULN)
Blinded study drug MUST be 
discontinued.
Blinded study drug MUST
be discontinued.
ALT Increased with 
increased total bilirubin, 
in the absence of 
cholestasis
(Sections 9.4.1.1.4.2)
Grade 3 increased ALT (˃5.0 
× ULN) with total bilirubin >2 
× ULN
Blinded study drug MUST be 
discontinued
Blinded study drug MUST
be discontinued
Abbreviation: ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note: MUST = mandatory.
a
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:
•
shows stable hematological counts (Grade ≤2) during that timeframe
•
has absence of any signs or risk of infection 
•
is benefiting from study treatment
b Additional guidance for renal and hepatic monitoring is in Sections 10.3.3.1 and 10.3.3.2
c
Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section
10.3.1.1 for additional guidance for hepatic monitoring
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 JPBQ.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 JPBQ.9.3.
Dose Adjustments for Abemaciclib
Dose Adjustment
Oral Dose
Frequency
0
150 mg
Q12H
1
100 mg
Q12H
2
50 mg
Q12H
Abbreviation: Q12H = every 12 hours.
Blinded study drug must be discontinued if further dose reduction is required beyond 50 mg 
Q12H. If a patient who, in the judgment of the investigator, is receiving clinical benefit from 
study therapy requires further dose reduction than is outlined in Table JPBQ.9.3, then the 
investigator must discuss with the Lilly CRP prior to any further dose reduction.
In the event that blinded study drug must be discontinued, a patient may continue to receive 
anastrozole, letrozole, or fulvestrant.

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9.4.1.1.1.2.
NSAI/Fulvestrant
Per NSAI labels, dose adjustment for anastrozole or letrozole is not applicable, as only a single-
dose strength is approved for each medication.  In exceptional cases, or in the absence of 
evidence of PD, the investigator may discuss a change in the specific NSAI administration (eg, 
switching from anastrozole to letrozole) with the Lilly CRP.  In the event that anastrozole or 
letrozole must be discontinued, a patient may continue to receive blinded study drug per the 
investigator’s clinical judgment.  
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 Delay
Both dose suspension (within a cycle) and cycle delay are permitted.  When a dose suspension or 
cycle delay occurs related to toxicity (defined as an AE possibly related to study treatment per 
investigator judgment), the blinded study drug and/or NSAI/fulvestrant may be suspended or 
delayed as determined by the investigator’s judgment. 
Study treatment may be held up to 14 days within a cycle or at start of next cycle to permit 
sufficient time for recovery from the toxicity.  If a dose suspension occurs within a cycle, the 
investigator may resume blinded study drug dosing at the same dose level for the remainder of 
the cycle or at reduced dose (assuming resolution to at least Grade 1 for non-hematological 
toxicity and at least Grade 2 for hematological toxicity).  If the patient experiences the same 
toxicity with the same or greater severity (Common Terminology Criteria for Adverse Events 
[CTCAE] grade) requiring a dose suspension within a cycle or at start of the next cycle, the 
patient must be dose reduced and not re-challenged a second time at the prior dose level.
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 NSAI/fulvestrant is administered but blinded study drug is suspended, the date of 
NSAI/fulvestrant administration shall constitute Day 1 of the next cycle.  
Patients not recovering from toxicity within 14 days should be considered for discontinuation of 
the blinded study drug and/or co-administered NSAI/fulvestrant.  In exceptional circumstances, a 
delay >14 days is permitted upon agreement between the investigator and the Lilly CRP and 
blinded study drug dose adjustment is to be considered.
In the event of a cycle delay due to logistical reasons (eg, due to patient availability), the patient 
should continue on study treatment if the patient has adequate drug supply.  If a patient’s 
treatment is interrupted as a result of not having sufficient drug supply, the cycle may be delayed 

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up to 7 days (and not be considered a protocol violation). In exceptional circumstances, a delay 
>7 days is permitted upon agreement between the investigator and the Lilly CRP. 
The start of a cycle may be delayed, or a current cycle interrupted, to allow a patient with 
locoregionally recurrent 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 study treatment 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 JPBQ.9.3.
If a patient experiences Grade 3 hematologic toxicity, then study treatment must be suspended 
(until the toxicity resolves to at least Grade 2) and the dose of blinded study drug may be reduced 
by 1 dose level as outlined in Table JPBQ.9.3 at the discretion of the investigator.
If the patient experiences a recurrent episode of Grade 3 hematologic toxicitywithin 8 weeks, 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 as outline in Table JPBQ.9.3.
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
The patient showed stable hematological counts (Grade ≤2) during that timeframe
•
In the absence of any signs or risk of infection 
•
The patient is benefiting from study treatment
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 reduced by 1 dose level as outlined in Table
JPBQ.9.3, 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 at least Grade 1) and the dose of blinded study drug
must be reduced as outlined in Table JPBQ.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
see Section 9.4.1.1.4.1 or ALT increased, refer to Section 9.4.1.1.4.2 ) possibly related to blinded 

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study drug that does not resolve with maximal supportive measures within 7 days to either 
baseline or Grade 1, 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 JPBQ.9.3.
Before re-initiation of blinded study drug, nonhematologic toxicity (except alopecia and fatigue) 
must resolve to either baseline or at least 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 1 dose level as outlined in Table JPBQ.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 must be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
blinded study drug must be reduced by 1 dose level as outlined in Table JPBQ.9.3.
9.4.1.1.4.2.
Hepatic Toxicity
Does modifications and management for increased ALT are provided in Table JPBQ.9.2. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, blinded study drug 
must be suspended until the toxicity has resolved to at least Grade 1 and the dose must be 
reduced by 1 dose level. Discontinue blinded study drug for Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, 
the patient must be discontinued from blinded study drug. Refer to Section 10.3.3.1 for 
additional hepatic monitoring guidance.
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 Statistical Analysis Plan (SAP), and/or a separate unblinding plan 
document.
Efficacy information will not be shared between sites until the study is completed.  Upon overall 
study completion (see Section 8.1.1), investigators may unblind patients to study treatment 
assignment.

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9.5.1. Unblinding at Interim Analyses
One interim analysis for efficacy and safety will be conducted on Cohort A, using unblinded data
of the cohort, 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 analyses 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 12.2.14 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 v1.1 (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 be discontinued from study treatment 
and will undergo postdiscontinuation follow-up (see Attachment 1).  
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 treatment 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 

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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 hormonal 
anticancer therapies, chemotherapy, immunotherapy and herbal medicine) 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 (Study I3Y-MC-JPBD) and in vitro human recombinant 
cytochrome P450 (CYP) phenotyping studies indicate that abemaciclib is extensively 
metabolized primarily via CYP3A.  Based on these findings, grapefruit juice as well as inducers 
(eg, phenytoin or carbamazepine) and strong inhibitors of CYP3A should be substituted or 
avoided if possible (see Attachment 8).  
In addition, in vitro studies in cultured human hepatocytes indicate that abemaciclib and its 
major metabolites LSN2839567 (M2) and LSN3106726 (M20) down regulate messenger 
ribonucleic acid (mRNA) of 1 or more CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, and CYP3A, at clinically relevant concentrations.  The mechanism of down regulation 
and its clinical relevance are presently not understood.  Therefore, caution should be exercised 
when coadministering substrate drugs of the above CYPs with narrow therapeutic margin (see 
Attachment 8).
9.6.1. Surgery and/or Radiotherapy for Locoregionally Recurrent
Breast Cancer
A patient with locoregionally recurrent 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 
ends, study treatment may resume.  Importantly, a patient who receives surgery radiotherapy 
for locoregionally recurrent 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 locoregionally recurrent 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 

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regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported on the eCRFs.
9.6.4. Growth Factor
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. In the event of a patient experiences Grade 3 hematologic toxicity and requires 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 (eg 
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up.

Patients should also be encouraged to drink fluids (eg, 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 Grade 1.

When blinded study drug recommences dosing should be adjusted as outlined in Section 
9.4.1.1.1.1 and Table JPBQ.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 should be appropriately treated with 
bisphosphonates or RANK-L targeted agents, 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 

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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.
9.7.
Treatment Compliance
Treatment compliance information for study treatment will be collected through patient dosing 
diaries and/or capsule/tablet counts at each visit, with the number of capsules/tablets taken 
relative to the number expected to be taken summarized for each cycle.  The patient must take 
≥75% of the planned doses for study treatment in a cycle to be deemed compliant.  As outlined 
in Section 9.4.1.1.2, dose suspensions or delays may occur and will not result in a patient being 
considered as noncompliant.  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 
treatment in a cycle.
Importantly, a patient who receives surgery radiotherapy for locoregionally recurrent 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.
9.7.1. Patient Diaries
The study will include patient diaries to provide dosing instructions, help patients with treatment 
planning, and track actual doses of study treatment taken by the patient.  Information from the 
diaries may be used for documenting study treatment compliance, as well as for dosing time 
relative to PK blood draws and electrocardiogram (ECG) collection.  

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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, and 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.  The method of assessment used at baseline must be used consistently for serial tumor 
assessment throughout the study.  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 all patients, imaging studies (CT, including spiral CT, or MRI scan of the chest, abdomen, 
and pelvis) will be performed locally at baseline and repeated between last 7 days of every 
second cycle beginning with Cycle 2 and continuing through Cycle 18, in the last 7 days of every 
third cycle after Cycle 18 (inclusive), and within 14 days of clinical progression per the Study 
Schedule (Attachment 1).  It is recommended that CT imaging of the abdomen and pelvis be 
performed with IV contrast, whenever possible.  For patients with known hypersensitivity to CT 
contrast material, a CT scan of the chest without contrast and gadolinium-enhanced MRI of the 
abdomen and pelvis are encouraged.  The CT portion of a 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 IV and oral contrast). A PET scan alone 
or as part of a PET-CT may be performed as part of routine clinical care but cannot be used to 
assess response according to RECIST v1.1.
For only those patients with bone lesions identified by bone scintigraphy at baseline, directed 
imaging using 1 of the following methods will be performed at baseline:  X-ray, CT scan with 
bone windows, or MRI.  Directed imaging using the same method as at the baseline bone lesion 
assessment should be repeated between last 7 days of every second cycle beginning with Cycle 2 
and continuing through Cycle 18, in the last 7 days of every third cycle after Cycle 18
(inclusive), and within 14 days of clinical progression.  
For patients with locoregionally recurrent breast cancer not amenable to curative treatment, MRI 
scan of the breast will be performed at baseline, if applicable.  Breast MRI, if applicable, will be 
repeated between last 7 days of every second cycle beginning with Cycle 2 and continuing 

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through Cycle 18, in the last 7 days of every third cycle after Cycle 18 (inclusive), and within 14 
days of clinical progression.  
For patients with visible tumor (such as skin lesions), photography will be performed at baseline 
and each photographic image of the tumor should include a ruler.  Photography should be 
repeated on Day 1 of every second cycle beginning with Cycle 3 and continuing through Cycle 
19 (inclusive), on Day 1 of every third cycle after Cycle 19, and within 14 days of clinical 
progression.  Photographic images may be taken more frequently based upon the discretion of 
the investigator or following the identification of new skin lesions post-baseline.
For patients continuing treatment during the continued access period (after study completion), 
efficacy assessments (frequency and type of assessments) will be at the discretion of the 
investigator.
The assessments should be performed prior to dosing at the beginning of the required cycle 
unless otherwise indicated.
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 18 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 primary analysis of PFS.  In addition, anticancer 
therapies initiated after study treatment discontinuation will be collected during this follow-up 
period.  After the patient has objective disease progression, radiologic imaging and photographic 
images are no longer required and the patient will be followed up approximately every 12 weeks 
(14 days) until the patient’s death or overall study completion.
After study completion, efficacy assessments (frequency and type of assessments) will be at the 
discretion of the investigator.
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 PFS in Cohort A as defined by RECIST v1.1 (Eisenhauer et al. 
2009), provided in Attachment 5.  
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.  

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For those patients with nonmeasurable, bone-only disease (refer to Inclusion Criterion [4]), 
objective progression will be established if at least 1 of the following criteria is met:

the appearance of 1 or more new lesions (in bone or outside of bone), or

unequivocal progression of existing bone lesions.
According to RECIST v1.1, the finding of a new lesion should be unequivocal and not 
attributable to findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or flare of preexisting lesions).  Pathologic fracture, new 
compression fracture, or complications of bone metastases will not be considered as evidence of 
disease progression, unless at least 1 of the above criteria is met.
For those patients with locoregionally recurrent 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:

local and/or regional recurrence, or

new development of metastatic disease.
For those patients with locoregionally recurrent disease for whom surgery is performed while on
study 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 12.2.6 for detailed 
censoring rules.
10.1.4. Secondary Efficacy Measures
The key secondary efficacy measure is PFS for Cohort B as defined by RECIST v1.1 
(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 may be performed by an 
independent panel of radiologists in the future to retrospectively validate investigator bias if 
there are any concerns.
The measurements to determine the secondary efficacy endpoints shown in Table JPBQ.10.1 will 
also be collected at the times shown in the Study Schedule (Attachment 1) for both cohorts.

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Table JPBQ.10.1.
Other 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 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; PS = performance status; 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 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.  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.
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 Measures
The exploratory measures of this study are listed in Table JPBQ.10.2.
Table JPBQ.10.2.
Exploratory Measures
Pain intensity 
Measure of cancer pain intensity
Biomarkers
Potential biomarkers related to the mechanism of action of abemaciclib, NSAI, 
fulvestrant, the cell cycle, and/or the pathogenesis of breast cancer
CTS 
Change from baseline in the size of target lesions
Abbreviations:  CTS = change in tumor size; NSAI = nonsteroidal aromatase inhibitor.

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Pain intensity:  Cancer pain intensity will be measured using the mBPI-sf assessment (see 
Section 10.2.1.1 for details). 
Biomarkers:  Exploratory analysis using blood will be done to explore potential biomarkers 
related to the mechanism of action of abemaciclib, NSAI, fulvestrant, the cell cycle, and/or the 
pathogenesis of breast cancer to better understand relationships of cellular signaling defects with 
clinical outcomes.
Change in Tumor Size (CTS):  Change in tumor size will be measured using target lesion 
measurements selected for radiological evaluation.  This measurement will only be available on 
patients with measureable disease.
10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
The primary health outcomes research goal is to assess if abemaciclib combination therapy is 
able to impact the symptom burden and quality of life, as measured by the EORTC QLQ-C30 
(Aaronson et al. 1993), and pain, as measured by the mBPI-sf.  
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 
and the EORTC QLQ-C30 questionnaires should be administered to the patient prior to 
extensive interaction with site staff and study drug administration.
10.2.1.1. 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 
text in the European Medicines Evaluation Agency 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-C30 questionnaire is administered per the Study Schedule (Attachment 1).  
The recall period is the past week, completion time is typically 5 to 7 minutes, and the 
questionnaire will be scored as described by the European Organization for Research and 
Treatment of Cancer (EORTC) scoring manual (Fayers et al. 2001).  The EORTC population 
will include all patients who completed at least 1 baseline assessment followed by at least 1 
EORTC assessment after 1 dose of study drug.

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10.2.1.2. 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 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; 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 categories, using an analgesic 
ladder approach with medication category based on a World Health Organization scale.  A 
therapy category will be assigned according to the maximum category of therapy administered 
based on analgesic data for that cycle.  
The mBPI-sf population will include all patients who completed at least 1 baseline followed by 
at least 1 mBPI-sf “worst pain” assessment after 1 cycle of study drug (Cycle 2, Day 1 or later).
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.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  Table 
JPBQ.10.3 presents a summary of AE and SAE reporting guidelines and also shows which 
database or system is used to store AE and SAE data.

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Table JPBQ.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
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access 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 that the investigator 
becomes aware of
x
Abbreviations:  AE = adverse event; SAE = serious adverse event.
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 in humans, whether or not it is considered related to that drug.  
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 ECGs, labs, vital sign measurements, and other 
procedures that result in a diagnosis should be reported to Lilly or its designee.
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.
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.
The investigator will record all AE/SAE information in the CRF. Investigators will be instructed 
to report to Lilly or its designee their assessment of the potential relatedness of each AE to 
protocol procedure and/or 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 

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assess the relationship of the AE to study drug or study 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 National Cancer Institute (NCI) CTCAE (Version 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 (SOC) 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) dictionary.
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
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  An SAE is any AE from this study that results in 1 of the following outcomes:

death

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

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.

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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 SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If study site personnel contact Lilly or 
its designee by telephone regarding an SAE, study site personnel must also immediately provide 
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 (eg, for the 
administration of study treatment 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.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, 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 or study drug, 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.
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.

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10.3.2. Other Safety Measures
10.3.2.1. Electrocardiograms 
For each patient, 12-lead digital ECGs will be collected according to the Study Schedule 
(Attachment 1) as single ECGs.  Patients must be resting for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.
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, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT interval/corrected QT interval 
(QTc) from baseline, or other clinically significant quantitative or qualitative change from 
baseline, is present, the investigator will assess the patient for symptoms (eg, palpitations, near 
syncope, 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 appropriate, consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical scientist, and review:

trends in safety data

laboratory analytes 

AEs 
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; see Section 12.2.14) can conduct additional analyses of the safety data.
Hematological and chemistry tests should be performed prior to dosing at the beginning of the 
required cycle unless otherwise indicated
10.3.3.1. Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT ≥5×ULN and elevated total bilirubin (TBL)≥2×
ULN, or ALT >8× ULN for patients with underlying baseline hepatic metastases, liver tests 
(Attachment 4), including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), 
and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 

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worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests (Attachment 3) and in consultation with the Lilly CRP.  Monitoring of 
ALT, AST, and TBL should continue until levels normalize or return to approximate baseline 
levels.  Additional diagnostic testing should be considered to rule out cause of increased liver 
enzymes per the investigator’s discretion.
Hepatic monitoring tests (Attachment 3) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:
•
ALT ≥5×ULN and TBL ≥2×ULN
•
ALT>8× ULN for patients with underlying hepatic metastasis
•
discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
10.3.3.2. Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation. If deterioration 
of renal function is suspected, serum creatinine should not be the only measure used to assess a 
patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPBQ 
9.2).
10.3.3.3. Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (eg. deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice.
10.3.4. Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and facilitate process and product improvements.
Complaints related to unblinded concomitant drugs are reported directly to the manufacturers of 
those drugs/devices in accordance with the Package Insert.

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For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or its designee will be reported.
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 
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. In addition to protocol-specified tests, investigators should 
consider monitoring of cholesterol and bone mineral density if needed, per the recommendations 
for anastrozole and letrozole in the Package Insert and Summary of Product Characteristics. 
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 Biomarkers 
Where local regulations and ERBs allow, samples for biomarker research to be collected from all 
patients in this study are the following:

whole blood (Section 10.4.2.1)

plasma (Section 10.4.2.2)
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.

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These samples are described in the following sections.
10.4.2.1. Whole Blood Sample for Pharmacogenetic Evaluations
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 may be genotyped and analysis may be performed to evaluate a genetic association with 
response to abemaciclib, NSAI, and fulvestrant.  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 or 
as local regulations and ERBs allow 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.
10.4.2.2. Plasma Samples for Exploratory Biomarker Evaluations
Ethylenediamine tetraacetic acid(EDTA)-anticoagulated plasma samples will be collected and 
analysis may be performed on biomarkers that may play a role in the abemaciclib mechanism of 
action, the cell cycle, and/or breast cancer pathogenesis (refer to Attachment 1). Markers related 
to the NSAI and fulvestrant may also be assessed. 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 or as 
local regulations and ERBs allow.  
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics 
At the visits and times specified in the PK Sampling Schedule (Attachment 7), venous blood 
samples will be collected from at least 150 of the patients randomized in Cohort A and all 
patients randomized in Cohort B.  These samples will be used to determine the plasma 
concentrations of abemaciclib and abemaciclib metabolites, as well as plasma concentrations of 
anastrozole, letrozole, or 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 

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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.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib plus its major metabolites LSN2839567 and LSN3106726 will be 
assayed using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) 
method.  Plasma concentrations of anastrozole or letrozole or 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 CRFs, 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 CRF 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.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (eg, a rating scale), a daily dosing schedule, or an event diary.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Clinical Laboratory 
Results Modernization 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 NSAI versus placebo plus 
NSAI in terms of PFS in postmenopausal women with HR+, HER2- locoregionally recurrent or 
metastatic breast cancer.  
The key secondary objective of this study is to compare abemaciclib plus fulvestrant versus 
placebo plus fulvestrant with respect to PFS for postmenopausal women with HR+, HER2-
locoregionally recurrent or metastatic breast cancer.
The study plan is to enroll approximately 450 patients in total, with 300 HR+, HER2-
locoregionally recurrent or metastatic breast cancer patients who have not received prior 
endocrine therapy in Cohort A and 150 HR+, HER2- locoregionally recurrent or metastatic 
breast cancer patients in Cohort B. Assuming approximately 10% screening failure, the study 
will enter approximately 500 patients.
The approximate 300 patients qualified for Cohort A will be randomized in a 2:1 ratio to Arm 
A1 (abemaciclib plus NSAI; 200 patients) and Arm A2 (placebo plus NSAI; 100 patients). 
Patients will be randomized using the following stratification factors:  nature of disease (visceral 
metastases vs. non-visceral metastases) and prior (neo)adjuvant endocrine therapy (prior therapy 
with disease-free interval > 12 months from completion of treatment vs. prior therapy with 
disease-free interval ≤12 months from completion of treatment vs. no prior therapy).
A 2-look group-sequential design of the primary endpoint will be used to accommodate an event-
driven plan for the interim and primary PFS analyses (see Section 12.2.6 for details). The 
primary PFS analysis will be performed after approximately 170 PFS events in Cohort A have 
occurred (ie, approximately 43% censoring rate).  Assuming a hazard ratio of 0.626, this sample 
size yields about 81.40% statistical power to detect superiority of the abemaciclib plus NSAI arm 
over the placebo plus NSAI 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 NSAI arm is 14.4 months, then the hazard 
ratio of 0.626 amounts to an approximately 8.6-month (59.7%) improvement in median PFS for 
the abemaciclib plus NSAI arm under an additional assumption of exponential survival 
distribution. 
Approximately 150 patients will be randomized in a 2:1 ratio to Arm B1 (abemaciclib plus 
fulvestrant; 100 patients) and Arm B2 (placebo plus fulvestrant; 50 patients).  Patients will be 
randomized using the following stratification factors:  nature of disease (visceral metastases vs.
non-visceral metastases) and sensitivity to endocrine therapy (primary resistance vs. secondary 
resistance).
The design of Cohort B is to ensure 100 patients’ exposure of abemaciclib plus fulvestrant and to 
show 50% of the global study JPBL trial effect size with roughly 80% probability (ie, 80% of 
chance to observe a hazard ratio less than 0.824, assuming a true hazard ratio of 0.703 by study 
assumption).

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Here, the effect size of the drug is defined as:
MSTTest and MSTControl are median survival time in test drug group and control drug group,
respectively; effect size can be regarded as the percent change of median survival time.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is 
defined as all patients randomized to study treatment.  Patients will be grouped according to 
randomized treatment.
Safety analyses will be based on the randomized and treated population (ie, Safety Population), 
defined as all randomized patients receiving at least 1 dose of blinded study drug or
NSAI/fulvestrant.  Patients will be grouped according to treatment received in Cycle 1.
Pharmacodynamic and/or 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 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 sponsor 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 (CSR).
The assumptions for each statistical method may 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.
12.2.2. 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 
well as the number and percentage of patients completing the study or discontinuing (overall and 
by reason for discontinuation).

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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.
12.2.3.Patient Characteristics
Patient characteristics will include a descriptive summary, by treatment arm, of the following:
patient demographics
baseline disease characteristics
preexisting conditions
historical illnesses
prior (neo)adjuvant endocrine therapy
prior (neo)adjuvant chemotherapy (including both cytotoxic and targeted agents)
prior endocrine therapy
prior chemotherapy (including both cytotoxic and targeted agents)
Other patient characteristics will be summarized as deemed appropriate.
12.2.4.Concomitant Therapy
Concomitant medication will be summarized by treatment arm in a frequency table listing the 
terms recorded on the eCRF.
12.2.4.1.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.
12.2.5.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 abemaciclibwill be collected through capsulescounts 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 takenx100
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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12.2.6. Primary Outcome and Methodology
The primary endpoint of this study is PFS in Cohort A.  Progression-free survival time is 
measured from randomization until the date of 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 (ie, post-baseline) radiographic assessment is available.  The detailed censoring rules 
are described in Table JPBQ.12.1.
Table JPBQ.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 plus NSAI to placebo plus NSAI in 
improving PFS time will use the stratified log-rank test stratified by nature of disease (visceral 
metastases vs. non-visceral metastases) and prior (neo)adjuvant endocrine therapy (prior therapy
with disease-free interval > 12 months from completion of treatment vs. prior therapy with 
disease-free interval ≤12 months from completion of treatment vs. no prior therapy).  The 
Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curves, as well 

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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.  
A group-sequential design of the primary endpoint will be used to accommodate an event-driven 
plan for the interim and primary analysis. One interim analysis will be conducted by the DMC 
after approximately 119 (corresponding to 70% information rate) PFS events have been 
observed. The purpose of the interim analysis is to provide early efficacy information and allow 
for potential early communication with regulatory agencies. The O’Brien Fleming alpha 
spending function (Lan and DeMets 1983) will be used to preserve the overall type I error.
Therefore, if the interim analysis is performed after exactly 119 events have been observed, a 1-
sided p-value of less than 0.0082 (corresponding approximately to an observed hazard ratio 
<0.627 under an exponential model) will need to be observed to declare statistical significance 
(see Table JPBQ.12.2).
Table JPBQ.12.2.
Properties of Design for Progression-Free Survival
Information 
Fraction
Cumulative 
Events
Cumulative 
Alpha Spent
Cumulative Beta 
Spent
Boundary Reject H0
(1-sided p-value)
0.70
119
0.0082
0
<0.0082
1
170
0.0250
0.2
<0.0223
The actual alpha spent will be calculated based on the actual number of events observed at the 
time of analysis using software that implements the alpha-spending function noted above (eg, 
ADDPLAN 6.0 or SAS 9.2). 
If the interim analysis crosses the boundary of significance at the pre-specified level, the study is 
considered positive. If statistical significance is not declared at the interim, the final PFS 
analysis will be conducted with approximately 170 PFS events. All remaining alpha will be 
spent at the final analysis on Cohort A. Once statistical significance is declared at either interim 
analysis or the final analysis, the study is considered positive.
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the hazard ratio and corresponding 95% CI with Wald’s test p-value after stratifying for 
the same randomization variables specified for the primary analysis.  
12.2.7. Secondary Outcomes and Methodology
The secondary objectives of the study are listed in Section 6.2.
12.2.7.1. Progression-Free Survival in Cohort B
Progression-free survival in Cohort B is the key secondary endpoint for this study.  The 
measurement, rules of censoring, and analysis methods of PFS in Cohort B are the same as those 
of PFS in Cohort A. Only if statistical significance is declared at the Cohort A interim analysis, 

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the interim analysis of Cohort B will be conducted based on the same data cutoff. No alpha 
specified for interim of Cohort B. If patients in Cohort A continue being followed for PFS until 
final analysis, the final analysis of Cohort B will be conducted at the same time of Cohort A final 
analysis. If Cohort A stops early at interim due to efficacy, the final analysis of Cohort B may be 
conducted after approximately 105 PFS events have been observed in Cohort B (that is, an 
approximately 30% censoring rate). 
12.2.7.2. Overall Survival
Overall survival will be analyzed for each cohort. Overall survival time is measured from 
randomization until death from any cause.  Patients who are alive will be censored at the data 
cut-off date of study completion. The final analysis of OS will be conducted together with the 
analysis of PFS at study completion.
Overall survival will be analyzed using the Kaplan-Meier method and the Cox proportional 
hazard model. 
12.2.7.3. Objective Response Rate, Disease Control Rate, Clinical Benefit Rate,
and Duration of Response
For each cohort, 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 within the cohort 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 in each cohort.
12.2.8. Sensitivity Analysis
Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to 
evaluate the robustness of the analysis.  Details can be found in the SAP. 
12.2.9. Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetics analyses will be conducted on all patients who have received at least 1 dose of 
study treatment and have had samples collected (see PK sampling schedule in Attachment 7).
Mean population PK parameters for abemaciclib and its metabolites in plasma (clearance, area 
under the plasma concentration versus time curve [AUC], volume of distribution, and half-lives) 
and inter-individual PK variability will be computed using nonlinear mixed-effect modeling 
implemented in NONMEM.  Covariate effects (such as age, weight, sex, creatinine clearance, 
and plasma protein levels) on the PK parameters of abemaciclib and its metabolites in plasma 
will also be investigated.

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Likewise, and if warranted by the data, mean population PK parameters for anastrozole,  
letrozole, or fulvestrant in plasma and inter-individual variability estimates will also be 
computed using nonlinear mixed-effect modeling implemented in NONMEM.
Finally, potential pharmacodynamic data (such as neutrophils, lymphocytes, or platelet 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 NSAI or fulvestrant in a PK/PD model. Also, CTS 
associated with PFS and OS may be analyzed for exploratory objectives.  
12.2.10.
Biomarker Analyses
Correlative analyses may be performed to investigate associations between biomarkers and 
clinical endpoints as deemed appropriate.  
12.2.11.
Health Outcome/Quality-of-Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

EORTC QLQ-C30 

mBPI-sf 
For each patient with data from baseline and at least 1 post-baseline visit, the maximum change 
from baseline score will be calculated and summarized for EORTC scale scores and mBPI-sf
“worst pain.”  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.
12.2.11.1.
Health-Related Quality of Life
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30 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 item will be calculated.  Descriptive statistics will be 
calculated for each dimension and the total score for each treatment arm in a cohort.
12.2.11.2.
Pain Intensity
Individual pain items on the mBPI-sf (ie, worst, least, average, and current pain) will be 
described using descriptive statistics (eg, n, mean, median, standard deviation, minimum, and 
maximum) by treatment arm and time points.  A mixed effects model, repeated measures model 
may be applied to compare between treatment arms, which may 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 mBPI-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 (ie, 50% of the questions were answered).  Separate 
similar analyses will be conducted using the average of the mBPI-sf/worst pain assessments 
associated with each cycle.

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Pain analysis will be based on all randomized patients with at least 1 baseline mBPI-sf “worst 
pain” and 1 mBPI-sf “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 Kaplan-Meier method and will be made 
between the 2 treatment 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 treatment 
arms within each cohort. The number of events due to each criterion will be described.
12.2.11.3.
Resource Utilization
Utilization data will be summarized descriptively by category across arms in a cohort (eg, 
analgesic use, bisphosphonate use, transfusions, radiation, surgery, and hospitalization days), 
including a frequency table with tabular statistics.  Tests for differences in proportions between 
treatment groups and between response groups will be performed.  
12.2.12.
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 the entire treatment period as well as for each cycle.  The 
number of patients with dose reductions, delays, or omissions will also be summarized, as will 
the reasons for dose adjustments.  
Adverse events will be reported using MedDRA.  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 v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and 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 AEs that begin prior to the first dose of study drug.
A 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.

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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.
12.2.13.
Subgroup Analyses
Subgroup analyses of PFS will be performed for potential prognostic subgroup variables within 
each cohort, including:

All baseline stratification factors

NSAI received for Cohort A while on study (letrozole vs. anastrozole)

Study entry disease status (de novo metastatic vs. recurrent metastatic vs. locoregionally 
recurrent)

Measurable disease at baseline (yes vs. no)

Number of organs involved (1 vs. 2 vs. 3+)

Age (<65 years vs. ≥65 years)

Country (China vs. Other)

Race (Asian vs. Other)

PgR status (positive vs. negative)

Baseline ECOG PS (0 vs. 1)
If a level of a factor consists of fewer than 5% of total randomized patients in the study, analysis 
within that level may be omitted.  The final list of subgroup analyses will be provided in the 
SAP. 
Analyses will be done within subgroups and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.
Other subgroup analyses may be performed as deemed appropriate.  
12.2.14.
Interim Analysis and Other Planned Analyses
An interim analysis on Cohort A will be conducted by the DMC after approximately 119 PFS 
events have been observed. The interim analysis will be conducted to provide early efficacy 
information and could potentially result in early communication with regulatory agencies.  The 
O’Brien Fleming alpha spending function (Lan and DeMets 1983) will be used to preserve the 
overall type I error. If the analysis of PFS is significant using the cutoff described in 
Section 12.2.6, the DMC will be instructed to engage the SMD, who may subsequently convene 
an IRC to propose actions based upon the DMC’s recommendation. All patients will continue 

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follow-up for PFS until study completion, and will remain blinded for the duration of the study 
unless emergency unblinding (Section 9.5.2) are met. If Cohort A show early efficacy at interim, 
the sponsor may consider early stop, unblinding and crossover for this cohort; however,
regulatory agencies will be consulted before any action is taken.  
The unblinded analysis, including review of the efficacy along with the safety data, will be 
conducted by the DMC.  Only the DMC is authorized to evaluate unblinded interim efficacy and 
safety analyses. Study sites will receive information about interim results ONLY if they need to 
know for the safety of their patients.
If statistical significance is not declared at the interim, a final analysis of Cohort A will be 
conducted with about 170 PFS events.
The interim analysis of Cohort B is triggered only if statistical significance is declared at the 
Cohort A interim analysis. No DMC is required for the analysis of Cohort B. The analysis will 
provide both safety and efficacy information of Cohort B and could potentially result in early 
communication with regulatory agencies, including consultation of potential decisions regarding 
early stop, unblinding and crossover before any action is taken. 
In the case of early stop and crossover for Cohort A or Cohort B after the interim analysis, Lilly 
will notify investigators when the crossover begins.  
If patients in Cohort A continue being followed for PFS until final analysis, the final analysis of 
Cohort B will be conducted at the same time of Cohort A final analysis. If Cohort A stops early 
at interim due to efficacy, the final analysis of Cohort B may be conducted after approximately 
105 PFS events have been observed in Cohort B.  
Unblinding details are specified in the unblinding plan section of the SAP.

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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, 
where permitted by local law or regulation, by the patient's 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 sites.  
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 sites. 
The study site’s ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the 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 
International Ethical Guidelines 

International Conference on Harmonisation (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 (TPO).

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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 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 JC, Kaasa S, Klee M, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw K, Sullivan M, Takeda F. The European Organization 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(5):365-376.
Bray F, Ren JS, Masuyer E, Ferlay J. Global estimates of cancer prevalence for 27 sites in the 
adult population in 2008. Int J Cancer. 2013;132(5):1133-1145.
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.
Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, Pestell RG. Overview of cyclins D1 
function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Investig 
Drugs. 2014; 23(3):295-304.
Cleeland CS. Pain assessment in cancer. In: Osoba D, editor. Effect of cancer on quality of life. 
Boca Raton (FL): CRC Press; 1991:p 293-305.
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;34(2):187-220.
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.
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. Brussels:  
European Organisation for Research and Treatment of Cancer, Brussels; 2001.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, 
Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:  
IARC CancerBase No. 11. Lyon, France:  International Agency for Research on Cancer. 
Available at: http://globocan.iarc.fr. Accessed January 19, 2016.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, 
Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, 
Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff 
JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and progesterone 
receptors in breast cancer [published correction appears in J Clin Oncol. 2010;28(21):354]. J 
Clin Oncol. 2010;28(16):2784-2795.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53(282):457-481.

I3Y-CR-JPBQ (e) Clinical Protocol
Page 77
LY2835219
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-663.
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(6):649-655.
Ortega S, Malumbres M, Barbacid M. Cyclin-D dependent kinases INK4 inhibitors and cancer. 
Biochim Biophys Acta. 2002;1602(1):73-87.
Sherr CJ. Cancer cell cycles. Science. 1996;274(5293(:1672-1677.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; 
American Society of Clinical Oncology. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin 
Oncol. 2015;33(28):3199-3212.
Velasco-Velazquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of 
cyclin D1 in breast cancer. Future Oncol. 2011;7(6):753-765.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, 
Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
Press MF, Spears PA, Vance GH, Viale G, Hayes DF; American Society of Clinical 
Oncology; College of American Pathologists. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-
4013.

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Protocol JPBQ Study Schedule
Attachment 1.

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Study Schedule, Protocol I3Y-CR-JPBQ
Perform procedure as indicated.
Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2
3
4 – X
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2
3
4 – X
801
802 - 8XX
Relative day 
within a cycle
28
14
1
15±3
1b
15±3
last 7 
days
1b
1b
last 7 
days
Procedure 
Category
Procedure
Protocol 
Reference
Study Entry/
Enrollment
Informed Consent Form signed 
(prior to performance of any 
protocol-specific 
tests/procedures)c
Section 8.1
Xc
Inclusion/Exclusion evaluation
Section 7
X
Medical 
History
Initial history/preexisting 
conditions/ previous treatment
Section 12.2.3
X
Physical 
Examination 
(Obtain prior 
to drug 
administration
for on-therapy 
cycles)
Height 
Section 12.2.3
X
Weight
Section 12.2.3
X
X
X
X
X
X
Vital Signs (Temp, BP, HR, 
RR)
Section 12.2.3
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)d
Section 10.1.1
Xd
Xd
Xd
Xd
Xd
Radiologic imaging according 
to RECISTe
Section 10.1.1
Attachment 5
Xe
Xe
Xe
Xe
Xe
Bone Scintigraphyf
Section 10.1.1
Attachment 5
Xf
Xf
Xf
Xf
X-ray, or CT scan with bone 
windows, or MRIg
Section 10.1.1
Attachment 5
Xg
Xg
Xg
Xg
Xg
Randomizationh
Section 9.3
Xh
Survival informationi
Section 10.1
Xi
Xi

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Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2
3
4 – X
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2
3
4 – X
801
802 - 8XX
Relative day 
within a cycle
28
14
1
15±3
1b
15±3
last 7 
days
1b
1b
last 7 
days
Procedure 
Category
Procedure
Protocol 
Reference
Adverse Event Collection/CTCAE Gradingj
Section 10.3
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Concomitant Medication Notation
Section 9.6
X
X
X
X
X
X
Study Diaries
Dispense Study Diaries
Section 9.7.1
X
X
X
X
Review/Collect Study Diaries
Section 9.7.1
X
X
X
X
Lab/
Diagnostic 
Tests
Central hematologyk
Attachment 2
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Central chemistryk
Attachment 2
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Local FSH and estradiol 
levelsl
Attachment 2
Xl
Central pharmacokinetic (PK) 
samplingm
Attachment 7
Xm
Xm
Xm
Xm
Pharmacogenetic whole blood 
samplingn
Section 10.4.2.1
Xn
Biomarker plasma sampleo
Section 10.4.2.2
Xo
Xo
Xo
Local ECGp
Section 10.3.2.1
Xp
Xp
Study 
Treatment
Abemaciclib/Placeboq
Section 9.1
Q12H on Days 1 through 28 of every cycleq
Cohort A
Anastrozole
q
Section 9.1
Take 1 mg tablet orally Q24H on Days 1 through 28q
Letrozole
q
Section 9.1
Take 2.5 mg tablet orally Q24H on Days 1 through 28q
Cohort B
Fulvestrant
q
Section 9.1
Days 1 and 15 of Cycle 1, then Day 1 of Cycle 2 and beyondq
Health 
Outcomes
EORTC QLQ-C30 , mBPI-sfr
Section 12.2.11
Xr
Xr
Xr
Xr
Xr
Xr
Hospitalization
Section 12.2.11.3
X
X
X
X
X
Transfusion
Section 12.2.11.3
X
X
X
X
X

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Abbreviations:  BL = baseline; BP = blood pressure; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30; FSH = follicular stimulating hormone; HR = heart; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short 
form; MRI = magnetic resonance imaging; NSAI = nonsteroidal aromatase inhibitor; PD = progressive disease; PK = pharmacokinetics; Q12H = every 12 
hours; Q24H = every 24 hours; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory rate; SAE = serious adverse event; temp = 
temperature.
a
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study drug and lasts approximately 30 
days (7 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.
b 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.
c
Informed consent form is signed within 28 days prior to randomization of study drug and prior to performance of any protocol-specific tests/procedures.
d Visible tumor (such as skin lesions) identified at baseline require repeat photographic images on Day 1of every second cycle beginning with Cycle 3 and 
continuing through Cycle 19 (inclusive), on Day 1 of every third cycle after Cycle 19, and within 14 days of clinical progression.  Photographic images may 
be taken more frequently based upon the discretion of the investigator or following the identification of new skin lesions post-baseline.  Each photographic 
image of the tumor should include a ruler if applicable.  For patients who discontinue study treatment without objectively measured 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. Assessments should be performed prior to dosing at the beginning of the required cycle unless otherwise indicated.
e
For patients with inoperable locoregionally recurrent breast cancer, MRI scan of the breast is performed locally at baseline (Day -28 to Day -1), in the last 7 
days of every second cycle beginning with Cycle 2 and continuing through Cycle 18, in the last 7 days of every third cycle after Cycle 18, 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), in the last 7 
days of every second cycle beginning with Cycle 2 and continuing through Cycle 18, in the last 7 days of every third cycle after Cycle 18, and within 14 days 
of clinical progression. 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 PD, continue to evaluate tumor response approximately every 8 weeks for the first 18 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. Assessments should be performed prior to dosing at the 
beginning of the required cycle unless otherwise indicated.
f
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 Cycle 1, Day 1 is also acceptable.  Bone scintigraphy should be repeated for all patients between last 7 days of every sixth 

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cycle beginning with Cycle 6, when complete response is identified in target disease, or when progression in bone is suspected.  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. Assessments should be performed prior to dosing at the beginning of the required cycle unless otherwise indicated.
g 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), in the last 7 days of every 
second cycle beginning with Cycle 2 and continuing through Cycle 18, in the last 7 days of every third cycle after Cycle 18, and within 14 days of clinical 
progression only for patients with bone lesions identified by bone scintigraphy at baseline.  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. Assessments should be performed prior to 
dosing at the beginning of the required cycle unless otherwise indicated.
h The period between randomization to blinded study drug and the first dose (Cycle 1, Day 1) should not exceed 7 days.
i
Although preferable to collect during a clinic visit, survival information may be collected by contacting the patient or family directly (eg, via telephone) if no 
procedures are required.  This should be collected at minimum every 90 days if no other procedures are performed.  Additional long-term follow-up data 
collection will include postdiscontinuation anticancer therapies.
j
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.
k Central hematology/central chemistry labs can be drawn up to 5 days prior to Day 1 of each cycle. Local hematology/local chemistry during the cycle can be 
performed for treatment decisions at the discretion of the investigator.  If the treatment was suspended due to hematologic/non-hematologic toxicity, the 
decision to perform hematology and/or chemistry labs before re-initiation of the blinded study drug is at the discretion of the investigator. Assessments 
should be performed prior to dosing at the beginning of the required cycle unless otherwise indicated.
l
FSH and estradiol levels are required only for women age <60 years and amenorrheic for at least 12 months.
m See PK Sampling Schedule (Attachment 7).
n Draw sample before patient is dosed on Cycle 1, Day 1
o During the treatment study, draw sample for all patients before dosed on Cycle 1, Day 1 and upon arrival at site on Cycle 2, Day 1.  During the short-term 
follow-up period, draw sample only for patients discontinuing due to PD.
p A local ECG (no replicates required) should be obtained at baseline (Day -14 to Day -1), and at the short-term follow-up visit. Patients must be resting for 
approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
q Blinded study drug should be administered orally Q12H on Days 1 through 28 of each cycle;  For patients in Cohort A, on Cycle 2, Day 1, patients will take 

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NSAI and blinded study drug at home at least 4 hours prior to arrival at the clinic.  For PK purposes, NSAI should be administered at the same time (or up to 
20 minutes after) the first dose of blinded study drug through Cycle 4, Day 1.  Subsequently, the interval between administration of blinded study drug and 
NSAI may be adjusted based on the judgment of the investigator.  For patients in cohort B, on Cycle 2 Day 1, patients will take the blinded study drug at 
home at least 4 hours prior to arrival at the clinic. For PK purposes, fulvestrant should be administered at the same time as (or up to 20 minutes after) the first
dose of  blinded study drug, except when specified otherwise in the PK Sampling Schedule (Attachment 7) through Cycle 4 Day 1. Subsequently, the interval 
between administration of blinded study drug and fulvestrant may be adjusted based on the judgment of the investigator. 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. 
r
EORTC QLQ-C30, mBPI-sf should be administered twice at baseline (Day -14 to Day -1, and at C1D1), 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. 

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Study Schedule for the Continued Access Period Only, Protocol I3Y-CR-JPBQ
Perform procedure as indicated.
Patients on Study Treatment
Continued Access
Follow-Up
Cycle
X-Y
Follow-Upa
Visit
501-5XX
901
Approximate Visit 
Duration (days)
28
30±5
Relative day within a 
cycle
1
Procedure Category
Procedure
Protocol Reference
Adverse Events Collection/CTCAE Gradingb
Section 10.3
X
X
Study Treatment
Abemaciclibc
Section 9.1
Daily Q12Hc
Cohort A
Anastrozolec
Section 9.1
Daily Q24Hc
Letrozolec
Section 9.1
Daily Q24Hc
Cohort B
Fulvestrantc
Section 9.1
Day 1 of each cyclec
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; SAE= serious adverse event; Q12H = every 12 hours, Q12H = every 12 hours.
a
The continued access 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/placebo should be administered Q12H on Days 1 thought 28 of each cycle. 
Anastrozole or letrozole should be administered Q24H on Days 1 thought 28 of each cycle. Patients receiving clinical benefits will continue to receive 
anastrozole or letrozole during the continued access period.
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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Protocol JPBQ Clinical Laboratory Tests
Attachment 2.
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 
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Calcium
Platelets
Total Protein
Albumin
Cholesterolb
FSH levelc,d
Estradiol levelc,d
Abbreviations:  FSH = follicle-stimulating hormone; RBC = red blood cells; WBC = white blood cells.
a
Lilly-designated (central) laboratory.
b Per the letrozole and anastrozole labels, investigators should consider monitoring cholesterol (local or central
laboratory).  The decision to monitor and frequency of monitoring are at the discretion of the investigator.
c   Local or investigator-designated laboratory.
d   To be performed at baseline only in order to establish eligibility.  Follicle-stimulating hormone and estradiol 
levels are required only for women age <60 years and amenorrheic for at least 12 months.

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Protocol JPBQ Hepatic Monitoring Tests 
Attachment 3.
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
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 laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Protocol JPBQ ECOG Performance Status
Attachment 4.
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 self-care but unable to 
carry out any work activities. Up and about more than 
50% of waking hours
3
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair
5
Dead
Abbreviation:  ECOG = Eastern Cooperative Oncology Group.
Source:  Oken et al. 1982.

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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Protocol JPBQ Sampling Summary
Attachment 6.
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 (eg, patients who 
discontinue from the study).
Protocol I3Y-MC-JPBQ 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
20
140 mL
Pharmacokinetic sample
Blood
4  mL
5
20 mL
Pharmacogenetic blood sample
Blood
10 mL
1
10 mL
Biomarker plasma sample
Blood
6 mL
3
18 mL
Total blood volume 
Blood
195 mL
Hepatic monitoringb
Blood
3 - 30 mL
-
-
a
Covers Cycles 1 through 16 and 1 postdiscontinuation follow-up visit.
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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Protocol JPBQ Pharmacokinetic
Attachment 7.
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
PK Sample 
Number
Cycle and 
Day
Dosing of 
Abemaciclib
Dosing of 
NSAIs/Fulvestrant
Sampling Time for PK from Blooda
1
C1D1
X
X
2 to 4 hrs after blinded study drug dosed in 
clinic
2
C2D1
Xb
X
Cohort A: Upon arrival at site (ie, at least 
4 hrs after taking NSAI and blinded study 
drug doses at home)
Or
Cohort B: Upon arrival at site but prior to 
fulvestrant dose (ie, at least 4 hrs after 
taking blinded study drug dose at home)
3
C2D1
3 ± 0.5 hrs after PK Sample Number 2 (ie, 
at least 7 ± 0.5 hrs after taking blinded 
study drug dose at home)
4
C3D1
X
X
Prior to blinded study drug dose 
5
C4D1
X
X
Prior to blinded study drug dose 
Abbreviations:  C = cycle; D = day; hr = hour; PK = pharmacokinetic; NSAI = nonsteroidal aromatase inhibitor.
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 abemaciclib and its metabolites’
concentrations and the other for measurement of NSAI/fulvestrant concentrations.  In the event of a dose 
suspension of blinded study drug due to toxicity at the beginning of a cycle, the PK Sampling Schedule may 
require adjustment.  In these exceptional circumstances, the sponsor should be notified.
b On Cycle 2 Day 1 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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Protocol JPBQ Inducers of CYP3A, Strong
Attachment 8.
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
Abbreviation:  CYP = cytochrome P450.
a  Important note: All patients may receive supportive therapy with dexamethasone, preferably 7 days, if clinically
indicated.
Strong inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin 
Diltiazem
Erythromycin
Fluconazole
Itraconazole 
Ketoconazole
Nefazodone
Verapamil
Abbreviations:  CYP = cytochrome P450; HIV = human immunodeficiency virus.

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Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil 
Astemizole 
Cisapride 
Cyclosporine 
Dihydroergotamine 
Ergotamine 
Fentanyl
Pimozide
Quinidine 
Sirolimus 
Tacrolimus 
Terfenidine
Abbreviation:  CYP = cytochrome P450.
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably ≤7 days, if 
clinically indicated.  Patients requiring more than 7 days of dexamethasone therapy will not incur a protocol 
deviation. 

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Protocol JPBQ CTCAE 4.03 Diarrhea 
Attachment 9.
Definition

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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
Life-threatening 
consequences; urgent 
intervention indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements

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Protocol JPBQ Amendment (e) Summary 
Attachment 10.
A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study to Compare 
NSAI (Anastrozole or Letrozole) plus 
Abemaciclib, a CDK4 and CDK6 Inhibitor, 
or plus Placebo, and to Compare 
Fulvestrant plus Abemaciclib or plus 
Placebo in Postmenopausal Women with 
Hormone Receptor-Positive, HER2-
Negative Locoregionally Recurrent or 
Metastatic Breast Cancer
Overview
Protocol I3Y-CR-JPBQ, A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Compare NSAI (Anastrozole or Letrozole) plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or 
plus Placebo, and to Compare Fulvestrant plus Abemaciclib or plus Placebo in Postmenopausal 
Women with Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or 
Metastatic Breast Cancer, has been amended.  The new protocol is indicated by amendment (e) 
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Remove the wording of forbid crossover in the continued access period.

Statistical analysis plan was updated regarding final analysis for Cohort A and Cohort B in 
different scenarios.

Incorporated safety monitoring language for hepatic conditions, renal function and VTEs.

In case of under treatment of another effective therapeutic agent, patients need to be 
discotinuated of study drug instead of discontinuation from study.

Clarified and updated when study drug need to be suspended or reduced.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Synopsis
Statistical Methods:  
…
An interim analysis will be conducted on Cohort A when 119 PFS events have been observed. If positive, an interim 
of Cohort B will also be conducted on the same cutoff.  If patients in Cohort A continue being followed for PFS 
until final analysis, the final analysis of Cohort B will be conducted at the same time of Cohort A final analysis.  If 
Cohort A stops early at interim due to efficacy, the final analysis of Cohort B may be conducted after approximately 
105 PFS events have been observed in Cohort B.
Section 4. Abbreviations…
VTE
venous thromboembolic event
7.3.2. Discontinuation of Study Drug(s)

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study
If patients discontinue NSAIs/fulvestrant but continue to receive blinded study drug, this will not 
be considered as discontinuation of study drug.
7.3.3. Discontinuation from the Study 
Patients will be discontinued from the study in the following circumstances:

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study
8.1 Summary of Study Design
The primary analysis of the PFS endpoint will occur after approximately 170 PFS events have 
been observed in Cohort A.  An interim analysis will be conducted after approximately 119 PFS 
events are observed to provide early efficacy information and allow for potential early 
communication with regulatory agencies.allow for early stop of Cohort A due to efficacy (see 
Section 12.2.6 for details). 
The interim analysis of Cohort B will follow the timeline of Cohort A, which .  An interim of 
Cohort B will occur only if the interim of Cohort A turns out to be positive. If patients in Cohort 
A continue being followed for PFS until final analysis, t The final analysis of Cohort B will be 
conducted at the same time of Cohort A final analysis. If Cohort A stops early at interim due to 
efficacy, the final analysis of Cohort B may be conducted after approximately 105 PFS events 
have been observed in Cohort B.. (see Section 12.2.14 for details).

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For each cohort, aAll patients will be followed for progression and survival information until 
death or study completion, whichever occurs first.
…

Continued Access Period:  begins after study completion and ends at the end of trial.  During 
the continued access period, patients on study treatment who continue to experience clinical 
benefit may continue to receive study treatment (except placebo) until one of the criteria for 
discontinuation is met.  
8.1.1 Study Completion and End of Trial
This study will be considered complete following the last required PFS event from Cohort A or 
Cohort B (Figure JPBQ.8.2), whichever is longer, as determined by Lilly, when all of the 
required short-term follow-up assessment is completed. In case Cohort A stops early at interim 
due to efficacy and Cohort B continues thereafter, Cohort B will be considered complete 
following the final analysis of PFS in Cohort B. Investigators will continue to follow the study 
schedule for all patients until notified by Lilly that study completion has occurred.  
8.1.2 Continued Access Period
After study completion, all patients who are on study treatment and who are eligible for 
continued access will be unblinded. Patients receiving study treatment and experiencing ongoing 
clinical benefit and no undue risks may continue to receive study treatment in the continued 
access period until one of the criteria for discontinuation is met (see Section 7.3).  During the 
continued access period, placebo will no longer be administered, and crossover will not be 
permitted.  Lilly will notify investigators when the continued access period begins.  
Table JPBQ.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose Day 
Arm A1
Abemaciclib
Treatment/28-day cycle
150 mg PO Q12H on Days 1-28
Anastrozole
or
Letrozole
Treatment/28-day cycle
1 mg PO Q24H on Days 1-28a
or
2.5 mg PO Q24H on Days 1-28a
Arm A2b
Placebo
Treatment/28-day cycle
PO Q12H on Days 1-28
Anastrozole
or
Treatment/28-day cycle
1 mg PO Q24H on Days 1-28a
or

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Letrozole
2.5 mg PO Q24H on Days 1-28a
Arm B1
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 beyondcb
Arm B2 d
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 beyondbc
Abbreviations:  IM = intramuscular; NSAI = nonsteroidal aromatase inhibitor; Q12H = once 
every 12 hours; Q24H = once every 24 hours; PK = pharmacokinetic; PO = orally.
a
For PK purposes, NSAI should be administered at the same time (or up to 20 minutes 
after) the first dose of blinded study drug through Cycle 4, Day 1.  Subsequently, the interval 
between administration of blinded study drug and NSAI may be adjusted based on the judgment 
of the investigator.
b   For patients in Arm A2 who crossover to Arm A1, the Arm A1 treatment schedule should be 
followed.
c b   For PK purposes, fulvestrant should be administered at the same time as (or up to 20 minutes 
after) the first dose of blinded study drug, except when specified otherwise in the PK Sampling 
Schedule (Attachment 7) through Cycle 4 Day 1. Subsequently, the interval between 
administration of blinded study drug and fulvestrant may be adjusted based on the judgment of 
the investigator.
d   For patients in Arm B2 who crossover to Arm B1, the Arm B1 treatment schedule should be 
followed.
Table JPBQ.9.2.
Toxicity Dose Adjustments and Delays of Blinded Study Drug for Study 
JPBQ
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 at investigator’s
discretion

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Hematologic Toxicity
Section 9.4.1.1.3
Recurrent Grade 3 within 8 
weeks
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
Grade 3
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
Hematologic Toxicity
Section
Recurrent Grade 3 within 8 
weeks
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: If 
patient requires
administration of blood cell
growth factors 
Sections 9 4 1 1 3 and 9 6 4
Regardless of severity
(Use growth factors 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 Toxicityb
(except diarrhea and ALT 
increased) 
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 MUST be suspended 
until toxicity resolves to either
baseline or Grade 1.
Dose MAY MUST be 
reduced by 1 dose level at 
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
Grade 2 that does not resolve
within 24 hours to at least 
Grade 1Requires
Dose MUST be suspended until
toxicity resolves to at least Grade
1.
Dose MUST be reduction is 
NOT requireded 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, 
or any Grade of diarrhea that 
Dose SHOULD MUST be 
suspended until toxicity resolves
to at least Grade 1.
Dose MAY MUST be 
reduced by 1 dose level at 
investigator's discretion.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Grade 3 or 4Diarrhea recurs
despite maximal supportive
measures after resuming same
dose level after initial
Dose MUST be suspended until
toxicity resolves to at least Grade
1.
Dose MUST be reduced by 1
dose level.
ALT Increased 
(Sections 9.4.1.1.4.2. and 
10 3 3 1)
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN), or
Dose MUST be suspended until 
toxicity resolves to baseline or 
Grade 1.
Dose MUST be reduced by 1 
dose level.

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ALT Increased 
(Sections 9.4.1.1.4.2 and 
10.3.3.1)
Grade 4 (>20.0×ULN)
Blinded study drug MUST be 
discontinued.
Blinded study drug MUST
be discontinued.
ALT Increased with increased 
total bilirubin, in the absence of 
cholestasis
(Sections 9.4.1.1.4.2)
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
Blinded study drug MUST be 
discontinued
Blinded study drug MUST
be discontinued
Abbreviation: ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; SHOULD = not mandatory but highly recommended; MUST
= mandatory.
a
Determination of persistent events will be at the discretion of the investigator.  Recurrent 
toxicity refers to the same event occurring within the next 8 weeks (as measured from the stop 
date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
shows stable hematological counts (Grade ≤2) during that timeframe
•
has absence of any signs or risk of infection 
•
is benefiting from study treatment
b
Additional guidance for renal and hepatic monitoring is in Sections 10.3.3.1 and 10.3.3.2
c    Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic 
monitoring.  See Section 10.3.1.110.3.1.1 for additional guidance for hepatic monitoring
9.4.1.1.3. Hematologic Toxicity
If the patient experiences a recurrent episode of Grade 3 hematologic toxicity within 8 weeks, 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 as outline in Table JPBQ.9.3
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
The patient showed stable hematological counts (Grade ≤2) during that timeframe

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•
In the absence of any signs or risk of infection 
•
The patient is benefiting from study treatment
If a patient experiences Grade 3 hematologic toxicity and requires administration of blood cell 
growth factors
9.4.1.1.4. Nonhematologic Toxicity
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
see Section 9.4.1.1.4.1 or ALT increased, refer to Section 9.4.1.1.4.2 ) possibly related to blinded 
study drug that does not resolve with maximal supportive measures within 7 days to either 
baseline or Grade 1, then dosing may must be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of  blinded study drug may must be reduced by 1 dose 
level as outlined in Table JPBQ.9.3.
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 1 dose level . as outlined in Table JPBQ.9.3.Table JPBQ.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 must be suspended (until the toxicity resolves to at least Grade 1) and the dose 
of blinded study drug may must be reduced by 1 dose level as outlined in Table JPBQ.9.3 at the 
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 JPBQ.9.3.
9.4.1.1.4.2. Hepatic Toxicity
Does modifications and management for increased ALT are provided in Table JPBQ 9.2. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, blinded study drug 
must be suspended until the toxicity has resolved to at least Grade 1 and the dose must be 
reduced by 1 dose level. Discontinue blinded study drug for Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, 
the patient must be discontinued from blinded study drug. Refer to Section 9.4.1.1.4.2 for 
additional hepatic monitoring guidance.
10.3.1 Adverse Events
The investigator will record all AE/SAE information in the CRF. Investigators will be instructed 
to report to Lilly or its designee their assessment of the potential relatedness of each AE to 
protocol procedure and/or study drugs via eCRF.
10.3.1.1. Serious Adverse Events

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All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  An SAE is any AE from this study that results in 1 of the following outcomes:
10.3.3. Safety Monitoring

AEs 

If a patient experiences elevated ALT ≥5× ULN and elevated total bilirubin ≥2× ULN, 
clinical and laboratory monitoring should be initiated by the investigator. For patients 
entering the study with ALT ≥3× ULN, monitoring should be triggered at ALT ≥2× baseline.

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 specific 
recommended clinical information and follow-up laboratory tests (see Attachment 3).
10.3.3.1. Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT ≥5×ULN and elevated total bilirubin (TBL)≥2×
ULN, or ALT >8x ULN for patients with underlying baseline hepatic metastases, liver tests 
(Attachment 4), including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), 
and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests (Attachment 3) and in consultation with the Lilly CRP.  Monitoring of 
ALT, AST, and TBL should continue until levels normalize or return to approximate baseline 
levels.  Additional diagnostic testing should be considered to rule out cause of increased liver 
enzymes per the investigator’s discretion.
Hepatic monitoring tests (Attachment 3) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:
•
ALT ≥5×ULN and TBL ≥2×ULN
•
ALT>8× ULN for patients with underlying hepatic metastasis
•
discontinuation from study treatment due to a hepatic event or an abnormality of liver 
tests
10.3.3.2. Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation. If deterioration 
of renal function is suspected, serum creatinine should not be the only measure used to assess a 
patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 

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deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPBQ 
9.2).
10.3.3.3. Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known. For suspected or confirmed VTE (eg. deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice.
12.2.1. General Considerations
Safety analyses will be based on the randomized and treated population (ie, Safety Population), 
defined as all randomized patients receiving at least 1 dose of blinded study drug or
NSAI/fulvestrant control.
12.2.6. Primary Outcome and Methodology
The purpose of the interim analysis is to provide early efficacy information and allow for 
potential early communication with regulatory agencies stop the study early for positive efficacy.
12.2.7.1 Progression-Free Survival in Cohort B
If patients in Cohort A continue being followed for PFS until final analysis, the final analysis of 
Cohort B will be conducted at the same time of Cohort A final analysis. If Cohort A stops early 
at interim due to efficacy, the final analysis of Cohort B may be conducted after approximately 
105 PFS events have been observed in Cohort B (that is, an approximately 30% censoring 
rate)The final analysis of Cohort B will be conducted together with the final analysis of Cohort A. 
12.2.13. Subgroup Analyses
Subgroup analyses of PFS will be performed for potential prognostic subgroup variables within 
each cohort, including:

All baseline stratification factors

NSAI received for Cohort A while on study (letrozole vs. anastrozole)

Study entry disease statusDisease setting (de novo metastatic vs. recurrent metastatic vs. 
locoregionally recurrent)
12.2.14. Interim Analysis and Other Planned Analyses
An interim analysis on Cohort A will be conducted by the DMC after approximately 11970% of 
the required PFS events have been observed. The interim analysis will be conducted to provide 
early efficacy information and could potentially result in early communication with regulatory 

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agencies.  The O’Brien Fleming alpha spending function (Lan and DeMets 1983) will be used to 
preserve the overall type I error. If the analysis of PFS is significant using the cutoff described 
in Section 12.2.6, the DMC will be instructed to engage the SMD, who may subsequently 
convene an IRC to propose actions based upon the DMC’s recommendation. All patients will 
continue follow-up for PFS until study completion, and will remain blinded for the duration of 
the study unless emergency unblinding (Section 9.5.2) are met. If Cohort A show early efficacy
at interim, enrollment in this cohort will be terminated and the sponsor may consider early stop, 
unblinding and crossover for this cohortsubjects that randomized to the control group will not be 
permitted to cross over to the experimental group.  In addition, patients will remain blinded for 
the duration of the study unless emergency unblinding (Section 9.5.2) are met.  ; however,,
regulatory agencies will be consulted before any action is takenAll patients will continue follow-
up for PFS until study completion.  
…
If statistical significance is not declared at the interim, aA final analysis of Cohort A will be 
conducted with about 170 PFS events, regardless of the result of the Cohort A interim.
The interim analysis of Cohort B is triggered only if statistical significance is declared at the 
Cohort A interim analysis.  No DMC is required for the analysis of Cohort B. The analysis will 
provide both safety and efficacy information of Cohort B and could potentially result in early 
communication with regulatory agencies, including consultation of potential . decisions 
regarding early stop, unblinding and crossover before any action is taken. 
In the case of early stop and crossover for Cohort A or Cohort B after the interim analysis, Lilly 
will notify investigators when the crossover begins.  
If patients in Cohort A continue being followed for PFS until final analysis, the final analysis of 
Cohort B will be conducted at the same time of Cohort A final analysis. If Cohort A stops early 
at interim due to efficacy, the final analysis of Cohort B may be conducted after approximately 
105 PFS events have been observed in Cohort BThe final analysis is planned at the same time of 
Cohort A final. The sponsor has no intent to stop Cohort B; all patients will continue follow-up 
for PFS until study completion.  
Attachment 8.
Protocol JPBQ Inducers of CYP3A, Strong Inhibitors of CYP3A, or 
Substrates of CYPs with Narrow Therapeutic Range
Strong inhibitors of CYP3A
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin 
Diltiazem
Erythromycin
Fluconazole
Itraconazole 
Ketoconazole

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Nefazodone
Verapamil
Abbreviations:  CYP = cytochrome P450; HIV = human immunodeficiency virus.
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel

Leo Document ID = 6776d7fb-f6f9-4c46-857a-08ad09e38232
Approver:
Approval Date & Time: 14-May-2019 09:29:39 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 14-May-2019 11:32:41 GMT
Signature meaning: Approved
PPD
PPD