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

 
 
 
 
 
 
Protocol I3Y-MC-JPBL 
 
 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without 
LY2835219, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative 
Locally Advanced or Metastatic Breast Cancer 
 
 
 
 
 
NCT02107703 
 
 
 
 
 
Approval Date: 01-Apr-2014  

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LY2835219
1.
Protocol I3Y-MC-JPBL
A Randomized, Double-Blind, Placebo-Controlled, 
Phase 3 Study of Fulvestrant with or without LY2835219, 
a CDK4/6 Inhibitor, for Women with Hormone Receptor 
Positive, HER2 Negative Locally Advanced or Metastatic 
Breast Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY2835219, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act Exemption 4.
LY2835219
This study is a global, multicenter, double-blind, placebo-controlled, Phase 3 trial for 
women with hormone receptor positive, HER2 negative locally advanced or metastatic 
breast cancer randomized to receive fulvestrant with or without LY2835219.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 01-Apr-2014 GMT

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LY2835219
2.
Synopsis
Study Rationale
LY2835219 is an oral, selective, and potent small molecule cyclin-dependent kinases (CDKs) 4 
and 6 (CDK4/6) dual inhibitor with antitumor activity within multiple preclinical pharmacology 
models and an acceptable toxicity profile in nonclinical species.  LY2835219 mesylate has been 
shown to significantly inhibit tumor growth in multiple murine xenograft models for human 
cancer.  Published studies that evaluated in vitro growth inhibition with other CDK4/6 inhibitors 
across a diverse panel of 47 breast cell lines showed greater sensitivity to CDK4/6 inhibition in 
estrogen receptor positive (ER+) lines. Specifically, studies with LY2835219 indicate 
differential sensitivity to CDK4/6 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 CDK4/6 inhibition is 
greater in ER+ breast cancers with luminal histology.
Importantly, LY2835219 has demonstrated evidence of clinical activity in a tumor-specific 
cohort of women with metastatic breast cancer (mBC).  In Study I3Y-MC-JPBA, 47 patients 
with a median of 7 prior systemic regimens received therapy with LY2835219.  Among the 
36 patients with hormone receptor positive (HR+) mBC, the median progression-free survival
(PFS) was 9.1 months (with 18 patients still on LY2835219 therapy) and there were 9 confirmed 
partial responses (PR) for an objective response rate of 25%.  In the same study, the combination 
of LY2835219 plus fulvestrant was also evaluated and demonstrated an acceptable safety profile 
for women with HR+ mBC.  These results support further investigation of LY2835219 in 
combination with fulvestrant for women with HR+ locally advanced or metastatic breast cancer.
Study I3Y-MC-JPBL is a randomized, double-blind, placebo-controlled Phase 3 study of 
fulvestrant with or without LY2835219 for women with HR+, human epidermal growth factor 
receptor 2 negative (HER2-) locally advanced (not amenable to curative treatment by surgery) or 
metastatic breast cancer.

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Clinical Protocol Synopsis:  Study I3Y-MC-JPBL
Name of Investigational Product:  LY2835219
Title of Study:  A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without 
LY2835219, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative Locally Advanced 
or Metastatic Breast Cancer 
Number of Planned Patients:  550
Entered:  600
Enrolled:  550
Completed:  550
Phase of Development:  3
Length of Study:  Approximately 72 months
Planned first patient visit:  July 2014
Planned last patient visit:  August 2020
Planned interim analysis:  270 progression-free survival (PFS) events
Objectives:  The primary objective of Study I3Y-MC-JPBL (JPBL) is to compare LY2835219 plus fulvestrant 
versus placebo plus fulvestrant with respect to PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
The secondary objectives of the study are to compare LY2835219 plus fulvestrant versus placebo plus fulvestrant 
with respect to each of the following:
•
overall survival (OS)

OS rate at 1, 2, and 3 years
•
objective response rate [complete response (CR) + partial response (PR)]
•
duration of response (DoR) [CR + PR]
•
disease control rate (DCR) [CR + PR + stable disease (SD)]
•
clinical benefit rate (CBR) [CR + PR + SD ≥6 months]
•
safety and tolerability using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE Version 4.0)
•
pain and symptom burden using the Brief Pain Inventory (BPI), the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
and the EORTC QLQ-BR23 (breast) questionnaires, and health status scores from the EuroQol
5-Dimension 5 Level (EQ-5D 5L)
•
pharmacokinetics (PK) of LY2835219, its metabolites, and fulvestrant
•
time to worsening of Eastern Cooperative Oncology Group (ECOG) performance status of ≥2
•
time to first skeletal-related event (SRE; defined as either pathological fracture, spinal cord 
compression, radiation to the bone, or surgery to the bone)
The exploratory objectives are:
•
To explore potential biomarkers related to the retinoblastoma (Rb) pathway and/or the 
pathogenesis of breast cancer
•
To explore if change in tumor size is associated with PFS and OS
•
To explore time to progressive bone metastases by treatment arm

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Study Design:  Study JPBL is a multicenter, randomized, double-blind, Phase 3 trial for women with HR+, HER2-
locally advanced or metastatic breast cancer.  Approximately 550 patients will be randomized 2:1 between the 
2 arms.  Patients will be randomized using the following stratification factors:  nature of disease (visceral
metastases versus bone only metastases versus other) and sensitivity to endocrine therapy (no prior endocrine 
therapy versus primary resistance versus secondary resistance).  The presence of visceral metastases refers to lung, 
liver, pleural, or peritoneal involvement at the time of randomization. Primary clinical resistance to endocrine 
therapy is defined as follows:  1) for endocrine therapy in the adjuvant setting, recurrence within the first 2 years of 
adjuvant endocrine therapy while on endocrine therapy or 2) for endocrine therapy in the locally advanced or 
metastatic setting, progression within first 6 months of initiating first-line endocrine therapy while on endocrine 
therapy.  Patients receiving prior endocrine therapy who do not meet the definition of primary clinical resistance 
will be considered to have secondary clinical resistance.
Diagnosis and Main Criteria for Inclusion and Exclusions: Patients are eligible to be included in the study if 
they meet following criteria:  1) have a diagnosis of HR+, HER2- breast cancer; 2) have inoperable locally 
advanced or metastatic disease and relapsed with radiologic evidence of progression after prior endocrine therapy
or have not received prior endocrine therapy; 3) have postmenopausal status due to either surgical/natural 
menopause or ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin; 
4) have a negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use 
medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of 
LY2835219 if postmenopausal status is due to ovarian suppression with a GnRH agonist; 5) have either 
measurable disease or nonmeasurable bone only disease; 6) are female and >18 years of age; 7) have given written 
informed consent prior to any study-specific procedures; 8) have adequate organ function; 9) have a performance 
status ≤1 on the ECOG scale; 10) have discontinued previous therapies for cancer, for at least 21 days for 
myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered 
from the acute effects of therapy;11) are willing to participate for the duration of the study and to follow study 
procedures; and 12) are able to swallow capsules.
Patients will be excluded from the study if they meet any of the following criteria:  13) are currently receiving an 
investigational drug in a clinical trial or participating in any other type of medical research judged not to be 
scientifically or medically compatible with this study; 14) have visceral crisis, lymphangitic spread, or 
leptomeningeal carcinomatosis; 15) have a history of central nervous system metastasis; 16) have received prior 
treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, everolimus, or any 
CDK4/6 inhibitor; 17) have received treatment with a drug that has not received regulatory approval for any 
indication within 14 or 21 days prior to randomization of study drug for a nonmyelosuppressive or 
myelosuppressive agent, respectively; 18) have received recent (within 28 days prior to randomization) yellow 
fever vaccination; 19) have had major surgery within 14 days of the initial dose of study drug; 20) have a personal 
history of any of the following conditions:  presyncope or syncope of either unexplained or cardiovascular 
etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest; 21) have serious preexisting 
medical conditions that, in the judgment of the investigator, would preclude participation in this study; 22) have 
inflammatory breast cancer or a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ
of the cervix), unless in complete remission with no therapy for a minimum of 3 years; 23) have received an 
autologous or allogeneic stem-cell transplant; 24) have active bacterial or fungal infection, or detectable viral 
infection; or 25) are pregnant or breastfeeding.
Test Product, Dosage, and Mode of Administration:
LY2835219 will be supplied as capsules administered orally, 200 mg every 12 hours on Days 1 to 28 of a 28-day 
cycle, plus fulvestrant will be administered 500 mg intramuscularly into the buttocks slowly (1 to 2 minutes per 
injection) as two 250-mg injections, one in each buttock, on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 
and beyond.

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Planned Duration of Treatment:
Treatment period: until disease progression or other discontinuation criteria are fulfilled.
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death
Reference Therapy, Dose, and Mode of Administration:  Placebo will be supplied as capsules administered
orally every 12 hours on Days 1 to 28 of a 28-day cycle plus fulvestrant will be administered 500 mg
intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, one in each 
buttock, on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond.
Criteria for Evaluation:
Efficacy:

PFS

OS 

OS at 1, 2, and 3 years

Objective Response Rate

DoR

DCR

Time to Worsening ECOG Performance Status

Time to First Skeletal-Related Event (TTFSRE)
Safety:

Adverse events using NCI CTCAE Version 4.03
Health Outcomes:

BPI:  proportion of patients with “worst pain” increase of 2 points or more at any time on-therapy, 
compared to baseline 

EORTC QLQ-C30 and EORTC QLQ-BR23: Describe target tumor symptom changes 

EQ-5D 5L: Describe health status changes 

Changes in utilization between arms (e.g. analgesic, hospitalization, transfusion)
Pharmacokinetics:

Population PK parameters for LY2835219 and fulvestrant 

Plasma concentration levels of fulvestrant during Cycle 1/Cycle 2
Exploratory

Potential biomarkers related to the Rb pathway and/or the pathogenesis of breast cancer.

Time course of change in tumor size

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LY2835219
Statistical Methods:
Statistical:  The primary objective of this study is to compare LY2835219 plus fulvestrant versus placebo plus 
fulvestrant in terms of PFS for women with HR+, HER2- locally advanced or metastatic breast cancer.  An 
important secondary objective of this study is to compare the 2 arms with respect to OS.
A 2-look group sequential design on the primary endpoint of PFS will be utilized, with interim and primary PFS 
analyses occurring at approximately 270 PFS events and 385 PFS events, respectively.  The Lan-Demets method 
with an O’Brien-Fleming like spending function will be used to maintain the cumulative 1-sided Type I error rate 
of .025.  Assuming a hazard ratio (HR) of 0.703, this design yields at 90% statistical power to detect superiority of 
the LY2835219 plus fulvestrant arm over placebo plus fulvestrant arm with the use of a 1-sided log-rank test and a 
cumulative type I error rate of 0.025.
OS is an important secondary endpoint for this study. OS will be tested only if the test of PFS is significant. A 
4-look approach to testing OS with a cumulative 1-sided type I error rate of .025 will be utilized to allow for 
analyses of OS at the interim PFS analysis, the primary PFS analysis, 289 OS events, and 385 OS events (final OS 
analysis).
Efficacy:
The PFS and OS analyses to test the superiority of LY2835219 to placebo in improving PFS and OS time will use 
the log-rank test stratified by stratification variables.  Additional analyses will be performed using the 
Kaplan-Meier method to estimate the PFS and OS curves and rates, and the Cox proportional hazard model will be 
used to estimate the PFS and OS HRs and corresponding 95% confidence interval.
Safety:
All safety summaries and analyses will be based on the Safety Population, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to treatment received in Cycle 1.
Health Outcomes:
The maximum change from baseline score will be calculated and summarized for BPI “worst pain” and EORTC 
composite scores.  The number and reason for missing and incomplete questionnaires/assessments will be 
summarized for each instrument and study arm.
Pharmacokinetics:
PK parameters for LY2835219 in plasma (clearance, exposure, volume of distribution, and half-lives) and 
inter-individual PK variability will be computed using nonlinear mixed effect modeling implemented in 
NONMEM.  If warranted by the data, PK parameters for fulvestrant in plasma and inter-individual variability 
estimates will also be computed using nonlinear mixed effect modeling implemented in NONMEM.
Pharmacodynamics:
Pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) may be analyzed by means 
of NONMEM and connected to the population PK model for LY2835219 and/or fulvestrant in a 
PK/pharmacodynamic model.
Tailoring biomarkers:
Summary statistics will include means, medians, corresponding standard errors, quartiles, and ranges.  Biomarkers 
with discrete measures, such as genotype locus, will be summarized in frequency tables.  Correlative analyses may 
be performed to investigate associations between biomarkers and clinical endpoints.

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3.
Table of Contents
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study of Fulvestrant with or without LY2835219, a CDK4/6 
Inhibitor, for Women with Hormone Receptor Positive, HER2 
Negative Locally Advanced or Metastatic Breast Cancer
Section
Page
1.
Protocol I3Y-MC-JPBL  A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Fulvestrant with or without 
LY2835219, a CDK4/6 Inhibitor, for Women with Hormone 
Receptor Positive, HER2 Negative Locally Advanced or Metastatic 
Breast Cancer......................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
6.
Objectives.........................................................................................................................21
6.1.
Primary Objective ........................................................................................................21
6.2.
Secondary Objectives...................................................................................................21
6.3.
Exploratory Objectives.................................................................................................21
7.
Study Population...............................................................................................................22
7.1.
Inclusion Criteria..........................................................................................................22
7.2.
Exclusion Criteria ........................................................................................................24
7.3.
Discontinuations ..........................................................................................................25
7.3.1.
Discontinuation of Patients...................................................................................25
7.3.2.
Discontinuation of Study Sites .............................................................................26
7.3.3.
Discontinuation of the Study................................................................................26
8.
Investigational Plan...........................................................................................................27
8.1.
Summary of Study Design............................................................................................27
8.1.1.
Study Completion and End of Trial......................................................................28
8.1.2.
Extension Period..................................................................................................29
8.2.
Discussion of Design and Control ................................................................................30
9.
Treatment..........................................................................................................................31
9.1.
Treatments Administered .............................................................................................31
9.2.
Materials and Supplies .................................................................................................32
9.3.
Method of Assignment to Treatment ............................................................................32
9.4.
Selection and Timing of Doses.....................................................................................32

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9.4.1.
Special Treatment Considerations ........................................................................33
9.4.1.1.
Dose Adjustments and Delays ........................................................................33
9.4.1.1.1.
Dose Adjustments.....................................................................................33
9.4.1.1.1.1.
LY2835219.........................................................................................33
9.4.1.1.1.2.
Fulvestrant ..........................................................................................33
9.4.1.1.2.
Dose Delays..............................................................................................33
9.4.1.1.3.
Hematologic Toxicity ...............................................................................34
9.4.1.1.4.
Nonhematologic Toxicity..........................................................................34
9.5.
Blinding .......................................................................................................................34
9.5.1.
Unblinding at Interim Analyses............................................................................35
9.5.2.
Emergency Unblinding ........................................................................................35
9.5.3.
Inadvertent Unblinding ........................................................................................35
9.6.
Concomitant Therapy...................................................................................................36
9.6.1.
Surgery and/or Radiotherapy for Locally Advanced Breast 
Cancer..................................................................................................................36
9.6.2.
Radiotherapy........................................................................................................36
9.6.3.
Supportive Care ...................................................................................................37
9.6.4.
Growth Factors ....................................................................................................37
9.6.5.
Therapy for Diarrhea............................................................................................37
9.6.6.
Bisphosphonates and RANK-L Targeted Agents..................................................37
9.6.7.
Ovarian Suppression with Gonadotropin-Releasing Hormone 
Agonists...............................................................................................................37
9.7.
Treatment Compliance .................................................................................................37
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................39
10.1. Efficacy Measures........................................................................................................39
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................39
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................40
10.1.3.
Primary Efficacy Measure....................................................................................40
10.1.4.
Secondary Efficacy Measures...............................................................................41
10.1.5.
Exploratory Efficacy Measures ............................................................................42
10.2. Health Outcome/Quality of Life Measures ...................................................................42
10.2.1.
Patient-Reported Outcomes..................................................................................42
10.2.1.1.
Pain Intensity..................................................................................................43
10.2.1.2.
Health-Related Quality of Life........................................................................43
10.2.1.3.
Health Status ..................................................................................................44

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10.2.2.
Resource Utilization.............................................................................................44
10.3. Safety Evaluations........................................................................................................45
10.3.1.
Adverse Events ....................................................................................................45
10.3.1.1.
Serious Adverse Events ..................................................................................47
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................48
10.3.2.
Other Safety Measures .........................................................................................48
10.3.2.1.
Electrocardiograms.........................................................................................48
10.3.3.
Safety Monitoring ................................................................................................49
10.3.4.
Complaint Handling.............................................................................................49
10.4. Sample Collection and Testing.....................................................................................50
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................50
10.4.2.
Samples for Tailoring Biomarkers........................................................................50
10.4.2.1.
Archived Tumor Tissue ..................................................................................51
10.4.2.2.
Blood Samples for Pharmacogenetic Evaluations............................................51
10.4.2.3.
Plasma Samples for Exploratory Biomarker Evaluations.................................51
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................52
10.5. Appropriateness of Measurements................................................................................52
11.
Data Quality Assurance.....................................................................................................53
11.1. Data Capture System....................................................................................................53
12.
Sample Size and Statistical Methods .................................................................................54
12.1. Determination of Sample Size ......................................................................................54
12.2. Statistical and Analytical Plans.....................................................................................54
12.2.1.
General Considerations ........................................................................................54
12.2.2.
Patient Disposition...............................................................................................55
12.2.3.
Patient Characteristics..........................................................................................55
12.2.4.
Concomitant Therapy...........................................................................................55
12.2.4.1.
Postdiscontinuation Therapy...........................................................................56
12.2.5.
Treatment Compliance .........................................................................................56
12.2.6.
Primary Outcome and Methodology.....................................................................56
12.2.7.
Secondary Outcome and Methodology.................................................................58
12.2.8.
Sensitivity Analysis..............................................................................................60
12.2.9.
Pharmacokinetic and Pharmacodynamic Analyses ...............................................61
12.2.10. Tailoring Biomarker Analyses..............................................................................62
12.2.11. Health Outcome/Quality of Life Analyses............................................................62
12.2.11.1. Pain Intensity..................................................................................................62
12.2.11.2. Pain Assessment.............................................................................................63
12.2.11.3. Health-Related Quality of Life........................................................................63

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12.2.11.4. Utilization ......................................................................................................63
12.2.11.5. Health State Utility.........................................................................................63
12.2.11.6. Time to First Skeletal-Related Event (TT1SRE) .............................................64
12.2.11.7. Time to Worsening ECOG Performance Status...............................................64
12.2.11.8. Exploratory Analyses .....................................................................................64
12.2.12. Safety Analyses....................................................................................................64
12.2.13. Subgroup Analyses ..............................................................................................65
12.2.14. Interim Analyses..................................................................................................66
12.2.14.1. Safety Interim Analyses..................................................................................66
12.2.14.2. Efficacy Interim Analyses...............................................................................66
12.2.14.3. Pharmacokinetic/Pharmacodynamic Interim Analyses....................................67
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................68
13.1. Informed Consent.........................................................................................................68
13.2. Ethical Review.............................................................................................................68
13.3. Regulatory Considerations ...........................................................................................68
13.3.1.
Investigator Information.......................................................................................69
13.3.2.
Protocol Signatures ..............................................................................................69
13.3.3.
Final Report Signature .........................................................................................69
14.
References ........................................................................................................................70

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List of Tables
Table
Page
Table JPBL.9.1.
Treatment Regimens/Dosing Schedule ...................................................31
Table JPBL.9.2.
Dose Adjustments for LY2835219..........................................................33
Table JPBL.10.1.
Secondary Efficacy Endpoints................................................................41
Table JPBL.10.2.
World Health Organization Pain Scale....................................................43
Table JPBL.10.3.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........45
Table JPBL.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................57
Table JPBL.12.2.
Property of the Design for Progression-Free Survival .............................58
Table JPBL.12.3.
Property of the Design for Overall Survival............................................59

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List of Figures
Figure
Page
Figure JPBL.8.1.
Illustration of study design......................................................................27
Figure JPBL.8.2.
Study period and extension period diagram.............................................29

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBL Study Schedule ...............................................................72
Attachment 2.
Protocol JPBL Clinical Laboratory Tests................................................79
Attachment 3.
Protocol JPBL Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................80
Attachment 4.
Protocol JPBL ECOG Performance Status..............................................81
Attachment 5.
Protocol JPBL RECIST Criteria 1.1........................................................82
Attachment 6.
Protocol JPBL Sampling Summary.........................................................89
Attachment 7.
Protocol JPBL Pharmacokinetic
Sampling Schedule .................................................................................90
Attachment 8.
Protocol JPBL Inducers and Strong Inhibitors of CYP3A4 .....................91

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

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LY2835219
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
EORTC BR23
EORTC Breast subscale, 23 items
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
EQ-5D 5L
EuroQol 5-Dimension 5 Level
extension period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit may continue to receive study 
therapy until one of the criteria for discontinuation is met.
FSH
follicle-stimulating hormone
GCP
good clinical practice
GnRH
gonadotropin-releasing hormone

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HER
human epidermal growth factor receptor
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IND
Investigational New Drug application
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LLT
Lower Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute

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OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PR
partial response
PRO/ePRO
patient-reported outcome/electronic patient-reported outcome
PS
performance status
PT
Preferred Term
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SMD
Lilly Senior Management Designee
SOC
System Organ Class
SRE
skeletal-related event
Study completion
This study will be considered complete following evaluation of additional overall 
survival data as determined by Lilly.  

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SUSARs
suspected unexpected serious adverse reactions 
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limits of normal
US
United States
VAS
visual analog scale

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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study of Fulvestrant with or without LY2835219, a CDK4/6 
Inhibitor, for Women with Hormone Receptor Positive, HER2 
Negative Locally Advanced or Metastatic Breast Cancer 
5.
Introduction
Breast cancer is one of the most common cancers among women in the United States and Europe
and is the second leading cause of cancer death in women. Early stage disease is treatable, but
metastatic breast cancer (mBC) has a median overall survival (OS) of only 2 to 3 years (Cardoso 
et al. 2012). While women who have been diagnosed with hormone receptor positive (HR+) 
mBC are typically treated with endocrine therapy, de novo or acquired resistance to endocrine 
therapy is a common clinical problem in this population.  Clinical studies have demonstrated that 
cyclinD is overexpressed in more than 50% of breast cancers, the majority of which are also 
estrogen receptor positive (ER+). CyclinD interacts directly with cyclin-dependent kinases 4 and 
6 (CDK4/6) in an active protein complex.  Therefore, CDK4/6 represents a potentially important 
target to address the unmet need for patients with mBC, in particular those with HR+ disease.
LY2835219 is a potent and selective small molecule inhibitor of CDK4/6.  In the Phase 1 Study 
I3Y-MC-JPBA (JPBA), LY2835219 has shown acceptable safety across five tumor-specific 
cohorts, with the most common treatment-emergent adverse events (TEAEs) possibly related to 
study drug including diarrhea, nausea, fatigue, vomiting, and neutropenia. Importantly, 
LY2835219 has demonstrated evidence of clinical activity in a tumor-specific cohort of women 
mBC.  In Study I3Y-MC-JPBA, 47 patients with a median of 7 prior systemic regimens received 
therapy with LY2835219.  Among the 36 patients with HR+ mBC, the median progression-free 
survival (PFS) was 9.1 months (with 18 patients still on LY2835219 therapy) and there were 
9 confirmed partial responses (PR) for an objective response rate of 25%.  In the same study, the 
combination of LY2835219 plus fulvestrant was also evaluated and demonstrated an acceptable 
safety profile for women with HR+ mBC.  These results support further investigation of 
LY2835219 in combination with fulvestrant for women with HR+ locally advanced or metastatic 
breast cancer.
Study I3Y-MC-JPBL is a randomized, double-blind, placebo-controlled Phase 3 study of 
fulvestrant with or without LY2835219 for women with HR+, human epidermal growth factor 
receptor 2 negative (HER2-) locally advanced (not amenable to curative treatment by surgery) or 
metastatic breast cancer.
More information about the known and expected benefits and risks of LY2835219 may be found 
in the Investigator’s Brochure (IB).  Information on adverse events (AEs) expected to be related 
to the study drug may be found in Section 7 (Development Core Safety Information) of the IB.  
Information on serious adverse events (SAEs) expected in the study population independent of 
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.

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More detailed information about the known and expected benefits and risks of fulvestrant may be 
found in the following:  Patient Information Leaflet, Package Insert, or Summary of Product 
Characteristics.

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6.
Objectives
6.1.
Primary Objective
The primary objective of Study JPBL is to compare LY2835219 plus fulvestrant versus placebo 
plus fulvestrant with respect to PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
6.2.
Secondary Objectives
The secondary objectives of the study are to compare LY2835219 plus fulvestrant versus 
placebo plus fulvestrant with respect to each of the following:

overall survival (OS)

OS rate at 1, 2, and 3 years

objective response rate [complete response (CR) + partial response (PR)]

duration of response (DoR) [CR + PR]

disease control rate (DCR) [CR + PR + stable disease (SD)]

clinical benefit rate (CBR) [CR + PR + SD ≥6 months]

safety and tolerability using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE Version 4.03)

pain and symptom burden using the Brief Pain Inventory (BPI), the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30) and the EORTC QLQ-BR23 (breast) questionnaires, 
and health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L)

pharmacokinetics (PK) of LY2835219, its metabolites, and fulvestrant

time to worsening of Eastern Cooperative Oncology Group (ECOG) performance 
status

time to first skeletal-related event (SRE; defined as either pathological fracture, spinal 
cord compression, radiation to the bone, or surgery to the bone)
(Refer to Table JPBL.10.1 Secondary Time-to-Event Efficacy Endpoints)
6.3.
Exploratory Objectives

To explore potential biomarkers related to the retinoblastoma (Rb) pathway and/or 
the pathogenesis of breast cancer

To explore if change in tumor size is associated with PFS and OS

To explore time to progressive bone metastases by treatment arm

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

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[3]
have postmenopausal status due to either surgical/natural menopause or 
ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with 
a gonadotropin-releasing hormone (GnRH) agonist such as goserelin. 
Postmenopausal status due to surgical/natural menopause requires at least 1 of 
the following:

prior bilateral oophorectomy

age ≥60 years

age <60 years and amenorrheic for at least 12 months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression) and 
follicle-stimulating hormone (FSH) and estradiol levels in the 
postmenopausal range
[4]
have a negative serum pregnancy test at baseline (within 14 days prior to 
randomization) and agree to use medically approved precautions to prevent 
pregnancy during the study and for 12 weeks following the last dose of 
LY2835219 if postmenopausal status is due to ovarian suppression with a 
GnRH agonist
[5]
have either measurable disease or nonmeasurable bone only disease.  
Measurable and nonmeasurable disease are defined according to the Response 
Evaluation Criteria in Solid Tumors (RECIST Version 1.1 [v1.1], Eisenhauer 
et al. 2009; refer to Attachment 5).  Nonmeasurable bone only disease may 
include any of the following:  blastic bone lesions, lytic bone lesions without a 
measurable soft tissue component, or mixed lytic-blastic bone lesions without 
a measurable soft tissue component.
[6]
are female and >18 years of age
[7]
have given written informed consent prior to any study-specific procedures
[8]
have adequate organ function, including:

hematologic:  absolute neutrophil count 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator; however, initial study drug treatment must not begin earlier 
than the day after the erythrocyte transfusion.

hepatic:  bilirubin 1.5 times upper limit of normal (ULN) and alanine 
aminotransferase (ALT) ≤3.0 times ULN

renal:  serum creatinine 1.5 times ULN
[9]
have a performance status ≤1 on the ECOG scale

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[10] have discontinued previous therapies for cancer (including specifically,
aromatase inhibitors, anti-estrogens, chemotherapy, radiotherapy, and
immunotherapy) for at least 21 days for myelosuppressive agents or 14 days 
for nonmyelosuppressive agents prior to receiving study drug, and recovered 
from the acute effects of therapy (until the toxicity resolves to either baseline
or at least Grade 1) except for residual alopecia or peripheral neuropathy
[11] are willing to participate for the duration of the study and to follow study 
procedures
[12] are able to swallow capsules
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[13] are currently receiving an investigational drug in a clinical trial or 
participating in any other type of medical research judged not to be 
scientifically or medically compatible with this study.  If a patient is currently 
enrolled in a clinical trial involving non-approved use of a device, then 
agreement with the investigator and Lilly clinical research physician (CRP) is 
required to establish eligibility.
[14] have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis.  
Visceral crisis is not the mere presence of visceral metastases but implies 
severe organ dysfunction as assessed by symptoms and signs, laboratory 
studies, and rapid progression of the disease.
[15] have clinical evidence or history of central nervous system metastasis. 
Screening is not required for enrollment.
[16] have received prior treatment with chemotherapy (except for neoadjuvant/ 
adjuvant chemotherapy), fulvestrant, everolimus, or any CDK4/6 inhibitor
[17] have received treatment with a drug that has not received regulatory approval
for any indication within 14 or 21 days prior to randomization of study drug 
for a nonmyelosuppressive or myelosuppressive agent, respectively
[18] have received recent (within 28 days prior to randomization) yellow fever 
vaccination
[19] have had major surgery within 14 days prior to randomization of study drug to 
allow for post-operative healing of the surgical wound and site(s).
[20] have a personal history of any of the following conditions: presyncope or 
syncope of either unexplained or cardiovascular etiology, ventricular
tachycardia, ventricular fibrillation, or sudden cardiac arrest
[21] have serious preexisting medical conditions that, in the judgment of the
investigator, would preclude participation in this study (for example, history
of major surgical resection involving the stomach or small bowel)

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

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

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8.
Investigational Plan
8.1.
Summary of Study Design
Study I3Y-MC-JPBL (JPBL) is a multicenter, randomized, double-blind, Phase 3 trial for 
women with HR+, HER2- locally advanced or metastatic breast cancer.  Figure JPBL.8.1
illustrates the study design.
Abbreviations:  HR+ = hormone receptor positive; HER2- = human epidermal growth factor 
receptor 2 negative; N = number; PD = progressive disease.
Figure JPBL.8.1.
Illustration of study design.
Approximately 550 patients will be randomized 2:1 between the 2 arms:

Experimental Arm A:  LY2835219 200 mg orally every 12 hours on Days 1 to 28 of a 
28-day cycle plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then 
on Day 1 of Cycle 2 and beyond

Control (Placebo) Arm B:  Placebo orally every 12 hours 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
Patients will be randomized using the following stratification factors: nature of disease (visceral
metastases versus bone only metastases versus other) and sensitivity to endocrine therapy (no 
prior endocrine therapy versus primary resistance versus secondary resistance).  The study 
population will be monitored upon enrollment to include no more than 100 endocrine therapy 
naïve patients.  The presence of visceral metastases refers to lung, liver, pleural, or peritoneal 
involvement at the time of randomization. Primary clinical resistance to endocrine therapy is 
defined as follows:  1) for endocrine therapy in the adjuvant setting, recurrence within the first 
2 years of adjuvant endocrine therapy while on endocrine therapy or 2) for endocrine therapy in 
the locally advanced or metastatic setting, progression within first 6 months of initiating first-line 
endocrine therapy while on endocrine therapy.  Patients receiving prior endocrine therapy who 
do not meet the definition of primary clinical resistance will be considered to have secondary 
clinical resistance.

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Data base lock for the interim analysis for efficacy will occur when at least 270 investigator-
assessed PFS events have been observed. Database lock for the primary analysis of the PFS 
endpoint will occur when at least 385 investigator-assessed PFS events have been observed. All 
patients will be followed for progression and survival information until death or study 
completion, whichever occurs first.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form (ICF) is signed and ends at the first 
study treatment (or at discontinuation, if no treatment is given).

Study Period:  begins at the first study treatment and ends at study completion. The 
study period does not include the extension period.
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from study treatment.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.
Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment and lasts 
approximately 30 days.
Long-term follow-up begins the day after short-term follow-up is completed 
and continues until the patient’s death or overall study completion.

Extension Period:  begins after study completion and ends at the end of trial.  During the 
extension period, patients on study therapy who continue to experience clinical benefit 
may continue to receive study therapy until one of the criteria for discontinuation is met.  
The extension period includes extension period short-term follow-up.
o
Extension period short-term follow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment in the 
extension period and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the evaluation of final OS data (refer to Figure JPBL.8.2), as determined 
by Lilly.  Investigators will continue to follow the study schedule for all patients until notified by 
Lilly that study completion has occurred.  “End of trial” refers to the date of the last visit or last 
scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed extension period follow-up (Figure JPBL.8.2).

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

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

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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Experimental Arm A:  LY2835219 200 mg orally every 12 hours on Days 1 to 28 of a 
28-day cycle plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then 
on Day 1 of Cycle 2 and beyond

Control (Placebo) Arm B:  Placebo orally every 12 hours 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
For both experimental and control arms, fulvestrant 500 mg should be administered 
intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, 
one in each buttock; however, for patients with moderate hepatic impairment (defined as 
Child-Pugh Class B), including any patient who develops moderate hepatic impairment during 
study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock 
slowly (1 to 2 minutes) as one 250-mg injection.
Table JPBL.9.1 shows the treatment regimens.
Table JPBL.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose Day
Experimental Arm A
LY2835219
Treatment/28-day cycle
200 mg PO Q12H on Days 1-28
Fulvestrant
Treatment/28-day cycle
500 mg IM on Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyond
Control (Placebo) Arm B
Placebo
Treatment/28-day cycle
PO Q12H on Days 1-28
Fulvestrant
Treatment/28-day cycle
500 mg IM on Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyond
Abbreviations:  IM = intramuscular; PO = orally; Q12H = once every 12 hours.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative

verifying that instructions are followed properly

maintaining accurate records for dispensing and collection of study drugs

returning all unused medication to Lilly or its designee at the end of the study
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 so that the situation can be assessed.
9.2.
Materials and Supplies
LY2835219 will be supplied as capsules for oral administration. LY2835219 capsules should be 
stored at room temperature according to the product label, and not opened, crushed, or dissolved.  
Investigators should instruct patients to store the capsules in the original package and in a
location inaccessible to children. LY2835219 will be labeled according to the country’s 
regulatory requirements.
Depending on country requirements, fulvestrant will be supplied by the site or centrally sourced 
by Lilly as 250-mg prefilled syringes (250 mg/5 mL). Sites should confirm fulvestrant source to 
ensure adequate supply.  Fulvestrant should be stored according to the instructions on the 
product label and administered according to the instructions in the protocol. Where fulvestrant is
supplied by Lilly, it will be labeled according to the country’s regulatory requirements.
9.3.
Method of Assignment to Treatment
Upon obtaining informed consent, site personnel should access the interactive web response 
system (IWRS) which will assign a patient number. Patients who meet all criteria for enrollment 
will be randomly assigned to receive either LY2835219 plus fulvestrant or placebo plus 
fulvestrant.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using the IWRS.
Randomization will be stratified by the following: nature of disease (visceral metastases versus 
bone only metastases versus other) and sensitivity to endocrine therapy (no prior endocrine 
therapy versus primary resistance versus secondary resistance).
The IWRS will be used to assign LY2835219/placebo and fulvestrant (where supplied). Site 
personnel will confirm that they have located the correct study medication packages by entering 
a confirmation number found on the packages into the IWRS.
9.4.
Selection and Timing of Doses
LY2835219 will be taken orally every 12 (±2) hours on Days 1 through 28 of a 28-day cycle, for 
a total of 56 doses per cycle.  Patients should not consume food beginning 1 hour before and 
ending 1 hour after taking LY2835219.  During all cycles, LY2835219 should be taken at 
approximately the same times each day.  If a patient misses or vomits a dose, that dose should be 
omitted.
Fulvestrant should be administered at the same time as (or up to 20 minutes after) the morning 
dose of LY2835219, except when specified otherwise in the PK Sampling Schedule 
(Attachment 7).  Fulvestrant will be administered intramuscularly on Days 1 and 15 of Cycle 1, 
then on Day 1 of Cycle 2 and beyond.  For Cycle 3 and beyond, the interval between LY2835219 
and fulvestrant may be adjusted based on the judgment of the investigator.

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A cycle is defined as the planned treatment interval of 28 days plus any subsequent delay prior to 
start of the next cycle.  A delay in the start of a cycle due to holidays, weekends, bad weather, or 
other unforeseen circumstances will be permitted up to 7 days and not counted as a protocol 
deviation). No more than 56 doses of LY2835219 should be dispensed for each 28-day cycle.
A patient may continue to receive study drug(s) until she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3.1).
9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
9.4.1.1.1. Dose Adjustments
9.4.1.1.1.1.
LY2835219
LY2835219 dose adjustments are allowed both within a cycle and between cycles.  LY2835219 
must be reduced as outlined in Table JPBL.9.2.
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 JPBL.9.2, then the investigator
must discuss with the Lilly CRP prior to any further dose reduction.
For patients requiring dose reduction(s), re-escalation to a prior dose level is permitted only after
consultation with the Lilly CRP.
Table JPBL.9.2.
Dose Adjustments for LY2835219
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
3
50 mg
Every 12 hours
In the event that LY2835219 or placebo must be discontinued, a patient may continue to receive 
fulvestrant.
9.4.1.1.1.2.
Fulvestrant
Dose adjustment for fulvestrant will be determined by the investigator in accordance with the 
label.  For patients with moderate hepatic impairment (defined as Child-Pugh Class B), including 
any patient who develops moderate hepatic impairment during study treatment, fulvestrant 
250 mg should be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one 
250-mg injection.  In the event that fulvestrant must be discontinued, a patient may continue to 
receive LY2835219 or placebo.
9.4.1.1.2. Dose Delays
The start of a cycle may be delayed up to 14 days to allow sufficient time for recovery from 
toxicity possibly related to a study drug.  During such a delay, LY2835219/placebo and 
fulvestrant should not be administered.  Patients not recovering from toxicity within 14 days 

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beyond the last day of the prior cycle should be considered for dose adjustment or 
discontinuation of the relevant study drug(s).  In exceptional circumstances, a delay >14 days is 
permitted upon agreement between the investigator and the Lilly CRP.
The start of a cycle may be delayed up to 7 days for logistical reasons (for example, due to 
patient availability).  During such a delay, LY2835219/placebo and fulvestrant should not be 
administered.  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 a 
locally advanced breast cancer rendered operable by study treatment to receive surgery 
radiotherapy.  For additional information, refer to Section 9.6.1.
9.4.1.1.3. Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity possibly related to LY2835219, then
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 2) and
the dose of LY2835219 must be reduced as outlined in Table JPBL.9.2.
Before the start of each cycle, hematologic toxicity possibly related to LY2835219 must resolve
to either baseline or at least Grade 2.
9.4.1.1.4. Nonhematologic Toxicity
If a patient experiences ≥ Grade 3 nonhematologic toxicity possibly related to LY2835219, then
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 1) and
the dose of LY2835219 must be reduced as outlined in Table JPBL.9.2.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (such as
diarrhea) possibly related to LY2835219 that does not resolve with maximal supportive measures
within 7 days to either baseline or Grade 1, then dosing may be suspended (until the toxicity
resolves to either baseline or at least Grade 1) and the dose of LY2835219 may be reduced as
outlined in Table JPBL.9.2.
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) possibly
related to LY2835219 must resolve to either baseline or at least Grade 1.
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.

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Efficacy information will not be shared with sites until the study is completed.  Upon overall 
study completion (see Section 8.1.1), investigators may unblind patients to study treatment 
assignment.
9.5.1. Unblinding at Interim Analyses
Interim analyses for safety and efficacy will be conducted, using unblinded data, under the 
guidance of an independent Data Monitoring Committee (DMC).  The DMC will consist of at 
least 3 members, including at least 1 clinician and 1 statistician.  The DMC will communicate 
any recommendations based on interim analysis to the Lilly Senior Management Designee 
(SMD). If necessary, the SMD may form an Internal Review Committee (IRC) to review and act 
upon the recommendations of the DMC.  See Section 12.2.14 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. It is not acceptable to unblind a patient’s treatment assignment through direct
discussions with unblinded site staff. Every effort should be made to maintain a separation
between blinded and unblinded site staff during the course of the study.
All calls resulting in an unblinding event are recorded and reported by the IWRS. If the
investigator or patient becomes unblinded, that patient will undergo postdiscontinuation 
follow-up (Attachment 1).
9.5.3. Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms.  If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 
for that patient to be discontinued from study therapy or excluded from any safety or efficacy 
analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.

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9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRFs and should be recorded throughout the 
patient’s participation in the study.  Concomitant medications and supportive care therapies must 
also be documented at the time of discontinuation and at the 30-day short-term follow-up visit.
With the exceptions listed in the sections below, therapies for cancer (including specifically 
aromatase inhibitors, anti-estrogens other than fulvestrant, chemotherapy, and immunotherapy) 
will not be permitted while patients are on study treatment.  Use of megestrol acetate as an 
appetite stimulant is not permitted.
The results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study 
indicate that oxidative metabolism of LY2835219 is primarily catalyzed by CYP3A4. However, 
the extent of oxidative metabolism responsible for the systemic clearance of LY2835219 in 
humans is presently unknown. Based on these in vitro findings, grapefruit juice as well as 
inducers (for example, phenytoin or carbamazepine) and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 8).  In addition, in vitro studies in primary cultures 
of human hepatocytes indicate that LY2835219 might inhibit the metabolism of CYP2B6 
substrate drugs in vivo in humans.  Based on this finding, bupropion and efavirenz, which are 
sensitive CYP2B6 substrates, should be substituted or avoided if possible.
9.6.1. Surgery and/or Radiotherapy for Locally Advanced Breast 
Cancer
A patient with locally advanced breast cancer may receive surgery radiotherapy if study 
treatment renders the tumor operable.  However, such a patient should not receive study 
treatment for the period beginning at least 7 days prior to surgery and continuing until at least 
14 days after completion of surgery radiotherapy to allow for tissue healing and recovery.  
There is no restriction on the duration of this period without study treatment and, after this period 
ends, study treatment and protocol procedures (Attachment 1) should either resume based upon 
the most recent cycle completed prior to surgery radiotherapy or the patient should be 
discontinued from study treatment.  Importantly, a patient who receives surgery radiotherapy 
for locally advanced breast cancer is not considered noncompliant and does not incur a protocol 
deviation.
9.6.2. Radiotherapy
Except as described in Section 9.6.1, radiotherapy is not permitted without permanent 
discontinuation from study treatment.  Except for a patient with locally advanced breast cancer 
rendered operable by study treatment who subsequently undergoes surgery + radiotherapy, all 
other patients requiring radiotherapy should discontinue permanently from study treatment and 
have a tumor assessment of the lesion(s) before receiving radiotherapy.

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9.6.3. Supportive Care
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care as judged by their treating physician.  If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported in the eCRFs.
9.6.4. Growth Factors
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2006; 
Rizzo et al. 2008).
9.6.5. Therapy for Diarrhea
For diarrhea, at the first sign of loose stools, initiation of treatment with antidiarrheal agents (for 
example, loperamide) is recommended.  For patients with persistent diarrhea, refer to the dose 
adjustment guidelines in Section 9.4.1.1.1.1.
9.6.6. Bisphosphonates and RANK-L Targeted Agents
Use of bisphosphonates or approved RANK-L targeted agents (for example, denosumab) is 
permitted during participation in the study. Patients should if possible begin treatment with 
bisphosphonates or RANK-L targeted agents before or concurrently with initial study treatment.  
Patients who start the study receiving bisphosphonates or RANK-L targeted agents should, if 
possible, avoid switching treatments (for example, replacing a bisphosphonate with denosumab) 
while on study treatment.  After study treatment discontinuation, use of bisphosphonates or 
RANK-L targeted agents is at the discretion of the treating physician.
9.6.7. Ovarian Suppression with Gonadotropin-Releasing Hormone 
Agonists
Patients who are postmenopausal due to ovarian suppression should, if possible, continue GnRH 
agonist therapy during study treatment.
9.7.
Treatment Compliance
Treatment compliance information for study drugs will be collected through counts at each visit, 
and the number of capsules taken relative to the number expected to be taken will be summarized 
for each cycle.  The patient must take ≥75% of the planned doses for assigned study drug in a 
cycle to be deemed compliant.  Similarly, a patient may be considered noncompliant if she is 
judged by the investigator to have intentionally or repeatedly taken ≥125% of the planned doses 
of study drug in a cycle.
Importantly, a patient who receives surgery radiotherapy for locally advanced breast cancer is 
not considered noncompliant and does not incur a protocol deviation.  For additional 
information, refer to Section 9.6.1.

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Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP or clinical research scientist before any determination is made 
to discontinue the patient.

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

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with bone windows, or MRI will be performed to confirm findings as described in the 
Study Schedule (Attachment 1).
Responses (CR or PR) must be confirmed no less than 28 days from the first evidence of 
response.
For patients continuing treatment after study completion, efficacy assessments (frequency and 
type of assessments) will be at the discretion of the investigator.
10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1).
For those patients who discontinue study treatment without objectively measured progressive 
disease (PD), the investigative sites will continue to monitor patients and periodically evaluate 
tumor response approximately every 8 weeks for the first 12 months following randomization 
and thereafter approximately every 12 weeks by the same method used at baseline and 
throughout the study until the patient has objective disease progression, or until the primary 
analysis of PFS.  After the patient has objective disease progression, radiologic tests are no 
longer required and the patient will be followed up approximately every 12 weeks (14 days)
until the patient’s death or overall study completion.
After study completion, efficacy assessments (frequency and type of assessments) will be at the 
discretion of the investigator.
10.1.3. Primary Efficacy Measure
The primary efficacy measure is progression-free survival as defined by RECIST Version 1.1 
(Eisenhauer et al. 2009) provided in Attachment 5.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  An independent review of imaging scans will be performed by an
independent panel of radiologists.
The PFS time is measured from the date of randomization to the date of objective progression or 
the date of death due to any cause, whichever is earlier.
For those patients with nonmeasurable, bone only disease (refer to Inclusion Criterion [5]), 
objective progression will be established if at least 1 of the following criteria is met:

the appearance of 1 or more new lesions (in bone or outside of bone), or

unequivocal progression of existing bone lesions.
Pathologic fracture, new compression fracture, or complications of bone metastases will not be 
considered as evidence of disease progression, unless at least 1 of the above criteria is met.

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For those patients with locally advanced disease for whom surgery is performed with no 
evidence of residual disease post-operatively, objective progression will be established if at least 
1 of the following criteria is met:

local recurrence, or

new development of metastatic disease.
For those patients with locally advanced disease for whom surgery is performed with evidence of 
residual disease post-operatively, new baseline measurements should be taken and RECIST 
applied.
If a patient is not known to have progressed or died at the time of analysis, PFS time will be 
censored at the last known progression-free assessment.  See Section 12.2.6 for detailed 
censoring rules.
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBL.10.1) will be collected at the times 
shown in the Study Schedule (Attachment 1).
Table JPBL.10.1.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall Survival (OS)
The time from the date of randomization to the date of death from any cause
Objective Response Rate
The proportion of patients with CR or PR according to RECIST v1.1
Disease Control Rate (DCR)
The proportion of patients with CR, PR, or SD according to RECIST v1.1
Duration of Response (DoR)
The time from the date of first evidence of a confirmed CR or PR to the date of 
objective progression or death from any cause, whichever is earlier
Time to Worsening ECOG 
Performance Status (PS)
The time from the date of randomization to the date of first PS ≥2
Time to First Skeletal-
Related Event (TTFSRE)
The time from the date of randomization to the date of first:

Spinal cord compression OR

Pathological fracture OR

Radiation to bone OR

Surgery to bone
Abbreviations:  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.

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Duration of Response (DoR):  The DoR time is defined only for responders (patients with a 
confirmed CR or PR).  It is measured from the date of first evidence of CR or PR to the date of 
objective progression or the date of death due to any cause, whichever is earlier.  For clarity, the 
start date should be determined by the initial assessment of CR or PR, not the date of 
confirmation of CR or PR.  If a responder is not known to have died or have objective 
progression as of the data inclusion cutoff date scores, duration of response will be censored at 
the last complete objective progression-free disease assessment date.
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.
Time to First Skeletal-Related Event (TTFSRE): Patients will be monitored for development 
of SREs at each cycle.  An SRE will be defined as any of the following: spinal cord 
compression, pathological fracture, radiation to bone, or surgery to bone. The anatomic location, 
days of hospitalization, relatedness to breast cancer, and procedure(s) used for treatment will be 
captured.  Bone survey will be monitored according to the Study Schedule (Attachment 1).
TTFSRE and a comparison of the frequency of SREs between treatments will be conducted at 
the end of the study. TTFRSE is defined as the time from randomization to documentation of the 
first postbaseline occurrence of any SRE. Patients not known to have had an SRE at the time of 
the analysis will be censored at the date of their last complete documented assessment for SRE.
SRE-specific information should be collected until patient death, loss to follow-up, or study 
completion.
Time to Worsening ECOG Performance Status:  will be defined as the time from 
randomization to an ECOG performance status evaluation of 2 or worse.  Patients with no 
evaluation of 2 or worse will have their time to deterioration of performance status censored at 
the date of the last performance status evaluation.
10.1.5. Exploratory Efficacy Measures
Time to 
Progression of 
Bone Metastases
The time from the date of randomization to the date of earliest development of new bone 
metastases 
10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
The primary health outcomes research goal is to determine if LY2835219 combination therapy is 
able to palliate pain, as measured by the mBPI-sf (Cleeland 1991).  Additionally, the EORTC 
QLQ-C30 (Aaronson et al. 1993) will assess the broader impact of LY2835219 combination 
therapy on quality of life, the EORTC QLQ-BR23 (Sprangers et al. 1996) will collect disease-
specific data, and the EQ-5D 5L (Janssen et al. 2008) health status assessment will allow for 
comparison with other tumor types and disease states.

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Patient-reported questionnaires should be completed by patients when a language translation is 
available in which the patient is fluent or literate.
At each time point identified in the Study Schedule (Attachment 1), a paper copy of the mBPI-sf, 
EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D 5L questionnaires should be administered 
to the patient prior to extensive interaction with site staff and study drug administration.
10.2.1.1. Pain Intensity
The mBPI-sf (Cleeland 1991) is an 11-item instrument used as a multiple-item measure of cancer 
pain intensity.  In addition to pain intensity (4 items), the mBPI-sf is designed for patients to 
record the presence of pain in general, pain relief, and pain interference with function (general 
activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, and 
enjoyment of life).
Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales 
anchored at 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can 
imagine or completely interferes).  The mBPI-sf recall period is 24 hours, and pain relief is 
assessed with a scale range from 0% (no relief) through 100% (complete relief).  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 1 of 6 categories, using an 
analgesic ladder approach with medication category based on a World Health Organization scale 
outlined in Table JPBL.10.2.  A therapy category will be assigned according to the maximum 
category of therapy administered based on analgesic data for that cycle.  Category of pain 
medication for each cycle will be determined based on the data collected on analgesic use by 
Anatomical Therapeutic Chemical code.
The BPI population will include all patients who completed at least 1 baseline followed by at 
least 1 BPI “worst pain” assessment after 1 cycle of study drug (Cycle 2 Day 1 or later).
Table JPBL.10.2.
World Health Organization Pain Scale
Code
Description
0
No analgesia
1
Aspirin (for pain, not cardiovascular prophylaxis), acetaminophen, nonsteroidal anti-inflammatory drugs
2
Codeine, hydrocodone, pentazocine, oxycodone
3
Oral morphine, hydromorphone, methadone, transdermal fentanyl
4
Parenteral opiates
5
Neurosurgical procedures (blocks)
10.2.1.2. Health-Related Quality of Life
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC 
QLQ-C30 (Aaronson et al. 1993) is a reliable and validated tool that has supported quality-of-life 

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claims in both Food and Drug Administration (FDA) and European Medicines Evaluation 
Agency (EMA) labels.  The EORTC QLQ-C30 self-reported general cancer instrument 
(Aaronson et al. 1993) consists of 30 items covered by 1 of 3 dimensions:

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact)
The EORTC QLQ-BR23 (Sprangers et al. 1996) consists of 23 items covered by the following 
scales:

functional (body image and sexuality)

symptom scales (arm, breast, and systemic therapy side effects)
The EORTC QLQ-C30 and EORTC QLQ BR23 questionnaires are administered per the 
Study Schedule (Attachment 1). The recall period is the past week, completion time is typically 
5 to 7 minutes, and both questionnaires will be scored as described by the EORTC scoring 
manual (Fayers et al. 2001).  The EORTC population will include all patients who completed at 
least 1 baseline followed by at least 1 EORTC assessment after 1 dose of study drug (Cycle 2 
Day 1 or later).
10.2.1.3. Health Status
The EQ-5D 5L (Janssen et al. 2008) is a standardized instrument for use across diseases as a 
measure of self-reported health status.  Specifically, this questionnaire is included in this trial to 
evaluate health-state utilities associated with advanced breast cancer.  These utility measures are 
an important input for economic evaluations concerning the value of treatment interventions.
The EQ-5D 5L is designed to be used in conjunction with other patient-reported measures.  
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the Study Schedule (Attachment 1).  A visual analog scale (VAS) 
"thermometer" measures current health state.  EQ-5D 5L responses may be incorporated into 
cost utility analyses, but will not be included in the clinical study report.
Administration is preferably scheduled after the BPI and the EORTC, and before extensive 
contact with study personnel or clinicians, which could result in biased patient response.  The 
recall period is “today.”  The EQ-5D 5L is designed for self-completion by respondents and is 
cognitively simple, taking only a few minutes to complete.
The EQ-5D 5L population will include all patients who completed at least 1 baseline followed by 
at least 1 EQ-5D 5L assessment after 1 dose of study drug.
10.2.2. Resource Utilization
Investigators will be asked to report the use of concomitant medications (in particular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 

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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 JPBL.10.3 presents a summary of AE and SAE reporting guidelines.  Table JPBL.10.3
also shows which database or system is used to store AE and SAE data.
Table JPBL.10.3.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study drug or drug delivery system
x
x
Extension period
All AEs
x
All SAEs
x
x
Extension period follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study therapy and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study drug or drug delivery system
that the investigator becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 

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associated with the use of a drug or drug delivery system in humans, whether or not it is 
considered related to that drug or drug delivery system.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, and other procedures that result in a diagnosis should be reported to Lilly or its 
designee.
Cases of pregnancy that occur during maternal exposures to study drug should be reported.  Data 
on fetal outcome and breast-feeding are collected for regulatory reporting and drug safety 
evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drugs via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug or procedure, the following terminologies are 
defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug/study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator will be responsible 

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for selecting the appropriate system organ class and assessing severity grade based on the 
intensity of the event.
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA®).
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If alerts are 
issued via telephone, they are to be immediately followed with official notification on study-
specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for

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example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
When a condition related to the prefilled fulvestrant syringes necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent damage to 
a body structure, the serious outcome of “required intervention” will be assigned on the eCRF.
If an investigator becomes aware of an SAE occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure, a study 
drug, or prefilled fulvestrant syringes, the investigator should report the SAE to the sponsor, and 
the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.3.1.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 
related to the study drug or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
10.3.2. Other Safety Measures
10.3.2.1.
Electrocardiograms
For each patient, a local 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, if clinically indicated.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present for immediate patient management, should any clinically relevant findings 
be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, or syncope) and to determine if the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation.

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10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as is appropriate, consult with the functionally independent GPS therapeutic area physician 
or clinical scientist, and review:

trends in safety data

laboratory analytes

adverse events

If a patient experiences elevated ALT 5 times ULN and elevated total bilirubin 2
times ULN, clinical and laboratory monitoring should be initiated by the investigator.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of 
specifically recommended clinical information and follow-up laboratory tests. See
Attachment 3.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (an advisory group for this study formed to protect 
the integrity of data; refer to Section 12.2.14) can conduct additional analyses of the safety data.
For the purpose of this study, in which survival is a key efficacy endpoint, all deaths and SAE 
reports will be reviewed in a blinded manner by Lilly during the clinical trial.  These reports will 
be reviewed to assure completeness and accuracy but will not be unblinded to Lilly during the 
clinical trial.  If a death or other clinical AE is deemed serious, unexpected, and possibly related 
to study drug, only Lilly GPS representatives external to the study team will be unblinded for 
regulatory reporting and safety monitoring purposes.  These measures will preserve the integrity 
of the data collected during this trial and minimize any potential for bias while providing for 
appropriate safety monitoring.
10.3.4. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Complaints related to fulvestrant or the prefilled fulvestrant syringes should be reported directly 
to the manufacturer in accordance with the package insert.
Complaints related to LY2835219 should be reported directly to Lilly.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee

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If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
Attachment 7 lists the schedule for PK sampling during the study.
10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Enrollment and treatment decisions may be based upon results of 
tests performed locally.  If local laboratory tests are used for this purpose, then a duplicate 
specimen must be submitted to the central laboratory.  Discrepancies between local and central 
laboratory that may have an impact on eligibility or treatment decisions will not be considered 
protocol deviations.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Tailoring Biomarkers
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Samples for biomarker research to be collected from all patients in this study:

blood

tumor tissue
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.
These samples are described in the following sections.

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10.4.2.1. Archived Tumor Tissue
For patients in the study, a small amount of preserved tumor tissue, previously taken to evaluate 
the patient’s disease, should be requested for biomarker research.  Formalin-fixed paraffin-
embedded tumor tissue should be in a whole block, partial block, or unstained slides.  Any whole 
block submitted will be returned to the site.  Any partial blocks or slides will either be returned 
or discarded within 5 years after last patient visit for the trial.
In tumor tissue samples, the CDK4/6 pathway components (for example, Rb) and markers 
relevant breast cancer pathogenesis may be evaluated to assess any potential correlation with 
response to LY2835219.  Tumor samples may be analyzed to explore potential tumor gene
signature(s) associated with response or resistance to LY2835219 therapy. These studies may be 
analyzed at a laboratory designated by the sponsor and may include IHC of proteins, FISH for 
copy number amplifications, RNA gene-expression profiling, and/or genetic analyses of the 
tumor specimen DNA.  Such analyses may employ targeted or high-throughput sequencing 
approaches. For this purpose, the results of this analysis will be correlated with clinical efficacy 
data.
10.4.2.2. Blood Samples for Pharmacogenetic Evaluations
Where local regulations and ERBs allow, a blood sample will be collected for pharmacogenetic 
analysis. Samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to LY2835219.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.4.2.3. Plasma Samples for Exploratory Biomarker Evaluations
Plasma samples will be collected and analysis may be performed on biomarkers that may play a 
role in the LY2835219 mechanism of action (refer to Attachment 1).  The evaluation of these 
samples may involve analysis of DNA, RNA, and proteins (including any of these components 
derived from exosomes) to investigate their association with observed clinical outcomes to study 
drug. The samples will be coded with the patient number and stored for up to a maximum 
15 years.  Details for collecting, processing, and storing the samples are similar those provided in 
Section 10.4.2.2.

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10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics
At the visits and times specified in the Pharmacokinetic Sampling Schedule (Attachment 7), 
venous blood samples of approximately 4 mL each will be collected to determine the plasma 
concentrations of LY2835219 and its metabolites LSN2839567, LSN3106726, and 
LSN3106729, as well as plasma concentrations of fulvestrant.
Separate blood samples are not required for the parent, its metabolites, and fulvestrant. After 
obtaining plasma, samples will be aliquoted into 2 approximately equal portions by site 
personnel, one for the determination of plasma concentrations of LY2835219 and its metabolites 
and the other for the determination of plasma concentrations of fulvestrant.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  It is preferred that the 
blood samples be obtained from a peripheral location.  Blood samples will be allowed from 
central access devices, but a sample drawn from a central catheter of any type for PK must take 
precautions to prevent obtaining a dilute sample.  If multiple samples are obtained centrally, the 
PK sample should be the last specimen drawn to reduce the potential for a diluted or improperly 
drawn sample.  The actual date and time (24-hour clock time) of each sampling will be recorded.
A maximum of 5 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and Lilly.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of LY2835219 plus its metabolites LSN2839567, LSN3106726, and 
LSN3106729 will be assayed using a validated liquid chromatography/tandem mass 
spectrometry (LC/MS/MS) method.  Plasma concentrations of fulvestrant will also be analyzed 
using a validated LC/MS/MS method. Bioanalytical samples collected to measure study drug
concentration and metabolism and/or protein binding, will be retained for a maximum of 1 year 
following last patient visit for the study. The PK samples will be stored at a facility designated 
by the sponsor.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between effective and ineffective 
agents.
Safety measurements by laboratory monitoring are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between agents with acceptable and 
unacceptable safety profiles.

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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
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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 LY2835219 plus fulvestrant versus placebo 
plus fulvestrant in terms of PFS for women with HR+, HER2- locally advanced or metastatic 
breast cancer.
The study will enroll approximately 550 patients in 2:1 randomization. Patients will be 
randomized using the following stratification factors:  nature of disease (visceral metastases
versus bone only metastases versus other) and sensitivity to endocrine therapy (no prior 
endocrine therapy versus primary resistance versus secondary resistance).
A 2-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and primary PFS analyses (see Section 12.2.6 for details). The 
primary PFS analysis will be performed after 385 PFS events have occurred (that is, a 30%
censoring rate).  Assuming a hazard ratio (HR) of 0.703, this sample size yields at least 90% 
statistical power to detect superiority of the LY2835219 plus fulvestrant arm over the placebo 
plus fulvestrant arm with the use of a 1-sided log-rank test and a type I error of 0.025. If the true 
median PFS for the placebo plus fulvestrant arm is 6.5 months, then the HR of 0.703 amounts to 
an approximately 2.75-month (42%) improvement in median PFS for the LY2835219 plus 
fulvestrant arm under an additional assumption of exponential survival distribution.  Assuming 
approximately 10% screening failure, the study will enter approximately 600 patients.
OS is an important secondary endpoint for this study. OS will be tested only if the test of PFS is 
significant. A 4-look approach to testing OS with a cumulative 1-sided type I error rate of 0.025 
will be utilized to allow for analyses of OS at:  the interim PFS analysis, the primary PFS 
analysis, 289 OS events, and the final OS analysis at 385 OS events (see Section 12.2.7 for 
details).
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 Safety Population, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to treatment received in 
Cycle 1.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.

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All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all 
confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the statistical analysis plan.
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. 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 number and percentage of patients completing the study or discontinuing (overall and by 
reason for discontinuation).
All patients entered in the study will be accounted for in the summation. The number of patients 
who do not qualify for analysis, who die, or who discontinue before treatment begins will be 
specified.
A summary of all important protocol deviations will be provided.
12.2.3. Patient Characteristics
Patient characteristics will include a summary, by treatment arm, of the following:

patient demographics

baseline disease characteristics

preexisting conditions

historical illnesses

prior endocrine therapy

prior chemotherapy (including both cytotoxic and targeted agents)
Other patient characteristics will be summarized as deemed appropriate.
12.2.4. Concomitant Therapy
Concomitant medication will be summarized by treatment arm in a frequency table listing the
terms recorded on the eCRF.

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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 LY2835219 will be collected through capsulecounts 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 takenx 100
The actual cumulative dosetaken 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 doseto be taken will be determined based on the assigned dose and taking 
into account any dose reductions or omissions.
12.2.6.Primary Outcome and Methodology
The primary endpoint of this study is PFS.PFS timeis measured from the dateofrandomization 
tothe date of investigator-determined objective progression as defined by RECIST v1.1, or death 
from any cause. Patients who have neitherprogressed nor died will be censored at the day of 
their last radiographic tumor assessment(ifavailable)or date of randomization if no post 
initiation (that is, postbaseline) radiographicassessment is available. The detailed censoring 
rules are described below(TableJPBL.12.1).

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Table JPBL.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no 
death 
Date of Randomization
Censored
3
No documented progression and no 
death (with a post-baseline tumor 
assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) 
before documented progression or 
death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented 
progression 
Date of death 
Progressed
7
Documented progression or death 
after missing ≥2 consecutive post-
baseline tumor assessments
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
The PFS analysis to test the superiority of LY2835219 to placebo in improving PFS time will use 
the log-rank test stratified by nature of disease (visceral metastases versus bone only metastases
versus other) and sensitivity to endocrine therapy (no prior endocrine therapy versus primary 
resistance versus secondary resistance). In addition, the Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the PFS curves as well as PFS rates at every 3 months for 
each treatment group. These rates will be compared based on a normal approximation for the 
difference between the rates.
The 2-look group-sequential design of the primary endpoint will be used to accommodate an 
event-driven plan for the interim and primary analysis. There is 1 planned interim analysis and 
1 primary analysis for PFS in this study. The interim analysis is planned to take place after 
approximately 270 (70%) investigator-assessed PFS events have occurred. The cumulative 
1-sided type I error rate of .025 will be maintained using the Lan-Demets method. Specifically, 
an α-spending function corresponding to an O’Brien-Fleming type stopping boundary (as
implemented in ADDPLAN 6.0) will be used for this interim efficacy analysis:





















k
k
t
t
2
/
1
1
2
1
*


.

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Here, tk is the information fraction at time k, Φ is the standard normal cumulative distribution 
function, and Φ-1 is the standard normal quantile function.
Therefore, if the interim analysis is performed after exactly 270 events have been observed, a 
nominal 1-sided p-value of less than 0.0074 (corresponding approximately to an observed 
HR <0.73 under an exponential model) will need to be observed to declare statistical significance 
(see Table JPBL.12.2).
Table JPBL.12.2.
Property of the Design for Progression-Free Survival
Information 
Fraction
Cumulative 
Events
Cumulative 
Alpha Spent
Cumulative
Beta Spent
Boundary Reject H0
(1-sided p-value)
0.7
270
0.0074
0
<.0074
1
385
0.025
0.1
<.0228
Abbreviation:  H0 = null hypothesis.
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 (for 
example, ADDPLAN 6.0 or SAS 9.2).
If statistical significance is not declared at the interim PFS analysis, the primary PFS analysis 
will be performed after 385 PFS events have been observed based on investigator assessment.  
The primary PFS analysis will compare 2 treatment groups using a log-rank test stratified by the 
randomization factors.
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the HR and corresponding 95% CI with Wald’s test p-value after adjusting for the same 
randomization variables specified for the primary analysis. All randomized patients, according 
to the ITT principle, will be included in the analysis of this endpoint. An additional unstratified 
Cox regression model will be employed to explore the effects of prognostic variables, such as of 
the stratification variables and intrinsic/extrinsic factors, on treatment response.
12.2.7. Secondary Outcome and Methodology
The secondary objectives of the study are to:

compare the following efficacy endpoint between treatment arms:
-
overall survival (OS)
-
OS at 1, 2, and 3 years
-
objective response rate (CR + PR)
-
duration of response (CR + PR)
-
disease control rate (DCR) (CR + PR + stable disease SD)
-
clinical benefit rate (CBR) (CR + PR + SD ≥6 months)

compare AEs between treatment arms

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
compare pain and symptom burden between treatment arms using the BPI, 
EORTC QLQ-C30, EORTC QLQ-BR23, and health status using the EQ-5D 5L
OS is an important secondary endpoint for this study. OS will be tested only if PFS is 
significant.  Up to a total of 3 interim analyses and a final analysis for OS may be performed in 
this study.  The interim analyses on OS will occur at the interim PFS analysis, the primary PFS 
analysis, and when 289 OS events have been observed.  The final OS analysis will be performed 
after 385 OS events have occurred. The type I error rate will be controlled at 2.5% by using a 
4-look Lan-Demets design with an O’Brien-Fleming type stopping boundary (using the same 
spending function as described for PFS).  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 (for example, ADDPLAN 6.0 or SAS 9.2).  
Table JPBL.12.3 summarizes expected OS events, critical boundary, and cumulative alpha 
spending for OS analysis.  The exact nominal p-values required to declare statistical significance 
at the time of these analyses for OS will depend on the number of OS events that have been
observed at the time of each analysis.
Table JPBL.12.3.
Property of the Design for Overall Survival
Time Point
Expected 
Information 
Fraction
Cumulative 
Events
Cumulative Alpha 
Spent
Boundary Reject H0
(1-sided p-value)
Interim PFS 
0.25
96
0.00001
<0.00001
Primary PFS 
0.50
193
0.00153
<0.00152
289 OS Events
.75
289
0.00965
<0.00916
385 OS Events
1
385
0.025
<0.02200
Abbreviations:  H0 = null hypothesis; OS = overall survival; PFS = progression-free survival.
To maintain the experiment-wise type I error rate, OS will be hierarchically tested in the 
following way:  only if the test of PFS is significant will OS also be tested inferentially for 
significance (Glimm et al. 2010); specifically:

The first potential time point for OS analysis will be at the time of the PFS interim 
analysis. If PFS is significant at this stage, the first interim analysis of OS will also 
be performed. If OS is not significant at this stage, the second interim analysis of OS 
will be performed after 193 deaths. If OS is not significant at this stage, a third 
interim analysis of OS will be performed after 289 deaths. If OS is not significant at 
this stage, a final analysis will be performed after 385 deaths have been recorded.

If PFS is not significant at the time of the interim analysis of PFS but is significant at 
a primary analysis for PFS, the second interim analysis of OS will be performed. In 
terms of alpha spending, this analysis will be performed as if an analysis of OS had 
occurred at the interim PFS analysis.  If OS is not significant at this stage, the next 
analysis on OS will be performed when a total of 289 deaths have been recorded. If 
OS is not significant at this stage, a final analysis will be performed after 385 deaths 
have been recorded.

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
If PFS is not significant after the primary analysis for PFS is performed, OS will not 
be statistically evaluated.
The OS analysis to test the superiority of LY2835219 to placebo in improving OS time will use 
the log-rank test stratified by nature of disease (visceral metastases versus bone only metastases
versus other) and sensitivity to endocrine therapy (no prior endocrine therapy versus primary 
resistance versus secondary resistance).
The following additional analyses will be conducted for OS:

Kaplan-Meier curves (Kaplan and Meier 1958) will be generated; medians, quartiles,
and appropriate point probabilities will be calculated. Interval estimates will be 
calculated using 95% CI.

The Cox regression stratified by the randomization factors will be used to estimate 
the HR between the 2 treatment groups, along with 95% CI.
In addition, OS rate at 1 year in each treatment arm will be calculated by determining OS time 
for each patient and using Kaplan-Meier techniques to assess OS time for each treatment arm.  
The Kaplan-Meier estimate of the OS rate at 1 year will be used to compare treatment arms using 
a standard normal test of the difference in OS rate at 1 year. The same techniques will be used to 
calculate and compare OS rates at 2 years and 3 years between arms.
The objective response rate, DCR, and CBR of each treatment arm will be calculated as defined 
by RECIST v1.1. All rates will be compared between treatment arms based on a normal 
approximation for the difference between the rates.
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. The following sensitivity analyses will be performed for 
PFS:
Progression-Free Survival Sensitivity Analysis 1 (censoring for receiving subsequent systemic 
anticancer therapy):  if a patient is initiated on another anticancer therapy prior to objective 
progression, including any postdiscontinuation treatment systemic therapy, radiotherapy, or 
surgical intervention, PFS will be censored at the date of the last complete objective 
progression-free disease assessment before initiation of the new therapy.
Progression-Free Survival Sensitivity Analysis 2 (censoring for study treatment 
discontinuation due to toxicity):  if a patient is discontinued from study treatments due to toxicity 
prior to objective progression, then the PFS time will be censored at the last complete objective 
progression-free disease assessment date prior to the discontinuation, regardless of whether or 
not this patient subsequently had objective progression or died.
Progression-Free Survival Sensitivity Analysis 3 (censoring for any of above situations):  if a 
patient has any of the following situations outlined for sensitivity analyses 1 through 2 prior to 
objective progression, then the PFS time will be censored at the last objective progression-free 

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disease assessment date prior to the earliest occurrence of any of these situations, regardless of 
whether or not this patient subsequently had objective progression or died.
Progression-Free Survival Sensitivity Analysis 4 (nonobjective progression as a PFS event):  if 
a patient is discontinued from study treatment due to investigator determined non-objective 
progression (for example, symptomatic deterioration), then the patient’s PFS time will be 
calculated using the date of non-objective progression as the progression date.
Progression-Free Survival Sensitivity Analysis 5 (back-dating progressions at unscheduled 
assessments):  if a patient has objective progression at an unscheduled disease assessment, then 
the PFS time for that patient will be back-dated to the prior scheduled disease assessment.
In addition, a PFS analysis based on independent central review data will be conducted by 
applying the censoring rules from Table JPBL.12.1. The analysis will be conducted on a 
randomly selected subset of patients to evaluate the presence of investigator bias with the 
intention of evaluating the reliability of the treatment effect based on investigator assessment. 
Dodd (Dodd et al. 2011), Pharmaceutical Research and Manufacturers Association (PhRMA) 
methodology (Amit et al. 2011), or similar methodology will be used to determine audit size and 
evaluate the results and determine whether independent review of the remaining patients is 
warranted. Details can be found in the SAP.
An additional OS analysis will also be conducted based on the following definition using similar 
methods as stated in Section 12.2.7: time is defined as the time from the date of study
enrollment to the date of death due to disease. Survival time will be censored on the date the
patient was last known to be alive for patients who have no reported event. For patients that 
have died due to reasons not disease related, survival time will be censored at the date of death.
12.2.9. Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetics analyses will be conducted on all patients who have received at least 1 dose of 
LY2835219 and have had samples collected (see PK sampling schedule in Attachment 7).
Mean population PK parameters for LY2835219 and its metabolites in plasma (clearance, 
exposure, volume of distribution, and half-lives) and inter-individual PK variability will be 
computed using nonlinear mixed effect modeling implemented in NONMEM.  The current PK 
model for LY2835219, which has been developed using plasma concentration data available 
from the Phase 1 Study JPBA, will be updated using the plasma data collected in this study.  
Covariate effects (such as age, weight, sex, creatinine clearance, and plasma protein levels) on 
the PK parameters of LY2835219 in plasma will also be investigated.
If warranted by the data, mean population PK parameters for fulvestrant in plasma and 
inter-individual variability estimates will also be computed using nonlinear mixed effect 
modeling implemented in NONMEM.
Finally, pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) 
collected in this study may be analyzed by means of NONMEM and connected to the population 
PK model for LY2835219 and/or fulvestrant in a PK/pharmacodynamic model.

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The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.10.
Tailoring Biomarker Analyses
The distributions of biomarkers with continuous measures, such as gene or protein expression, 
will be described.  Summary statistics will include means, medians, corresponding standard 
errors, quartiles, and ranges.  Biomarkers with discrete measures, such as genotype locus, will be 
summarized in frequency tables.  Correlative analyses may be performed to investigate 
associations between biomarkers and clinical endpoints as deemed appropriate.
12.2.11.
Health Outcome/Quality of Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

mBPI-sf (modified Brief Pain Inventory, Short Form)

EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30)

EORTC QLQ-BR23 (The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Breast cancer)

EQ-5D 5L (EuroQol 5-Dimension 5 Level)
For each patient with data from baseline and at least 1 other visit, the maximum change from 
baseline score will be calculated and summarized for BPI “worst pain”, EORTC composite 
scores.  The reason and number of missing and incomplete questionnaires/assessments by visit 
will be summarized for each instrument and study arm.
Exploratory analysis may be performed to investigate associations between patient-reported data 
(BPI, EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D) and additional clinical, efficacy, and 
/or utilization measures as appropriate.
Additionally, exploratory joint-modeling analyses may be conducted to identify composite 
patient-reported outcome (PRO) scores or single items that are related to survival or response.  
This exploratory analysis may include one or more of the patient-reported instruments (see 
Section 10.2).
Further analysis details will be described in the SAP.
12.2.11.1.
Pain Intensity
Individual pain items on the mBPI-sf (that is, worst, least, average, and current pain) will be 
described using descriptive statistics (for example, n, mean, median, standard deviation, 
minimum, and maximum) by treatment arm and time points. A mixed effects model, repeated 
measures model will 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 
BPI-sf, the mean score for the 7 pain interference items will be calculated based on those 
answered questions when at least 4 out of 7 questions were completed (that is, 50% of the 

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questions were answered).  Separate similar analyses will be conducted using the average of the 
BPI-sf/worst pain assessments associated with each cycle.
12.2.11.2.
Pain Assessment
Pain analysis will be based on all randomized patients with at least 1 baseline BPI “worst pain” 
and one BPI “worst pain” score on Cycle 2 Day 1 or later.
The mBPI-sf will be administered at baseline prior to study drug dosing and the Cycle 1, Day 1 
score will be treated as a baseline observation and the Day 1 score of each subsequent cycle will 
be attributed to the previous cycle.  The mBPI-sf will be administered at treatment 
discontinuation and grouped with observations from the previous cycle.
Time to worsening in pain will be described using the method of Kaplan and Meier and will be 
made between 2 arms by a log-rank test.  “Worsening” will be defined as either a “worst pain” 
increase of >2 points postbaseline or an analgesic drug class increase of >1 level.  Worsening 
rate at Years 1, 2, and 3 will be estimated and compared between the 2 arms. Number of events 
due to each criterion will be described.
12.2.11.3.
Health-Related Quality of Life
EORTC QLQ-C30 instrument data will be scored as described by Aaronson and colleagues 
(Aaronson et al. 1993).  If not already addressed in the EORTC scoring manual (Fayers et al. 
2001), descriptive statistics for each EORTC QLQ-C30 item will be calculated.  Frequency 
distributions and measures of central tendency and variability (for example, n, mean, median, 
standard deviations, minimum, and maximum) will be calculated for each dimension and the 
total score, and compared between arms.
EORTC QLQ-BR23 data will be scored as described by the EORTC scoring manual
(Fayers et al. 2001).
12.2.11.4.
Utilization
Utilization data will be summarized descriptively by category across arms (for example,
analgesic use, bisphosphonate use, transfusions, radiation, surgery, and hospitalization days), 
including a frequency table with tabular statistics. For categorical variables, frequency and the 
corresponding percentage will be derived and measures of central tendency and variability (for 
example, n, mean, median, standard deviations, minimum, and maximum) will be calculated for 
continuous variables. Tests for differences in proportion between treatment groups and between 
response groups will be performed. Exploratory analyses may be performed to investigate 
associations between the utilization data and the clinical endpoints.
12.2.11.5.
Health State Utility
The EQ-5D 5L data will be scored as described in an article that is under review for publication 
(van Hout et al. 2012).  The index score is calculated from a set of item weights to derive a score 
of 0 to 1, with 1 representing the best health status. Geographic-specific weights will be used as 
appropriate and when available.  The VAS is scored from 0 (worst imaginable health state) 
through 100 (best imaginable health state) to represent the patient’s self-report for each day.  
EQ-5D 5L responses for each item will be summarized by frequency and corresponding 

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percentages. Descriptive statistics for the index and VAS will be calculated, including (n, mean, 
median, standard deviations, minimum, and maximum) Psychometric analyses, including 
calculation of reliability coefficients (Cronbach’s alpha), will also be performed.  The index 
scores and VAS may be analyzed using a mixed effects analysis of variance model.  Of interest 
is a significant time-by-group interaction for each of the items, addressing whether treatment 
group profiles are different over time (from randomization through the last assessment following 
discontinuation).
12.2.11.6.
Time to First Skeletal-Related Event (TT1SRE)
Time from randomization to documentation of the first occurrence of any SRE will be 
evaluated. Patients not known to have had an SRE at the time of the analysis will be censored at 
the date of their last complete documented assessment for SRE. A stratified log-rank test will be 
used to evaluate the difference of time to first SRE between treatments. Stratification factors 
will include whether a patient had at least 1 SRE prior to randomization, and the presence of 
bone lesions, as well as those factors used to stratify treatment randomization.
12.2.11.7.
Time to Worsening ECOG Performance Status
Time from randomization to documentation of the first occurrence of any PS of ≥2 will be 
evaluated. Log-rank test will be used to evaluate the difference of time to worsening in ECOG 
between treatments.
12.2.11.8.
Exploratory Analyses
Joint modeling may be explored to characterize the relationship between features of the 
longitudinal PRO trajectories (individual items or composite scores) and the event times.
Time from randomization to earliest development of new bone metastases may be analyzed and 
compared between arms.
Proportion of patients who experience a “worst pain” increase of ≥2 points at any post-baseline 
visit (on or after Day 1 Cycle 2) will be compared between treatment arms. Changes in analgesic 
and bone agent use will be collected and summarized by arms.
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 entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments.
AEs will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.03 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) of the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify’.

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
If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as adverse events that begin prior to the first dose of study 
drug.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline. Comparisons of preexisting conditions to on-treatment 
events at the LLT level will be used in the treatment-emergent computation.
The following summaries will be produced by PT within SOC: preexisting conditions, SAEs, 
TEAEs, drug-related TEAEs, and procedure-related TEAEs.
The following summaries will be produced by PT within SOC and maximum CTCAE grade: 
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs, 
and drug-related nonlaboratory-based TEAEs.
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation.
Hospitalizations and transfusions during the study treatment period or during the 30-day
short-term follow-up period will be summarized by treatment group.
12.2.13.
Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic
subgroup variables:

All baseline stratification factors

Measurable disease at baseline (yes versus no)

Number of organs involved (1 versus 2 vs. 3+)

Age (<65 years versus ≥65 years)

Region (North America, Europe, Asia, and Other)

Race (Caucasian, Asian, and Other)

PgR status (positive versus negative)

Baseline ECOG PS (0 versus 1)
If a level of a factor consists of fewer than 5% of randomized patients, analysis within that level 
may be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.
Other subgroup analyses may be performed as deemed appropriate. If any safety analyses 
described in Section 12.2.12 identify important imbalances between arms, subgroup analyses of 
these endpoints may be performed.

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12.2.14.
Interim Analyses
12.2.14.1.
Safety Interim Analyses
The DMC is responsible for providing external oversight of patient safety in Study JPBL 
independently of the Lilly study team and Lilly GPS.
During the study, safety interim analyses will be performed every 3 months.  The first safety 
interim analysis will be triggered by the 90th patient enrolling, with the data cutoff for this 
analysis occurring 1 month after the trigger.  The safety interim analyses will be conducted to 
evaluate the overall safety profile of LY2835219 when given in combination with fulvestrant.  
At the recommendation of the DMC, the frequency of safety interim analyses may be modified.
At each interim analysis, the DMC may recommend the trial continue without modifications, 
continue with specific modifications, or be stopped for safety concerns. There will be no 
prespecified rules for stopping the trial due to safety concerns.  The DMC members will review 
unblinded safety data at each interim analysis. If a significant safety signal is identified, the 
DMC may recommend a protocol amendment, termination of enrollment, and/or termination of 
study treatment.  The recommendations of the DMC will be communicated to the Lilly SMD
and, if necessary, an IRC.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the treatment group level, members of the DMC can conduct additional analyses of the safety 
data. Additionally, unblinding of a limited number of Lilly representatives external to the study 
team may be required for evaluation of selected SAEs for determination of regulatory reporting.
12.2.14.2.
Efficacy Interim Analyses
One efficacy interim analysis of PFS and 3 interim analyses of OS (1 corresponding to the 
interim PFS analysis and 1 corresponding to the primary PFS analysis) are planned, as described 
in Sections 12.2.6 and 12.2.7.  The interim PFS analysis will be conducted to provide early 
efficacy information and could potentially result in early communication with regulatory 
agencies. 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. OS will be analyzed as described is 
Section 12.2.7.  Results of OS analyses will not be communicated until a significant result is 
observed or the primary PFS analysis is performed.
The sponsor has no intent to stop the study based on interim analysis of efficacy, and all patients 
will continue follow-up for PFS and OS until study close.  Patients randomized to the control 
group will not be permitted to cross over to the experimental group in case early efficacy is 
observed during interim review, as this will confound the assessment of OS.
The unblinded analysis, including review of the efficacy along with the safety data, will be 
conducted by DMC. Study sites will receive information about interim results ONLY if they 
need to know for the safety of their patients.
Unblinding details are specified in the unblinding plan section of the SAP.

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12.2.14.3.
Pharmacokinetic/Pharmacodynamic Interim Analyses
A limited number of preidentified individuals independent of the study team may receive access 
to unblinded data, as specified in the unblinding plan, prior to the interim or final database lock, 
in order to initiate the final population PK/pharmacodynamic model development processes for 
interim or final analyses.  Information that may unblind the study during the analyses will not be 
reported to study sites or blinded study team until the study has been unblinded.

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

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

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14. References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F.The European Organisation for Research and Treatment 
of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85:365-376.
Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J, Burger HU. Blinded 
independent central review of progression in cancer clinical trials: results from a meta-
analysis. Eur J Cancer. 2011;47(12):1772-1778.
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, 
Kyriakides S, Lin N, Pagani O, Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El 
Saghir N, Ganz PA, Gelmon K, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, 
Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van't Veer L, Viale G, 
Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). 
Breast. 2012;21(3):242-252.
Cleeland CS. Pain assessment in cancer. In: Osoba D(ed). Effect of Cancer on Quality of Life, 
Chapter 21. CRC Press, Boca Raton FL, 1991
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
Dodd LE, Korn EL, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-free 
survival. Biometrics. 2011;67(3):1092-1099.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med. 2010;29(2):219-228.
Hammond MEH, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College 
of American Pathologists guideline recommendations for immunohistochemical testing of 
estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value in Health. 2008;11(2):274-284.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Publish date:  
29 May 2009.

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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5:649-655.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149. 
Erratum in: J Clin Oncol. 2008;26(7):1192.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, 
Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, 
Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, 
Wolff AC. Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187-3205.
Sprangers MAG, Groenvold M, Arraras JI, Franklin J, te Velde A, ,Muller M, Franzini L, 
Williams A, Henneke CJM, Hopwood P, Cull A, Aaronson NK. The European Organization 
for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol. 1996;14(10):2756-2768.
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012;15(5):708-715.
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC,  
Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
Press MF, Spears PA, Vance GH, Viale G, Hayes DF. 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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Attachment 1.Protocol JPBL Study Schedule

I3Y-MC-JPBL Clinical Protocol 
 
Page 73 
LY2835219 
Study Schedule, Protocol I3Y-MC-JPBL 
Perform procedure as indicated. 
 
 
 
Baseline 
Patients on Study Treatment 
Postdiscontinuation 
Follow-Up 
 
 
Cycle 
BL 
1 
2 – 3 
4 and Beyond 
(if Applicable) 
Short-Term 
Follow-Upa 
Long-Term 
Follow-Upa 
 
 
Visit 
0 
1 
2 – 3 
4 and Beyond 
(if Applicable) 
801 
802 - 8XX 
 
 
Approximate 
Duration (days) 
28  
28 
28 
28 
30 
Variable 
 
 
Relative day 
within a cycle 
≤28 
≤14 
1 
15±3 
1p 
1p 
 
 
Procedure 
Category 
Procedure 
Protocol 
Reference 
 
 
 
 
 
 
Study Entry 
/Enrollment 
Informed Consent Form 
signedq 
Section 8.1 
Xq 
 
 
 
 
 
Inclusion/Exclusion 
evaluation 
Section 7 
 
X 
 
 
 
 
 
Medical 
History 
Medical History 
 
 
X 
 
 
 
 
 
Historical illnesses 
Section 12.2.3 
 
X 
 
 
 
 
 
Habits assessment 
Section 12.2.3 
 
X 
 
 
 
 
 
Physical 
Examination 
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)
c
 
Section 10.1.1 
X
c
 
 
X
c
 
X
c
 
X
c
 
X
c
 
Radiologic imaging 
according to RECISTb 
Section 10.1.1 
Attachment 5 
Xb 
 
Xb 
Xb 
Xb 
Xb 
Bone Scintigraphyi 
Section 10.1.1 
Attachment 5 
Xi 
 
 
Xi 
Xi 
Xi 
X-ray or CT scan with 
bone windows or MRIj 
Section 10.1.1 
Attachment 5 
Xj 
 
Xj 
Xj 
Xj 
Xj 

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

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Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
BL
1
2 – 3
4 and Beyond 
(if Applicable)
Short-Term 
Follow-Upa
Long-Term 
Follow-Upa
Visit
0
1
2 – 3
4 and Beyond 
(if Applicable)
801
802 - 8XX
Approximate 
Duration (days)
28
28
28
28
30
Variable
Relative day 
within a cycle
28
14
1
15±3
1p
1p
Procedure 
Category
Procedure
Protocol 
Reference
Study Drug
Fulvestrant Therapy g
Section 9.1
Days 1 and 15 of Cycle 1, then Day 1 of Cycle 2 and beyondg
LY2835219 Therapyg
Section 9.1
Every 12 hours on Days 1 through 28 of every cycleg
Health 
Outcomes
BPI, EORTC QLQ-
C30, EORTC BR23, 
EQ-5D 5Lk
Section 
12.2.11
Xk
Xk
Xk
Xk
Skeletal-Related Events 
assessmentl
Section 
12.2.11
Xl
Xl
Xl
Xl
Xl
Hospitalization
Section 
12.2.11.4
X
X
X
X
Transfusion
Section 
12.2.11.4
X
X
X
X
Abbreviations:  BL = baseline; Temp = Temperature; BP = Blood Pressure; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GnRH = gonadotropin-releasing hormone; HR = heart rate;
IV = intravenous; PK = pharmacokinetics; MRI = magnetic resonance imaging; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory 
rate; SAEs = serious adverse events; FSH = follicular stimulating hormone.
a
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts 
approximately 30 days; the associated study procedures are performed once at the end of this period.  Long-term follow-up begins the day after short-term 
follow-up is completed and continues until the patient’s death or overall study completion; the associated study procedures are performed approximately 
every 12 weeks (14 days) for the duration of this period.

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Study Schedule, Protocol I3Y-MC-JPBL (continued)
b For patients with inoperable locally advanced breast cancer, MRI scan of the breast is performed locally at baseline (Day -28 to Day -1), between Day 1 and 
Day 7 of every second cycle beginning with Cycle 3 and continuing through Cycle 13, between Day 1 and Day 7 of every third cycle after Cycle 13, and 
within 14 days of clinical progression.  For all patients, CT or MRI scan of the chest, abdomen, and pelvis is performed locally at baseline (Day -28 to Day -
1), between Day 1 and Day 7 of every second cycle beginning with Cycle 3 and continuing through Cycle 13, between Day 1 and Day 7 of every third cycle 
after Cycle 13, and within 14 days of clinical progression. It is recommended that CT imaging of the abdomen and pelvis be performed with IV contrast 
whenever possible. If this is not feasible due to hypersensitivity or other conditions, then gadolinium-enhanced MRI is preferred. For patients with known 
serious allergic reactions to CT contrast material, a CT of the chest without contrast and gadolinium-enhanced MRI of the abdomen/pelvis are encouraged.  
For patients who discontinue study treatment without objectively measured progressive disease (PD), continue to evaluate tumor response approximately 
every 8 weeks for the first 12 months following randomization and thereafter approximately every 12 weeks by the same method used at baseline and 
throughout the study until the patient has objective disease progression or until study completion. After the patient has objective disease progression, 
radiologic tests are no longer required and the patient will continue with post-discontinuation follow-up until the patient’s death or overall study completion.
c
Visible tumor (such as skin lesions) should be documented by photography and each photographic image of the tumor should include a ruler.  For patients 
who discontinue study treatment without objectively measured progressive disease (PD), continue to evaluate tumor response approximately every 8 weeks 
for the first 12 months following randomization and thereafter approximately every 12 weeks by the same method used at baseline and throughout the study 
until the patient has objective disease progression or until study completion. After the patient has objective disease progression, tumor assessments are no 
longer required and the patient will continue with post-discontinuation follow-up until the patient’s death or overall study completion.
d Survival information is collected at baseline and during both study treatment and postdiscontinuation follow-up. During Long-Term Follow-Up, survival 
information is collected approximately every 12 weeks for the duration of this period. Although preferable to collect during a clinic visit, survival 
information may be collected by contacting the patient or family directly (for example, via telephone).  Long-Term Follow-up data collection may include
anticancer therapies.
e
A local ECG (no replicates required) should be obtained at baseline (Day -14 to Day -1), 2 to 4 hours after the LY dose on Cycle 1 Day 1, upon arrival at site 
but prior to fulvestrant dose on Cycle 1 Day 15, 2 to 4 hours after the LY dose on Cycle 4 Day 1, and at the short-term follow-up visit.
f
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety System.  During Long-Term Follow-Up, only 
SAEs that are related to study drugs or protocol procedures will be collected. All adverse events possibly related to study drugs or protocol procedures should 
be followed until they resolve, are no longer considered to be possibly related, become stable or return to baseline, the patient starts a new therapy, the patient 
expires, or the patient becomes lost to follow-up.  The frequency of evaluation is determined according to the judgment of the investigator.
g LY2835219 should be administered orally every 12 hours on Days 1 through 28 of each cycle; patients should not consume food beginning 1 hour before and 
ending 1 hour after taking LY2835219. Fulvestrant 500 mg should be administered intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as 
two 250-mg injections, one in each buttock; however, for patients with moderate hepatic impairment (defined as Child-Pugh Class B), including any patient 
who develops moderate hepatic impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock slowly (1 to 2 
minutes) as one 250-mg injection.
h Formalin-fixed paraffin-embedded tumor tissue (either block or 15-20 unstained slides) should be requested at the time of randomization.  However, if this 
sample is not available for a patient, it will not constitute a protocol deviation

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

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Study Schedule for the extension period only, Protocol I3Y-MC-JPBL
Perform procedure as indicated.
Patients on Study Treatment
Extension Period Follow-Up
Cycle
X-Y
Follow-Upa
Visit
501-5XX
901
Duration (days)
28
30
Relative day within a cycle
1
15
Procedure Category
Procedure
Protocol Reference
Adverse Events Collection/CTCAE Gradingb
Section 10.3
X
X
Study Drug
Fulvestrant Therapyc
Section 8.1.2
Days 1 and 15 of Cycle 1, then 
Day 1 of Cycle 2 and beyondc
LY2835219 Therapyc
Section 8.1.2
Daily every 12 hoursc
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; PK = pharmacokinetics; SAEs = serious adverse events.
a
The extension period begins after study completion and ends at the end of trial.
b
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly safety system.
c
LY2835219 should be administered every 12 hours on Days 1 through 28 of each cycle. Patients should not consume food beginning 1 hour before and 
ending hour after taking study drug.
Fulvestrant 500 mg should be administered intramuscularly into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg injections, one in each 
buttock; however, for patients with moderate hepatic impairment (defined as Child-Pugh Class B), including any patient who develops moderate hepatic 
impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one 250-mg 
injection.

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

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

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

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

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

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

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

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

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

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

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

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Attachment 7.Protocol JPBL Pharmacokinetic
Sampling Schedule
The schedule for PK sampling is summarized in the table below.  The date and exact time of 
collection for each venous blood sample should be documented on the laboratory requisition.
Pharmacokinetic Sampling Schedule
PK Sample 
Number
Cycle (C)
and Day
(D)
Dosing of 
LY2835219
Dosing of Fulvestrant
Sampling Time for PK from 
Blooda
1
C1D1
X
X
2 to 4 hrs after fulvestrant and 
LY dose
2
C1D15
Xb
X
Upon arrival at site but prior to 
fulvestrant dose (that is, at least 
4 hrs after taking LY dose at 
home)
3
C1D15
3 ± 0.5 hrs after PK Sample 
Number 2 (that is, at least 7 ± 
0.5 hrs after taking LY dose at 
home)
4
C2D1
X
X
Prior to fulvestrant and LY dose 
5
C2D1
3 ± 0.5 hrs after LY dose 
6
C3D1
X
X
Prior to fulvestrant and LY dose
Abbreviations:  hr = hour; LY = LY2835219; PK = pharmacokinetic.
a
Samples of approximately 4 mL of whole blood will be drawn. After obtaining plasma, site personnel will 
aliquot samples into 2 approximately equal portions, one for measurement of LY2835219 and its metabolites
concentrations and the other for measurement of fulvestrant concentrations. Only samples No. 1, 2, 4, and 6 will 
be used for measurement of fulvestrant.
b On Cycle 1 Day 15 only, patient should take LY dose at home at least 4 hours before arrival at site.  The time of 
LY dose intake must be recorded that day.

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Attachment 8.Protocol JPBL Inducers and Strong Inhibitors 
of CYP3A4
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 CYP3A4
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
a
Important note:  A patient who develops brain metastases may receive acute or chronic therapy with 
dexamethasone if clinically indicated.  All patients may receive supportive therapy with dexamethasone, 
preferably 7 days, if clinically indicated.

Leo Document ID = 239a81ff-42ae-4146-b437-100c32ce214b
Approver: 
Approval Date & Time: 31-Mar-2014 18:46:19 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Apr-2014 06:53:23 GMT
Signature meaning: Approved