A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Eli Lilly and Company

Protocol I3Y-MC-JPBM 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Study of Nonsteroidal Aromatase Inhibitors 
(Anastrozole or Letrozole) plus LY2835219, a CDK4/6 
Inhibitor, or Placebo in Postmenopausal Women with 
Hormone Receptor-Positive, HER2-Negative 
Locoregionally Recurrent or Metastatic Breast Cancer 
with No Prior Systemic Therapy in this Disease Setting 
 
NCT02246621 
 
Approval Date: 03-Sep-2014 

I3Y-MC-JPBM Clinical Protocol 
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LY2835219 
 
 
 
1. Protocol I3Y-MC-JPBM 
A Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Study of Nonsteroidal Aromatase Inhibitors 
(Anastrozole or Letrozole) plus LY2835219, a CDK4/6 
Inhibitor, or Placebo in Postmenopausal Women with 
Hormone Receptor-Positive, HER2-Negative 
Locoregionally Recurrent or Metastatic Breast Cancer 
with No Prior Systemic Therapy in this Disease Setting 
 
 
 
 
 
 
 
LY2835219 
 
 
 
 
 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
 
 
 
Protocol Electronically Signed and Approved by Lilly on date provided below. 
 
 
 
 
 
Approval Date: 03-Sep-2014 GMT 
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. 
This study is a global, multicenter, double-blind, placebo-controlled, Phase 3 trial for 
postmenopausal women with hormone receptor-positive, HER2-negative locoregionally 
recurrent or metastatic breast cancer randomized to receive nonsteroidal aromatase 
inhibitors (anastrozole or letrozole) with or without LY2835219. 

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2. Synopsis 
Study Rationale 
LY2835219 is an oral, selective, and potent small molecule cyclin-dependent kinase (CDK) 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. Studies with LY2835219 across breast cancer cell lines 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 estrogen receptor- 
positive (ER+) breast cancers with luminal histology. 
LY2835219 has demonstrated evidence of single-agent clinical activity in a tumor-specific 
cohort of women with metastatic breast cancer (mBC). In Study I3Y-MC-JPBA (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, there were 9 patients with 
confirmed partial responses (PR) for an objective response rate (ORR) of 25%. Further, of these 
36 patients with HR+ mBC, the clinical benefit rate (CBR: PR + stable disease [SD] ≥24 weeks) 
was 61%, and the disease control rate (DCR: PR + SD) was 80.6%. A total of 14 patients were 
continuing treatment at the time of analysis (Patnaik et al. 2014). In the same study, LY2835219 
demonstrated an acceptable safety profile for women with HR+ mBC. The most common 
treatment-emergent adverse events (TEAEs) were diarrhea, nausea, fatigue, neutropenia, and 
vomiting. There were no treatment discontinuations attributable to an AE. The clinical activity 
and safety profile support further evaluation of LY2835219 in mBC. 
Non-steroidal aromatase inhibitors (NSAI, letrozole and anastrazole) are approved and 
commonly used endocrine therapy in the first-line setting for postmenopausal women with HR+ 
mBC. The evaluation of LY2835219 in combination with an NSAI is of interest since both 
classes of drugs have acceptable and distinct safety profiles. The current study will assess if 
additional clinical benefit may be achieved in this disease setting with this drug combination. 
Study I3Y-MC-JPBM (JPBM) is a randomized, double-blind, placebo-controlled, Phase 3 study 
evaluating treatment of LY2835219 with NSAI or placebo with NSAI in postmenopausal women 
with HR+, human epidermal growth factor receptor 2-negative (HER2-) locoregionally recurrent 
or metastatic breast cancer who have not received prior systemic therapy in this disease setting. 

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Clinical Protocol Synopsis:  Study I3Y-MC-JPBM 
 
Name of Investigational Product: LY2835219 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase 
Inhibitors (Anastrozole or Letrozole) plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women 
with Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer with No 
Prior Systemic Therapy in this Disease Setting 
Number of Planned Patients: 450 
Entered:  500 
Enrolled/Randomized: 450 
Completed:  450 
Phase of Development: 3 
Length of Study: approximately 91 months 
Planned first patient visit:  Oct 2014  
Planned last patient visit:  May 2022 
Planned interim analysis:  218 progression-free survival (PFS) events 
Objectives: The primary objective of Study I3Y-MC-JPBM is to compare treatment with LY2835219 plus NSAI 
therapy versus placebo plus NSAI therapy with respect to PFS in postmenopausal women with HR+, HER2- 
locoregionally recurrent or metastatic breast cancer who have not received prior systemic therapy in this disease 
setting. 
The secondary objectives of the study are to compare the combination treatment of LY2835219 and NSAI therapy 
versus placebo plus NSAI therapy with respect to the following: 
 
overall survival [OS]; 
 
OS rate at 1, 2, and 3 years; 
 
ORR (complete response [CR] + PR); 
 
duration of response [DoR] (CR + PR); 
 
DCR (CR + PR + SD); 
 
CBR (CR + PR + SD ≥ 6 months); 
 
safety and tolerability 
 
change in symptom burden using the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), EORTC QLQ-BR23 (breast) questionnaire, and 
health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L). 
 
pharmacokinetics (PK) of LY2835219, its metabolites, and NSAI therapy 
The exploratory objectives are: 
• 
To explore potential biomarkers related to the mechanism of action of LY2835219, the cell cycle, and/or 
the pathogenesis of breast cancer. 
• 
To explore change in tumor size. 
Study Design: Study JPBM is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study 
evaluating treatment of LY2835219 with NSAI or placebo with NSAI in postmenopausal women with HR+, 
HER2- locoregionally recurrent (not amenable to curative therapy) or metastatic breast cancer who have not 
received prior systemic therapy in this disease setting. Approximately 450 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 prior (neo)adjuvant endocrine therapy 
(aromatase inhibitor therapy versus other versus no prior endocrine therapy). 

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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 locoregionally recurrent 
disease not amenable to resection or radiation therapy with curative intent or metastatic disease; 3) have 
postmenopausal status due to either surgical/natural menopause or amenorrheic (non-treatment-induced) for at 
least 12 months; 4) have either measurable disease or nonmeasurable bone-only disease; 5) have a performance 
status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale; 6) have adequate organ function; 7) have 
discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture prior to 
randomization and recovered from the acute effects of therapy; 8) are female and ≥18 years of age; 9) are able to 
swallow capsules; 10) have given written informed consent prior to any study-specific procedures; 11) are reliable, 
willing to be available for the duration of the study, and are willing to follow study procedures. 
Patients will be excluded from the study if they meet any of the following criteria: 12) have visceral crisis, 
lymphangitic spread, or leptomeningeal carcinomatosis; 13) have inflammatory breast cancer; 14) have clinical 
evidence or a history of central nervous system (CNS) metastasis; 15) are currently receiving or have previously 
received endocrine therapy for locoregionally recurrent or metastatic breast cancer; 16) have received prior 
(neo)adjuvant endocrine therapy with a disease-free interval ≤12 months from completion of treatment; 17) are 
currently receiving or have previously received chemotherapy for locoregionally recurrent or metastatic breast 
cancer; 18) have received prior treatment with everolimus; 19) have received prior treatment with any CDK4/6 
inhibitor (or participated in any CDK4/6 inhibitor clinical trial for which treatment assignment is still blinded); 20) 
have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents <7 days prior to 
randomization; 21) 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; 22) have received 
treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of 
randomization for a nonmyelosuppressive or myelosuppressive agent, respectively; 23) have had major surgery 
within 14 days prior to randomization; 24) have received recent (within 28 days prior to randomization) yellow 
fever vaccination; 25) have serious preexisting medical conditions that, in the judgment of the investigator, would 
preclude participation in this study; 26) have a personal history of any of the following conditions: syncope of 
cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest; 27) have a history 
of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete 
remission with no therapy for a minimum of 3 years; 28) have received an autologous or allogeneic stem-cell 
transplant; 29) 
have active bacterial or fungal infection or detectable viral infection. 
Test Product, Dosage, and Mode of Administration: LY2835219 will be supplied as capsules administered 
orally, 150 mg every 12 hours on Days 1 to 28 of a 28-day cycle. 
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. In both arms, either letrozole or anastrazole will be 
administered orally.  Where required, anastrazole 1-mg or letrozole 2.5-mg tablets will be supplied. 

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Criteria for Evaluation: 
Efficacy: 
• 
• 
• 
• 
• 
•     
Safety: 
• 
PFS (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) 
OS 
OS at 1, 2, and 3 years 
ORR (RECIST v1.1) 
DoR (RECIST v1.1) 
DCR (RECIST v1.1) 
AEs using MedDRA 
Health Outcomes: 
 
EORTC QLQ-C30 and EORTC QLQ-BR23:  Describe target tumor symptom changes 
 
EQ-5D 5L: Describe health status changes 
Pharmacokinetics: 
 
Population PK parameters for LY2835219 and possibly LY2835219 metabolites and letrozole or 
anastraszole 
Exploratory: 
 
Potential biomarkers related to the mechanism of action of LY2835219, the cell cycle, and/or the 
pathogenesis of breast cancer 
 
Time course of change in tumor size 

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Statistical Methods: 
Statistical: 
The primary objective of this study is to compare treatment with LY2835219 plus NSAI therapy versus placebo 
plus NSAI therapy with respect to progression-free survival (PFS) in postmenopausal women with HR+, HER2- 
locoregionally recurrent or metastatic breast cancer. An important secondary objective of this study is to compare 
the 2 arms with respect to OS. 
A group sequential design on the primary endpoint of PFS will be utilized, with interim and primary PFS analyses 
occurring at approximately 218 PFS events and 312 PFS events, respectively. The Lan-DeMets method, utilizing a 
power alpha spending function with a power parameter of 14, will be used to maintain the cumulative 1-sided type 
I error rate of .025. Assuming a hazard ratio of 0.714, this design yields at least 80% statistical power to detect 
superiority of the LY2835219 plus NSAI arm over placebo plus NSAI 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.  OS 
will be tested after approximately 315 OS events have been observed, with a cumulative 1-sided type I error rate of 
.025.  The test of OS will be a pooled analysis including a subset of patients from Study I3Y-MC-JPBL. 
Efficacy: 
The PFS and OS analyses to test the superiority of LY2835219 to placebo in improving PFS and OS will use the 
log-rank test stratified by the stratification variables. Additional analyses will be performed using the 
Kaplan-Meier method to estimate the PFS and OS curves and rates, and the Cox proportional hazard model will be 
used to estimate the PFS and OS hazard ratios and corresponding 95% confidence interval. 
 
Safety: 
All safety summaries and analyses will be based on the Safety Population, defined as all enrolled patients receiving 
at least 1 dose of study treatment. Patients will be grouped according to treatment received in Cycle 1. 
 
Health Outcomes: 
Change in pain and symptom burden will be analyzed descriptively and treatment arms will be compared using a 
repeated measures model, where appropriate. 
 
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 LY2835219 metabolites and anastrozole or letrozole 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 anastrozole or letrozole in a 
PK/pharmacodynamic model. 
 
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 Nonsteroidal Aromatase Inhibitors (Anastrozole or 
Letrozole) plus LY2835219, a CDK4/6 Inhibitor, or Placebo in 
Postmenopausal Women with Hormone Receptor-Positive, 
HER2-Negative Locoregionally Recurrent or Metastatic 
Breast Cancer with No Prior Systemic Therapy in this 
Disease Setting 
 
Section 
Page 
1. 
Protocol I3Y-MC-JPBM A Randomized, Double-Blind, Placebo- 
Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors 
(Anastrozole or Letrozole) plus LY2835219, a CDK4/6 Inhibitor, or 
Placebo in Postmenopausal Women with Hormone Receptor- 
Positive, HER2-Negative Locoregionally Recurrent or Metastatic 
Breast Cancer with No Prior Systemic Therapy in this Disease 
Setting ......................................................................................................................................1 
2. Synopsis ...................................................................................................................................2 
3. Table of Contents ....................................................................................................................7 
4. Abbreviations and Definitions ...............................................................................................14 
5. Introduction ...........................................................................................................................20 
6. Objectives ..............................................................................................................................23 
6.1. Primary Objective ............................................................................................................ 23 
6.2. Secondary Objectives ....................................................................................................... 23 
6.3. Exploratory Objectives ..................................................................................................... 23 
7. Study Population ....................................................................................................................24 
7.1. Inclusion Criteria .............................................................................................................. 24 
7.2. Exclusion Criteria............................................................................................................. 25 
7.2.1. 
Rescreening ..............................................................................................................27 
7.3. Discontinuations ............................................................................................................... 27 
7.3.1. 
Discontinuation of Patients ......................................................................................27 
7.3.2. 
Discontinuation of Study Sites .................................................................................28 
7.3.3. 
Discontinuation of the Study ....................................................................................28 
8. Investigational Plan ...............................................................................................................29 
8.1. Summary of Study Design ............................................................................................... 29 
8.1.1. 
Study Completion and End of Trial .........................................................................30 

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8.1.2. 
Continued Access Period ........................................................................................ 31 
8.2. 
Discussion of Design and Control ................................................................................... 32 
9. Treatment .............................................................................................................................. 33 
9.1. 
Treatments Administered ................................................................................................ 33 
9.2. 
Materials and Supplies .................................................................................................... 35 
9.3. 
Method of Assignment to Treatment ............................................................................... 35 
9.4. 
Selection and Timing of Doses ........................................................................................ 35 
9.4.1. 
Special Treatment Considerations .......................................................................... 36 
9.4.1.1. 
Dose Adjustments and Delays ................................................................. 36 
9.4.1.1.1. 
Dose Adjustments........................................................................................ 36 
9.4.1.1.1.1. 
Blinded Study Drug ............................................................................... 36 
9.4.1.1.1.2. 
Anastrozole or Letrozole ....................................................................... 36 
9.4.1.1.2. 
Dose Suspension (within a Cycle) and Cycle Delay ................................... 36 
9.4.1.1.3. 
Hematologic Toxicity .................................................................................. 37 
9.4.1.1.4. 
Nonhematological Toxicity ......................................................................... 37 
9.4.1.1.4.1. 
Diarrhea ................................................................................................. 38 
9.5. 
Blinding ........................................................................................................................... 38 
9.5.1. 
Unblinding at Interim Analyses .............................................................................. 38 
9.5.2. 
Emergency Unblinding ........................................................................................... 39 
9.5.3. 
Inadvertent Unblinding ........................................................................................... 39 
9.6. 
Concomitant Therapy ...................................................................................................... 39 
9.6.1. 
Surgery and/or Radiotherapy for Locoregionally Recurrent 
Breast Cancer .......................................................................................................... 40 
9.6.2. 
Radiotherapy ........................................................................................................... 40 
9.6.3. 
Supportive Care ....................................................................................................... 40 
9.6.4. 
Growth Factor ......................................................................................................... 41 
9.6.5. 
Supportive Management for Diarrhea ..................................................................... 41 
9.6.6. 
Bisphosphonates and RANK-L Targeted Agents ................................................... 41 
9.7. 
Treatment Compliance .................................................................................................... 41 
9.7.1. 
Patient Diaries ......................................................................................................... 42 
10. Efficacy, Health Outcome/Quality-of-Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements ........................................................................................................................43 
10.1. Efficacy Measures ........................................................................................................... 43 
10.1.1. 
Efficacy Assessments at Baseline and during Study                                Treatment   
43 
10.1.2. 
Efficacy Assessments during Postdiscontinuation Follow-Up ............................... 44 
10.1.3. 
Primary Efficacy Measure ....................................................................................... 44 
10.1.4. 
Secondary Efficacy Measures ................................................................................. 45 

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10.1.5. 
Exploratory Measures ...................................................................................... 46 
10.2. Health Outcome/Quality-of-Life Measures ..................................................................... 47 
10.2.1. 
Patient-Reported Outcomes ............................................................................. 47 
10.2.1.1. 
Health-Related Quality of Life ................................................................ 47 
10.2.1.2. 
Health Status ........................................................................................ 48 
10.2.2. 
Resource Utilization ......................................................................................... 48 
10.3. Safety Evaluations ........................................................................................................... 48 
10.3.1. 
Adverse Events ................................................................................................ 49 
10.3.1.1. 
Serious Adverse Events ........................................................................... 50 
10.3.1.2. 
Suspected Unexpected Serious Adverse Reactions ........................................... 51 
10.3.2. 
Other Safety Measures ..................................................................................... 52 
10.3.2.1. 
Electrocardiograms .................................................................................. 52 
10.3.3. 
Safety Monitoring ............................................................................................ 52 
10.3.4. 
Complaint Handling ......................................................................................... 53 
10.4. Sample Collection and Testing ........................................................................................ 53 
10.4.1. 
Samples for Study Qualification and Health Monitoring ........................................ 53 
10.4.2. 
Samples for Biomarkers ................................................................................... 54 
10.4.2.1. 
Archived Tumor Tissue ........................................................................... 54 
10.4.2.2. 
Blood Samples for Pharmacogenetic Evaluations ............................................ 55 
10.4.2.3. 
Plasma Samples for Exploratory Biomarker Evaluations ................................. 55 
10.4.3. 
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................... 55 
10.5. Appropriateness of Measurements .................................................................................. 56 
11. Data Quality Assurance ......................................................................................................... 57 
11.1. Data Capture System ....................................................................................................... 57 
12. Sample Size and Statistical Methods .................................................................................... 58 
12.1. Determination of Sample Size ......................................................................................... 58 
12.2. Statistical and Analytical Plans ....................................................................................... 58 
12.2.1. 
General Considerations .................................................................................... 58 
12.2.2. 
Patient Disposition ........................................................................................... 59 
12.2.3. 
Patient Characteristics ...................................................................................... 59 
12.2.4. 
Concomitant Therapy ....................................................................................... 59 
12.2.4.1. 
Postdiscontinuation Therapy ................................................................... 60 
12.2.5. 
Treatment Compliance ..................................................................................... 60 
12.2.6. 
Primary Outcome and Methodology ................................................................ 60 
12.2.7. 
Secondary Outcomes and Methodology .......................................................... 62 
12.2.7.1. 
Overall Survival ...................................................................................... 63 

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12.2.7.2. 
Objective Response Rate, Disease Control Rate, and 
Clinical Benefit Rate ..........................................................................................63 
12.2.8. 
Sensitivity Analysis ..........................................................................................64 
12.2.9. 
Pharmacokinetic and Pharmacodynamic Analyses ..........................................65 
12.2.10. Biomarker Analyses .........................................................................................65 
12.2.11. Health Outcome/Quality-of-Life Analyses ......................................................65 
12.2.11.1. Health-Related Quality of Life ................................................................ 66 
12.2.11.2. Resource Utilization ................................................................................ 66 
12.2.11.3. Health State Utility .................................................................................. 66 
12.2.12. Safety Analyses ................................................................................................66 
12.2.13. Subgroup Analyses ..........................................................................................67 
12.2.14. Interim Analyses ..............................................................................................68 
12.2.14.1. Safety Interim Analyses .......................................................................... 68 
12.2.14.2. Efficacy Interim Analyses ....................................................................... 68 
12.2.14.3. Pharmacokinetic/Pharmacodynamic Interim Analyses ......................................69 
13. Informed Consent, Ethical Review, and Regulatory Considerations ....................................70 
13.1. Informed Consent .............................................................................................................70 
13.2. Ethical Review ..................................................................................................................70 
13.3. Regulatory Considerations ...............................................................................................70 
13.3.1. 
Investigator Information...................................................................................71 
13.3.2. 
Protocol Signatures ..........................................................................................71 
13.3.3. 
Final Report Signature .....................................................................................71 
14. References .............................................................................................................................72 

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List of Tables 
Table 
Page 
Table JPBM.9.1. 
Treatment Regimens/Dosing Schedule ......................................................34 
Table JPBM.9.2. 
Dose Adjustments for Blinded Study Drug ...............................................36 
Table JPBM.10.1. 
Secondary Efficacy Endpoints ...................................................................46 
Table JPBM.10.2. 
Exploratory Measures ................................................................................46 
Table JPBM.10.3. 
Adverse Event and Serious Adverse Event Reporting Guidelines ............49 
Table JPBM.12.1. 
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival ..........................................................................61 
Table JPBM.12.2. 
Properties of Design for Progression-Free Survival ..................................62 

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List of Figures 
Figure 
Page 
Figure JPBM.8.1. 
Illustration of study design. ........................................................................29 
Figure JPBM.8.2. 
Study period and continued access period diagram. ..................................31 

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List of Attachments 
Attachment 
Page 
Attachment 1. 
Protocol JPBM Study Schedule .................................................................75 
Attachment 2. 
Protocol JPBM Clinical Laboratory Tests .................................................84 
Attachment 3. 
Protocol JPBM Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...............................................................................................85 
Attachment 4. 
Protocol JPBM ECOG Performance Status ...............................................86 
Attachment 5. 
Protocol JPBM RECIST Criteria 1.1 .........................................................87 
Attachment 6. 
Protocol JPBM Sampling Summary ..........................................................94 
Attachment 7. 
Protocol JPBM Electrocardiogram and Pharmacokinetic Sampling 
Schedule .....................................................................................................95 
Attachment 8. 
Protocol JPBM Inducers and Strong Inhibitors of CYP3A4 ......................96 
Attachment 9. 
Protocol JPBM CTCAE 4.03 Diarrhea Definition .....................................97 

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4. Abbreviations and Definitions 
 
Term 
Definition 
 
AE 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
ALT 
alanine aminotransferase 
 
ANC 
absolute neutrophil count 
 
ASCO 
American Society of Clinical Oncology 
 
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). 
A procedure in which one or more parties to the trial are kept unaware of the treatment 
blinding/masking 
assignment(s). Unless otherwise specified, blinding will remain in effect until final 
database lock. 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not. 
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received. 
 
CAP 
College of American Pathologists 
 
CBR 
clinical benefit rate 
 
CDK 
cyclin-dependent kinase 
 
CI 
confidence interval 
 
CNS 
central nervous system 

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LY2835219 
 
 
 
 
collection database 
A computer database where clinical trial data are entered and validated. 
 
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. 
 
continued access 
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. 
 
CR 
complete response 
 
CRF/eCRF 
case report form/electronic case report form 
Sometimes referred to as clinical report form: A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol. 
 
CRP 
clinical research physician 
Individual responsible for the medical conduct of the study. Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer. 
 
CSR 
clinical study report 
 
CT 
computed tomography 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
CTS 
change in tumor size 
A measure of tumor dynamics from which tumor response is derived. Tumor size is the 
sum of tumor measurements across all target tumors at a given evaluation (RECIST 
criteria). 
 
DCR 
disease control rate 
 
DMC 
Data Monitoring Committee 
 
DoR 
duration of response 
 
ECG 
electrocardiogram 
 
ECOG 
Eastern Cooperative Oncology Group 

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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. 
 
EORTC QLQ-BR23 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Breast Cancer 
 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
 
EQ-5D 5L 
EuroQol 5-Dimension 5 Level 
 
ER+ 
estrogen receptor-positive 
 
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. 
 
GCP 
good clinical practice 
 
H0 
null hypothesis 
 
Ha 
alternative hypothesis 
 
HER2- 
human epidermal growth factor receptor 2-negative 
 
HIV 
human immunodeficiency virus 
 
HR+ 
hormone receptor-positive 
 
IB 
Investigator’s Brochure 
 
ICF 
informed consent form 
 
ICH 
International Conference on Harmonisation 
 
IHC 
immunohistochemistry 

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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. 
 
IRC 
Internal Review Committee 
 
ITT 
intention-to-treat 
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given. It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment. 
 
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 
 
mBC 
metastatic breast cancer 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MRI 
magnetic resonance imaging 
 
NCI 
National Cancer Institute 
 
NSAI 
nonsteroidal aromatase inhibitor 

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ORR 
objective response rate 
 
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 
 
PK 
pharmacokinetic 
 
PR 
partial response 
 
PS 
performance status 
 
PT 
Preferred Term 
 
QTc 
corrected QT interval 
 
randomize 
the process of assigning patients to an experimental group on a random basis 
 
RANK-L 
receptor activator of nuclear factor kappa-B ligand 
 
Rb 
retinoblastoma 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
 
reporting database 
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data. 
 
re-screen 
to screen a patient who was previously declared a screen failure for the same study 
 
SAE 
serious adverse event 
 
SAP 
Statistical Analysis Plan 

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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 
Senior Management Designee 
 
SOC 
System Organ Class 
 
study completion 
This study will be considered complete after the final analysis/evaluation of overall 
survival is performed. 
 
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 limit of normal 
 
VAS 
visual analog scale 

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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or 
Letrozole) plus LY2835219, a CDK4/6 Inhibitor, or Placebo in 
Postmenopausal Women with Hormone Receptor-Positive, 
HER2-Negative Locoregionally Recurrent or Metastatic 
Breast Cancer with No Prior Systemic Therapy in this 
Disease Setting 
5. Introduction 
Breast cancer is one of the most common cancers in women. In 2012, there were approximately 
1.7 million new cases of breast cancer worldwide; since 2008, the worldwide incidence of breast 
cancer has increased by more than 20% and mortality has increased by 14% (Bray et al. 2013; 
Ferlay et al. 2013). While early stage disease is treatable, patients with mBC have a median OS 
of only 2 to 3 years (Cardoso et al. 2012). The treatment for women diagnosed with HR+ mBC 
includes endocrine therapy. In postmenopausal women, aromatase inhibitors (including 
anastrozole and letrozole) are recommended for the initial treatment of mBC, if not used in the 
adjuvant setting or if discontinued for at least 12 months (Cardoso et al. 2012). However, 
de novo or acquired resistance to adjuvant endocrine therapy and metastatic breast cancer 
remains an important clinical challenge. 
Cyclin D1 interacts with cyclin-dependent kinases 4 and 6 (hereafter CDK4/6) in an active 
protein complex that promotes cell proliferation (Velasco-Velázquez et al. 2011). Many HR+ 
breast cancers demonstrate an intact retinoblastoma tumor suppressive function, however, 
overexpression of cyclin D1 protein by oncogenic signaling occurs in approximately 30% to 
50% of cancers. Cyclin D1 is regarded as the most frequently overexpressed gene in primary 
breast cancer, with amplification of the encoding gene, CCND1, occurring in approximately 15% 
of breast cancers (Casimiro et al. 2014). Therefore, CDK4/6 represents a potential therapeutic 
target for HR+ breast cancer. Consequently, further evaluation of CDK4/6 inhibitors to improve 
clinical outcomes for women with HR+ breast cancer is warranted. 
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002). CDK4/6 participates in a 
complex with the D-type cyclins to initiate progression through the G1 restriction point. The 
CDK4/6 – cyclin D1 complex regulates the G1 restriction point through phosphorylation and 
inactivation of the retinoblastoma (Rb) tumor suppressor protein, thereby promoting S phase 
entry. Alterations in this pathway occur frequently in human cancers and involve: 1) loss of 
functional CDK inhibitors through deletion or epigenetic silencing; 2) activating mutations 
and/or overexpression of CDK4/6 or the D-type cyclins; and 3) loss of functional Rb through 
mutation or deletion. Except for tumors with functional loss of Rb, which functions downstream 
of the CDK4/6 – cyclin D1 complex, most cancers are potentially sensitive to pharmacologic 
inhibition of CDK4/6. From a therapeutic standpoint, the goal of inhibiting CDK4/6 with a 

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small molecule is to prevent cell cycle progression through the G1 restriction point, thus 
arresting tumor growth. 
LY2835219 represents a selective and potent small molecule inhibitor of CDK4/6 with 
acceptable physical characteristics, pharmacokinetic (PK) properties, and safety profile in 
nonclinical species. There may be important opportunities to tailor therapy with LY2835219 for 
patients with breast cancer.  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. In accordance with the known biology of CDK4/6, 
the results also indicate that many of these sensitive cell lines are also characterized as having 
amplification of CCND1, which is the gene that encodes cyclin D1. These results are consistent 
with previous studies which demonstrate that effective induction of G1 cell cycle arrest by 
LY2835219 is dependent upon the presence of Rb. 
Findings from the Phase 1 Study JPBA indicate that the LY2835219 single-agent maximum 
tolerated dose of 200 mg administered orally every 12 hours demonstrates an acceptable safety 
profile. LY2835219 has demonstrated evidence of clinical activity in women with mBC at doses 
of both 150 mg and 200 mg every 12 hours. Additionally, preliminary analysis of PK data from 
Study JPBA for LY2835219 as a single agent at 150 mg and 200 mg every 12 hours indicates 
that the range of steady-state exposures is comparable for the 2 doses.  In Study JPBA, 47 
patients with a median of 7 prior systemic regimens received therapy with LY2835219. In the 
mBC cohort, the most common treatment-emergent adverse events (TEAEs) possibly related to 
study drug included diarrhea, nausea, fatigue, neutropenia, and vomiting.  Among 36 patients 
with HR+ mBC receiving LY2835219, there were 9 patients with confirmed partial responses 
(PR) for an objective response rate of 25%. Further, in these 36 patients, the clinical benefit rate 
(CBR; PR + stable disease [SD] ≥24 weeks) was 61%, and the disease control rate (DCR; [PR + 
SD]) was 80.6%.  A total of 14 patients were continuing treatment at the time of analysis 
(Patnaik et al. 2014). 
Study JPBA findings support further investigation of LY2835219 in combination with standard 
endocrine therapy for women with HR+ locoregionally recurrent or metastatic breast cancer. 
Non-steroidal aromatase inhibitors (NSAI, anastrazole and letrozole) are approved and 
commonly used endocrine therapy in the first-line setting for postmenopausal women with HR+ 
mBC. The evaluation of LY2835219 in combination with an NSAI is of interest since both 
classes of drugs have acceptable and distinct safety profiles. Safety and tolerability of 
LY2835219 in combination with endocrine therapies (including anastrozole and letrozole) are 
being further evaluated in patients with HR+, HER2- mBC, in an ongoing Phase 1b study, I3Y- 
MC-JPBH (JPBH). As of 21 July 2014, 35 patients received at least one dose of combination 
therapy (20 with letrozole, 15 with anastrazole). Preliminary safety data from Study JPBH have 
shown a consistent adverse event profile for LY2835219 administered at 200 mg every 12 hours 
in combination with NSAI as was observed in the Study JPBA mBC single-agent cohort. 
However, at the 200 mg dose, the incidence of treatment-emergent Grade 3 diarrhea was greater 

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LY2835219 
 
 
 
in combination with NSAI than when LY2835219 was administered alone (25.7% and 13.6%, 
respectively). Clinical and PK findings from the single-agent Phase 1 Study JPBA and 
preliminary safety data from the LY2835219/NSAI combination in Study JPBH support 150 mg 
every 12 hours as the recommended dose for LY2835219 in Study I3Y-MC-JPBM (JPBM). 
The current Phase 3 Study JPBM will evaluate the clinical safety and efficacy of NSAI plus 
LY2835219 or placebo in postmenopausal women with HR+, HER2- locoregionally recurrent 
(not amenable to curative therapy) or metastatic breast cancer who have not previously received 
systemic therapy in this disease setting. 
More information about the known and expected benefits and risks of LY2835219 may be found 
in the Investigator’s Brochure (IB).  Information on AEs expected to be related to the 
LY2835219 may be found in Section 7 (Development Core Safety Information) of the IB. 
Information on serious adverse events (SAEs) expected in the study population independent of 
drug exposure and that will be assessed by the sponsor in aggregate, periodically during the 
course of the study, may be found in Section 6 (Effects in Humans) of the IB. 
More detailed information about the known and expected benefits and risks of anastrozole or 
letrozole may be found in the following: Patient Information Leaflet, Package Insert, or 
Summary of Product Characteristics. 

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LY2835219 
 
 
 
 
 
6.1. Primary Objective 
6. Objectives 
The primary objective of this study is to compare treatment with LY2835219 plus NSAI therapy 
versus placebo plus NSAI therapy with respect to PFS in postmenopausal women with HR+, 
HER2- locoregionally recurrent or metastatic breast cancer who have not received prior systemic 
therapy in this disease setting. 
 
6.2. Secondary Objectives 
The secondary objectives of the study are to compare the combination treatment of LY2835219 
and NSAI therapy versus placebo plus NSAI therapy with respect to the following: 
 OS 
 OS rate at 1, 2, and 3 years; 
 ORR (CR + PR); 
 duration of response (CR + PR); 
 DCR (CR + PR + SD); 
 CBR (CR + PR + SD ≥6 months); 
 the safety and tolerability; 
 change in symptom burden from baseline using the EORTC QLQ-C30, EORTC QLQ- 
BR23 (breast) questionnaire, and health status scores from the EQ-5D 5L; 
 the PK of LY2835219, its metabolites, and NSAI therapy. 
 
6.3. Exploratory Objectives 
 
 To explore potential biomarkers related to the mechanism of action of LY2835219, 
the cell cycle, and/or the pathogenesis of breast cancer. 
 To explore change in tumor size. 

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7. Study Population 
Individuals who do not initially meet the criteria for participation in this study (screen failure) 
may be re-screened (Section 7.2.1). 
Study participants should be instructed not to donate blood or blood products during the study or 
for 2 weeks following the last dose of study drug. 
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted. 
 
7.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
[1] have a diagnosis of HR+, HER2- breast cancer. Although not required as a 
protocol procedure, metastatic disease should be considered for biopsy 
whenever possible to reassess HR and HER2 status if clinically indicated. 
• 
To fulfill the requirement for HR+ disease, a breast cancer must express, 
by immunohistochemistry (IHC), at least one of the hormone receptors 
(ER, progesterone receptor [PgR]) as defined in the relevant American 
Society of Clinical Oncology (ASCO)/College of American Pathologists 
(CAP) Guidelines (Hammond et al. 2010). 
• 
To fulfill the requirement of HER2- disease, a breast cancer must not 
demonstrate, at initial diagnosis or upon subsequent biopsy, 
overexpression of HER2 by either IHC or in-situ hybridization (ISH) as 
defined in the relevant ASCO/CAP guidelines (Wolff et al. 2013). 
[2] have locoregionally recurrent disease not amenable to resection or radiation 
therapy with curative intent or metastatic disease 
[3] have postmenopausal status, defined as meeting one of the following 
conditions: 
• 
Prior bilateral oophorectomy 
• 
Age ≥60 years 
• 
Age <60 years and amenorrheic (non-treatment-induced amenorrhea 
secondary to tamoxifen, toremifene, ovarian suppression, or 
chemotherapy) for at least 12 months. Follicle-stimulating hormone 
(FSH) and estradiol must be in the postmenopausal range. 
[4] 
have one of the following as defined by the RECIST v1.1 (Eisenhauer et al. 
2009; refer to Attachment 5): 
• 
Measurable disease 

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• 
Nonmeasurable bone-only disease. Nonmeasurable bone-only disease 
may include any of the following: blastic bone lesions, lytic bone 
lesions without a measurable soft tissue component, or mixed lytic- 
blastic bone lesions without a measurable soft tissue component. 
[5] have a PS of ≤1 on the ECOG scale (see Attachment 4) 
[6] have adequate organ function, including: 
 hematologic:  absolute neutrophil count (ANC) 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 8 g/dL. Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator; however, initial study drug treatment must not begin earlier 
than the day after the erythrocyte transfusion. 
 hepatic: bilirubin 1.5 times the upper limit of normal (ULN) and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) 3.0 times 
ULN (or ALT and AST ≤5 times ULN if liver metastases are present). 
 renal:  serum creatinine 1.5 times ULN. 
[7] have discontinued previous localized radiotherapy for palliative purposes or 
for lytic lesions at risk of fracture at least 2 weeks prior to randomization and 
recovered from the acute effects of therapy (until the toxicity resolves to either 
baseline or at least Grade 1) except for residual alopecia or peripheral 
neuropathy. 
[8] are female and ≥18 years of age 
[9] are able to swallow capsules 
[10] have given written informed consent prior to any study-specific procedures 
[11] are reliable, willing to be available for the duration of the study, and are 
willing to follow study procedures. 
 
7.2. Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
[12] have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. 
Visceral crisis is not the mere presence of visceral metastases but implies 
severe organ dysfunction as assessed by symptoms and signs, laboratory 
studies, and rapid progression of the disease. 
[13] have inflammatory breast cancer. 
[14] have clinical evidence or a history of CNS metastasis. Screening is not 
required for enrollment. 

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LY2835219 
 
 
 
[15] are currently receiving or have previously received endocrine therapy for 
locoregionally recurrent or metastatic breast cancer. [Note: A patient may be 
enrolled if she received prior (neo)adjuvant endocrine therapy (including , but 
not limited to anti-estrogens or aromatase inhibitors) for localized disease. In 
addition, a patient may be enrolled if she has received ≤2 weeks of NSAI in 
this disease setting immediately preceding screening and agrees to discontinue 
NSAI until study treatment initiation.] 
[16] have received prior (neo)adjuvant endocrine therapy (e.g., anti-estrogens or 
aromatase inhibitors) with a disease-free interval ≤12 months from completion 
of treatment. 
[17] are currently receiving or have previously received chemotherapy for 
locoregionally recurrent or metastatic breast cancer. [Note: Patients may be 
enrolled if they received prior (neo)adjuvant chemotherapy for localized 
disease.] 
[18] have received prior treatment with everolimus 
[19] have received prior treatment with any CDK4/6 inhibitor (or participated in 
any CDK4/6 inhibitor clinical trial for which treatment assignment is still 
blinded) 
[20] have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted 
agents (for example, denosumab) <7 days prior to randomization 
[21] 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. 
[22] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of randomization for a 
nonmyelosuppressive or myelosuppressive agent, respectively. 
[23] have had major surgery within 14 days prior to randomization to allow for 
post-operative healing of the surgical wound and site(s). 
[24] have received recent (within 28 days prior to randomization) yellow fever 
vaccination. 
[25] 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, or 
preexisting Crohn’s disease or ulcerative colitis). 
[26] have a personal history within the last 12 months of any of the following 
conditions: syncope of cardiovascular etiology, ventricular tachycardia, 
ventricular fibrillation, or sudden cardiac arrest. 

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LY2835219 
 
 
 
[27] have a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years. 
[28] have received an autologous or allogeneic stem-cell transplant. 
[29] 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. 
 
7.2.1. Rescreening 
A patient who fails screening is allowed to screen again after signing a new informed consent 
form (ICF) and will be assigned a new patient number under the conditions specified in this 
section. 
The following patients may be eligible for rescreening if any of the following circumstances: 
 Patients who have become eligible to enroll in the study as the result of a protocol 
amendment. 
 Patient status has changed such that the eligibility criterion that caused the patient 
to screen fail would no longer cause the patient to screen fail again. 
 Patients who complete screening and meet all inclusion and exclusion 
requirements but are unable to be enrolled due to extenuating circumstances (such 
as, severe weather, death in family, child illness). 
The investigator should contact the Lilly CRP prior to rescreening a patient. 
 
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 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 treatment (that is, blinded study drug 
and/or NSAI) and/or from the study in the following circumstances: 
 progressive disease (PD) as defined by RECIST v1.1 

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LY2835219 
 
 
 
 enrollment in any other clinical trial involving an investigational drug 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 treatment 
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 treatment occurs prior to 
introduction of the new agent 
 patient decision 
o the patient or the patient’s designee (for example, legal guardian) requests to 
be withdrawn from the study or study treatment 
 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 of 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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LY2835219 
 
 
 
8. Investigational Plan 
8.1. Summary of Study Design 
Study JPBM is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study 
evaluating treatment of LY2835219 with NSAI or placebo with NSAI in postmenopausal women 
with HR+, HER2- locoregionally recurrent (not amenable to curative therapy) or  metastatic 
breast cancer who have not received prior systemic therapy in this disease setting . 
Figure JPBM.8.1 illustrates the study design. 
 
 
Abbreviations: HER2- = human epidermal growth factor receptor 2-negative; HR+ = hormone receptor- 
positive; N = number; NSAI = nonsteroidal aromatase inhibitor; PD = progressive disease. 
 
Figure JPBM.8.1. 
Illustration of study design. 
Approximately 450 patients will be randomized 2:1 between the 2 arms: 
 Experimental Arm A: LY2835219 150 mg orally every 12 hours on Days 1 to 28 plus 
either anastrozole 1 mg or letrozole 2.5 mg once daily of a 28-day cycle 
 Control (Placebo) Arm B: Placebo orally every 12 hours on Days 1 to 28 plus either 
anastrozole 1 mg or letrozole 2.5 mg once daily of a 28-day cycle 
 
Patients will be randomized using the following stratification factors: nature of disease 
(visceral metastases versus bone-only metastases versus other) and prior (neo)adjuvant 
endocrine therapy (aromatase inhibitor therapy versus other versus no prior endocrine 
therapy). The presence of visceral metastases refers to lung, liver, pleural, peritoneal, or 
adrenal gland involvement at the time of randomization. Prior (neo)adjuvant endocrine 
therapy refers to aromatase inhibitor therapy (e.g., anastrozole, exemestane and letrozole) vs. 
other (e.g., tamoxifen and fulvestrant) vs. no prior endocrine therapy. 

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LY2835219 
 
 
 
Database lock for the interim analysis for efficacy will occur when approximately 
218 investigator-assessed PFS events have been observed. Database lock for the primary 
analysis of the PFS endpoint will occur when approximately 312 investigator-assessed 
PFS events have been observed. The final analysis of OS will occur when approximately 
315 OS events have been observed.  All patients will be followed for survival 
information until death or study completion, whichever comes first. 
Terms used to describe the periods during the study are defined below: 
 Baseline: begins when the ICF is signed and ends at the first study treatment dose (or at 
discontinuation, if no treatment is given). This may be up to 28 days prior to the first 
study treatment dose. 
 Study Period: begins at the first study treatment dose and ends at study completion. 
The study period does not include the continued access period. 
o Study Treatment Period: begins at the first study treatment dose and ends when 
the patient and the investigator agree that the patient will no longer continue study 
treatment. This date is to be reported on the electronic case report form (eCRF) as 
the Date of Discontinuation from study treatment. 
 Postdiscontinuation Follow-Up: begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment. 
o 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. 
o 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. 
 Continued Access Period: begins after study completion and ends at the end of trial. 
During the continued access period, patients on study treatment who continue to 
experience clinical benefit may continue to receive study treatment (except placebo) until 
one of the criteria for discontinuation is met. 
o The continued access period includes continued access period short-term follow- 
up. 
o Continued access short-term follow-up: begins the day after the patient and the 
investigator agree that the patient will no longer continue treatment in the 
continued access period and lasts approximately 30 days. 
 
8.1.1. Study Completion and End of Trial 
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the evaluation of final OS data (refer to Figure JPBM.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 continued access period follow-up (Figure JPBM.8.2). 

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LY2835219 
 
 
 
 
 
Abbreviations:  OS = overall survival; PFS = progression-free survival. 
 
Figure JPBM.8.2. 
Study period and continued access period diagram. 
 
8.1.2. Continued Access Period 
After study completion, all patients who are on study treatment and who are eligible for the 
continued access period will be unblinded. Patients receiving study treatment and experiencing 
ongoing clinical benefit may continue to receive study treatment in the continued access period 
until one of the criteria for discontinuation is met (Section 7.3.1). During the continued access 
period, placebo will no longer be administered, and crossover will not be permitted. Lilly will 
notify investigators when the continued access period begins. 
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed. Long-term 
follow-up does not apply. 
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up. 
During the continued access period, all AEs, SAEs, and study drug exposure will be reported on 
the CRF. Serious adverse events will also be reported to Lilly Global Patient Safety (see Section 
10.3.1). In the event that an SAE occurs, Lilly may request additional information (such as local 
laboratory results, concomitant medications, and hospitalizations) in order to evaluate the 
reported SAE. 
a 
Lilly will notify sites when this begins and ends. 

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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 investigational 
treatment assignments for any patients. This design feature minimizes potential bias due to 
knowledge of patient’s treatment during evaluation of study endpoints, at the patient level or 
aggregated across patients. 

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9. Treatment 
9.1. Treatments Administered 
The following treatments will be administered in this study: 
 Experimental Arm A: LY2835219 150 mg orally every 12 hours plus either anastrozole 
1 mg or letrozole 2.5 mg orally every 24 hours on Days 1 to 28 of a 28-day cycle. 
 Control (Placebo) Arm B:  Placebo orally every 12 hours plus either anastrozole 1 mg or 
letrozole 2.5 mg orally every 24 hours on Days 1 to 28 of a 28-day cycle. 
Blinded study drug is defined as LY2835219 or placebo. Study treatment is defined as blinded 
study drug and/or NSAI. 
The specific NSAI (anastrozole or letrozole) administered to patients is determined by the 
investigator. Patients should remain on the same NSAI throughout the study. In exceptional 
cases, in the absence of evidence of PD, the investigator may discuss a change in NSAI with the 
Lilly CRP. NSAI is a co-administered standard-of-care treatment. The investigator should refer 
to the NSAI label (that is, Patient Information Leaflet, Package Insert, or Summary of Product 
Characteristics).  Table JPBM.9.1 shows the treatment regimens. 

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Table JPBM.9.1. 
Treatment Regimens/Dosing Schedule 
Regimen 
Period/Cycle 
Dose Day 
Experimental Arm A 
LY2835219 
Treatment/28-day cycle 
150 mg PO every 12 hours on Days 1-28a 
 
 
Anastrozole 
or      
Letrozole 
Control (Placebo) Arm B 
 
Treatment /28-day cycle 
1 mg PO every 24 hours on Days 1-28b 
or 
2.5 mg PO every 24 hours on Days 1-28b 
 
 
Placebo 
Treatment/28-day cycle 
PO every 12 hours on Days 1-28a 
 
 
Anastrozole 
or      
Letrozole 
 
Treatment /28-day cycle 
1 mg PO every 24 hours on Days 1-28b 
or 
2.5 mg PO every 24 hours on Days 1-28b 
 
Abbreviations: ECG = electrocardiogram; PK = pharmacokinetic; NSAI = nonsteroidal aromatase inhibitor; PO = 
orally. 
a 
On Cycle 1 Day 1 only, patients should take one single dose of blinded study drug and initiate chronic every- 
12-hours dosing on Cycle 1, Day 2. 
b   For PK and ECG purposes, NSAI should be administered at the same time (or up to 20 minutes after) the 
morning dose of blinded study drug through Cycle 4, Day 1. Subsequently, the interval between administration 
of blinded study drug and NSAI may be adjusted based on the judgment of the investigator. 
The investigator or his/her designee is responsible for the following: 
 explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative, 
 verifying that instructions are followed properly, 
 maintaining accurate records of study drug dispensing and collection (including the co- 
administered NSAI doses taken by the patient), 
 and returning all unused medication supplied by Lilly 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 of clinical trial materials. 
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed. 

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9.2. Materials and Supplies 
LY2835219 or placebo (blinded study drug) will be supplied as capsules for oral administration. 
Blinded study drug capsules should be stored according to the product label, and not opened, 
crushed, or dissolved. Blinded study drug will be labeled according to the country’s regulatory 
requirements. 
Where required, letrozole and anastrazole will be supplied by Lilly and labeled according to 
country regulatory requirements. Letrozole and anastrazole should be stored according to the 
product label and will be provided as anastrazole 1-mg or letrozole 2.5-mg tablets. 
Investigators should instruct patients to store the blinded study drug and NSAI in the original 
package provided and in a location inaccessible to children. 
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 or placebo. Assignment to treatment 
groups will be determined by a computer-generated random sequence using the IWRS.  Sites 
will be prompted to enter the specific NSAI at time of randomization. 
Randomization will be stratified by the following: nature of disease (visceral metastases versus 
bone-only metastases versus other), and prior (neo)adjuvant endocrine therapy (aromatase 
inhibitor therapy versus other versus no prior endocrine therapy). 
The IWRS will be used to assign LY2835219 or placebo and distribute NSAI supplied by Lilly. 
Site personnel will confirm that they have located the correct study medication packages by 
entering a confirmation number found on the packages into the IWRS. 
The period between randomization to blinded study drug and the first dose (Cycle 1, Day 1) 
should not exceed 7 days. 
 
9.4. Selection and Timing of Doses 
Blinded study drug will be taken orally every 12 (±2) hours on Days 1 through 28 of a 28-day 
cycle, for a total of 56 doses per cycle. During all cycles, blinded study drug should be taken at 
approximately the same times each day. If a patient misses or vomits a blinded study drug dose, 
that dose should be omitted. 
Anastrozole or letrozole will be administered orally every 24 hours (±2) on Days 1 through 28 of 
a 28-day cycle for a total of 28 doses per cycle. For PK and electrocardiogram (ECG) purposes, 
anastrozole or letrozole should be administered at the same time as (or up to 20 minutes after) the 
morning dose of blinded study drug through Cycle 4, Day 1. Subsequently, the interval between 
administration of blinded study drug and anastrozole or letrozole may be adjusted based on the 
judgment of the investigator. If a patient misses or vomits an anastrozole or letrozole dose, that 
dose should be omitted. 

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A cycle is defined as an interval of 28 days plus any subsequent delay prior to start of the next 
cycle. A delay in the start of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances will be permitted up to 7 days and not counted as a protocol 
deviation). For each 28-day cycle, a total of 56 doses of blinded study drug will be dispensed. 
In exceptional cases, for planned delays (including but not limited to vacation or holidays), 
additional study treatment may be dispensed. 
A patient may continue to receive study treatment until she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3.1). 
 
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. 
Blinded Study Drug 
Blinded study drug dose adjustments as outlined in Table JPBM.9.2 are allowed both within a 
cycle and between cycles. Blinded study drug must be reduced sequentially by one dose level. 
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly CRP. 
Table JPBM.9.2. 
Dose Adjustments for Blinded Study Drug 
 
Dose Adjustment Level 
Oral Dose 
Frequency 
0 
150 mg 
Every 12 hours 
1 
100 mg 
Every 12 hours 
2 
50 mg 
Every 12 hours 
 
Blinded study drug must be discontinued if further dose reduction is required beyond 50 mg 
every 12 hours. In the event that blinded study drug must be discontinued, a patient may 
continue to receive anastrozole or letrozole. 
 
9.4.1.1.1.2. 
Anastrozole or Letrozole 
Per NSAI labels, dose adjustment for anastrozole or letrozole is not applicable, as only a single- 
dose strength is approved for each medication. In exceptional cases in the absence of evidence 
of PD, the investigator may discuss a change in the specific NSAI administration (for example, 
switching from anastrozole to letrozole) with the Lilly CRP. In the event that anastrozole or 
letrozole must be discontinued, a patient may continue to receive blinded study drug per the 
investigator’s clinical judgment. 
9.4.1.1.2. Dose Suspension (within a Cycle) and Cycle Delay 
Both dose suspension (within a cycle) and cycle delay are permitted. When a dose suspension or 
cycle delay occurs related to toxicity (defined as an AE possibly related to study treatment per 

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investigator judgment), the blinded study drug and/or NSAI may be suspended or delayed as 
determined by the investigator’s judgment. 
Study treatment may be held up to 14 days within a cycle or at start of next cycle to permit 
sufficient time for recovery from the toxicity. If a dose suspension occurs within a cycle, the 
investigator may resume blinded study drug dosing at the same dose level for the remainder of 
the cycle or at reduced dose (assuming resolution to at least Grade 1 for non-hematological and 
at least Grade 2 for hematological toxicity). If the patient experiences the same toxicity with the 
same or greater severity (CTCAE grade) requiring a dose suspension within a cycle or at start of 
the next cycle, the patient must be dose reduced and not re-challenged a second time at the prior 
dose level. 
Patients not recovering from toxicity within 14 days should be considered for discontinuation of 
the blinded study drug and/or co-administered NSAI. In exceptional circumstances, a delay >14 
days is permitted upon agreement between the investigator and the Lilly CRP and blinded study 
drug dose adjustment is to be considered. 
In the event of a cycle delay due to logistical reasons (for example, due to patient availability), 
the patient should continue on study treatment if the patient has adequate drug supply. If a 
patient’s treatment is interrupted as a result of not having sufficient drug supply, the cycle may 
be delayed up to 7 days (and not be considered a protocol violation). In exceptional 
circumstances, a delay >7 days is permitted upon agreement between the investigator and the 
Lilly CRP. 
The start of a cycle may be delayed, or a current cycle interrupted, to allow a patient with a 
locoregionally recurrent breast cancer rendered operable by study treatment to receive surgery  
radiotherapy.  For additional information, refer to Section 9.6.1. 
9.4.1.1.3. Hematologic Toxicity 
If a patient experiences Grade 4 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to either baseline or at least Grade 2) and the dose of blinded study drug must 
be reduced by one dose level as outlined in Table JPBM.9.2. 
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to either baseline or at least Grade 2) and the dose of blinded study drug may be 
reduced by one dose level as outlined in Table JPBM.9.2 at the discretion of the investigator. 
Before the start of each cycle, hematologic toxicity must resolve to either baseline or at least 
Grade 2. 
9.4.1.1.4. Nonhematological Toxicity 
If a patient experiences ≥Grade 3 nonhematologic toxicity, then blinded study drug and/or NSAI 
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 1) and 
the dose of blinded study drug must be reduced by one dose level as outlined in Table JPBM.9.2. 

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If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 9.4.1.1.4.1) that does not resolve with maximal supportive measures within 
7 days to either baseline or at least Grade 1, then blinded study drug and/or NSAI dosing may be 
suspended (until the toxicity resolves to either baseline or at least Grade 1) and the dose of 
blinded study drug may be reduced by one dose level as outlined in Table JPBM.9.2 at the 
discretion of the investigator. 
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or at least Grade 1. 
 
9.4.1.1.4.1. 
Diarrhea 
A patient experiencing diarrhea requiring hospitalization (irrespective of grade, that is, requiring 
intravenous [IV] rehydration) or severe diarrhea (Grade 3 or 4; see Attachment 9) must have 
study treatment suspended (until the toxicity resolves to either baseline or at least Grade 1) and 
must have the blinded study drug dose reduced by one dose level as outlined in Table JPBM.9.2. 
If a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve with 
maximal supportive measures (refer to Section 9.6.5) within 3 days to either baseline or at least 
Grade 1, then study treatment should be suspended (until the toxicity resolves to either baseline 
or at least Grade 1) and the dose of blinded study drug may be reduced by one dose level as 
outlined in Table JPBM.9.2 at the discretion of the investigator. If the same dose level was 
resumed and diarrhea recurs despite maximal supportive measures, the dose of blinded study 
drug must be reduced by one dose level as outlined in Table JPBM.9.2. 
 
9.5. Blinding 
This is a double-blind study. 
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete. Access to 
unblinded data/documents will be controlled by restricting access to the data/documents in 
Lilly’s data and statistical warehouse. Any changes to this unblinding plan may be described in 
a protocol amendment, the Statistical Analysis Plan (SAP), and/or a separate unblinding plan 
document. 
Efficacy information will not be shared between sites until the study is completed. Upon overall 
study completion (see Section 8.1.1), investigators may unblind patients to study treatment 
assignment. 
 
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 

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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. 
All calls resulting in an unblinding event are recorded and reported by the IWRS. If the 
investigator or patient becomes unblinded, that patient will be discontinued from study treatment 
and will undergo postdiscontinuation follow-up (Attachment 1).  Long-term follow up 
procedures will be followed until death or study completion. 
9.5.3. Inadvertent Unblinding 
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur. A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms. If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 
for that patient to be discontinued from study therapy or excluded from any safety or efficacy 
analyses. 
Additionally, there may be ethical reasons to have the patient remain on the study treatment. For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study. 
9.6. Concomitant Therapy 
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRF. Concomitant medications and 
supportive care therapies must also be documented at the time of discontinuation and at the 30- 
day short-term follow-up visit. 
With the exceptions listed in the sections below, therapies for cancer (including hormonal 
anticancer therapies, chemotherapy, and immunotherapy) will not be permitted while patients are 
on study treatment. Use of megestrol acetate as an appetite stimulant is not permitted. 

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The results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study 
indicate that oxidative metabolism of LY2835219 is primarily catalyzed by CYP3A. 
Radiolabeled human disposition study indicates that LY2835219 is mostly cleared by oxidative 
metabolism and therefore inhibitors and or inducers of CYP3A may alter the metabolism of 
LY2835219.  Based on these 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). All patients may receive supportive therapy with dexamethasone, 
preferably ≤7 days, if clinically indicated. Patients requiring more than 7 days of dexamethasone 
therapy will not incur a protocol deviation. 
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 Locoregionally Recurrent 
Breast Cancer 
A patient with locoregionally recurrent breast cancer may receive surgery  radiotherapy if study 
treatment renders the tumor operable.  However, such a patient should not receive study 
treatment for the period beginning at least 7 days prior to surgery and continuing until at least 
14 days after completion of surgery  radiotherapy to allow for tissue healing and recovery. 
There is no restriction on the duration of this period without study treatment and, after this period 
ends, study treatment may resume.  Importantly, a patient who receives surgery  radiotherapy 
for locoregionally recurrent breast cancer is not considered noncompliant and does not incur a 
protocol deviation. 
 
9.6.2. Radiotherapy 
Except as described in Section 9.6.1, radiotherapy is not permitted without permanent 
discontinuation from study treatment. Except for a patient with locoregionally recurrent breast 
cancer rendered operable by study treatment who subsequently undergoes surgery + 
radiotherapy, all other patients requiring radiotherapy should discontinue permanently from 
study treatment and have a tumor assessment of the lesion(s) before receiving radiotherapy. 
 
9.6.3. Supportive Care 
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care as judged by their treating physician. If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported on the eCRFs. 

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9.6.4. Growth Factor 
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2006; 
Rizzo et al. 2008). 
 
9.6.5. Supportive Management for Diarrhea 
In the event of diarrhea, supportive measures should be initiated as early as possible. These 
include the following: 
 At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (e.g. 
loperamide) and notify the investigator for further instructions and appropriate follow- 
up. 
 Site personnel should assess response within 1 to 3 days. 
 If diarrhea does not resolve with anti-diarrheal therapy within 3 days to either baseline or 
Grade 1, then dosing should be adjusted as outlined in Section 9.4.1.1.1.1 and 
Table JPBM.9.2. 
 Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids 
per day). 
In potentially severe cases of diarrhea, the measuring of neutrophil counts and body temperature 
and proactive management of diarrhea with antidiarrheal agents should be considered. 
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe (Grade 3 or 
4) neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting should 
be carefully monitored and given fluid (IV hydration) and electrolyte replacement. 
9.6.6. Bisphosphonates and RANK-L Targeted Agents 
Patients with bone metastases present on baseline imaging should be appropriately treated with 
bisphosphonates or RANK-L targeted agents (for example, denosumab), per respective approved 
labels. Initiation of treatment with bone-modifying agents must begin at least 7 days prior to 
randomization.  Patients receiving bisphosphonates or RANK-L targeted agents should not 
switch treatments (for example, replace a bisphosphonate with denosumab) while on study 
treatment.  However, exceptional cases without evidence of PD may be considered in 
consultation with the Lilly CRP.  These exceptional cases will not incur a protocol deviation. 
 
9.7. Treatment Compliance 
Treatment compliance information for study treatment will be collected through patient dosing 
diaries and/or capsule/tablet counts at each visit, with the number of capsules/tablets taken 
relative to the number expected to be taken summarized for each cycle. The patient must take 
≥75% of the planned doses for study treatment in a cycle to be deemed compliant. As outlined 
in Section 9.4.1.1.2, dose suspensions or delays may occur and will not result in a patient being 
considered as noncompliant. A patient may be considered noncompliant if she is judged by the 

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investigator to have intentionally or repeatedly taken ≥125% of the planned doses of study 
treatment in a cycle. 
Importantly, a patient who receives surgery  radiotherapy for locoregionally recurrent breast 
cancer is not considered noncompliant and does not incur a protocol deviation. For additional 
information, refer to Section 9.6.1. 
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP before any determination is made to discontinue the patient. 
9.7.1. Patient Diaries 
The study will include patient diaries to provide dosing instructions, help patients with treatment 
planning, and track actual doses of study treatment taken by the patient. Information from the 
diaries may be used for documenting study treatment compliance as well as dosing time relative 
to PK blood draws and ECG collection. 

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10. Efficacy, Health Outcome/Quality-of-Life Measures, 
Safety Evaluations, Sample Collection and Testing, 
and Appropriateness of Measurements 
Written informed consent must be obtained prior to any study-specific pretreatment evaluations. 
Study procedures related to efficacy, safety, health outcome/quality-of-life measures, 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 assessments will be performed for each patient. 
The method of assessment used at baseline must be used consistently for serial tumor assessment 
throughout the study. 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. All tumor assessment images 
must be submitted for central review. 
For all patients, imaging studies (computed tomography [CT], including spiral CT, or magnetic 
resonance imaging [MRI] scan of the chest, abdomen, and pelvis) will be performed locally at 
baseline and repeated between Day 21 and Day 28 of every second cycle beginning with Cycle 2 
and continuing through Cycle 18 (inclusive), between Day 21 and 28 of every third cycle after 
Cycle 18, and within 14 days of clinical progression per the Study Schedule (Attachment 1). It is 
recommended that CT imaging of the abdomen and pelvis be performed with IV contrast, 
whenever possible.  For patients with known hypersensitivity to CT contrast material, a CT scan 
of the chest without contrast and gadolinium-enhanced MRI of the abdomen and pelvis are 
encouraged.  The CT portion of a positron emission tomography (PET)-CT scan may be used as 
a method of response assessment if the site can document that the CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast). A PET scan alone or as part of a PET-CT 
may be performed as part of routine clinical care but cannot be used to assess response according 
to RECIST v1.1. 
For all patients, bone scintigraphy will be performed locally at baseline and repeated between 
Day 21 and Day 28 of every sixth cycle beginning with Cycle 6. In addition, bone scans should 
be repeated even if a complete response in target disease is identified or progression in bone is 
suspected. For patients with new lesions identified by post-baseline bone scintigraphy, targeted 
assessment by X-ray, CT scan with bone windows, or MRI will be performed to confirm 
findings. 
For only those patients with bone lesions identified by bone scintigraphy at baseline, directed 
imaging using one of the following methods will be performed at baseline: X-ray, CT scan with 
bone windows, or MRI. Directed imaging using the same method as at the baseline bone lesion 

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assessment should be repeated between Day 21 and Day 28 of every second cycle beginning 
with Cycle 2 and continuing through Cycle 18 (inclusive), between Day 21 and Day 28 of every 
third cycle after Cycle 18, and within 14 days of clinical progression. 
For patients with locoregionally recurrent breast cancer not amenable to curative treatment, MRI 
scan of the breast will be performed at baseline, if applicable. Breast MRI, if applicable, will be 
repeated between Day 21 and Day 28 of every second cycle beginning with Cycle 2 and 
continuing through Cycle 18 (inclusive), between Day 21 and Day 28 of every third cycle after 
Cycle 18, and within 14 days of clinical progression. 
For patients with visible tumor (such as skin lesions), photography will be performed at baseline 
and each photographic image of the tumor should include a ruler. Photography should be 
repeated on Day 1 of every second cycle beginning with Cycle 3 and continuing through Cycle 
19 (inclusive), on Day 1 of every third cycle after Cycle 19, and within 14 days of clinical 
progression.  Photographic images may be taken more frequently based upon the discretion of 
the investigator or following the identification of new skin lesions post-baseline. 
For patients continuing treatment during the Continued Access Period (after study completion), 
efficacy assessments (frequency and type of assessments) will be at the discretion of the 
investigator. 
10.1.2. Efficacy Assessments during 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 PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response 
approximately every 8 weeks for the first 18 months following randomization and thereafter 
approximately every 12 weeks by the same method used at baseline and throughout the study 
until the patient has objective disease progression, or until the primary analysis of PFS. In 
addition, anticancer therapies initiated after study treatment discontinuation will be collected 
during this follow-up period. After the patient has objective disease progression, radiologic 
imaging and photographic images are no longer required and the patient will be followed up 
approximately every 12 weeks until the patient’s death or overall study completion. 
Lilly will continue to collect survival data on all patients but may reduce data collection for other 
efficacy data.  Lilly will notify investigators when this reduced data collection can begin. 
 
10.1.3. Primary Efficacy Measure 
The primary efficacy measure is PFS as defined by [RECIST v1.1 (Eisenhauer et al. 2009)] 
provided in Attachment 5. 
Lilly or its designee will collect and store all tumor assessment images on all enrolled patients 
throughout the study. An independent review of a randomly selected subset of patient scans will 
be performed by independent panel of radiologists (Section 12.2.8). 

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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 [4]), 
objective progression will be established if at least 1 of the following criteria is met: 
 the appearance of 1 or more new lesions (in bone or outside of bone), or 
 unequivocal progression of existing bone lesions. 
According to RECIST v1.1, the finding of a new lesion should be unequivocal and not 
attributable to findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of preexisting lesions). Pathologic fracture, 
new compression fracture, or complications of bone metastases will not be considered as 
evidence of disease progression, unless at least 1 of the above criteria is met. 
For those patients with locoregionally recurrent disease for whom surgery is performed with no 
evidence of residual disease post-operatively, objective progression will be established if at least 
1 of the following criteria is met: 
 local and/or regional recurrence, or 
 new development of metastatic disease. 
For those patients with locoregionally recurrent disease for whom surgery is performed while on 
study with evidence of residual disease post-operatively, new baseline measurements should be 
taken and RECIST applied. 
If a patient is not known to have progressed or died at the time of analysis, PFS time will be 
censored at the last known progression-free assessment. See Section 12.2.6 for detailed 
censoring rules. 
 
10.1.4. Secondary Efficacy Measures 
The following secondary efficacy measures (Table JPBM.10.1) will be collected at the times 
shown in the Study Schedule (Attachment 1). 

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Table JPBM.10.1. 
Secondary Efficacy Endpoints 
 
Endpoint 
Definition 
Overall Survival (OS) 
The time from the date of study 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 
Clinical Benefit Rate (CBR) 
The proportion of patients with CR, PR, or SD ≥6 months 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 (according to RECIST v1.1) or death from any cause, 
whichever is earlier 
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 last known alive date. 
Objective Response Rate (ORR): The objective response rate is the percentage of patients with 
a best response of CR or PR. 
Duration of Response (DoR): The DoR time is defined only for responders (patients with a 
confirmed CR or PR). It is measured from the date of first evidence of CR or PR to the date of 
objective progression or the date of death due to any cause, whichever is earlier. For clarity, the 
start date should be determined by the initial assessment of CR or PR, not the date of 
confirmation of CR or PR. If a responder is not known to have died or have objective 
progression as of the data inclusion cutoff date scores, DoR will be censored at the last complete 
objective progression-free disease assessment date. 
Disease Control Rate (DCR): The DCR is the percentage of patients with a best response of 
CR, PR, or SD. 
Clinical Benefit Rate (CBR): The CBR is the percentage of patients with a best response of CR 
or PR, or SD for at least 6 months. 
 
10.1.5. Exploratory Measures 
Table JPBM.10.2. 
Exploratory Measures 
 
Biomarkers 
Potential biomarkers related to the mechanism of action of LY2835219, the cell 
cycle, and/or the pathogenesis of breast cancer 
CTS (change in tumor size) 
Change in the size of target lesions 

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Biomarkers: Exploratory analysis using blood and tumor tissues will be done to explore 
potential biomarkers related to the mechanism of action of LY2835219, the cell cycle, and/or the 
pathogenesis of breast cancer to better understand relationships of cellular signaling defects with 
clinical outcomes. 
Change in Tumor Size: Change in tumor size will be measured using target lesion 
measurements selected for radiological evaluation. This measurement will only be available on 
patients with measureable disease. 
 
10.2. Health Outcome/Quality-of-Life Measures 
10.2.1. Patient-Reported Outcomes 
The primary health outcomes research goal is to assess if LY2835219 combination therapy is 
able to impact the quality of life, as measured by the EORTC QLQ-C30 (Aaronson et al. 1993). 
Additionally, 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. 
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 EQ-5D 
5L, EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires should be administered to the 
patient prior to extensive interaction with site staff and study drug administration. 
10.2.1.1. Health-Related Quality of Life 
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC 
QLQ-C30 (Aaronson et al. 1993) is a reliable and validated tool. The EORTC QLQ-C30 self- 
reported general cancer instrument 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). 

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10.2.1.2. 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. Additionally, EQ-5D 5L responses may be 
incorporated into cost utility analyses. 
Administration is preferably scheduled after 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. 
10.2.2. Resource Utilization 
Investigators will be asked to report the use of concomitant medications (in particular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 
radiation therapy, surgery, and hospitalization days. Data on neurosurgical blocks will be 
recorded on the Concomitant Medication and/or surgery eCRF as appropriate. This information 
should be collected during the study and at the 30-day follow-up visit. 
 
10.3. Safety Evaluations 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient. 
The investigator is responsible for the appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study. The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator. 
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1). Table 
JPBM.10.3 presents a summary of AE and SAE reporting guidelines and also shows which 
database or system is used to store AE and SAE data. 

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Table JPBM.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 
All AEs 
SAEs related to protocol procedures 
x 
x 
x 
x 
Study treatment period 
All AEs 
All SAEs 
x 
x 
x 
30-day short-term 
postdiscontinuation follow-up 
All AEs 
All SAEs 
x 
x 
x 
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study drug 
x 
x 
Continued access period 
All AEs 
All SAEs 
x 
x 
x 
Continued access  period follow-up 
All AEs 
All SAEs 
x 
x 
x 
After the patient is no longer 
participating in the study (that is, no 
longer receiving study therapy and 
no longer in follow-up) 
All SAEs related to protocol procedures 
or study drug that the investigator 
becomes aware of 
x 
Abbreviations:  AEs = adverse events; SAEs = serious adverse events. 
 
10.3.1. Adverse Events 
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent. A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug. 
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect. 
Any clinically significant findings from ECGs, labs, vital sign measurements, and other 
procedures that result in a diagnosis should be reported to Lilly or its designee. 
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study. 

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After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s). All AEs related to protocol procedures are reported to 
Lilly or its designee. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drug 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 National Cancer Institute (NCI)-CTCAE v 4.0 will serve as the reference document for 
choosing appropriate terminology for, and grading the severity of, all AEs and other symptoms. 
For AEs without matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator 
will be responsible for selecting the appropriate system organ class and assessing severity grade 
based on the intensity of the event. 
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary. 
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 
10.3.1.1. Serious Adverse Events 
An SAE is any AE 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 

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 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 SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms. 
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information. 
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study. 
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs. 
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug. 
If an investigator becomes aware of an SAE occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAE to the sponsor, and the SAE will be entered in the 
Lilly Safety System. 
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB. 
10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information (DCSI) 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 

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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, 12-lead digital ECGs 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 (QTc) 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, syncope) and to determine if the patient can continue in the study. The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation. 
10.3.3. Safety Monitoring 
The Lilly CRP will monitor safety data throughout the course of the study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review: 
 trends in safety data 
 laboratory analytes 
 AEs 
 if a patient experiences elevated ALT or AST >5× ULN in the absence of liver 
metastases and elevated total bilirubin >2× ULN, clinical and laboratory monitoring 
should be initiated by the investigator.  For patients entering the study with ALT or AST 
>3x ULN in the presence of liver metastases, monitoring should be triggered if ALT or 
AST is elevated to >2x baseline. 
 details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests. See Attachment 3. 

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In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (an advisory group for this study formed to protect 
the integrity of data; refer to Section 12.2.14) 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 treatment used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements. 
All product complaints associated with material packaged, labeled, and released by Lilly or its 
designee will be reported directly to Lilly. 
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study: 
 recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose 
 faxing the completed product complaint form within 24 hours to Lilly or its designee 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product. 
 
10.4. Sample Collection and Testing 
Attachment 1 lists the schedule for sample collections in this study. 
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory. 
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study. 
Attachment 7 lists the schedule for PK sampling during the study. 
 
10.4.1. Samples for Study Qualification and Health Monitoring 
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. 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 

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laboratory that may have an impact on eligibility or treatment decisions will not be considered 
protocol deviations. In addition to protocol-specified tests, investigators should consider 
monitoring of cholesterol and bone mineral density if needed, per the recommendations for 
anastrozole and letrozole in the Package Insert and Summary of Product Characteristics. 
Investigators must document their review of each laboratory safety report. 
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid. Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards. 
10.4.2. Samples for Biomarkers 
Samples for biomarker research to be collected from all patients in this study are the following: 
 
whole blood 
 
plasma 
 
tumor tissue 
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers. 
These samples are described in the following sections. 
10.4.2.1. Archived Tumor Tissue 
For patients in the study, a small amount of preserved tumor tissue, previously taken to evaluate 
the patient’s disease, is required to be provided by sites upon patient randomization for 
biomarker research. However, if this sample is not available for a patient or the patient declines, 
a protocol deviation will not be incurred and the patient is eligible for the study. 
Available formalin-fixed, paraffin-embedded primary and/or metastatic tumor tissue should be in 
a whole block, partial block, or unstained slides. Any whole block submitted will be returned to 
the site.  Any partial blocks or slides will either be returned or discarded within 15 years after 
last patient visit for the trial. 
In tumor tissue samples, the CDK4/6 pathway components (for example, Rb) and markers 
relevant to 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. 

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10.4.2.2. Blood Samples for Pharmacogenetic Evaluations 
There is growing evidence that genetic variation may impact a patient’s response to therapy. 
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated. Therefore, where local 
regulations and ethical review boards (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 
EDTA-anticoagulated 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. 
 
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 will be collected from at least 150 of the patients randomized in the study. 
These samples will be used to determine the plasma concentrations of LY2835219 and possibly 
LY2835219 metabolites, as well as plasma concentrations of anastrozole or letrozole. 
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 

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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 anastrozole or letrozole 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 Lilly. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 

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12. Sample Size and Statistical Methods 
12.1. Determination of Sample Size 
The primary objective of this study is to compare LY2835219 plus NSAI versus placebo plus 
NSAI in terms of PFS in postmenopausal women with HR+, HER2- locoregionally recurrent or 
metastatic breast cancer who have not received prior endocrine therapy in this disease setting. 
The study will enroll approximately 450 patients in 2:1 randomization (300 patients in 
LY2835219 plus NSAI and 150 patients in placebo plus NSAI). Patients will be randomized 
using the following stratification factors: nature of disease (visceral metastases versus bone-only 
metastases versus other) and prior (neo)adjuvant endocrine therapy (aromatase inhibitor therapy 
versus other versus no prior endocrine therapy). 
A group-sequential design of the primary endpoint will be used to accommodate an event-driven 
plan for the interim and primary PFS analyses (see Section 12.2.6 for details). The primary PFS 
analysis will be performed after approximately 312 PFS events have occurred (that is, a 30% 
censoring rate). Assuming a hazard ratio of 0.714, this sample size yields at least 80% statistical 
power to detect superiority of the LY2835219 plus NSAI arm over the placebo plus NSAI arm 
with the use of a 1-sided log-rank test and a cumulative type I error of 0.025. If the true median 
PFS for the placebo plus NSAI arm is 10 months, then the hazard ratio of 0.714 amounts to an 
approximately 4-month (40%) improvement in median PFS for the LY2835219 plus NSAI arm 
under an additional assumption of exponential survival distribution. Assuming approximately 
10% screening failure, the study will enter approximately 500 patients. 
 
12.2. Statistical and Analytical Plans 
12.2.1. General Considerations 
Statistical analysis of this study will be the responsibility of Lilly. 
 
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set. This population is 
defined as all patients randomized to study treatment. Patients will be grouped according to 
randomized treatment. 
 
Safety analyses will be based on the randomized and treated population (RT), defined as all 
randomized patients receiving at least 1 dose of blinded study drug or NSAI. Patients will be 
grouped according to treatment received in Cycle 1. 
 
Pharmacodynamic and/or biomarker analyses will be based on the subset of patients from the 
above populations from whom a valid assay result (according to laboratory guideline) has been 
obtained. 

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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 confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise 
stated. 
 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. 
 
Before sponsor unblinding of the aggregate database, minor modifications or clarifications to the 
data analysis methods may be described and justified in the 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 may be evaluated. If there is violation of 
assumptions, alternative statistical methods may be used. 
 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
 
12.2.2. Patient Disposition 
A detailed description of patient disposition will be provided. It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated, as 
well as number and percentage of patients completing the study or discontinuing (overall and by 
reason for discontinuation). 
 
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 (neo)adjuvant endocrine therapy 
 prior (neo)adjuvant chemotherapy (including both cytotoxic and targeted agents) 
Other patient characteristics will be summarized as deemed appropriate. 
12.2.4. Concomitant Therapy 
Concomitant medications will be summarized by treatment arm. 

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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, delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients per treatment arm. 
 
Compliance information for blinded study drug will be collected through capsule counts at each 
cycle/visit.  The estimate of percent compliance will be given by: 
Actual cumulative dose taken 
Percent Compliance = Expected cumulative dose to be taken  x 100 
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed. The 
expected cumulative dose to be taken will be determined based on the assigned dose and taking 
into account any dose reductions or suspensions. 
 
Compliance information for anastrozole or letrozole will be collected at each cycle/visit. This 
may be collected by tablet counts and/or review of the completed patient diary. For NSAI that 
has been centrally supplied by Lilly, tablet counts are required. The estimate of percent 
compliance will be done using the same formula/calculation for blinded study drug percent 
compliance. 
12.2.6. Primary Outcome and Methodology 
The primary endpoint of this study is PFS. PFS time is measured from randomization until the 
date of investigator-determined objective progression as defined by RECIST v1.1, or death from 
any cause. Patients who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment, if available, or date of randomization if no post-initiation (that is, 
post-baseline) radiographic assessment is available.  The detailed censoring rules are described 
in Table JPBM.12.1. 

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Table JPBM.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 
3 
No documented progression and no 
death (with a post-baseline tumor 
assessment) 
Date of Randomization 
Censored 
 
 
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 prior (neo)adjuvant endocrine therapy (aromatase inhibitor therapy versus 
other versus no prior endocrine therapy). 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 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 218 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, a power α- 
spending function with a power parameter (rho) of 14 will be used for this interim efficacy 
analysis: 

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k
k
 
 * t     * t14 . 
 
Here, tk is the information fraction at time k, and α is the cumulative 1-sided type 1 error rate, 
.025. 
 
Therefore, if the interim analysis is performed after exactly 218 events have been observed, a 
nominal 1-sided p-value of less than 0.000169 (corresponding approximately to an observed 
hazard ratio <0.6 under an exponential model) will need to be observed to declare statistical 
significance (see Table JPBM.12.2). 
 
Table JPBM.12.2. 
Properties of Design for Progression-Free Survival 
 
Information 
Fraction 
Cumulative 
Events 
Cumulative 
Alpha Spent 
Cumulative 
Beta Spent 
Boundary Reject H0 
(one-sided p-value) 
0.7 
218 
0.000169 
0 
<0.000169 
1.0 
312 
0.025 
0.2 
<0.024997 
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 the interim analysis crosses the boundary of significance at the pre-specified level, this 
analysis will be considered the primary PFS analysis. If statistical significance is not declared at 
the interim PFS analysis, the primary PFS analysis will be performed after approximately 
312 PFS events have been observed. 
 
There is no intent to stop the study if the interim analysis crosses the boundary of significance at 
the pre-specified level.  Treatment and follow-up of patients per the study schedule (Attachment 
1) will continue and patients will not be crossed over. The study will continue and the pre- 
specified analysis of PFS at 312 events will be performed to meet requirements of certain 
regulatory authorities. The study will only be stopped early if both the DMC and global 
regulatory authorities agree that the scientific objectives of the study are clearly met and 
unequivocal. 
 
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the hazard ratio and corresponding 95% CI with Wald’s test p-value after stratifying for 
the same randomization variables specified for the primary analysis. 
 
12.2.7. Secondary Outcomes and Methodology 
The secondary objectives of the study are listed in Section 6.2. 

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12.2.7.1. Overall Survival 
Overall survival is an important secondary endpoint for this study. Given that a hazard ratio for 
the effect of LY2835219 on OS is anticipated to be smaller than that anticipated for PFS, to 
improve the precision of estimating the effect of LY2835219 on OS in this setting, a pooled 
analysis is planned for the main analysis of OS. As noted in the Food and Drug Administration 
(FDA) Guidance for Industry on Integrated Summary of Effectiveness (2008) and in the EMA 
Guidance “Points to Consider on Application with 1.Meta-analyses; 2.One Pivotal Study 
(CPMP/EWP/2330/99, 2001),” an appropriate use of pooled analyses is during the assessment of 
drug effects on a secondary endpoint that requires more power than the individual trials can 
provide. 
 
Study I3Y-MC-JPBL (JPBL) is a study which randomizes patients with either locally advanced 
disease not amenable to curative treatment by surgery or metastatic disease to LY2835219 plus 
fulvestrant or placebo plus fulvestrant as either a first or second therapy for locally advanced or 
metastatic disease. 
 
Given the inclusion of patients receiving a first therapy for locally advanced or metastatic disease 
in the 2 trials (Studies JPBL and JPBM), that patients in both studies receive endocrine therapy 
in combination with LY2835219 or placebo, and the similarity of the study schedules 
(Attachment 1), it is rational and scientifically valid to conduct a pooled OS analysis using all 
patients from Study JPBM and those patients from Study JPBL who receive initial therapy for 
locally advanced or metastatic disease on study. 
 
To maintain the study-wise type I error rate, OS will be hierarchically tested. Overall survival 
will only be tested inferentially for significance if the test of PFS is significant, and an alpha- 
spending scheme will be employed to maintain a study-wise type I error rate of .025. The final 
pooled OS analysis will occur when at least 315 OS events have been observed events in Study 
JPBM and all events for the final analysis have been observed in Study JPBL, as specified in the 
study’s protocol. Note: while the pooled analysis is considered the primary OS analysis for this 
study, a subgroup analysis of Study JPBM OS data alone will be performed for descriptive 
purposes.  Further details of the pooled testing of OS, including interim analyses, are described 
in the Study JPBM SAP. 
12.2.7.2. Objective Response Rate, Disease Control Rate, and Clinical Benefit 
Rate 
The ORR, 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. 

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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, regardless of whether or not this 
patient subsequently had objective progression or died. 
 
Progression-Free Survival Sensitivity Analysis 2 (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 3 (forward-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 forward-dated to the next scheduled disease assessment. 
 
Progression-Free Survival Sensitivity Analysis 4. PFS will also be analyzed after adjusting for 
selected prognostic factors. Potential prognostic factors included the stratification factors and 
other factors as outlined in the SAP.  The hazard ratio for treatment effect will be estimated using 
a multivariate Cox proportional hazard model constructed by selecting variables among all the 
potential variables listed in the SAP, using stepwise selection method with entry p-value 0.05 
and exit p-value 0.01.  The treatment factor will be kept out of the model throughout the 
covariate selection process and only added into the final model. 
 
Although this study is double-blinded, a blinded independent central review (BICR) of scans will 
be conducted on a randomly selected subset of patients to evaluate the potential for investigator 
bias in evaluation of time to progression, and hence the reliability of the treatment effect based 
on investigator assessment. Details concerning the size of the subset of patients, the analysis of 
this BICR data, and decision rules for conducting a central review of all patients will be 
described in a separate 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. 
Cause of death as reported by the investigator will be used in this analysis. 

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12.2.9. Pharmacokinetic and Pharmacodynamic Analyses 
Pharmacokinetics analyses will be conducted on all patients who have received at least 1 dose of 
study treatment and have had samples collected (see PK sampling schedule in Attachment 7). 
 
Mean population PK parameters for 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. 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. 
 
Likewise, and if warranted by the data, mean population PK parameters for anastrozole or 
letrozole 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 platelet 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 NSAI in a PK/pharmacodynamic model. 
 
12.2.10. 
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: 
 
• 
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 post-baseline visit, the maximum change 
from baseline score will be calculated and summarized for EORTC scale scores. The reason and 
number of missing and incomplete questionnaires/assessments by visit will be summarized for 
each instrument and study arm. 
 
Further analysis details will be described in the SAP. 

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12.2.11.1. 
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. Descriptive 
statistics will be calculated for each dimension and the total score for each arm. 
 
EORTC QLQ-BR23 data will be scored as described by the EORTC scoring manual (Fayers et 
al. 2001). 
12.2.11.2. 
Resource 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. Tests for differences in proportions between 
treatment groups and between response groups will be performed. 
12.2.11.3. 
Health State Utility 
The EQ-5D 5L data will be scored as described in an article by van Hout and colleagues (van 
Hout et al. 2012).  The index score is calculated from a set of item weights to derive a score of 0 
to 1, with 1 representing the best health status. Geographic-specific weights will be used as 
appropriate and when available. The VAS is scored from 0 (worst imaginable health state) 
through 100 (best imaginable health state) to represent the patient’s self-report for each day. EQ- 
5D 5L responses for each item will be summarized by frequency and corresponding percentages. 
Descriptive statistics for the index and VAS will be calculated.  Psychometric analyses, 
including calculation of reliability coefficients (Cronbach’s alpha), will also be performed. The 
index scores and VAS will be analyzed using a repeated-measures model. 
 
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 the MedDRA dictionary. Investigators will report a verbatim AE 
term and a CTCAE v4.0 term and severity for all AEs. For analysis purposes, the following 
process will be used: 

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 The CTCAE v4 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) using the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify.’ 
 If the reported CTCAE term is ‘Other – specify,’ the MedDRA LLT, PT, and SOC 
centrally mapped from the verbatim AE term will be used. 
 All listings and summaries will use the PT resulting from this process. 
 
Preexisting conditions are defined as AEs 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 potential prognostic subgroup variables, 
including: 
 All baseline stratification factors 
 NSAI received while on study (letrozole versus anastrozole) 
 Disease setting (de novo metastatic versus recurrent metastatic versus locoregionally 
recurrent) 
 Measurable disease at baseline (yes versus no) 
 Number of organs involved (1 versus 2 versus 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. The final list of subgroup analyses will be provided in the SAP. 

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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. 
 
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 JPBM 
independently of the Lilly study team and Lilly GPS. 
 
During the study, safety interim analyses will be performed approximately every 3 months. The 
first safety interim analysis will be triggered by randomization of the 90th patient, with the data 
cutoff for this analysis occurring approximately 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 NSAI. 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 1 interim analysis of pooled OS data 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. This analysis will be 
performed by an independent Statistical Analysis Group and provided to the DMC. . 
 
The sponsor has no intent to stop the study based on interim analysis of efficacy, and all patients 
will continue follow-up for PFS until the primary PFS analysis and for OS until study close. 
Patients randomized to the control group will not be permitted to cross over to the experimental 
group, as this will confound the assessment of OS. 

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The unblinded review of the analyses, including review of the efficacy along with the safety 
data, will be conducted by DMC. Study sites will receive information about interim results 
ONLY if they need to know for the safety of their patients. 
 
Unblinding details are specified in the unblinding plan section of the SAP. 
 
12.2.14.3. 
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. 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 given by patients. 
 
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 International Conference on Harmonisation (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). 

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Some of the obligations of Lilly will be assigned to a third-party organization. 
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 clinical study 
report 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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Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, 
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Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, 
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IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on 
Cancer. Available from http://globocan.iarc.fr. 2013. 

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Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, 
Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, 
Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff 
JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and progesterone 
receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795. 
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health. 2008;11(2):274-284. 
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481. 
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. 
Ortega S, Malumbres M, Barbacid M. Cyclin-D dependent kinases INK4 inhibitors and Cancer. 
Biochim Biophys Acta. 2002;1602:73-87. 
Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, 
Dimery I, Webster A, Morris C, Elledge R, Buzdar A. Double-blind, randomized trial 
comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal 
women with advanced breast cancer progressing on prior endocrine therapy: results of a North 
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Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, 
Beeram M, Rasco DW, Myrand SP, Kulanthaivel P, Andrews JM, Frenzel M, Cronier D, Chan 
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Chicago. Abstract 534. J Clin Oncol. 2014;32:5s(suppl; abstr 534). 
Reed E, Simmonds P, Haviland J, Corner J. Quality of life and experience of care in women with 
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Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
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2007 Oct 22. Erratum in:  J Clin Oncol. 2008;26(7):1192. 
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van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
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LY2835219 
 
 
 
 
 
Attachment 1. Protocol JPBM Study Schedule 
 
 
 
Protocol I3Y-MC-JPBM 
 
Baseline Schedule 
Study Period 
Baseline (BL) 
Visit 
0 
Approximate 
Visit Duration 
(days) 
Up to 28 
Relative day to 
C1D1 
28 
14 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Study Entry 
/Enrollment 
Informed Consent Form 
signed 
Section 13.1 
X 
Prior to conducting any protocol-specific tests / 
procedures 
Inclusion/Exclusion 
evaluation 
Section 7 
X 
Medical 
History 
Initial medical 
history/preexisting conditions 
X 
Historical illnesses 
X 
Include habits assessment of alcohol and tobacco 
use 
Physical 
Examination 
Physical examination 
X 
Include but not limited to height and weight 
Vital Signs 
X 
Include blood pressure, pulse, respiratory rate, 
and temperature 
ECOG performance status 
Attachment 4 
X 
Tumor 
Assessment 
Tumor measurement 
(palpable or visible) 
Section 10.1.1 
X 
Photography of skin lesions with ruler required, if 
applicable 
Radiologic imaging according 
to RECIST 1.1 
Section 10.1.1 
Attachment 5 
X 
Performed locally. For patients with 
locoregionally recurrent breast cancer, MRI scan 
of the breast; additionally, for all patients, CT or 
MRI scan of the chest, abdomen, and pelvis. CT 
scan is the best currently available and 
reproducible method to measure lesions selected 
for response assessment; it is recommended that 
CT imaging of the abdomen and pelvis be 
performed with IV contrast whenever possible. 
MRI may be used instead of CT in selected 
instances. Gadolinium-enhanced MRI is 
preferred if hypersensitivity to contrast. 
Bone Scintigraphy 
Section 10.1.1 
Attachment 5 
X 
Performed locally. Bone scintigraphy performed 
as part of routine clinical care within 45 days 
before Cycle 1 Day 1 is also acceptable. 
X-ray, or CT scan with bone 
windows, or MRI 
Section 10.1.1 
Attachment 5 
X 
Performed locally. For only those patients with 
bone lesions identified by bone scintigraphy at 
baseline, all bone lesions will be evaluated at 
baseline by focused studies to enable serial 
assessment. 

I3Y-MC-JPBM Clinical Protocol 
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LY2835219 
 
 
 
 
Protocol I3Y-MC-JPBM 
 
Baseline Schedule 
Study Period 
Baseline (BL) 
Visit 
0 
Approximate 
Visit Duration 
(days) 
Up to 28 
Relative day to 
C1D1 
28 
14 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Adverse Event Collection/CTCAE Grading 
Section 10.3 
X 
CTCAE = Common Terminology Criteria for 
Adverse Events 
Concomitant Medication Notation 
Section 9.6 
X 
Note: RANK-L or bisphosphonate agents should 
be initiated ≥7 days prior to randomization, if 
applicable. 
Lab/ 
Diagnostic 
Tests 
Central hematology 
Attachment 2 
X 
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 
Central chemistry 
Attachment 2 
X 
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. 
Local FSH and estradiol level 
Attachment 2 
X 
Required only for women < 60 years with 
amenorrhea for at least 12 months to confirm 
post-menopausal status 
Local ECG 
Section 10.3.2.1 
X 
Patients must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine 
but awake during ECG collection. 
Abbreviations: CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; FSH = follicle stimulating hormone; IV = intravenous; MRI = magnetic resonance imaging; RANK-L = 
RANK ligand; RECIST = Response Evaluation Criteria in Solid Tumors. 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 77 
 
 
 
 
Protocol I3Y-MC-JPBM 
During Treatment Study 
Schedule 
Study Treatment Period 
Cycle / Visit 
1 
2 
3 
4-X 
Approximate 
Visit Duration 
(days) 
28 
28 
28 
28 
Relative day 
within a cycle 
1 
1 
21- 
28 
1 
1 
21- 
28 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Physical 
Examination 
Physical Exam 
X 
X 
X 
X 
Include but not limited to weight 
Vital Signs 
X 
X 
X 
X 
Include blood pressure, pulse, respiratory rate, and temperature 
ECOG performance status 
Attachment 4 
X 
X 
X 
X 
Archived Tumor Tissue 
Section 10.4.2.1 
X 
Whole or partial block or 15 – 20 slides should be provided upon 
patient randomization. 
Adverse Event Collection/CTCAE 
Grading 
Section 10.3 
X 
X 
X 
X 
Concomitant Medication Notation 
Section 9.6 
X 
X 
X 
X 
Lab/ 
Diagnostic 
Tests 
Central hematology 
Attachment 2 
X 
X 
X 
X 
Central hematology labs may be drawn up to 3 days prior to Day 1 of 
each cycle. Additional local hematology labs may be drawn for 
treatment adjustment and patient management purposes. 
Central chemistry 
Attachment 2 
X 
X 
X 
X 
Central chemistry labs may be drawn up to 3 days prior to Day 1 of 
each cycle. Additional local chemistry labs may be drawn for 
treatment adjustment and patient management purposes. 
Pharmacokinetic (PK) 
sampling 
Attachment 7 
X 
X 
X 
See Attachment 7 for specific timing 
Pharmacogenetic blood 
sample 
Section 
10.4.2.2 
X 
Draw sample before patient is dosed on C1D1 
Biomarker plasma sample 
Section 10.4.2 
X 
X 
Draw sample before patient is dosed on C1D1 and upon arrival at site 
on C2D1 
Local ECG 
Section 
10.3.2.1 
X 
X 
X 
2 to 4 hours after the LY dose on Cycle 1 Day 1, upon arrival at site on 
Cycle 2 Day 1, 2 to 4 hours after the LY dose on Cycle 4 Day 1. 
Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 78 
 
 
 
 
Protocol I3Y-MC-JPBM 
During Treatment Study Schedule 
Study Treatment Period 
Cycle / Visit 
1 
2 
3 
4-X 
Approximate 
Visit Duration 
(days) 
28 
28 
28 
28 
Relative day 
within a cycle 
1 
1 
21- 
28 
1 
1 
21- 
28 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Tumor 
Assessment 
Tumor measurement 
(palpable or visible) 
Section 10.1.1 
X 
X 
Skin lesions identified at baseline require repeat photographic 
images on Day 1of every second cycle beginning with Cycle 3 and 
continuing through Cycle 19 (inclusive), on Day 1of every third 
cycle after Cycle 19, and within 14 days of clinical progression. 
Photographic images may be taken more frequently based upon the 
discretion of the investigator or following the identification of new 
skin lesions post-baseline. 
Radiological imaging 
according to RECIST (CT 
scan/MRI) 
Section 10.1.1 
Attachment 5 
X 
X 
Performed locally. For patients with locoregionally recurrent breast 
cancer not amenable to curative treatment, MRI scan of the breast is 
performed, if applicable, in addition to other scans.   Imaging 
studies (Breast MRI and CT scan or MRI of the chest, abdomen, 
and pelvis) will be repeated on Day 21 to Day 28 of every second 
cycle beginning with Cycle 2 and continuing through Cycle 18 
(inclusive), on Day 21 to Day 28 of every third cycle after Cycle 
18, and within 14 days of clinical progression. The same method of 
imaging used at baseline should be used for each subsequent 
assessment. 
Bone Scintigraphy 
Section 10.1.1 
Attachment 5 
X 
Performed locally. Repeat for all patients on Day 21 to Day 28 of 
every sixth cycle beginning with Cycle 6. In addition, bone scans 
should be repeated even if a complete response is identified in 
target disease or 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. 
X-ray, CT scan with bone 
windows, or MRI 
Section 10.1.1 
Attachment 5 
X 
X 
Performed locally for patients with bone lesions identified by bone 
scintigraphy at baseline. Repeat on Day 21 to Day 28 of every 
second cycle beginning with Cycle 2 and continuing through Cycle 
18 (inclusive), on Day 21 to Day 28 of every third cycle after Cycle 
18, and within 14 days of clinical progression.  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. 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 79 
 
 
 
 
Protocol I3Y-MC-JPBM 
During Treatment Study 
Schedule 
Study Treatment Period 
Cycle / 
Visit 
1 
2 
3 
4-X 
Approximate 
Visit 
Duration 
(days) 
28 
28 
28 
28 
Relative 
day within 
a cycle 
1 
1 
21- 
28 
1 
1 
21- 
28 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Health 
Outcomes 
EORTC QLQ-C30, 
EORTC QLQ-BR23, 
EQ-5D 5L 
Section 
10.2 
X 
X 
X 
Patients complete prior to extensive interaction with site staff. 
On Cycle 1 Day 1, questionnaires must be administered prior to the first 
dose of study treatment. Questionnaires should be administered on 
Cycle1 Day 1, and then Day 1 of every second cycle beginning with 
Cycle 3 through Cycle 19, and on Day 1of every third cycle after Cycle 
19. 
Study Drug 
LY2835219 or Placebo 
(blinded randomization) 
Section 9.1 
Take 150 mg or prescribed dose orally every 12 
hours on Days 1 through 28 of every cycle, with the 
exception that the second dose on C1D1 should be 
omitted to allow for adequate study drug for at home 
dosing on C2D1. 
On Cycle 1 Day 1 only, patients should take one single dose of blinded 
study drug and initiate chronic every 12 hour dosing on Cycle 1 Day 2. 
On Cycle 2 Day 1, patients will take medication at home at least 4 hours 
prior to arrival at the clinic. On Cycle 4 Day 1, patients will take morning 
dose of blinded study drug in the clinic. 
Co- 
Administered 
Drug 
(per 
investigator 
selection) 
anastrozole 
Section 9.1 
Take 1mg tablet orally every 24 hours on Days 1 
through 28 
For PK and ECG purposes, should be taken at the same time as, or up to 
20 minutes after the morning dose of blinded study drug. Adjustment to 
timing of dose administration may be made at the discretion of the 
investigator after Cycle 4 Day 1. 
letrozole 
Section 9.1 
Take 2.5mg tablet orally every 24 hours on Days 1 
through 28 
For PK and ECG purposes, should be taken at the same time as, or up to 
20 minutes after the morning dose of blinded study drug. Adjustment to 
timing of dose administration may be made at the discretion of the 
investigator after Cycle 4 Day 1. 
Abbreviations: CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ- 
BR23 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Breast cancer; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30; EQ-5D 5L = EuroQol 5-Dimension 5 Level; MRI = magnetic resonance imaging; RECIST = Response Evaluation Criteria in Solid Tumors. 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 80 
 
 
 
 
Protocol I3Y-MC-JPBM 
Post Treatment Discontinuation 
Study Schedule 
Study Period 
Post-Discontinuation 
Short Term Follow-Up 
Postdiscontinuation 
Long Term Follow-Up 
Visit 
801 
802-X 
Approximate 
Visit Duration 
(days) 
30±5 
Variable 
Relative day 
30 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Physical 
Examination 
Physical Exam 
X 
Includes but not limited to weight 
Vitals 
X 
Includes blood pressure, pulse, respiratory rate, and temperature. 
ECOG Performance 
Status 
Attachment 4 
X 
Tumor 
Assessment 
Tumor measurement 
(palpable or visible) 
Section 10.1.1 
X 
X 
ONLY For patients who discontinue study treatment without objectively 
measured progressive disease (PD), continue to conduct tumor assessments 
approximately every 8 weeks for the first 18 months following randomization 
and thereafter approximately every 12 weeks until the patient has objective 
disease progression or until study completion. After the patient has objective 
disease progression, photographic images are no longer required and the 
patient will continue with post-discontinuation follow-up approximately 
every 12 weeks until the patient’s death or overall study completion. 
Bone Scintigraphy 
Section 10.1.1 
Attachment 5 
X 
X 
ONLY For patients who discontinue study treatment without objectively 
measured progressive disease (PD), continue to evaluate repeat bone scans 
approximately every 6 months until objective disease progression or study 
completion. 
Radiologic imaging 
according to RECIST 
Section 10.1.1 
Attachment 5 
X 
X 
The same method of imaging used at baseline should be used for each 
subsequent assessment. ONLY For patients who discontinue study 
treatment without objectively measured progressive disease (PD), 
continue to conduct tumor assessment approximately every 8 weeks for the 
first 18 months following randomization and thereafter approximately every 
12 weeks by the same method used at baseline and throughout the study until 
the patient has objective disease progression or until study completion. After 
the patient has objective disease progression, radiologic tests are no longer 
required and the patient will continue with post-discontinuation follow-up 
approximately every 12 weeks until the patient’s death or overall study 
completion 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 81 
 
 
 
 
Protocol I3Y-MC-JPBM 
Post Treatment Discontinuation 
Study Schedule 
Study Period 
Post-Discontinuation 
Short Term Follow-Up 
Postdiscontinuation 
Long Term Follow-Up 
Visit 
801 
802-X 
Approximate 
Visit Duration 
(days) 
30±5 
Variable 
Relative day 
30 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Tumor 
Assessment 
continued 
X-ray, CT scan with 
bone windows, or 
MRI 
Section 10.1.1 
Attachment 5 
X 
X 
ONLY For patients who discontinue study treatment without objectively 
measured progressive disease (PD), focused studies are performed for 
patients with bone lesions previously identified by bone scintigraphy. During 
long term follow up period, repeat scans should performed approximately 
every 8 weeks for the first 18 months following randomization, and 
subsequently approximately every 12 weeks until disease progression or 
study completion. 
Survival Information 
Section 10.1.4 
X 
X 
Although preferable to collect during a clinic visit, survival information may 
be collected by contacting the patient or family directly (for example, via 
telephone) if no procedures required. This should be collected at minimum 
every 90 days if no other procedures are performed. Additional long-term 
follow-up data collection will include post-discontinuation anticancer 
therapies. 
Adverse Events Collection/CTCAE 
Grading 
Section 10.3 
X 
X 
After Visit 801, only study protocol or drug-related events are reported. If a 
patient has ongoing AE or SAE possibly related to study drug (not co- 
administered drug) (for instance, abnormal electrolytes), the patient should be 
followed until the event is resolved, the event is no longer considered to be 
drug-related, the event becomes stable or returns to baseline, a new treatment 
is initiated for the patient, or the patient dies or is lost to follow-up. Any 
subsequent follow-up(s) for AEs will be no more than 30 days ± 5 days in 
duration. 
Concomitant Medications Notation 
Section 9.6 
X 
Lab/ Diagnostic 
Tests 
Central hematology 
Attachment 2 
X 
Central chemistry 
Attachment 2 
X 
Biomarker plasma 
sample 
Section 10.4.2 
X 
Draw sample only for patients discontinuing due to PD. 
ECG 
Section 
10.3.2.1 
X 
Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. 
Health 
Outcomes 
EORTC QLQ-C30, 
EORTC QLQ-BR23, 
EQ-5D 5L 
Section 10.2 
X 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 82 
 
 
 
Protocol I3Y-MC-JPBM 
Post Treatment Discontinuation Study Schedule 
 
Abbreviations: AE = adverse event; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EORTC QLQ-BR23 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Breast cancer; EORTC QLQ-C30 = European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-5D 5L = EuroQol 5-Dimension 5 Level; MRI = magnetic resonance imaging; PK = pharmacokinetics; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAEs = serious adverse events. 

LY2835219 
I3Y-MC-JPBM Clinical Protocol 
Page 83 
 
 
 
 
Protocol I3Y-MC-JPBM 
Study Schedule for the 
Continued Access Period only 
Study Period 
Patients on Study Treatment 
Continued Access Period 
Follow-Up 
Cycle 
X 
Follow-Upa 
Visit 
501-5XX 
901 
Approximate 
Visit Duration 
(days) 
28 
30 
Relative day 
within a cycle 
1 
Procedure 
Category 
Procedure 
Protocol 
Reference 
Comments 
Adverse Events Collection/CTCAE Grading 
Section 10.3 
X 
X 
Data on SAEs that occur before the end of trial will be 
stored in the collection database and the Lilly safety 
system 
Study Drug 
LY2835219 
Section 9.1 
X 
Only patients assigned to LY2835219 at randomization 
and receiving clinical benefit will continue to receive 
LY2835219 during the continued access period. 
LY2835219 is to be administered orally every 12 hours 
on Days 1 through 28 of each cycle. Patients who were 
assigned to placebo, will no longer receive placebo 
during the continued access period and cannot crossover 
to LY2835219. 
Co- 
Administered 
Drugs 
Anastrozole 
Section 9.1 
X 
Patients receiving clinical benefit will continue to 
receive anastrozole or letrozole during the continued 
access period. Anastrozole or letrozole is to be 
administered orally every 24 hours on Days 1 through 
28 of each cycle 
Letrozole 
Section 9.1 
X 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; OS = overall survival; SAEs = serious adverse events. 
a 
The continued access period begins after study completion (that is, after final OS analysis) and ends at the end of trial (that is, the last patient visit).. 

I3Y-MC-JPBM Clinical Protocol 
Page 84 
LY2835219 
 
 
 
 
 
Attachment 2. Protocol JPBM Clinical Laboratory Tests 
 
 
 
Clinical Laboratory Tests 
 
Hematologya: 
Clinical Chemistrya,d: 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Mean cell volume (MCV) 
Total Protein 
Mean cell hemoglobin concentration (MCHC) 
Total bilirubin 
Leukocytes (WBC) 
Direct bilirubin 
Neutrophils, (segmented and bands) 
Alkaline phosphatase 
Lymphocytes 
Alanine aminotransferase (ALT) 
Monocytes 
Aspartate aminotransferase (AST) 
Eosinophils 
Blood urea nitrogen (BUN) 
Basophils 
Creatinine 
Platelets 
Calcium 
Albumin 
 
 
Follicle Stimulating Hormone (FSH) levelb,c 
Estradiol levelb,c 
 
Abbreviations: RBC = red blood cells; WBC = white blood cells. 
a   Assayed by Lilly-designated (central) laboratory. 
b Local or investigator-designated laboratory. 
c To be performed at baseline in order to establish eligibility only for women <60 years and ammenorrheic for at 
least 12 months. 
d Per the letrozole and anastrozole labels, investigators should consider monitoring cholesterol. The decision to 
monitor and frequency of monitoring are at the discretion of the investigator. 

I3Y-MC-JPBM Clinical Protocol 
Page 85 
LY2835219 
 
 
 
 
 
Attachment 3. Protocol JPBM Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality 
 
 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician. 
Hepatic Monitoring Tests 
 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented and bands 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
ALT 
Anti-nuclear antibodya 
AST 
GGT 
CPK 
Anti-smooth muscle antibodya 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells. 
a Assayed by Lilly-designated laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 

I3Y-MC-JPBM Clinical Protocol 
Page 86 
LY2835219 
 
 
 
 
 
Attachment 4. Protocol JPBM 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. 
 
 
Abbreviation: ECOG = Eastern Cooperative Oncology Group. 
Source:  Oken et al. 1982. 

I3Y-MC-JPBM Clinical Protocol 
Page 87 
LY2835219 
 
 
 
 
 
Attachment 5. Protocol JPBM 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 
measureable 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. 

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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). 
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 JPBM Sampling Summary 
 
 
This table summarizes the purpose for sampling, sample types, maximum volume per sample, 
maximum number of samples, and maximum total volume during the study.  The summary 
below provides estimates. More samples could be required in the case of retests, additional 
health monitoring (if needed), or for patients continuing treatment beyond the protocol-specified 
number of cycles in the study. Fewer samples may actually be taken (for example, patients who 
discontinue from the study). 
Protocol I3Y-MC-JPBM 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 
17 
119 mL 
Pharmacokinetic sample 
Blood 
4  mL 
5 
20 mL 
Pharmacogenetic blood sample 
Blood 
10 mL 
1 
10 mL 
Biomarker plasma sample 
Blood 
6 mL 
3 
18 mL 
Total blood volume 
Blood 
174 mL 
Hepatic monitoringb 
Blood 
3 - 30 mL 
- 
- 
a Covers Cycles 1 through 16 and one post-discontinuation follow up visit. 
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated medical monitor. 

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Attachment 7. Protocol JPBM Electrocardiogram and 
Pharmacokinetic Sampling Schedule 
 
 
The schedule for PK sampling is summarized in the table below. The date and exact time of 
collection for each venous blood sample should be documented on the laboratory requisition. 
Pharmacokinetic Sampling Schedule 
 
Cycle(C) and 
Day(D) 
ECG 
PK 
Sample 
Number 
Study Drug 
Dose 
Dosing of 
anastrozole / 
letrozole 
Sampling Time for ECG and 
PK from Blooda 
Baseline  
(Day -14 to Day -1) 
X 
Day of visit 
C1D1 
X 
1 
Xb 
Xb 
2-4hrs after NSAI and blinded 
study drug dosed in clinic 
C2D1 
X 
2 
Xc 
Xc 
Upon arrival at site (that is, at 
least 4 hrs after taking NSAI 
and blinded study drug doses 
at home) 
C2D1 
3 
3±0.5 hrs after arrival at site 
(that is, at least 7±0.5 hrs after 
taking NSAI and blinded 
study drug doses at home. 
C3D1 
4 
Xb 
Xb 
Prior to NSAI and blinded 
study drug doses. Patient is 
dosed in clinic after sample 
collection. 
C3D1 
5 
3±0.5hrs after NSAI and 
blinded study drug dosing in 
clinic 
C4D1 
X 
Xb 
Xb 
2-4hrs after NSAI and blinded 
study drug dosing in clinic. 
30 Day Follow-Up 
X 
Day of visit 
Abbreviation:  hrs = hours; NSAI = nonsteroidal aromatase inhibitor; PK = pharmacokinetic. 
a Samples of approximately 4 mL of whole blood will be drawn from at least 150 patients randomized in the study 
for measurement of study treatment and LY2835219 metabolites concentrations. 
b Patient is administered NSAI and study drug doses in clinic. On Cycle 1 Day 1 only, patients should take one 
single dose of blinded study drug and initiate chronic every 12 hours dosing on Cycle 1 Day 2 
c Patient should take NSAI and study drug doses at home at least 4 hours before arrival at site. The time of NSAI 
and study drug dose intake must be recorded that day.. 

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Attachment 8. Protocol JPBM 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: All patients may receive supportive therapy with dexamethasone, preferably ≤7 days, if 
clinically indicated. Patients requiring more than 7 days of dexamethasone therapy will not incur a protocol 
deviation. 

 
 
 
 
LY2835219 
 
 
Attachment 9. Protocol JPBM CTCAE 4.03 Diarrhea Definition 
 
 
 
 
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 revised:  CTCAE 4.03-June 14, 2010:  Gastrointestinal disorders. 
 
Gastrointestinal Disorders 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Increase <= 7 stools per 
Diarrhea 
Increase of <4 stools 
per day over baseline; 
mild increase in 
ostomy output 
compared to baseline. 
Increase of 4-6 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
ADL 
Definition:  a disorder characterized by frequent and watery bowel movements 
Abbreviation:  ADL = Activities of Daily Living. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Leo Document ID = 6d4002b3-1936-489c-96a3-ae1f8e416e2a 
Approver: 
Approval Date & Time: 03-Sep-2014 15:11:41 GMT 
Signature meaning: Approved 
Approver: 
Approval Date & Time: 03-Sep-2014 23:57:08 GMT 
Signature meaning: Approved